Executive summary .uk



Guidelines for the prophylaxis of Pneumocystis Jirovecii Pneumonia (PJP) in Children with Solid TumoursIssued: July 2016AuthorsRebecca ProudfootPaediatric RegistrarJohn Radcliffe Hospital, OxfordRachel CoxConsultant Paediatric OncologistBristol Children’s HospitalBob PhillipsSenior Clinical AcademicHonorary Consultant in Paediatric OncologyCentre for Reviews and DisseminationUniversity of YorkSophie WilneConsultant Paediatric OncologistUniversity Hospitals Nottingham NHS TrustDisclaimerHealthcare providers need to use clinical judgment, knowledge and expertise when deciding whether it is appropriate to apply guidelines. The recommendations cited here are a guide and may not be appropriate for use in all situations. The decision to adopt any of the recommendations cited here must be made by practitioners in light of individual patient circumstances, the wishes of the patient, clinical expertise and resources. ?The CCLG disclaims any responsibility for damages arising out of the use or non-use of these guidelines and the literature used in support of these guidelines. Table of Contents TOC \o 1.Executive summary PAGEREF _Toc329421875 \h 42. Introduction and background PAGEREF _Toc329421876 \h 6Table 1: PJP attack rates in solid tumours PAGEREF _Toc329421877 \h 8Current practice in UK CCLG centres PAGEREF _Toc329421878 \h 10Table 2: Summary of current practice in UK CCLG centres (27) PAGEREF _Toc329421879 \h 103. Scope PAGEREF _Toc329421880 \h 114. Methods (see appendix C) PAGEREF _Toc329421881 \h 125. recommendatons PAGEREF _Toc329421882 \h 13Identifying who is at risk PAGEREF _Toc329421883 \h 13Corticosteroids PAGEREF _Toc329421884 \h 13Temozolamide (TMZ) PAGEREF _Toc329421885 \h 14Radiotherapy (RT) PAGEREF _Toc329421886 \h 14Rituximab PAGEREF _Toc329421887 \h 14Underlying lung pathology PAGEREF _Toc329421888 \h 14Previous PJP infection PAGEREF _Toc329421889 \h 15Comparison of Alternative PJP Prophylaxis Regimes PAGEREF _Toc329421890 \h 166. Other Considerations PAGEREF _Toc329421891 \h 18G6PD deficiency PAGEREF _Toc329421892 \h 18Potential for the development of resistant isolates PAGEREF _Toc329421893 \h 187. Research Recommendations PAGEREF _Toc329421894 \h 208. Glossary PAGEREF _Toc329421895 \h 219. Acknowledgements PAGEREF _Toc329421896 \h 2210. Appendices PAGEREF _Toc329421897 \h 22Appendix A: Drug doses, adverse effects & costs PAGEREF _Toc329421898 \h 23Appendix B – Guideline Development Group PAGEREF _Toc329421899 \h 24Disclosure of potential conflicts of interest: PAGEREF _Toc329421900 \h 24Appendix C – Methods PAGEREF _Toc329421901 \h 25How this Guideline was Developed: PAGEREF _Toc329421902 \h 25Developing the Clinical Questions and Outcomes PAGEREF _Toc329421903 \h 25Developing Recommendations and Stakeholder Review PAGEREF _Toc329421904 \h 25Updating the Guideline PAGEREF _Toc329421905 \h 25Funding PAGEREF _Toc329421906 \h 26Summary of Review Questions and Outcomes PAGEREF _Toc329421907 \h 27Searching for Evidence PAGEREF _Toc329421908 \h 32Search strategy: PAGEREF _Toc329421909 \h 32Appendix D: Structured clinical questions and answers identified in literature review PAGEREF _Toc329421910 \h 341.Background risk of PJP (Pneumocystis jirovecii Pneumonia) PAGEREF _Toc329421911 \h 34PJP attack rates in paediatric solid tumours PAGEREF _Toc329421912 \h 34Prevalence studies of PJP PAGEREF _Toc329421913 \h 342. Effectiveness of PJP prophylaxis PAGEREF _Toc329421914 \h 38Studies on PJP prophylaxis efficacy PAGEREF _Toc329421915 \h 38Studies of different co-trimoxazole regimens PAGEREF _Toc329421916 \h 423. Benefit v risk of PJP prophylaxis PAGEREF _Toc329421917 \h 45Studies of alternatives to co-trimoxazole PAGEREF _Toc329421918 \h 464. Use of lymphocyte/CD4 counts as a marker of risk PAGEREF _Toc329421919 \h 475. Corticosteroids and brain tumours PAGEREF _Toc329421920 \h 477. Rituximab and other immunomodulating agents PAGEREF _Toc329421921 \h 488. Underlying lung pathology PAGEREF _Toc329421922 \h 499. Previous PJP PAGEREF _Toc329421923 \h 5010. Myelosuppression with co-trimoxazole PAGEREF _Toc329421924 \h 5011. Methotrexate (mtx) PAGEREF _Toc329421925 \h 5112. Potential for development of resistant isolates PAGEREF _Toc329421926 \h 5213. G6PD deficiency PAGEREF _Toc329421927 \h 52Appendix E: Grading the Quality of Evidence PAGEREF _Toc329421928 \h 53Appendix F: GRADE profiles for outcomes identified from the literature review: PAGEREF _Toc329421929 \h 56Appendix G: Consensus Survey & Results PAGEREF _Toc329421930 \h 7411. References PAGEREF _Toc329421931 \h 77Executive summaryRecommendationStrength of Recommendation1. We suggest PJP prophylaxis is offered to all children with solid tumours undergoing treatment that is likely to render them lymphopaenic unless there are clear contraindications.Consensus2. First line prophylaxis should be with co-trimoxazole Strong recommendation, Moderate quality evidence3. Co-trimoxazole prophylaxis should be given twice weekly in dosage according to surface area (see appendix A).Strong recommendation,Low quality evidence4. For patients intolerant of co-trimoxazole the choice of alternative prophylaxis is controversial. This decision should be made according to patient and physician preference and experience. The risk/benefit of any prophylaxis at all should be re-evaluated on an individual basis as alternative drugs are all associated with poorer efficacy and increased toxicity and expense. Weak recommendation,Very low quality evidenceThe following children should not receive PJP prophylaxis with co-trimoxazole:5. Children undergoing treatment with high dose methotrexateWeak recommendation,Very low quality evidence6. Confirmed allergy to co-trimoxazoleStrong recommendation,Very low quality evidenceFor children undergoing autologous stem cell transplant:7. Unless specifically mandated by a trial protocol, do not interrupt prophylaxis with co-trimoxazole unless there is a delay in engraftmentWeak recommendation, Very low quality evidence8. If prophylaxis with co-trimoxazole is interrupted recommence once neutrophil count is >1 x109/litreConsensus9. The duration of prophylaxis is uncertain – a pragmatic choice is to continue until 6 months after stem cell transplant, as long as the lymphocyte count has returned to normal. Weak recommendation, Very low quality evidence10. Children who are immunocompromised due to treatment for a solid malignancy should receive prophylaxis against PJP from the start of treatment.Weak recommendation, Low quality evidence11. The Duration of prophylaxis is uncertainA pragmatic choice is to continue until 3 months after the end of treatment (or 6 months following stem cell transplant), as long as the lymphocyte count has returned to normal. Weak recommendation, Very low quality evidence2. Introduction and backgroundPneumocystis jirovecii, previously known as Pneumocystis carinii, is an opportunistic parasite that causes pneumonia (PJP) in immunocompromised hosts. P. jirovecii was originally thought to be a protozoan but more recent molecular studies have revealed greater homology to fungi ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/334519a0", "ISSN" : "0028-0836", "PMID" : "2970013", "abstract" : "Pneumocystis carinii pneumonia is the most common opportunistic infection in AIDS, and accounts for significant morbidity and mortality in these and other immunocompromised patients. P. carinii is a eukaryotic microorganism of uncertain taxonomy that can infect numerous mammalian hosts. Developing from a small, unicellular 'trophozoite' into a 'cyst' containing eight 'sporozoites', its life cycle superficially resembles those seen both in the Protozoa and Fungi. Morphological and ultrastructural observations have lead some investigators to conclude that the organism is a protozoan, while others have felt that it more closely resembles a fungus. Phylogenetic relationships can be inferred from comparisons of macromolecular sequences. Small subunit ribosomal RNAs (16S-like rRNAs) are well-suited for this purpose because they have the same function in all organisms and contain sufficient information to estimate both close and distant evolutionary relationships. Phylogenetic frameworks based upon such comparisons reveal that the plant, animal and fungal lineages are distinct from the diverse spectrum of protozoan lineages. In this letter, phylogenetic analysis of Pneumocystis 16S-like rRNA demonstrates it to be a member of the Fungi.", "author" : [ { "dropping-particle" : "", "family" : "Edman", "given" : "J C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kovacs", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masur", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Santi", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Elwood", "given" : "H J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sogin", "given" : "M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "6182", "issued" : { "date-parts" : [ [ "1988", "8", "11" ] ] }, "page" : "519-22", "title" : "Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi.", "type" : "article-journal", "volume" : "334" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(1)", "plainTextFormattedCitation" : "(1)", "previouslyFormattedCitation" : "(1)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(1). Most immunocompetent children acquire asymptomatic infection with P. jirovecii by the age of 4 years ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1086/319340", "ISSN" : "1058-4838", "PMID" : "11247708", "abstract" : "To determine whether Pneumocystis carinii is associated with clinical illness in the competent host, 107 normal, healthy infants were enrolled in a 2-year prospective cohort study in Chile. P. carinii was identified by specific stains and nested--deoxyribonucleic acid (DNA) amplification of the large subunit mitochondrial ribosomal ribonucleic acid gene of P. carinii f. sp. hominis, and seroconversion was assessed by enzyme-linked immunosorbent assay of serum samples drawn every 2 months. P. carinii DNA was identified in nasopharyngeal aspirates obtained during episodes of mild respiratory infection in 24 (32%) of 74 infants from whom specimens were available for testing. Three (12.5%) of those 24 infants versus 0 of 50 infants who tested negative for P. carinii had apnea episodes. Seroconversion developed in 67 (85%) of 79 infants who remained in the study by 20 months of age and occurred in the absence of any symptoms of disease in 14 (20.8%). The study indicates that P. carinii DNA can be frequently detected in healthy infants, and it raises the hypothesis that they may be an infectious reservoir of P. carinii in the community. Further investigation is needed to identify whether P. carinii causes overt respiratory disease in infants.", "author" : [ { "dropping-particle" : "", "family" : "Vargas", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Santolaya", "given" : "M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Ulloa", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ponce", "given" : "C A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cabrera", "given" : "C E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cumsille", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gigliotti", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2001", "3", "15" ] ] }, "page" : "855-61", "title" : "Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants.", "type" : "article-journal", "volume" : "32" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0031-4005", "PMID" : "400818", "abstract" : "Using Pneumocystis carinii organisms propagated through three passages in embryonic chick epithelial lung cultures, specific antigens and antisera were prepared for use in counterimmunoelectrophoresis and indirect immunofluorescent antibody techniques. These methods proved to be specific and sensitive for the detection of P. carinii antigen and antibody, respectively, in sera, and were applied to the study of cancer patients with P. carinii pneumonitis (PCP), cancer patients without pneumonitis, and normal children. Antigenemia was detected in 95% of patients with PCP, in 15% of cancer patients without pneumonitis, and in none of the normal children tested. In cross-sectional and longitudinal studies of normal infants and children, acquisition of serum antibody to P. carinii was demonstrated to occur progressively with increase in age. By 4 years of age two thirds of the normal children were found to have antibody to P. carinii in titers of 1:16 or greater. These studies indicate that subclinical P. carinii infection is highly prevalent in normal children, analogous to other opportunistic infections where active disease is manifest predominantly in the compromised host.", "author" : [ { "dropping-particle" : "", "family" : "Pifer", "given" : "L L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stagno", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Woods", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "1978", "1" ] ] }, "page" : "35-41", "title" : "Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children.", "type" : "article-journal", "volume" : "61" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2,3)", "plainTextFormattedCitation" : "(2,3)", "previouslyFormattedCitation" : "(2,3)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2,3), whilst symptomatic disease occurs almost exclusively in severely immunocompromised hosts. Pneumocystis has been recognized as a cause of pneumonia since the 1940s when epidemics of ‘plasma cell pneumonia’ were diagnosed in malnourished and premature infants in care homes in Eastern Europe ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0031-4005", "PMID" : "13419426", "author" : [ { "dropping-particle" : "", "family" : "GAJDUSEK", "given" : "D C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "4 Part 1", "issued" : { "date-parts" : [ [ "1957", "4" ] ] }, "page" : "543-65", "title" : "Pneumocystis carinii; etiologic agent of interstitial plasma cell pneumonia of premature and young infants.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(4)", "plainTextFormattedCitation" : "(4)", "previouslyFormattedCitation" : "(4)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(4). In the 1960s, as immunosuppressive therapy for malignancy became more widespread, the incidence of PJP increased. In the 1980s PJP was the first opportunistic infection associated with the newly recognised Acquired Immunodeficiency Syndrome (AIDS)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198112103052401", "ISSN" : "0028-4793", "PMID" : "6272109", "abstract" : "Four previously healthy homosexual men contracted Pneumocystis carinii pneumonia, extensive mucosal candidiasis, and multiple viral infections. In three of the patients these infections followed prolonged fevers of unknown origin. In all four cytomegalovirus was recovered from secretions. Kaposi's sarcoma developed in one patient eight months after he presented with esophageal candidiasis. All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin were markedly reduced. Monoclonal-antibody analysis of peripheral-blood T-cell subpopulations revealed virtual elimination of the Leu-3 / helper/inducer subset, an increased percentage of the Leu-2 + suppressor/cytoxic subset, and an increased percentage of cells bearing the thymocyte-associated antigen T10. The inversion of the T/ helper to suppressor/cytotoxic ratio suggested that cytomegalovirus infection was an important factor in the pathogenesis of the immunodeficient state. A high level of exposure of male homosexuals to cytomegalovirus-infected secretions may account for the occurrence of this immune deficiency.", "author" : [ { "dropping-particle" : "", "family" : "Gottlieb", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schroff", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schanker", "given" : "H M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weisman", "given" : "J D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fan", "given" : "P T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wolf", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saxon", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "24", "issued" : { "date-parts" : [ [ "1981", "12", "10" ] ] }, "page" : "1425-31", "title" : "Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency.", "type" : "article-journal", "volume" : "305" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1056/NEJM198112103052402", "ISSN" : "0028-4793", "PMID" : "6975437", "abstract" : "Eleven cases of community-acquired Pneumocystis carinii pneumonia occurred between 1979 and 1981 and prompted clinical and immunologic evaluation of the patients. Young men who were drug abusers (seven patients), homosexuals (six), or both (two) presented with pneumonia. Immunologic testing revealed that absolute lymphocyte counts, T-cell counts, and lymphocyte proliferation were depressed, and that humoral immunity was intact. Of the 11 patients, one was found to have Kaposi's sarcoma, and another had angioimmunoblastic lymphadenopathy. Eight patients died. In the remaining three, no diagnosis of an immunosuppressive disease was established, despite persistence of immune defects. These cases of pneumocystosis suggest the importance of cell-mediated immune function in the defense against P. carinii. The occurrence of this infection among drug abusers and homosexuals indicates that these groups may be at high risk for this infection.", "author" : [ { "dropping-particle" : "", "family" : "Masur", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michelis", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greene", "given" : "J B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Onorato", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stouwe", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holzman", "given" : "R S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wormser", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brettman", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lange", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murray", "given" : "H W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cunningham-Rundles", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-2", "issue" : "24", "issued" : { "date-parts" : [ [ "1981", "12", "10" ] ] }, "page" : "1431-8", "title" : "An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction.", "type" : "article-journal", "volume" : "305" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(5,6)", "plainTextFormattedCitation" : "(5,6)", "previouslyFormattedCitation" : "(5,6)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(5,6). Even with prompt antimicrobial treatment, PJP has a high mortality rate ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMra032588", "ISSN" : "1533-4406", "PMID" : "15190141", "author" : [ { "dropping-particle" : "", "family" : "Thomas", "given" : "Charles F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Limper", "given" : "Andrew H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "24", "issued" : { "date-parts" : [ [ "2004", "6", "10" ] ] }, "page" : "2487-98", "title" : "Pneumocystis pneumonia.", "type" : "article-journal", "volume" : "350" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(7)", "plainTextFormattedCitation" : "(7)", "previouslyFormattedCitation" : "(7)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(7) but prophylaxis with co-trimoxazole is safe, effective and inexpensive ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198706253162604", "ISSN" : "0028-4793", "PMID" : "3495732", "abstract" : "We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera", "given" : "G K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schell", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lott", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1987", "6", "25" ] ] }, "page" : "1627-32", "title" : "Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(8)", "plainTextFormattedCitation" : "(8)", "previouslyFormattedCitation" : "(8)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(8).With the implementation of antiretroviral therapy and PJP prophylaxis the incidence of PJP associated with the Human Immunodeficiency virus (HIV) has sharply declined ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1525-4135", "PMID" : "16284539", "abstract" : "BACKGROUND: Rapid changes in HIV epidemiology and highly active antiretroviral therapy (HAART) may have resulted in recent changes in patterns of inpatient utilization.\n\nOBJECTIVE: To examine trends in inpatient diagnoses and mortality in HIV patients.\n\nDESIGN/SETTING/PATIENTS: Serial cross-sectional analyses of HIV patients hospitalized in 1996, 1998, and 2000, using hospital discharge data from the Healthcare Costs and Utilization Project for 12 states. Each hospitalization was classified as an opportunistic illness, complication of injection drug use (IDU), liver-related complication, ischemic heart disease, cerebrovascular disease, non-Pneumocystis carinii pneumonia (PCP), diabetes, or chronic hepatitis C virus (HCV).\n\nMAIN OUTCOME MEASURES: Number of hospital admissions, inpatient mortality.\n\nRESULTS: We evaluated 316,963 admissions that occurred between 1996 and 2000, with an overall mortality of 7%. Hospitalizations for opportunistic infections significantly decreased from 40% to 27% of all HIV-related admissions. The overall proportion of IDU complications remained relatively stable (6%) each year. Hospitalizations increased for liver-related complications from 8% to 13% and for chronic HCV from 1% to 5% in this period. The number of hospitalizations for cerebrovascular disease and for ischemic heart disease was relatively negligible in all years. Overall, inpatient mortality decreased between 1996 and 2000. Relatively higher mortality was observed among African Americans, Hispanics, those with Medicaid, those with Medicare, and the uninsured, however. Opportunistic infections and liver-related complications were associated with greater inpatient mortality.\n\nCONCLUSION: Results do not show a significant recent rise in HIV-related inpatient utilization. Admissions to treat opportunistic infections have declined precipitously, consistent with the effects of HAART. Although not dramatic, liver-related disease is an increasing cause of hospitalization in HIV+ patients.", "author" : [ { "dropping-particle" : "", "family" : "Gebo", "given" : "Kelly A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fleishman", "given" : "John A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moore", "given" : "Richard D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of acquired immune deficiency syndromes (1999)", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2005", "12", "15" ] ] }, "page" : "609-16", "title" : "Hospitalizations for metabolic conditions, opportunistic infections, and injection drug use among HIV patients: trends between 1996 and 2000 in 12 states.", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(9)", "plainTextFormattedCitation" : "(9)", "previouslyFormattedCitation" : "(9)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(9), whereas that associated with treatment for malignancy in non-HIV infected hosts has increased ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3201/eid1903.121151", "ISSN" : "1080-6059", "PMID" : "23622345", "abstract" : "After an increase in the number of reported cases of Pneumocystis jirovecii pneumonia in England, we investigated data from 2000-2010 to verify the increase. We analyzed national databases for microbiological and clinical diagnoses of P. jirovecii pneumonia and associated deaths. We found that laboratory-confirmed cases in England had increased an average of 7% per year and that death certifications and hospital admissions also increased. Hospital admissions indicated increased P. jirovecii pneumonia diagnoses among patients not infected with HIV, particularly among those who had received a transplant or had a hematologic malignancy. A new risk was identified: preexisting lung disease. Infection rates among HIV-positive adults decreased. The results confirm that diagnoses of potentially preventable P. jirovecii pneumonia among persons outside the known risk group of persons with HIV infection have increased. This finding warrants further characterization of risk groups and a review of P. jirovecii pneumonia prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Maini", "given" : "Rishma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Katherine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sheridan", "given" : "Elizabeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lamagni", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nichols", "given" : "Gordon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delpech", "given" : "Valerie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phin", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Emerging infectious diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "386-92", "title" : "Increasing Pneumocystis pneumonia, England, UK, 2000-2010.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0003-9926", "PMID" : "7763117", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brown", "given" : "A E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Armstrong", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of internal medicine", "id" : "ITEM-2", "issue" : "11", "issued" : { "date-parts" : [ [ "1995", "6", "12" ] ] }, "page" : "1125-8", "title" : "Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. More patients, same risk.", "type" : "article-journal", "volume" : "155" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(10,11)", "plainTextFormattedCitation" : "(10,11)", "previouslyFormattedCitation" : "(10,11)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(10,11). Before the routine use of prophylaxis, Hughes et al estimated a PJP infection rate in children with acute lymphoblastic leukaemia (ALL) as 22-43%, depending on the stage of the disease, and 25% in children treated for rhabdomyosarcoma (RMS) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuhn", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaudhary", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "George", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1977", "12", "29" ] ] }, "page" : "1419-26", "title" : "Successful chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "297" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0008-543X", "PMID" : "1081905", "abstract" : "One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(12,13)", "plainTextFormattedCitation" : "(12,13)", "previouslyFormattedCitation" : "(12,13)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(12,13). Successful PJP chemoprophylaxis with daily co-trimoxazole was demonstrated in a randomised placebo-controlled trial (RCT) in children undergoing treatment for these 2 diseases ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuhn", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaudhary", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "George", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1977", "12", "29" ] ] }, "page" : "1419-26", "title" : "Successful chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "297" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(12)", "plainTextFormattedCitation" : "(12)", "previouslyFormattedCitation" : "(12)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(12). The incidence of PJP over a 2-year period in the placebo group was 21%, whereas there were no cases of PJP in the daily co-trimoxazole group. Later Hughes at al demonstrated that co-trimoxazole given on 3 days per week was equally effective ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198706253162604", "ISSN" : "0028-4793", "PMID" : "3495732", "abstract" : "We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera", "given" : "G K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schell", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lott", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1987", "6", "25" ] ] }, "page" : "1627-32", "title" : "Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(8)", "plainTextFormattedCitation" : "(8)", "previouslyFormattedCitation" : "(8)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(8) and more recently other groups have confirmed the use of cotrimoxazole for 2 days ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1002/pbc.21774", "ISSN" : "1545-5009", "abstract" : "Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.", "author" : [ { "dropping-particle" : "", "family" : "Ohata", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohta", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashii", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokimasa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ozono", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Blood Cancer", "edition" : "2008/09/27", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "142-144", "publisher-place" : "Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "title" : "Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14,15)", "plainTextFormattedCitation" : "(14,15)", "previouslyFormattedCitation" : "(14,15)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14,15), or even just one day per week ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jpeds.2013.10.021", "ISSN" : "0022-3476", "abstract" : "OBJECTIVE: To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN: A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS: The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION: A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.", "author" : [ { "dropping-particle" : "", "family" : "Caselli", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petris", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rondelli", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carraro", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colombini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muggeo", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ziino", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Melchionda", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pierani", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soncini", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desantis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zanazzo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barone", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cesaro", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cellini", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mura", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Milano", "given" : "G M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meazza", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cicalese", "given" : "M P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tropia", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masi", "given" : "S", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castagnola", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arico", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Pediatr", "edition" : "2013/11/21", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "389-392.e1", "publisher-place" : "Department of Pediatric Hematology-Oncology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Florence, Italy. Pediatric Hematology-Oncology, Padua, Italy. Pediatric Oncology and Hematology, Lalla Seragnoli Unit, University of Bologna, Bologna,", "title" : "Single-day trimethoprim/sulfamethoxazole prophylaxis for pneumocystis pneumonia in children with cancer", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(16)", "plainTextFormattedCitation" : "(16)", "previouslyFormattedCitation" : "(16)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(16) has similar efficacy.The use of cotrimoxazole for PJP prophylaxis is well established for children receiving treatment for ALL and bone marrow transplantation. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00277-013-1698-0", "ISSN" : "1432-0584", "PMID" : "23412562", "abstract" : "Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim-sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.", "author" : [ { "dropping-particle" : "", "family" : "Neumann", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krause", "given" : "S W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maschmeyer", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schiel", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lilienfeld-Toal", "given" : "M", "non-dropping-particle" : "von", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of hematology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "433-42", "title" : "Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (D", "type" : "article-journal", "volume" : "92" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "National Comprehensive Cancer Network (NCCN) guidelines. Prevention and Treatment of Cancer-Related Infections. Version 1.2013", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(17,18)", "plainTextFormattedCitation" : "(17,18)", "previouslyFormattedCitation" : "(17,18)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(17,18) However evidence – based recommendations for children treated for solid malignancies are less certain. A 2007 Cochrane review found only 11 RCTs addressedsing the question of PJP prophylaxis in non-HIV immunocompromised hosts. Of whichthese, justonly 5 included children, all of whom were undergoing treatment for acute leukaemia. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19) The review concluded that co-trimoxazole prophylaxis should be considered when the risk of PJP exceeds the rate of severe adverse events associated with the drug. A severe adverse event was defined as a complication requiring permanent discontinuation of co-trimoxazole and included leukopaenia, thrombocytopaenia and severe dermatological reactions. An adverse event rate of 3.1% in adults was described in the 11 RCTs, but no significant adverse events were identified in children receiving cotrimoxazole. Subsequent reviews and guidelines on the topic quote this ~3% risk of PJP as a threshold for advocating prophylaxis ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2013", "9", "15" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Thomas", "given" : "CF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Limper", "given" : "AH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "title" : "Treatment and prevention of Pneumocystis pneumonia in non-HIV-infected patients", "type" : "webpage" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1007/s00277-013-1698-0", "ISSN" : "1432-0584", "PMID" : "23412562", "abstract" : "Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim-sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.", "author" : [ { "dropping-particle" : "", "family" : "Neumann", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krause", "given" : "S W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maschmeyer", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schiel", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lilienfeld-Toal", "given" : "M", "non-dropping-particle" : "von", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of hematology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "433-42", "title" : "Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (D", "type" : "article-journal", "volume" : "92" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(17,20)", "plainTextFormattedCitation" : "(17,20)", "previouslyFormattedCitation" : "(17,20)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(17,20) but it cannot logically be applied to children if the adverse event rate is lower. Furthermore all the studies in the Cochrane review administered co-trimoxazole either daily or three times per week. The quoted toxicities may be lower with the equally efficacious twice-weekly regimen. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14)", "plainTextFormattedCitation" : "(14)", "previouslyFormattedCitation" : "(14)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14) One might conclude from the 2007 Cochrane review that all immunosuppressed children should be offered prophylaxis as the benefit exceeds the risk. However there are theoretical concerns regarding the development of antimicrobial resistance, hypersensitivity reactions and potential bone marrow suppression (see discussion below). Currently little is known regarding the background PJP risk for children undergoing treatment for solid malignancies. Historical data (summarised in table 1) is sparse and variable and cannot account for new more intensive chemotherapy regimens that may include immunomodulating agents. New therapies and increasing survival may explain the rising incidence of PJP in the non-HIV population ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3201/eid1903.121151", "ISSN" : "1080-6059", "PMID" : "23622345", "abstract" : "After an increase in the number of reported cases of Pneumocystis jirovecii pneumonia in England, we investigated data from 2000-2010 to verify the increase. We analyzed national databases for microbiological and clinical diagnoses of P. jirovecii pneumonia and associated deaths. We found that laboratory-confirmed cases in England had increased an average of 7% per year and that death certifications and hospital admissions also increased. Hospital admissions indicated increased P. jirovecii pneumonia diagnoses among patients not infected with HIV, particularly among those who had received a transplant or had a hematologic malignancy. A new risk was identified: preexisting lung disease. Infection rates among HIV-positive adults decreased. The results confirm that diagnoses of potentially preventable P. jirovecii pneumonia among persons outside the known risk group of persons with HIV infection have increased. This finding warrants further characterization of risk groups and a review of P. jirovecii pneumonia prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Maini", "given" : "Rishma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Katherine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sheridan", "given" : "Elizabeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lamagni", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nichols", "given" : "Gordon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delpech", "given" : "Valerie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phin", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Emerging infectious diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "386-92", "title" : "Increasing Pneumocystis pneumonia, England, UK, 2000-2010.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(10)", "plainTextFormattedCitation" : "(10)", "previouslyFormattedCitation" : "(10)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(10) and highlight the need to re-evaluate who is offered prophylaxis.Table 1: PJP attack rates in solid tumoursDiagnosisPopulationInfection rateReferenceDiagnostic technique%No. proven PJP/no. cases at riskNeuroblastoma*<19y0.05%3/58Perera el al, 1970 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0098-7484 (Print) 0098-7484 (Linking)", "author" : [ { "dropping-particle" : "", "family" : "Perera", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Western", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "H D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "W W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Akers", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA", "edition" : "1970/11/09", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1970" ] ] }, "page" : "1074-1078", "title" : "Pneumocystis carinii pneumonia in a hospital for children. Epidemiologic aspects", "type" : "article-journal", "volume" : "214" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21)Morphological evidence by pulmonary aspirate or necropsy or bothChildren & young people≤19 years3.8%3/78Hughes et al 1973ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-3476", "PMID" : "4572932", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "H K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coburn", "given" : "T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grigsby", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of pediatrics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1973", "3" ] ] }, "page" : "404-15", "title" : "Pneumocystis carinii pneumonitis in children with malignancies.", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(22)", "plainTextFormattedCitation" : "(22)", "previouslyFormattedCitation" : "(22)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(22)CXR appearance and organism detected in lung aspirateHodgkin’s lymphoma1.3%1/77‘Reticulum Cell Sarcoma’ =Non-Hodgkin’s Lymphoma4%1/26Rhabdomyosarcoma25%No figures given, origin of statistic not clear**Hughes et al 1975 & 1977 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. 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The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(12,13)", "plainTextFormattedCitation" : "(12,13)", "previouslyFormattedCitation" : "(12,13)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(12,13)CXR appearance and organism detected in lung aspirate<18 years3%5/159Wilber et al 1980 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. 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Epidemiologic aspects", "type" : "article-journal", "volume" : "214" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21)Morphological evidence by pulmonary aspirate or necropsy or bothPrimary or metastatic brain neoplasm3 months – 80 years (median age 43 years)1.3%8/595Septkowitz et al 1992ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25)", "plainTextFormattedCitation" : "(25)", "previouslyFormattedCitation" : "(25)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25)Morphological evidence in a respiratory specimen≥20 years1.7%10/587Henson et al 1991ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(26)", "plainTextFormattedCitation" : "(26)", "previouslyFormattedCitation" : "(26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(26)Morphological evidence in a respiratory specimen*stage of disease not specified**In 1977 Hughes et al ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. 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Consequently this figure should be interpreted with caution.Current practice in UK CCLG centresOnly 6 of the 20 UK CCLG centres currently have local guidelines for PJP prophylaxis. In most units prophylaxis tends to be given at the discretion of individual consultants and varying doses are used from daily to two or three times per week ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/archdischild-2014-307515", "ISSN" : "1468-2044", "PMID" : "25324566", "author" : [ { "dropping-particle" : "", "family" : "Proudfoot", "given" : "Rebecca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "Bob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilne", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of disease in childhood", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "10", "16" ] ] }, "page" : "archdischild-2014-307515-", "title" : "UK survey of Pneumocystis jirovecii Pneumonia (PJP) prophylaxis use in paediatric oncology patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(27)", "plainTextFormattedCitation" : "(27)", "previouslyFormattedCitation" : "(27)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(27).Table 2: Summary of current practice in UK CCLG centres ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/archdischild-2014-307515", "ISSN" : "1468-2044", "PMID" : "25324566", "author" : [ { "dropping-particle" : "", "family" : "Proudfoot", "given" : "Rebecca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "Bob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilne", "given" : "Sophie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of disease in childhood", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "10", "16" ] ] }, "page" : "archdischild-2014-307515-", "title" : "UK survey of Pneumocystis jirovecii Pneumonia (PJP) prophylaxis use in paediatric oncology patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(27)", "plainTextFormattedCitation" : "(27)", "previouslyFormattedCitation" : "(27)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(27)Number of Responses20 (100%)Number of centres with a PJP guideline6 (30%)Number of centres using co-trimoxazole dosing regimes other than twice weekly based on surface area 4 (20%)3. ScopePurpose:Guidelines on the indications and methods for prophylaxis against Pneumocystis Jirovecii Pneumonia (PJP) in Paediatric Oncology Patients.Target population:Children ≤19 years of age undergoing treatment for solid malignancies.Exclusion criteria:Adults undergoing treatment for solid malignancies.Children ≤19 years who are immunocompromised for reasons other than treatment for a solid malignancy.Healthcare Setting:Tertiary paediatric oncology units and 'shared care' centres in District General Hospitals.Types of interventions:Antibiotic prophylaxis with co-trimoxazole and alternatives, including atovaquone, pentamidine and dapsone.Key Stakeholders:Children's Cancer and Leukaemia Group (CCLG)UK CCLG treatment centresPaediatric oncology patientsExisting documents:None4. Methods (see appendix C)This guideline was developed in accordance with the methods outlined in the CCLG guideline development standard operating procedure, version 5. See appendix C for details.5. recommendatonsWe suggest PJP prophylaxis is offered to all children with solid tumours undergoing treatment that is likely to render them lymphopaenic unless there are clear contraindications(Consensus recommendation).Identifying who is at riskIdentifying which children are specifically at risk of PJP infection is difficult. 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There is no clear equivalent biological marker to guide practice in HIV negative patients. Although some authors have suggested using CD4 counts or total lymphocyte counts for this purpose ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.critrevonc.2012.08.002", "ISSN" : "1879-0461", "PMID" : "22925496", "abstract" : "High-grade glioma patients receiving concomitant chemoradiotherapy with temozolomide 75mg/m(2) during six to seven weeks or dose-dense temozolomide regimens especially in combination with chronic use of corticosteroids have a high risk for developing Pneumocystis jirovecii pneumonia. In this review, we define risk groups and propose a guideline for prophylaxis using risk stratification.", "author" : [ { "dropping-particle" : "", "family" : "Vos", "given" : "Filip Y", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gijtenbeek", "given" : "Johanna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bleeker-Rovers", "given" : "Chantal P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herpen", "given" : "Carla M", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Critical reviews in oncology/hematology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "373-82", "title" : "Pneumocystis jirovecii pneumonia prophylaxis during temozolomide treatment for high-grade gliomas.", "type" : "article-journal", "volume" : "85" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0012-3692", "PMID" : "10988193", "abstract" : "STUDY OBJECTIVES: To assess the potential use of peripheral blood CD4 + T-lymphocyte counts (CD4 + counts) as a clinically useful biological marker to identify specific immunocompromised patients (without HIV infection) at high risk for Pneumocystis carinii pneumonia (PCP).\n\nDESIGN: Prospective observational study.\n\nSETTING: Three hundred seventy-five-bed tertiary-care urban referral teaching hospital, and 250-bed community-based referral hospital.\n\nPATIENTS: One hundred seventy-one consecutive confirmed HIV-seronegative hospitalized and ambulatory adults, including 22 patients with active PCP, 8 patients with bacterial pneumonia, 24 persons in two groups considered at high clinical risk, 38 persons in two groups considered at low or undefined risk, and 79 persons in four groups considered not at risk for PCP (including healthy individuals).\n\nMEASUREMENTS AND RESULTS: Compared to counts in healthy individuals, median CD4 + counts were significantly decreased in patients with active PCP (61 cells/microL vs 832 cells/microL; p = 0.001) where 91% of patients had a CD4 + count < 300 cells/microL at the time of PCP diagnosis. Median CD4 + counts were also reduced in the high clinical risk groups of recent organ transplant recipients (117 cells/microL; p = 0.007), 64% with < 300 cells/microL, and patients receiving chemotherapy (221 cells/microL; p<0.01), 80% with < 300 cells/microL. For the low or undefined clinical risk groups, the median CD4 + counts were not significantly reduced, although 39 to 46% of individuals receiving long-term corticosteroid therapy (alone or in combination with other agents) had CD4 + counts < 300 cells/microL. Median CD4 + counts in individuals considered not at risk for PCP were similar to those in healthy subjects. Compared to counts in patients with active PCP, median CD4 + counts were significantly higher in bacterial pneumonia patients (486 cells/microL; p<0.05), but similar to those in healthy subjects.\n\nCONCLUSIONS: These data suggest that for immunosuppressed persons without HIV infection (especially in low or undefined PCP risk groups), CD4 + counts may be a useful clinical marker to identify specific individuals at particularly high clinical risk for PCP and may help to guide chemoprophylaxis.", "author" : [ { "dropping-particle" : "", "family" : "Mansharamani", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balachandran", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vernovsky", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garland", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koziel", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chest", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2000", "10" ] ] }, "page" : "712-20", "title" : "Peripheral blood CD4 + T-lymphocyte counts during Pneumocystis carinii pneumonia in immunocompromised patients without HIV infection.", "type" : "article-journal", "volume" : "118" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(29,30)", "plainTextFormattedCitation" : "(29,30)", "previouslyFormattedCitation" : "(29,30)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(29,30), lowering of these indices is not consistently associated with PJP infection in immunocompromised patients without HIV ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.clml.2011.07.006", "ISSN" : "2152-2669", "PMID" : "22000698", "abstract" : "BACKGROUND: Guidelines for primary Pneumocystis jirovecii pneumonia (PCP) prophylaxis for patients with hematologic malignancy (HM) are still lacking. Our objective was to identify risk factors for PCP among patients with HM to help recognize patients who would benefit from primary PCP prophylaxis.\n\nMATERIAL AND METHODS: We performed a case-control study of adult patients with HM and negative for human immunodeficiency virus and with confirmed PCP by using cytology or histopathology from 2 medical centers over an 11-year period. Each case was matched with 4 patients without PCP by type of HM and year of treatment. We compared demographic, clinical, and laboratory data among cases and controls. Data were analyzed by using SPSS version 18.0.\n\nRESULTS: Fourteen cases and 56 controls were included in the study period. No significant differences were seen in demographics between both groups. All identified patients had lymphoproliferative HM, the majority of patients (93%) had either non-Hodgkin lymphoma or chronic lymphocytic leukemia. Autoimmune diseases were more frequent in cases vs. controls (28.6% vs. 5.4% P = .01). The receipt and duration of chemotherapy were similar in both groups. Among chemotherapeutic agents, including steroids, only fludarabine was associated with increased risk for PCP (50% vs. 17.9%; P = .02). No difference was found in total or lymphocyte percentage in cases at the time of PCP diagnosis vs. nadir values in controls.\n\nCONCLUSION: Patients with lymphoproliferative HM, specifically chronic lymphocytic leukemia and non-Hodgkin lymphoma, who are receiving fludarabine and with autoimmune disorders are at increased risk for PCP and should be considered for PCP primary prophylaxis.", "author" : [ { "dropping-particle" : "", "family" : "Obeid", "given" : "Karam M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aguilar", "given" : "Javier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szpunar", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharma", "given" : "Mamta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Busto", "given" : "Ramon", "non-dropping-particle" : "del", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Al-Katib", "given" : "Ayad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "Leonard B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical lymphoma, myeloma & leukemia", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "2" ] ] }, "page" : "66-9", "title" : "Risk factors for Pneumocystis jirovecii pneumonia in patients with lymphoproliferative disorders.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1080/00365540601150497", "ISSN" : "0036-5548", "PMID" : "17577823", "abstract" : "A retrospective study was conducted to describe risk factors associated with Pneumocystis jiroveci pneumonia (PCP) among HIV-negative patients. During 2002-2004, 50 cases of PCP were identified at Rigshospitalet University Hospital on the basis of histology, PCR and clinical symptoms of PCP. Predisposing conditions included haematological malignancy (72%), inflammatory diseases (14%), solid organ transplantation (6%) and other conditions associated with immunodeficiency (8%). The most common treatment related risk factors were steroid usage (76%) and chemotherapy (72%). In 88% of patients who received steroids, dosage was either lowered or given as pulse-therapy in the 2 weeks preceding the onset of symptoms. Only 1 patient was on PCP prophylaxis at diagnosis and only 8 (16%) patients had previously been given PCP prophylaxis. At diagnosis, 78% of patients were lymphopenic. CD4 counts were available in 17 patients. Only 9 patients (52%) had CD4 count values below 300 cells/microl. The overall mortality attributable to PCP was 14% and was significantly associated with delayed diagnosis and treatment. Among immunocompromized HIV-negative patients, PCP should be particularly suspected in the context of steroid treatment and lymphopenia. Although low CD4 count is associated with a higher risk of PCP, the use of CD4 count as guidance for risk identification or prophylaxis among HIV-negative patients appears insufficient.", "author" : [ { "dropping-particle" : "", "family" : "Overgaard", "given" : "Ulrik M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helweg-Larsen", "given" : "Jannik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scandinavian journal of infectious diseases", "id" : "ITEM-2", "issue" : "6-7", "issued" : { "date-parts" : [ [ "2007", "1", "8" ] ] }, "language" : "en", "page" : "589-95", "publisher" : "Informa UK Ltd UK", "title" : "Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004.", "type" : "article-journal", "volume" : "39" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0012-3692", "PMID" : "10988193", "abstract" : "STUDY OBJECTIVES: To assess the potential use of peripheral blood CD4 + T-lymphocyte counts (CD4 + counts) as a clinically useful biological marker to identify specific immunocompromised patients (without HIV infection) at high risk for Pneumocystis carinii pneumonia (PCP).\n\nDESIGN: Prospective observational study.\n\nSETTING: Three hundred seventy-five-bed tertiary-care urban referral teaching hospital, and 250-bed community-based referral hospital.\n\nPATIENTS: One hundred seventy-one consecutive confirmed HIV-seronegative hospitalized and ambulatory adults, including 22 patients with active PCP, 8 patients with bacterial pneumonia, 24 persons in two groups considered at high clinical risk, 38 persons in two groups considered at low or undefined risk, and 79 persons in four groups considered not at risk for PCP (including healthy individuals).\n\nMEASUREMENTS AND RESULTS: Compared to counts in healthy individuals, median CD4 + counts were significantly decreased in patients with active PCP (61 cells/microL vs 832 cells/microL; p = 0.001) where 91% of patients had a CD4 + count < 300 cells/microL at the time of PCP diagnosis. Median CD4 + counts were also reduced in the high clinical risk groups of recent organ transplant recipients (117 cells/microL; p = 0.007), 64% with < 300 cells/microL, and patients receiving chemotherapy (221 cells/microL; p<0.01), 80% with < 300 cells/microL. For the low or undefined clinical risk groups, the median CD4 + counts were not significantly reduced, although 39 to 46% of individuals receiving long-term corticosteroid therapy (alone or in combination with other agents) had CD4 + counts < 300 cells/microL. Median CD4 + counts in individuals considered not at risk for PCP were similar to those in healthy subjects. Compared to counts in patients with active PCP, median CD4 + counts were significantly higher in bacterial pneumonia patients (486 cells/microL; p<0.05), but similar to those in healthy subjects.\n\nCONCLUSIONS: These data suggest that for immunosuppressed persons without HIV infection (especially in low or undefined PCP risk groups), CD4 + counts may be a useful clinical marker to identify specific individuals at particularly high clinical risk for PCP and may help to guide chemoprophylaxis.", "author" : [ { "dropping-particle" : "", "family" : "Mansharamani", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balachandran", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vernovsky", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garland", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koziel", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chest", "id" : "ITEM-3", "issue" : "3", "issued" : { "date-parts" : [ [ "2000", "10" ] ] }, "page" : "712-20", "title" : "Peripheral blood CD4 + T-lymphocyte counts during Pneumocystis carinii pneumonia in immunocompromised patients without HIV infection.", "type" : "article-journal", "volume" : "118" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(30\u201332)", "plainTextFormattedCitation" : "(30\u201332)", "previouslyFormattedCitation" : "(30\u201332)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(30–32). Furthermore most of these studies have excluded paediatric patients and lack sufficient statistical power. The lymphocyte count is unlikely to be a reliable predictor of risk in immunocompromised HIV negative infants and young children because, unlike older children and adults, HIV positive infants can develop PJP at CD4 counts well in excess of 200 cells/μl ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.idc.2009.10.010", "ISSN" : "1557-9824", "PMID" : "20171548", "abstract" : "Pneumocystis jirovecii has gained attention during the last decade in the context of the AIDS epidemic and the increasing use of cytotoxic and immunosuppressive therapies. This article summarizes current knowledge on biology, pathophysiology, epidemiology, diagnosis, prevention, and treatment of pulmonary P jirovecii infection, with a particular focus on the evolving pathophysiology and epidemiology. 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Nine studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-3476", "PMID" : "4572932", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "H K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coburn", "given" : "T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grigsby", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of pediatrics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1973", "3" ] ] }, "page" : "404-15", "title" : "Pneumocystis carinii pneumonitis in children with malignancies.", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0008-543X", "PMID" : "1081905", "abstract" : "One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuhn", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaudhary", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "George", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-4", "issue" : "26", "issued" : { "date-parts" : [ [ "1977", "12", "29" ] ] }, "page" : "1419-26", "title" : "Successful chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "297" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "ISSN" : "0098-7484 (Print) 0098-7484 (Linking)", "author" : [ { "dropping-particle" : "", "family" : "Perera", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Western", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "H D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "W W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Akers", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA", "edition" : "1970/11/09", "id" : "ITEM-5", "issued" : { "date-parts" : [ [ "1970" ] ] }, "page" : "1074-1078", "title" : "Pneumocystis carinii pneumonia in a hospital for children. Epidemiologic aspects", "type" : "article-journal", "volume" : "214" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-6", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] }, { "id" : "ITEM-7", "itemData" : { "ISSN" : "0031-3939", "PMID" : "6605512", "author" : [ { "dropping-particle" : "", "family" : "Cyklis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zieli\u0144ska", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatria polska", "id" : "ITEM-7", "issue" : "4", "issued" : { "date-parts" : [ [ "1983", "4" ] ] }, "page" : "337-40", "title" : "[Pneumocystis carinii infection in children with acute leukemia and non-Hodgkin malignant lymphoma].", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] }, { "id" : "ITEM-8", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-8", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(12,13,21\u201326)", "plainTextFormattedCitation" : "(12,13,21\u201326)", "previouslyFormattedCitation" : "(12,13,21\u201326)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(12,13,21–26) (see Table 1) identified PJP infection in 0.05 to 26% of children undergoing treatment for a solid malignancy. Studies varied in the definition of infection and not all children were symptomatic. Some cases were identified at post mortem and it is not clear whether PJP was the underlying cause of death. Nonetheless these studies do confirm that children undergoing treatment for solid tumours are at risk of PJP infection and therefore the guideline development group (GDG) felt that it is appropriate to offer these children PJP prophylaxis. CorticosteroidsCorticosteroids were identified as a risk factor in 4 studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "1058-4838", "PMID" : "8274607", "abstract" : "In the 1980s, tens of thousands of cases of Pneumocystis carinii pneumonia (PCP) occurred in persons with AIDS, making it the most common opportunistic infection encountered in this patient population. Thus, the presentation and clinical course of PCP became well-known to many physicians. Overshadowed by this epidemic was the continued occurrence of PCP in persons not infected with the human immunodeficiency virus, most notably those receiving immunosuppressive therapy for neoplastic disease or other indications. A review from Memorial Sloan-Kettering Cancer Center has demonstrated that, in addition to those patients previously defined as at risk--those with acute lymphocytic leukemia or allogeneic bone marrow transplantation--patients receiving corticosteroid therapy for a primary or metastatic brain neoplasm are at risk for PCP and should receive prophylaxis. Among patients with neoplastic disease, the disease may be more fulminant and the mortality rate higher--approaching 50% in most series. Wider use of prophylaxis should decrease the frequency of this disease, while prompt initiation of therapy in patients with a compatible syndrome should help to lower mortality rates.", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "1993", "11" ] ] }, "page" : "S416-22", "title" : "Pneumocystis carinii pneumonia in patients without AIDS.", "type" : "article-journal", "volume" : "17 Suppl 2" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1080/00365540601150497", "ISSN" : "0036-5548", "PMID" : "17577823", "abstract" : "A retrospective study was conducted to describe risk factors associated with Pneumocystis jiroveci pneumonia (PCP) among HIV-negative patients. During 2002-2004, 50 cases of PCP were identified at Rigshospitalet University Hospital on the basis of histology, PCR and clinical symptoms of PCP. Predisposing conditions included haematological malignancy (72%), inflammatory diseases (14%), solid organ transplantation (6%) and other conditions associated with immunodeficiency (8%). The most common treatment related risk factors were steroid usage (76%) and chemotherapy (72%). In 88% of patients who received steroids, dosage was either lowered or given as pulse-therapy in the 2 weeks preceding the onset of symptoms. Only 1 patient was on PCP prophylaxis at diagnosis and only 8 (16%) patients had previously been given PCP prophylaxis. At diagnosis, 78% of patients were lymphopenic. CD4 counts were available in 17 patients. Only 9 patients (52%) had CD4 count values below 300 cells/microl. The overall mortality attributable to PCP was 14% and was significantly associated with delayed diagnosis and treatment. Among immunocompromized HIV-negative patients, PCP should be particularly suspected in the context of steroid treatment and lymphopenia. Although low CD4 count is associated with a higher risk of PCP, the use of CD4 count as guidance for risk identification or prophylaxis among HIV-negative patients appears insufficient.", "author" : [ { "dropping-particle" : "", "family" : "Overgaard", "given" : "Ulrik M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helweg-Larsen", "given" : "Jannik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scandinavian journal of infectious diseases", "id" : "ITEM-4", "issue" : "6-7", "issued" : { "date-parts" : [ [ "2007", "1", "8" ] ] }, "language" : "en", "page" : "589-95", "publisher" : "Informa UK Ltd UK", "title" : "Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004.", "type" : "article-journal", "volume" : "39" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25,26,32,34)", "plainTextFormattedCitation" : "(25,26,32,34)", "previouslyFormattedCitation" : "(25,26,32,34)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25,26,32,34) of low or very low quality. There are no prospective trials. In a review of 264 case reports of PJP in non-HIV adults at a tertiary centre in the USA, corticosteroids were implicated in 90% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1058-4838", "PMID" : "8274607", "abstract" : "In the 1980s, tens of thousands of cases of Pneumocystis carinii pneumonia (PCP) occurred in persons with AIDS, making it the most common opportunistic infection encountered in this patient population. Thus, the presentation and clinical course of PCP became well-known to many physicians. Overshadowed by this epidemic was the continued occurrence of PCP in persons not infected with the human immunodeficiency virus, most notably those receiving immunosuppressive therapy for neoplastic disease or other indications. A review from Memorial Sloan-Kettering Cancer Center has demonstrated that, in addition to those patients previously defined as at risk--those with acute lymphocytic leukemia or allogeneic bone marrow transplantation--patients receiving corticosteroid therapy for a primary or metastatic brain neoplasm are at risk for PCP and should receive prophylaxis. Among patients with neoplastic disease, the disease may be more fulminant and the mortality rate higher--approaching 50% in most series. Wider use of prophylaxis should decrease the frequency of this disease, while prompt initiation of therapy in patients with a compatible syndrome should help to lower mortality rates.", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1993", "11" ] ] }, "page" : "S416-22", "title" : "Pneumocystis carinii pneumonia in patients without AIDS.", "type" : "article-journal", "volume" : "17 Suppl 2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(34)", "plainTextFormattedCitation" : "(34)", "previouslyFormattedCitation" : "(34)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(34). The report concluded that patients receiving corticosteroids for primary or metastatic brain neoplasm are particularly at risk for PJP and should receive PJP prophylaxis (type unspecified). A retrospective analysis of 116 adults without HIV at the Mayo Medical Centre revealed corticosteroid use in the preceding month in 90.5% of cases of PJP infection ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4065/71.1.5", "ISSN" : "00256196", "author" : [ { "dropping-particle" : "", "family" : "Yale", "given" : "Steven H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Limper", "given" : "Andrew H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Mayo Clinic Proceedings", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1996", "1" ] ] }, "page" : "5-13", "title" : "Pneumocystis carinii Pneumonia in Patients Without Acquired Immunodeficiency Syndrome: Associated Illnesses and Prior Corticosteroid Therapy", "type" : "article-journal", "volume" : "71" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(35)", "plainTextFormattedCitation" : "(35)", "previouslyFormattedCitation" : "(35)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(35). The median daily dose was 30mg of prednisolone equivalent and the median duration, 12 weeks prior to the development of infection. However significant numbers of patients were diagnosed with PJP at lower steroid doses given over shorter periods. More recently Worth et al ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/sj.bjc.6602412", "ISSN" : "0007-0920", "PMID" : "15726101", "abstract" : "Pneumocystis jirovecii pneumonia (PCP) is associated with high mortality in immunocompromised patients without human immunodeficiency virus infection. However, chemoprophylaxis is highly effective. In patients with solid tumours or haematologic malignancy, several risk factors for developing PCP have been identified, predominantly corticosteroid therapy. The aims of this study were to identify the potentially preventable cases of PCP in patients receiving corticosteroid therapy at a tertiary care cancer centre and to estimate the frequency of utilisation of chemoprophylaxis in these patients. Two retrospective reviews were performed. Over a 10-year period, 14 cases of PCP were identified: no cases were attributable to failed chemoprophylaxis, drug allergy or intolerance. During a 6-month period, 73 patients received high-dose corticosteroid therapy (> or =25 mg prednisolone or > or =4 mg dexamethasone daily) for > or =4 weeks. Of these, 22 (30%) had haematologic malignancy, and 51 (70%) had solid tumours. Fewer patients with solid tumours received prophylaxis compared to patients with haematologic malignancy (3.9 vs 63.6%, P<0.0001). Guidelines for PCP chemoprophylaxis in patients with haematologic malignancy or solid tumours who receive corticosteroid therapy are proposed. Successful primary prevention of PCP in this population will require a multifaceted approach targeting the suboptimal prescribing patterns for chemoprophylaxis.", "author" : [ { "dropping-particle" : "", "family" : "Worth", "given" : "L J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dooley", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seymour", "given" : "J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mileshkin", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Slavin", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thursky", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British journal of cancer", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2005", "3", "14" ] ] }, "page" : "867-72", "title" : "An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital.", "type" : "article-journal", "volume" : "92" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(36)", "plainTextFormattedCitation" : "(36)", "previouslyFormattedCitation" : "(36)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(36) analysed 14 cases of PJP in adults receiving corticosteroids for malignancy and concluded that prophylaxis should be given if ≥20mg prednisolone equivalent for longer than one month is anticipated. National Comprehensive Cancer Network (NCCN) guidelines give the same recommendation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "National Comprehensive Cancer Network (NCCN) guidelines. Prevention and Treatment of Cancer-Related Infections. Version 1.2013", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(18)", "plainTextFormattedCitation" : "(18)", "previouslyFormattedCitation" : "(18)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(18) and recently published guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Oncology refer to ‘long –term steroids’ without specifying a dose or duration ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00277-013-1698-0", "ISSN" : "1432-0584", "PMID" : "23412562", "abstract" : "Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim-sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.", "author" : [ { "dropping-particle" : "", "family" : "Neumann", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krause", "given" : "S W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maschmeyer", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schiel", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lilienfeld-Toal", "given" : "M", "non-dropping-particle" : "von", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of hematology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "433-42", "title" : "Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (D", "type" : "article-journal", "volume" : "92" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(17)", "plainTextFormattedCitation" : "(17)", "previouslyFormattedCitation" : "(17)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(17). Another retrospective case review of PJP cases with primary brain tumours at a tertiary centre in New York excluded those under 20 years old as children were routinely given co-trimoxazole as prophylaxis with ‘prolonged’ steroid treatment ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(26)", "plainTextFormattedCitation" : "(26)", "previouslyFormattedCitation" : "(26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(26). Temozolamide (TMZ)The literature review did not identify any studies specifically addressing the risk of PJP infection in children taking temozolamide (TMZ) to treat brain tumours. There are numerous case reports linking the use of TMZ with PJP infection, especially with concomitant steroid use ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1107-0625", "PMID" : "22006764", "abstract" : "Temozolomide (TMZ) is an alkylating, antineoplastic agent which is being used to treat cases of refractory anaplastic astrocytoma, newly-diagnosed glioblastoma multiforme and metastatic melanoma. TMZ causes lymphopenia and T-cell dysfunction in most of the patients. Related to this toxicity several opportunistic infections have been reported in the literature, but were not well characterized. To further investigate this topic, relevant English language studies were identified through Medline. There were 36 previously reported cases of infection related to TMZ. The median age of the cases was 55 years (range 33-73). The most frequently experienced infections were mucocutaneous candidiasis (n=11; 28.2%), herpes zoster (n=5; 12.8%), herpes simplex virus (n=4; 10.2%), cytomegalovirus (CMV) (n=5; 12.8%), pneumocystis carinii pneumonia (PCP) (n=3; 7.6%), hepatitis B virus (HBV) (n=2; 5.1%) and others (n=9; 23%). Mortality rates were 28.5% (n=4/14) in patients with reported outcome. In this survey, about one third of the TMZ-related severe infections resulted in death. Patients treated with TMZ are at increased risk for opportunistic viral and bacterial infection. Therefore, close monitoring of patients receiving TMZ for opportunistic infections should be carried out.", "author" : [ { "dropping-particle" : "", "family" : "Kizilarslanoglu", "given" : "M C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aksoy", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yildirim", "given" : "N O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ararat", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sahin", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Altundag", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of B.U.ON. : official journal of the Balkan Union of Oncology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "547-50", "title" : "Temozolomide-related infections: review of the literature.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "1574-8863", "PMID" : "18690931", "abstract" : "The temozolomide is a promising orally cytotoxic agent used in malignant glioma. The survival curve improvement after drug administration appears to be statistically significant. The review of temozolomide side effects is carried out by search on literature data found on web and is divided on the 4 grades of toxicity according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The adverse effects related with TMZ administration are divided in three categories: myelosuppression, non haematologic toxicity, and infections. The main adverse effect is the myelosuppression that appears to be rather low and reversible as well as the vomiting or nausea. The different schedules of administration are analysed. The frequency of concomitant infections is underlined. In particular, if available, the relationship between temozolomide and other cytotoxic agents or anticonvulsivant drugs is analysed to clarify the possibility of increase of toxicity. The temozolomide is used also in children but the toxicity could be more frequent.", "author" : [ { "dropping-particle" : "", "family" : "Dario", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tomei", "given" : "Giustino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current drug safety", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2006", "5" ] ] }, "page" : "205-22", "title" : "The safety of the temozolomide in patients with malignant glioma.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1200/JCO.2004.07.060", "ISSN" : "0732-183X", "PMID" : "14726505", "abstract" : "PURPOSE: Standard schedule temozolomide (TMZ; daily for 5 days every 4 weeks) is often used in melanoma patients, but phase III data show that it is no more effective than standard dacarbazine. Extended TMZ dosing regimens may be superior by delivering the drug continuously at a higher dose over time. Using an extended dosing schedule, we noted a high incidence of lymphopenia and occasional opportunistic infections (OIs). Here we report our retrospective experience in the first 97 patients.\n\nMATERIALS AND METHODS: TMZ was administered at 75 mg/m(2)/d orally for 6 weeks every 8 weeks, although nine patients were treated continuously without a break. Seventeen patients were treated with TMZ alone; 73 patients received TMZ with thalidomide; seven patients received TMZ with low-dose interferon alfa.\n\nRESULTS: Median duration of TMZ treatment was 113 days; 29% received > or = 24 weeks of therapy. Lymphopenia was seen in 60% of patients (absolute lymphocyte count < 800/microL) with a median of 101 days to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4(+) compartment preferentially. There were two documented OIs (Pneumocystis and Aspergillus pneumonia) as well as other infections indicative of T-cell dysfunction in another 21 patients.\n\nCONCLUSION: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.", "author" : [ { "dropping-particle" : "", "family" : "Su", "given" : "Y B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sohn", "given" : "Sejean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krown", "given" : "Susan E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Philip O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wolchok", "given" : "Jedd D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quinn", "given" : "Carolyn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "Linda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chapman", "given" : "Paul B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2004", "3", "15" ] ] }, "page" : "610-6", "title" : "Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "ISSN" : "0732-183X", "PMID" : "11870182", "abstract" : "PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM.\n\nPATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival.\n\nRESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome.\n\nCONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.", "author" : [ { "dropping-particle" : "", "family" : "Stupp", "given" : "Roger", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dietrich", "given" : "Pierre-Yves", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ostermann Kraljevic", "given" : "Sandrine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pica", "given" : "Alessia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maillard", "given" : "Ivan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maeder", "given" : "Phillipe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meuli", "given" : "Reto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Janzer", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pizzolato", "given" : "Gianpaolo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miralbell", "given" : "Raymond", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porchet", "given" : "Fran\u00e7ois", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Regli", "given" : "Luca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tribolet", "given" : "Nicolas", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mirimanoff", "given" : "Ren\u00e9 O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leyvraz", "given" : "Serge", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-4", "issue" : "5", "issued" : { "date-parts" : [ [ "2002", "3", "1" ] ] }, "page" : "1375-82", "title" : "Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(37\u201340)", "plainTextFormattedCitation" : "(37\u201340)", "previouslyFormattedCitation" : "(37\u201340)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(37–40) and TMZ is known to cause profound, long-lasting lymphopaenia with selective CD4 cell depletion ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1200/JCO.2004.07.060", "ISSN" : "0732-183X", "PMID" : "14726505", "abstract" : "PURPOSE: Standard schedule temozolomide (TMZ; daily for 5 days every 4 weeks) is often used in melanoma patients, but phase III data show that it is no more effective than standard dacarbazine. Extended TMZ dosing regimens may be superior by delivering the drug continuously at a higher dose over time. Using an extended dosing schedule, we noted a high incidence of lymphopenia and occasional opportunistic infections (OIs). Here we report our retrospective experience in the first 97 patients.\n\nMATERIALS AND METHODS: TMZ was administered at 75 mg/m(2)/d orally for 6 weeks every 8 weeks, although nine patients were treated continuously without a break. Seventeen patients were treated with TMZ alone; 73 patients received TMZ with thalidomide; seven patients received TMZ with low-dose interferon alfa.\n\nRESULTS: Median duration of TMZ treatment was 113 days; 29% received > or = 24 weeks of therapy. Lymphopenia was seen in 60% of patients (absolute lymphocyte count < 800/microL) with a median of 101 days to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4(+) compartment preferentially. There were two documented OIs (Pneumocystis and Aspergillus pneumonia) as well as other infections indicative of T-cell dysfunction in another 21 patients.\n\nCONCLUSION: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.", "author" : [ { "dropping-particle" : "", "family" : "Su", "given" : "Y B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sohn", "given" : "Sejean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krown", "given" : "Susan E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Philip O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wolchok", "given" : "Jedd D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quinn", "given" : "Carolyn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "Linda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chapman", "given" : "Paul B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2004", "3", "15" ] ] }, "page" : "610-6", "title" : "Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "1574-8863", "PMID" : "18690931", "abstract" : "The temozolomide is a promising orally cytotoxic agent used in malignant glioma. The survival curve improvement after drug administration appears to be statistically significant. The review of temozolomide side effects is carried out by search on literature data found on web and is divided on the 4 grades of toxicity according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The adverse effects related with TMZ administration are divided in three categories: myelosuppression, non haematologic toxicity, and infections. The main adverse effect is the myelosuppression that appears to be rather low and reversible as well as the vomiting or nausea. The different schedules of administration are analysed. The frequency of concomitant infections is underlined. In particular, if available, the relationship between temozolomide and other cytotoxic agents or anticonvulsivant drugs is analysed to clarify the possibility of increase of toxicity. The temozolomide is used also in children but the toxicity could be more frequent.", "author" : [ { "dropping-particle" : "", "family" : "Dario", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tomei", "given" : "Giustino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current drug safety", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2006", "5" ] ] }, "page" : "205-22", "title" : "The safety of the temozolomide in patients with malignant glioma.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1158/1078-R-11-0774", "ISSN" : "1078-0432", "PMID" : "21737504", "abstract" : "PURPOSE: Patients with high-grade gliomas (HGG) routinely receive radiation, temozolomide, and glucocorticoids. As each of these is immunosuppressive, we conducted a prospective, multicenter study to follow CD4 counts over time and determine whether low CD4 counts were associated with adverse outcomes.\n\nEXPERIMENTAL DESIGN: Patients with newly diagnosed HGG had CD4 counts drawn before initiating standard therapy and monthly thereafter for 1 year. Information on hospitalizations, infections, glucocorticoid use, survival, and cause of death were also collected.\n\nRESULTS: Ninety-six evaluable patients were accrued [85% glioblastoma, median age of 57, median Karnofsky performance status (KPS) = 90]. The median CD4 count before radiation and temozolomide treatment was 664 cells/mm(3). The CD4 count nadir occurred 2 months after initiating therapy when 73% of patients had CD4 counts less than 300 cells/mm(3) and 40% had less than 200 cells/mm(3). CD4 counts remained low throughout the year of follow-up. Patients with CD4 counts less than 200 cells/mm(3)at 2 months had shorter survival than those with higher counts (median: 13.1 vs. 19.7 months, P = 0.002). Median survival was related to CD4 toxicity grades (I = 23.8 months, II = 19.7 months, III-IV = 13.1 months, P = 0.009). The adjusted HR for death attributable to 2-month CD4 count below 200 was 1.66 (P = 0.03). Eighty-eight percent of deaths resulted from disease progression, whereas only 2.5% were due to infection.\n\nCONCLUSIONS: Severe reductions in CD4 counts in patients with newly diagnosed HGG treated with radiation and temozolomide treatment are common, treatment-related, long-lasting, and associated with early death from tumor progression.", "author" : [ { "dropping-particle" : "", "family" : "Grossman", "given" : "Stuart A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ye", "given" : "Xiaobu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lesser", "given" : "Glenn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sloan", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carraway", "given" : "Hetty", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desideri", "given" : "Serena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Piantadosi", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical cancer research : an official journal of the American Association for Cancer Research", "id" : "ITEM-3", "issue" : "16", "issued" : { "date-parts" : [ [ "2011", "8", "15" ] ] }, "page" : "5473-80", "title" : "Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(38,39,41)", "plainTextFormattedCitation" : "(38,39,41)", "previouslyFormattedCitation" : "(38,39,41)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(38,39,41). This recommendation was peer reviewed due to lack of identified evidence and peer review supported prophylaxis. Radiotherapy (RT)Radiotherapy in combination with corticosteroids and / or chemotherapy can cause profound lymphopaenia ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ijrobp.2004.12.085", "ISSN" : "0360-3016", "PMID" : "16029802", "abstract" : "PURPOSE: Patients with primary brain tumors are often treated with high doses of corticosteroids for prolonged periods to reduce intracranial swelling and alleviate symptoms such as headaches. This treatment may lead to immunosuppression, placing the patient at risk of life-threatening opportunistic infections, such as Pneumocystis carinii pneumonia. The risk of contracting some types of infection may be reduced with prophylactic antibiotics. The purpose of this study was to determine the occurrence of low CD4 counts and whether monitoring CD4 counts during and after radiotherapy (RT) is warranted.\n\nMETHODS AND MATERIALS: CD4 counts were measured during RT in 70 of 76 consecutive patients with newly diagnosed Grade III and IV astrocytoma and anaplastic oligodendroglioma treated with corticosteroids and seen at the Johns Hopkins Hospital. Weekly CD4 measurements were taken in the most recent 25 patients. Prophylactic trimethoprim-sulfamethoxazole (160 mg/800 mg p.o. every Monday, Wednesday, and Friday) or dapsone (100 mg p.o. daily) in those with sulfa allergy was prescribed only if patients developed a low CD4 count. Carmustine chemotherapy wafers were placed at surgery in 23% of patients, evenly distributed between the groups. No patient received any other chemotherapy concurrent with RT.\n\nRESULTS: CD4 counts decreased to <200/mm3 in 17 (24%) of 70 patients. For the 25 patients with weekly CD4 counts, all CD4 counts were >450/mm3 before RT, but 6 (24%) of 25 fell to <200/mm3 during RT. Patients with counts <200/mm3 were significantly more likely to be hospitalized (41% vs. 9%, p <0.01) and be hospitalized for infection (23% vs. 4%, p <0.05) during RT. Overall survival was not significantly different between the groups. All patients with low CD4 counts were treated with prophylactic antibiotics, and no patient developed Pneumocystis carinii pneumonia. No patients developed a serious adverse reaction to antibiotic therapy. The mean dose of steroids, mean minimal white blood cell count, and number of patients treated with Gliadel wafers were not significantly different between the groups.\n\nCONCLUSION: The results of this study have confirmed the clinical impression that the use of high-dose corticosteroids and RT in patients with primary brain cancer is sufficient to result in severe immunosuppression and place these patients at risk of life-threatening opportunistic infections. A protocol of prophylactic antibiotics for those at risk may help prevent a p\u2026", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "Michael A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parisi", "given" : "Michele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grossman", "given" : "Stuart", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kleinberg", "given" : "Lawrence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International journal of radiation oncology, biology, physics", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2005", "8", "1" ] ] }, "page" : "1423-6", "title" : "Primary brain tumors treated with steroids and radiotherapy: low CD4 counts and risk of infection.", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(42)", "plainTextFormattedCitation" : "(42)", "previouslyFormattedCitation" : "(42)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(42). There are no identified studies of the risk of PJP infection in children receiving radiotherapy in combination with steroids and/or chemotherapy. Peer review and the GDG supported prophylaxis on the basis that lymphopaenia is an identified risk factor for PJP infection. RituximabNo relevant studies were identified looking at the risk of PJP in children receiving rituximab in combination with other cancer treatments (chemotherapy, radiotherapy, corticosteroids). There are case reports of PJP infection in children receiving rituximab ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3978/j.issn.2072-1439.2013.08.35", "ISSN" : "2072-1439", "PMID" : "23991330", "abstract" : "Rituximab, a monoclonal antibody against CD20+ antigen specific B cell, has been increasingly used in the treatment of non-Hodgkin's lymphoma and some other autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. It is noted that Rituximab could enhanced the efficacy of CHOP-based chemotherapy. Meanwhile it could increase the opportunity of lung infection. Pneumocystis jiroveci pneumonia (PCP), a rare opportunistic infection that was not reported in the large-scale clinical trials of Rituximab, was found recently in patients with non-Hodgkin's lymphoma treated with remedy containing Rituximab. We herein report two cases of PCP in lymphoma patients after Rituximab-containing chemotherapy. Both patients were successfully treated, with trimethoprim-sulfamethoxazole (TMP-SMX) in one case and Caspofungin alone in the other. We also reviewed the literature and concluded that PCP is an infrequent but potentially life-threatening infection in patients with non-Hodgkin's lymphoma subjected to Rituximab-containing regimen. Therefore, adequate prophylaxis, timely diagnosis and treatment are necessary.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Xu-Qin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fang", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mei", "given" : "Xiao-Dong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Xiao-Jing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bao", "given" : "Ming-Hong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of thoracic disease", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "8" ] ] }, "page" : "E162-6", "title" : "Pneumocystis jiroveci pneumonia in patients with non-Hodgkin's lymphoma after Rituximab-containing regimen: two cases of report and literature review.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1159/000334113", "ISSN" : "1421-9662", "PMID" : "22178955", "abstract" : "Recent studies suggest an increased risk for Pneumocystis jirovecii pneumonia (PJP) in adults receiving short-interval rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy for diffuse large cell B cell lymphoma (DLBCL). This retrospective study evaluates precise PJP incidence and the efficacy of anti-PJP prophylaxis in DLBCL. Patients with DLBCL, aged \u226518 years and treated between December 2004 and December 2010, were included. Details of treatment-related respiratory infections, focusing on PJP incidence, risk factors and prophylaxis, were assessed. A total of 132 patients were analyzed; 47 were treated with rituximab-CHOP therapy every 21 days (R-CHOP-21) and 85 were treated every 14 days (R-CHOP-14). The incidence of treatment-related respiratory infections was higher in patients receiving R-CHOP-14. PJP was diagnosed in 5 patients: 4 in the R-CHOP-14 (6.6%) and 1 in the R-CHOP-21 cohort (2.6%), using triplex polymerase chain reaction (PCR) for PJ in bronchoalveolar fluid. None of the patients receiving P.jirovecii prophylaxis (n = 33) developed PJP, compared with 6.6% of those treated with R-CHOP-14 without such prophylaxis. An older age and R-CHOP administered every 14 rather than every 21 days increased the PJP risk. Trimethoprim/sulfamethoxazole prophylaxis is found to be highly efficient in preventing this life-threatening complication and, therefore, should be recommended for patients receiving the R-CHOP-14 regimen.", "author" : [ { "dropping-particle" : "", "family" : "Hardak", "given" : "Emilia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oren", "given" : "Ilana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dann", "given" : "Eldad J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yigla", "given" : "Mordechai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Faibish", "given" : "Tal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rowe", "given" : "Jacob M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Avivi", "given" : "Irit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Acta haematologica", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "110-4", "title" : "The increased risk for pneumocystis pneumonia in patients receiving rituximab-CHOP-14 can be prevented by the administration of trimethoprim/sulfamethoxazole: a single-center experience.", "type" : "article-journal", "volume" : "127" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1007/s00277-012-1592-1", "ISSN" : "1432-0584", "PMID" : "23053189", "abstract" : "R-CHOP chemotherapy composed of rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone which might increase the risk of Pneumocystis pneumonia in patients with non-Hodgkin lymphoma. We estimated the point prevalence of Pneumocystis pneumonia in non-Hodgkin lymphoma patients according to the number of R-CHOP cycles and investigated whether cytoreduction by chemotherapy is associated with Pneumocystis pneumonia development. We retrospectively established a cohort of patients who received R-CHOP for non-Hodgkin lymphoma in our institution. Using this cohort, we estimated the incidence rate and point prevalence of definite and probable Pneumocystis pneumonia. To assess factors associated with Pneumocystis pneumonia development several clinical variables, including absolute neutrophil and lymphocyte count at the time of non-Hodgkin lymphoma diagnosis and when the last R-CHOP cycle was administered, were compared between patients with and without Pneumocystis pneumonia. Of 713 patients in the cohort, 14 and 18 patients were diagnosed with definite and probable Pneumocystis pneumonia, respectively. The overall incidence of definite and definite plus probable PCP in NHL patients receiving R-CHOP were 2.0\u00a0% (14/713; 95\u00a0% CI, 1.1-3.3\u00a0%) and 4.5\u00a0% (32/713; 95\u00a0% CI, 3.2-6.4\u00a0%), respectively. This corresponded to 3.8 (95\u00a0% CI, 2.2-6.4) and 8.4 (95\u00a0% CI, 5.9-11.9) per 1000 persons. Many cases of Pneumocystis pneumonia (22/32, 68.7\u00a0%) developed after administration of the fourth R-CHOP cycle. However, there was no statistical difference in Pneumocystis pneumonia prevalence between patients receiving four or more cycles of R-CHOP and fewer than. Higher absolute neutrophil count (4,742/mm(3) vs. 2,627/mm(3); p\u2009<\u20090.01) was associated with Pneumocystis pneumonia development at the last R-CHOP cycle, while absolute lymphocyte count at the time of NHL diagnosis was not. Contrary to expectations, Pneumocystis pneumonia is not a frequent complication of R-CHOP treatment for non-Hodgkin lymphoma. Cytoreduction of R-CHOP might not be a risk factor of Pneumocystis pneumonia development. Universal prophylaxis against Pneumocystis pneumonia during R-CHOP treatment could not be strongly recommended.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Tark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Choi", "given" : "Sang-Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Sung-Han", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jeong", "given" : "Jin-Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Woo", "given" : "Jun Hee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Yang Soo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sung", "given" : "Heungsup", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Mi-Na", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yoon", "given" : "Dok Hyun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suh", "given" : "Cheolwon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Sang-Oh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of hematology", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "231-8", "title" : "Point prevalence of Pneumocystis pneumonia in patients with non-Hodgkin lymphoma according to the number of cycles of R-CHOP chemotherapy.", "type" : "article-journal", "volume" : "92" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "ISSN" : "1592-8721", "PMID" : "17229653", "abstract" : "We report six cases of Pneumocystis jirovecii pneumonia (PCP) verified by immunoflourescence/polymerase chain reaction of bronchoalveolar fluid among 46 lymphoma patients (13%) who received rituximab-CHOEP-14 at our institution. PCP prophylaxis should be standard management for this group of patients and also considered for patients treated with rituximab-CHOP-14, CHOP-14 or CHOEP-14.", "author" : [ { "dropping-particle" : "", "family" : "Kolstad", "given" : "Arne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holte", "given" : "Harald", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foss\u00e5", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lauritzsen", "given" : "Grete Fossum", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaustad", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Torfoss", "given" : "Dag", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Haematologica", "id" : "ITEM-4", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "139-40", "title" : "Pneumocystis jirovecii pneumonia in B-cell lymphoma patients treated with the rituximab-CHOEP-14 regimen.", "type" : "article-journal", "volume" : "92" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "abstract" : "Background: Pneumocystis pneumonia (PcP) is an opportunistic fungal infection. Although T-cell immunity is classically related to Pneumocystis defense, recent data support roles for B lymphocytes in the development of PcP in animals, and we have observed several cases of PcP in patients receiving rituximab. These observations prompted a systematic review of our experience to define the spectrum of clinical presentations in which PcP has occurred in the setting of rituximab therapy. Methods: Using a computer-based search, we reviewed the records of patients who received rituximab and developed PcP at Mayo Clinic Rochester over the years 1998 to 2011 to establish the underlying conditions, clinical course, possible risk factors, and potential association between this drug and the development of PcP. Results: Over this period, 30 patients developed PcP during treatment with rituximab. The underlying diseases included hematologic malignancies in 90% of cases. Glucocorticoids were used in 73% of these patients, under different chemotherapeutic regimens. Three patients (10%) developed PcP in the setting of rituximab without concomitant chemotherapy or significant glucocorticoid exposure. Of these 30 patients, 88% developed acute hypoxemic respiratory failure and 53% required ICU admission. The clinical course was fatal in 30%. Conclusion: PcP can occur in association with rituximab, with the majority of cases having also received cytotoxic chemotherapy or significant doses of glucocorticoids. The clinical course of cases of PcP in patients treated with rituximab can be quite fulminant, with significant mortality. Primary prophylaxis should be considered in patients at risk, and secondary prophylaxis provided unless immune reconstitution is well assured. 2013 American College of Chest Physicians.", "author" : [ { "dropping-particle" : "", "family" : "Martin-Garrido", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carmona", "given" : "E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Specks", "given" : "U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Limper", "given" : "A H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chest", "id" : "ITEM-5", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "258-265", "publisher-place" : "(Martin-Garrido, Carmona, Specks, Limper) Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 8-24 Stabile Bldg, 200 First St, Rochester, MN 55905, United States (Martin-Garrido) Servicio de Medicina Interna, Hospital Univer", "title" : "Pneumocystis pneumonia in patients treated with rituximab", "type" : "article-journal", "volume" : "144" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(43\u201347)", "plainTextFormattedCitation" : "(43\u201347)", "previouslyFormattedCitation" : "(43\u201347)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(43–47) and in paediatric oncology rituximab is usually administered in combination with chemotherapy to treat children with malignancies at high risk of treatment failure or relapsed disease. These children are therefore likely to be immunocompromised. The GDG and peer review supported PJP prophylaxis in children treated with rituximab in combination with corticosteroids, conventional chemotherapy and/or radiotherapy. Underlying lung pathologyOne low quality study ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3201/eid1903.121151", "ISSN" : "1080-6059", "PMID" : "23622345", "abstract" : "After an increase in the number of reported cases of Pneumocystis jirovecii pneumonia in England, we investigated data from 2000-2010 to verify the increase. We analyzed national databases for microbiological and clinical diagnoses of P. jirovecii pneumonia and associated deaths. We found that laboratory-confirmed cases in England had increased an average of 7% per year and that death certifications and hospital admissions also increased. Hospital admissions indicated increased P. jirovecii pneumonia diagnoses among patients not infected with HIV, particularly among those who had received a transplant or had a hematologic malignancy. A new risk was identified: preexisting lung disease. Infection rates among HIV-positive adults decreased. The results confirm that diagnoses of potentially preventable P. jirovecii pneumonia among persons outside the known risk group of persons with HIV infection have increased. This finding warrants further characterization of risk groups and a review of P. jirovecii pneumonia prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Maini", "given" : "Rishma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Katherine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sheridan", "given" : "Elizabeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lamagni", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nichols", "given" : "Gordon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delpech", "given" : "Valerie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phin", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Emerging infectious diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "386-92", "title" : "Increasing Pneumocystis pneumonia, England, UK, 2000-2010.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(10)", "plainTextFormattedCitation" : "(10)", "previouslyFormattedCitation" : "(10)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(10) of national PJP infections found that 17.5% patients had pre-existing lung disease including tuberculosis, chronic obstructive airway disease, cystic fibrosis, bronchiectasis, asthma or interstitial lung disease. Most of these patients were adults therefore the data may not be applicable to the paediatric population. Nonetheless the GDG felt that the evidence supported ensuring that children with pre-existing lung disease receiving chemotherapy should beare given PJP prophylaxis.Previous PJP infectionNo studies were identified looking at PJP prophylaxis in children previously treated for PJP infection whilst being treated for a solid malignancy. However previous infection will identify a high-risk group of immunocompromised patients. Peer review and the GDG supported PJP prophylaxis for children who had a previous PJP infection.First line prophylaxis should be with co-trimoxazole (trimethoprim and sulfamethoxazole)(Strong Recommendation, moderate quality evidence)Three studies, including one high quality systematic review ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19) and two low quality cohort studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISBN" : "0002-922X (Print)\\r0002-922X (Linking)", "PMID" : "6965335", "abstract" : "Owing to a 15% attack rate of Pneumocystis carinii pneumonitis (PCP) among the leukemic population of Riley Hospital, Indianapolis, a two-year study using continuous low-dosage sulfamethoxazole-trimethoprim to prevent PCP was started in January 1977. A total of 229 pediatric cancer patients considered at high risk for getting PCP received prophylaxis, while 19 additonal low-risk cancer patients did not receive sulfamethoxazole-trimethoprim. None of these 248 patients contracted PCP. However, five cases of PCP did occur among ten additional high-risk patients who failed to receive this preparation for a variety of reasons. Complications of the continuous prophylaxis program included neutropenia, rash, and gastrointestinal complaints. This study confirms that continuous, low-dosage sulfamethoxazole-trimethoprim prophylaxis is effective in preventing PCP in susceptible immunosuppressed patients but is ineffective in eradicating the organism from the population at risk.", "author" : [ { "dropping-particle" : "", "family" : "Harris", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCallister", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "S A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "A S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baehner", "given" : "R L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of diseases of children (1911)", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "35-38", "title" : "Prevention of pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethroprim therapy.", "type" : "legal_case", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23,48)", "plainTextFormattedCitation" : "(23,48)", "previouslyFormattedCitation" : "(23,48)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23,48) demonstrated that co-trimoxazole is highly effective prophylaxis against PJP in immunocompromised children. The systematic review reported a 91% reduction in the occurrence of PJP and a number needed to treat of 15 to prevent one case of PJP (95% confidence interval 13-20). The rate of PJP infection in the control group was 7.5% in patients of all ages with haematological malignancies and/or following bone marrow or solid organ transplantation. Co-trimoxazole prophylaxis should be given twice weekly in dosage according to surface area (see appendix A).(Strong recommendation, low quality evidence)Four studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198706253162604", "ISSN" : "0028-4793", "PMID" : "3495732", "abstract" : "We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera", "given" : "G K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schell", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lott", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1987", "6", "25" ] ] }, "page" : "1627-32", "title" : "Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.jpeds.2013.10.021", "ISSN" : "0022-3476", "abstract" : "OBJECTIVE: To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN: A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS: The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION: A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.", "author" : [ { "dropping-particle" : "", "family" : "Caselli", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petris", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rondelli", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carraro", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colombini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muggeo", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ziino", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Melchionda", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pierani", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soncini", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desantis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zanazzo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barone", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cesaro", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cellini", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mura", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Milano", "given" : "G M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meazza", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cicalese", "given" : "M P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tropia", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masi", "given" : "S", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castagnola", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arico", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Pediatr", "edition" : "2013/11/21", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "389-392.e1", "publisher-place" : "Department of Pediatric Hematology-Oncology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Florence, Italy. Pediatric Hematology-Oncology, Padua, Italy. Pediatric Oncology and Hematology, Lalla Seragnoli Unit, University of Bologna, Bologna,", "title" : "Single-day trimethoprim/sulfamethoxazole prophylaxis for pneumocystis pneumonia in children with cancer", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1002/pbc.21774", "ISSN" : "1545-5009", "abstract" : "Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.", "author" : [ { "dropping-particle" : "", "family" : "Ohata", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohta", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashii", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokimasa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ozono", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Blood Cancer", "edition" : "2008/09/27", "id" : "ITEM-4", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "142-144", "publisher-place" : "Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "title" : "Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(8,14\u201316)", "plainTextFormattedCitation" : "(8,14\u201316)", "previouslyFormattedCitation" : "(8,14\u201316)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(8,14–16) of high, low or very low quality showed that twice weekly (on consecutive or non-consecutive days), three times weekly or daily co-trimoxazole are all prevent PJP infection in children receiving chemotherapy. As all regimes are effective the GDG recommends that used in the UKALL 2011 trial (twice daily on 2 consecutive days, see appendix A) as this regime is well tolerated and found to be highly effective in a cohort of children who historically had a PJP infection rate of 22-43% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0008-543X", "PMID" : "1081905", "abstract" : "One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "Pneumocystis carinii pneumonitis (PCP) is fatal in 90 to 100% of the cases if no treatment is given. Trimethoprim-sulfamethoxazole (TMP-SMX) was used at one of two dosage levels in the treatment of 20 children with PCP and cancer. Of 14 patients treated with 20 mg TMP--100 mg SMX/kgd, 12 recovered and 2 died. Treatment of the fatal cases and one of the patients who recovered was supplemented with pentamidine. When six patients were treated with 4 to 7 mg TMP--20 to 35 mg SMX/kgd, four recovered and two died. Both fatal cases and one of the patients who recovered were also treated with pentamidine. There was no significant adverse effects from TMP-SMX.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanyal", "given" : "S K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Canadian Medical Association Journal", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "1975" ] ] }, "page" : "47-50", "title" : "Treatment of Pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole", "type" : "article-journal", "volume" : "112" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(13,49)", "plainTextFormattedCitation" : "(13,49)", "previouslyFormattedCitation" : "(13,49)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(13,49).4. For patients intolerant of co-trimoxazole the choice of alternative prophylaxis is controversial. This decision should be made according to patient and physician preference and experience. The risk/benefit of any prophylaxis at all should be re-evaluated on an individual basis as alternative drugs are all associated with poorer efficacy and increased toxicity and expense. (Weak recommendation, very low quality evidence)Four low or very low quality studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/INF.0b013e318292f560", "ISSN" : "1532-0987", "PMID" : "23538522", "abstract" : "BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy.\n\nMETHODS: We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected.\n\nRESULTS: One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count >1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit.\n\nCONCLUSIONS: Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.", "author" : [ { "dropping-particle" : "", "family" : "DeMasi", "given" : "James M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Jennifer A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leonard", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koh", "given" : "Andrew Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aquino", "given" : "Victor M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Pediatric infectious disease journal", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "933-6", "title" : "Intravenous pentamidine is safe and effective as primary pneumocystis pneumonia prophylaxis in children and adolescents undergoing hematopoietic stem cell transplantation.", "type" : "article-journal", "volume" : "32" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1002/pbc.21287", "ISSN" : "1545-5017", "PMID" : "17635000", "abstract" : "BACKGROUND: Pneumocystis jirovecii, formerly carinii, pneumonia (PCP) poses a life-threatening risk to oncology patients. The use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis virtually eliminates the risk of infection; however, many patients cannot tolerate TMP-SMZ. We performed a retrospective analysis to determine the PCP breakthrough rate in pediatric oncology patients receiving intravenous pentamidine as second line PCP prophylaxis.\n\nPROCEDURE: We conducted a retrospective chart review of pediatric oncology patients who received intravenous pentamidine from 2001 to 2006 at our institution. The diagnosis, age and bone marrow transplant (BMT) status were determined. A subset of patients had review of their records to determine the justification for discontinuing TMP-SMZ. Children who developed symptoms of pneumonia with a clinical suspicion of PCP underwent bronchoscopy, allowing for identification of Pneumocystis.\n\nRESULTS: A total of 232 patients received 1,706 doses of intravenous pentamidine and no toxicities were identified. The main reasons for discontinuing TMP-SMZ were bone marrow suppression and drug allergy. Three children developed PCP, equating to a breakthrough rate of 1.3%. Two of these children had undergone BMT (1.9% breakthrough rate) and both were under the age of two (6.5% breakthrough rate).\n\nCONCLUSIONS: The use of intravenous pentamidine as PCP prophylaxis results in a breakthrough rate of 1.3%. TMP-SMZ is the first choice for PCP prophylaxis. However, when necessary, the use of intravenous pentamidine has an acceptably low failure rate, even in high-risk BMT patients. Other options should be considered for children less than 2 years of age.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Su Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dabb", "given" : "Alix A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glenn", "given" : "Donald J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snyder", "given" : "Kristen M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chuk", "given" : "Meredith K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loeb", "given" : "David M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "779-83", "title" : "Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0732-183X", "PMID" : "8113834", "abstract" : "PURPOSE: Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX.\n\nPATIENTS AND METHODS: AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25).\n\nRESULTS: Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP.\n\nCONCLUSION: AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.", "author" : [ { "dropping-particle" : "", "family" : "Mustafa", "given" : "M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pappo", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winick", "given" : "N J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchanan", "given" : "G R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "1994", "2" ] ] }, "page" : "258-61", "title" : "Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1097/inf.0000000000000044", "ISSN" : "0891-3668", "abstract" : "Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.", "author" : [ { "dropping-particle" : "", "family" : "Orgel", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rushing", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Infect Dis J", "edition" : "2013/09/14", "id" : "ITEM-4", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "319-321", "publisher-place" : "From the *Jonathan Jaques Children's Cancer Center, Miller Children's Hospital Long Beach, Long Beach and daggerChildren's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA.", "title" : "Efficacy and tolerability of intravenous pentamidine isethionate for pneumocystis jiroveci prophylaxis in a pediatric oncology population", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(50\u201353)", "plainTextFormattedCitation" : "(50\u201353)", "previouslyFormattedCitation" : "(50\u201353)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(50–53) demonstrate that pentamidine is effective prophylaxis against PJP although probably not as effective as co-trimoxazole. The efficacy of intravenous pentamidine is likely to be inferior to co-trimoxazole as an observational study in paediatric HIV patients had a breakthrough PJP infection rate of 6.6% (2 out of 30 patients) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/ppul.19502308105", "ISSN" : "87556863", "author" : [ { "dropping-particle" : "", "family" : "Gupta", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stephenson", "given" : "K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gauar", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frenkel", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric Pulmonology", "id" : "ITEM-1", "issue" : "S16", "issued" : { "date-parts" : [ [ "1997", "4", "28" ] ] }, "page" : "199-200", "title" : "Intravenous pentamidine as an alternate for pneumocystis carinii pneumonia prophylaxis in children with HIV infection", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(54)", "plainTextFormattedCitation" : "(54)", "previouslyFormattedCitation" : "(54)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(54) , although there was no comparison group. Nonetheless this is concerning as breakthrough infections on co-trimoxazole are often due to non-compliance, whereas this is not an issue with intravenous pentamidine. From the available data in paediatric oncology patients nebulised and intravenous pentamidine are likely to be equally efficacious but the administration of nebulised medications to very young children is challenging. One low quality study ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21202", "ISSN" : "1545-5017", "PMID" : "17458875", "abstract" : "Pneumocystis pneumonia (PCP) is a serious complication of chemotherapy-induced immunosuppression. Trimethoprim-sulfamethoxazole (TMP-SMZ) given twice daily, 3 days every week is considered the best form of prophylaxis for PCP. We evaluated PCP prophylaxis in all children up to 18 years of age undergoing cancer chemotherapy over a 2-year period. Four children were diagnosed with PCP over 24 months. Two of 12 children on intravenous pentamidine, 1 of 143 on TMP-SMZ and 1 of 36 on dapsone for PCP prophylaxis developed PCP. Intravenous pentamidine may not be as effective as previously considered and should be used with caution.", "author" : [ { "dropping-particle" : "", "family" : "Prasad", "given" : "Pinki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nania", "given" : "Joseph J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shankar", "given" : "Sadhna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "896-8", "title" : "Pneumocystis pneumonia in children receiving chemotherapy.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(55)", "plainTextFormattedCitation" : "(55)", "previouslyFormattedCitation" : "(55)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(55) compared co-trimoxazole, dapsone, pentamidine and atovaquone. Co-trimoxazole was most effective (PJP rate 0.004/ person-year) when compared with dapsone (0.03 /person-year) and intravenous pentamidine (0.04 /person-year). One moderate quality study ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing >20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P =.016), whereas methemoglobinemia risk was increased with dosing >20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P <.001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. 2011 American Cancer Society.", "author" : [ { "dropping-particle" : "", "family" : "Esbenshade", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ho", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shintani", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhao", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "L A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "3485-3492", "publisher-place" : "(Esbenshade, Ho, Smith, Friedman) Department of Pediatrics, Vanderbilt University Medical Center, Monroe Carell Jr Children's Hospital at Vanderbilt, 2200 Pierce Avenue, 397 PRB, Nashville, TN 37232, United States (Shintani, Zhao) Department of Biostatist", "title" : "Dapsone-induced methemoglobinemia: A dose-related occurrence?", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(56)", "plainTextFormattedCitation" : "(56)", "previouslyFormattedCitation" : "(56)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(56) in paediatric patients treated for haematological malignancies and aplastic anaemia showed that the risk of symptomatic methaemaglobinaemia was higher with dapsone (19.8%) than the risk of PJP infection. This risk mightay be lower with less frequent dapsone dosingreduction in dose frequency but the study did not address this. However none of the patients in this study suffered a ‘major’ complication (i.e. intensive care admission or death) and the methaemaglobinaemia resolved on discontinuation of dapsone. One low quality study ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/sj.bmt.1702004", "ISSN" : "0268-3369", "PMID" : "10516703", "abstract" : "Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study dem\u2026", "author" : [ { "dropping-particle" : "", "family" : "Colby", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAfee", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sackstein", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Finkelstein", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fishman", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spitzer", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bone marrow transplantation", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1999", "10" ] ] }, "page" : "897-902", "title" : "A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(57)", "plainTextFormattedCitation" : "(57)", "previouslyFormattedCitation" : "(57)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(57) showed that atovaquone was well tolerated in adults undergoing stem cell transplants but there was a high incidence of adverse reactions to co-trimoxazole. However the rates of adverse reactions to co-trimoxazole have consistently be reported as higher in adults than children ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19). There was early discontinuation of this study so comparative efficacy could not be parison of Alternative PJP Prophylaxis RegimesIssueCo-trimoxazoleDapsoneNebulised PentamidineIntravenous PentamidineAtovaquoneEfficacyHighModerateModerateModerateModerateToxicityLowModerateHighHighModerateCostLowModerateHighHighVery HighRisk of extrapulmonary pneumocystosisNoNoYesNoNo See Appendix A for drug doses, adverse effects, costs and further details.The following children should not receive PJP prophylaxis with co-trimoxazole:5. Children undergoing treatment with high dose methotrexate(Weak recommendation, very low quality evidence)6. Confirmed allergy to co-trimoxazole(Strong recommendation, very low quality evidence)Two studies of moderate or low quality ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0022-3476(05)83351-7", "ISSN" : "00223476", "author" : [ { "dropping-particle" : "", "family" : "Ferrazzini", "given" : "Gianmario", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "Julla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sulh", "given" : "Hassan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chung", "given" : "Derrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griesbrecht", "given" : "Esther", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koren", "given" : "Gideon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Pediatrics", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "1990", "11" ] ] }, "page" : "823-826", "title" : "Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Relling", "given" : "MV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fairclough", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ayers", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crom", "given" : "WR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodman", "given" : "JH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pui", "given" : "CH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "WE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J. Clin. Oncol.", "id" : "ITEM-2", "issue" : "8", "issued" : { "date-parts" : [ [ "1994", "8", "1" ] ] }, "page" : "1667-1672", "title" : "Patient characteristics associated with high-risk methotrexate concentrations and toxicity", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(58,59)", "plainTextFormattedCitation" : "(58,59)", "previouslyFormattedCitation" : "(58,59)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(58,59) looked at the effect of concurrent co-trimoxazole on methotrexate administration. These gave conflicting results. One study did not demonstrate an association between co-trimoxazole and raised methotrexate levels however the patients received intermediate dose methotrexate (0.9-3.7 g/m2). The second study showed concurrent co-trimoxazole administration resulted in a 66% increase in exposure to free methotrexate but did not assess consequent toxicity or myelosuppression. Current practice is to omit co-trimoxazole in patients receiving high dose methotrexate and, given the toxicity of delayed methotrexate excretion and challenges of treating raised methotrexate levels, the GDG and peer review felt co-trimoxazole should be withheld in patients receiving high dose methotrexate. In children undergoing autologous stem cell transplant: 7. Unless specifically mandated by a trial protocol, do not interrupt prophylaxis with co-trimoxazole unless there is a delay in engraftment(Weak recommendation, very low quality evidence)8. If prophylaxis with co-trimoxazole is interrupted recommence once neutrophil count is >1 x109/litre(Consensus)9. The duration of prophylaxis is uncertain– a pragmatic choice is to continue until 6 months after stem cell transplant, as long as the lymphocyte count has returned to normal. (Weak recommendation, very low quality evidence)Three studies of low or very low quality ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1002/pbc.21774", "ISSN" : "1545-5009", "abstract" : "Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.", "author" : [ { "dropping-particle" : "", "family" : "Ohata", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohta", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashii", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokimasa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ozono", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Blood Cancer", "edition" : "2008/09/27", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "142-144", "publisher-place" : "Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "title" : "Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14,15,23)", "plainTextFormattedCitation" : "(14,15,23)", "previouslyFormattedCitation" : "(14,15,23)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14,15,23) considered the frequency of neutropaenia in children taking co-trimoxazole prophylaxis. They reported rates of presumed co-trimoxazole induced neutropaenia of only 0.5% to 2%. There are no studies of the effect of co-trimoxazole prophylaxis on time to neutrophil recovery in children undergoing autologous stem cell transplant. However a retrospective case-control study of 17 adult patients showed no difference in time to engraftment following SCT if prophylaxis with co-trimoxazole was interrupted versus given continuously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/bmt.2010.285", "ISSN" : "1476-5365", "PMID" : "21102496", "author" : [ { "dropping-particle" : "", "family" : "Fontanet", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chalandon", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roosnek", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mohty", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Passweg", "given" : "J R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bone marrow transplantation", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2011", "9" ] ] }, "page" : "1272-3", "publisher" : "Macmillan Publishers Limited", "title" : "Cotrimoxazole myelotoxicity in hematopoietic SCT recipients: time for reappraisal.", "title-short" : "Bone Marrow Transplant", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(60)", "plainTextFormattedCitation" : "(60)", "previouslyFormattedCitation" : "(60)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(60).The above recommendations are pragmatic as peer review reached no clear consensus. 10. Children who are immunocompromised due to treatment for a solid malignancy should receive prophylaxis against PJP from the start of treatment.(Weak recommendation, low quality evidence)11. The duration of prophylaxis is uncertainA pragmatic choice is to continue until 3 months after the end of treatment, as long as the lymphocyte count has returned to normal, or 6 months after SCT.(Weak recommendation, very low quality evidence)There are no studies looking at the duration of PJP prophylaxis however studies of prophylaxis efficacy observed that PJP infections occurred in children with ALL who had stopped prophylaxis during maintenance treatment ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1097/inf.0000000000000044", "ISSN" : "0891-3668", "abstract" : "Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.", "author" : [ { "dropping-particle" : "", "family" : "Orgel", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rushing", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Infect Dis J", "edition" : "2013/09/14", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "319-321", "publisher-place" : "From the *Jonathan Jaques Children's Cancer Center, Miller Children's Hospital Long Beach, Long Beach and daggerChildren's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA.", "title" : "Efficacy and tolerability of intravenous pentamidine isethionate for pneumocystis jiroveci prophylaxis in a pediatric oncology population", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23,53)", "plainTextFormattedCitation" : "(23,53)", "previouslyFormattedCitation" : "(23,53)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23,53). The GDG therefore recommended that prophylaxis should continue until lymphocyte recovery and advised a longer duration of prophylaxis in children post stem cell transplant as they experience a greater degree of immunosuppression.6. Other ConsiderationsG6PD deficiencyIn individuals with Glucose-6-phosphate Dehydrogenase (G6PD) deficiency haemolysis may be triggered by oxidant drugs, which include primaquine and dapsone. Dapsone should not be given unless G6PD deficiency is excluded, especially in susceptible ethnic groups. Haemolysis can also occur with sulphamethoxazole when given at the higher intravenous doses required for treatment of PJP. Prophylactic doses of sulphamethoxazole in co-trimoxazole are not usually problematic. Potential for the development of resistant isolatesTrimethoprim and sulfamethoxazole inhibit 2 different enzymes involved in the bacterial synthesis of folic acid and have been shown to act synergistically in vitro ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/archinte.163.4.402", "ISSN" : "0003-9926", "author" : [ { "dropping-particle" : "", "family" : "Masters", "given" : "Philip A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of Internal Medicine", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2003", "2", "24" ] ] }, "page" : "402", "publisher" : "American Medical Association", "title" : "Trimethoprim-Sulfamethoxazole Revisited", "type" : "article-journal", "volume" : "163" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(61)", "plainTextFormattedCitation" : "(61)", "previouslyFormattedCitation" : "(61)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(61). They were originally combined in the hope that, by acting on the same bacterial pathway, development of resistance to either component alone would be prevented. However, following widespread use in the 1970s for the treatment of urinary, respiratory and gastro-intestinal infections, widespread resistance has emerged and co-trimoxazole can no longer be recommended as empirical or first line therapy for such common indications ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/archinte.163.4.402", "ISSN" : "0003-9926", "author" : [ { "dropping-particle" : "", "family" : "Masters", "given" : "Philip A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of Internal Medicine", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2003", "2", "24" ] ] }, "page" : "402", "publisher" : "American Medical Association", "title" : "Trimethoprim-Sulfamethoxazole Revisited", "type" : "article-journal", "volume" : "163" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "1058-4838", "PMID" : "8994780", "abstract" : "Trimethoprim alone or in combination with a sulfonamide is an effective and relatively inexpensive antibacterial medication. However, a dramatic increase in the rate of resistance to trimethoprim along with high-level resistance to sulfonamides has been seen during the past two decades. The mechanisms of resistance show a remarkable evolutionary adaptation.", "author" : [ { "dropping-particle" : "", "family" : "Huovinen", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "1997", "1" ] ] }, "page" : "S63-6", "title" : "Increases in rates of resistance to trimethoprim.", "type" : "article-journal", "volume" : "24 Suppl 1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(61,62)", "plainTextFormattedCitation" : "(61,62)", "previouslyFormattedCitation" : "(61,62)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(61,62). The use of co-trimoxazole as PJP prophylaxis has also been temporally associated with an increase in resistant strains of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in HIV patients ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1086/315132", "ISSN" : "0022-1899", "PMID" : "10558935", "abstract" : "Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus (HIV)-infected patients, but little is known about the effects of this practice on the emergence of TMP-SMX-resistant bacteria. A serial cross-sectional study of resistance to TMP-SMX among all clinical isolates of Staphylococcus aureus and 7 genera of Enterobacteriaceae was performed at San Francisco General Hospital. Resistance among all isolates was <5.5% from 1979 to 1986 but then markedly increased, reaching 20.4% in 1995. This was most prominent in HIV-infected patients: resistance increased from 6.3% in 1988 to 53% in 1995. The largest increases in resistance were in Escherichia coli (24% in 1988 to 74% in 1995) and S. aureus (0% to 48%) obtained from HIV-infected patients. A rapid increase in the use of prophylactic TMP-SMX in HIV disease was also observed during this time in San Francisco and is likely responsible for the increase in TMP-SMX resistance.", "author" : [ { "dropping-particle" : "", "family" : "Martin", "given" : "J N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rose", "given" : "D A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hadley", "given" : "W K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perdreau-Remington", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lam", "given" : "P K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gerberding", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of infectious diseases", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1999", "12" ] ] }, "page" : "1809-18", "title" : "Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS era.", "type" : "article-journal", "volume" : "180" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(63)", "plainTextFormattedCitation" : "(63)", "previouslyFormattedCitation" : "(63)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(63). An RCT in renal transplant patients comparing daily co-trimoxazole versus placebo for prevention of urinary tract infections and bloodstream infections showed significantly reduced infection rates in the treatment group, but when infection did occur the isolate was more likely to show co-trimoxazole resistance (62% versus 18% for prophylaxis versus placebo, p<0.001)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9343", "PMID" : "2118307", "abstract" : "PURPOSE: To determine the efficacy of long-term prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) for prevention of bacterial infection following renal transplantation, the absorption of TMP-SMZ in transplant patients, the effects of prophylaxis on the microflora, and the cost-benefit of prophylaxis.\n\nPATIENTS AND METHODS: One hundred thirty-two adult patients selected to undergo renal transplantation participated in a randomized, double-blind, placebo-controlled trial.\n\nRESULTS: Patients randomized to receive TMP-SMZ experienced fewer hospital days with fever (3.3% versus 7.7%, p less than 0.001) and significantly fewer bacterial infections during the transplant hospitalization after removal of a urethral catheter (0.76 versus 1.88 per 100 days, p less than 0.005) and following discharge from the hospital (0.08 versus 0.30 per 100 days, p less than 0.001). During the transplant hospitalization, a daily dose of 320/1,600 mg was highly effective for prophylaxis whereas 160/800 mg daily gave unexpectedly low blood levels and was effective only for prevention of urinary tract infections after catheter removal. Prophylaxis was most effective in prevention of infections of the urinary tract (24 versus 54, p less than 0.005) and bloodstream (one versus nine, p less than 0.01) and infections caused by enteric gram-negative bacilli (four versus 46, p less than 0.001), enterococci (six versus 22, p = 0.006), or Staphylococcus aureus (one versus nine, p = 0.01). Prophylaxis did not prevent urinary tract infection associated with urethral catheters in the early posttransplant period, but after catheter removal, reduced the risk of urinary tract infection threefold (p less than 0.001). No significant differences in colonization by TMP-SMZ-resistant gram-negative bacilli were identified between the two groups; patients given TMP-SMZ were, paradoxically, less likely to become colonized by candida, probably because of less exposure to antibiotics for treatment of infection. Recipients of prophylaxis did not have a higher rate of infection caused by TMP-SMZ-resistant bacteria or Candida; however, their infections were more likely to be caused by resistant bacteria than infections in patients in the placebo group (62% versus 18%, p less than 0.001).\n\nCONCLUSIONS: Prophylaxis with TMP-SMZ, which is well tolerated, significantly reduces the incidence of bacterial infection following renal transplantation, especially infection of the urinary tract and bloodstream, c\u2026", "author" : [ { "dropping-particle" : "", "family" : "Fox", "given" : "B C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sollinger", "given" : "H W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belzer", "given" : "F O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maki", "given" : "D G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1990", "9" ] ] }, "page" : "255-74", "title" : "A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophy", "type" : "article-journal", "volume" : "89" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(64)", "plainTextFormattedCitation" : "(64)", "previouslyFormattedCitation" : "(64)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(64). There is concern that the use of co-trimoxazole as prophylaxis may promote the emergence of resistant P. jirovecii strains. Mutations resulting in amino acid substitutions in the enzymes targeted by co-trimoxazole have been implicated in failure of prophylaxis and treatment of PJP ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/AAC.01161-13", "ISSN" : "1098-6596", "PMID" : "23896474", "abstract" : "Pneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis includes trimethoprim/sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, I158V) showed resistance to inhibition by trimethoprim, with Ki values for trimethoprim 4-fold to 100-fold higher than wild type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C, L65P) also had increased Km values for dihydrofolic acid (DHFA). The catalytic rate constant (kcat) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C; one naturally occurring variant with two amino acid substitutions (S106P/E127G) showed a doubling of kcat, as well as a Km for NADPH half that of wild type. The strongest resistance to trimethoprim occurred with amino acid changes in the binding pocket for DHFA/trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.", "author" : [ { "dropping-particle" : "", "family" : "Queener", "given" : "S F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cody", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pace", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Torkelson", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gangjee", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Antimicrobial agents and chemotherapy", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "7", "29" ] ] }, "title" : "Trimethoprim resistance of dihydrofolate reductase (DHFR) variants from clinical isolates of Pneumocystis jirovecii.", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/AAC.48.11.4301-4305.2004", "ISSN" : "0066-4804", "PMID" : "15504856", "abstract" : "Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n = 15), prophylaxis without a DHFR inhibitor (n = 11), or no prophylaxis (n = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.", "author" : [ { "dropping-particle" : "", "family" : "Nahimana", "given" : "Aimable", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rabodonirina", "given" : "Meja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bille", "given" : "Jacques", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Francioli", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hauser", "given" : "Philippe M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Antimicrobial agents and chemotherapy", "id" : "ITEM-2", "issue" : "11", "issued" : { "date-parts" : [ [ "2004", "11" ] ] }, "page" : "4301-5", "title" : "Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(65,66)", "plainTextFormattedCitation" : "(65,66)", "previouslyFormattedCitation" : "(65,66)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(65,66). Thus far such treatment failures are rare but more widespread use of prophylaxis may accelerate the emergence of resistant strains. 7. Research RecommendationsThe evidence appraisal undertaken during the development of this guideline has identified areas where further information / research is required. The GDG has identified the following research questions:What is the true frequency of PJP infection in children undergoing autologous stem cell rescue and during treatment for solid tumours?What is the optimal second line agent in those who cannot tolerate co-trimoxazole?Does co-trimoxazole prophylaxis against PJP significantly delay time to engraftment in children undergoing autologous stem cell transplant and does it increase the neutropaenic window during the standard treatment of solid tumours?For how long following treatment do patients remain at risk of PJP? I.e. How long should prophylaxis continue at the end of treatment?What is the effect of concomitant co-trimoxazole administration on methotrexate levels and rates of methotrexate excretion in patients receiving high dose methotrexate? Whilst it is not advised that patients receive co-trimoxazole with high dose methotrexate there may be patients that have inadvertently received both drugs and they might provide anecdotal evidence of the effect of co-trimoxazole on the excretion rates and subsequent toxicity of high dose methotrexate. 8. GlossaryAIDSAcquired Immunodeficiency SyndromeALCLAnaplastic Large Cell LymphomaALLAcute Lymphoblastic LeukaemiaAMLAcute Myelocytic LeukaemiaAPAerosolized pentamidineBMTBone marrow transplantBNFBritish National FormularyCCLGChildren’s Cancer and Leukaemia GroupCFCystic fibrosisCOPDChronic obstructive pulmonary diseaseG6PDGlucose-6-Phosphate DehydrogenaseGDGGuideline Development GroupGIGastrointestinalGRADEGrading of Recommendations, Assessment, Development and EvaluationsHD/ HLHodgkin’s disease/lymphomaHGGHigh Grade GliomaHIVHuman Immunodeficiency VirusHPAHealth Protection AgencyHSCTHaematopoeitic stem cell transplantLCHLangerhans cell histiocytosisMATMyeloablative therapyMTXMethotrexateNBLNeuroblastomaNR-STSNon-rhabdomyosarcoma soft tissue sarcomaPCPPneumocystis carinii PneumoniaPJPPneumocystis jirovecii PneumoniaRCTRandomised Controlled TrialRMSRhabdomyosarcomaRTRadiotherapySCRStem cell rescueSCTStem cell transplantTBTuberculosisWBCWhite blood cell count9. AcknowledgementsNia RobertsInformation SpecialistCairns LibraryJohn Radcliffe Hospital, Oxford10. AppendicesAppendix A: Drug doses, adverse effects & costsDrugDose CalculationRouteFrequencyAdverse Effects Cost for 40Kg child per week ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "2", "12" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "BNF for Children February 2016", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(67)", "plainTextFormattedCitation" : "(67)", "previouslyFormattedCitation" : "(67)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(67)Surface areaDoseCo-trimoxazole<0.5m224mg/kgoralTwice Daily on 2 consecutive days per weekFever, rash, transaminase elevationGI intolerance, cholestatic hepatitis, renal failure and hyperkalaemia, pruritus, photosensitivity, Stevens-Johnson syndrome, potential bone marrow suppressionTablets?0.450.5-0.75m2240mg0.76-1m2360mgSuspension?0.88>1m2480mgPentamidineAge 5-18y300mgnebulisedOnce every 4 weeksCough, wheezing, extrapulmonary pneumocystosis, nephrotoxicity (25–50%), hypoglycaemia and hyperglycaemia, GI intolerance, hypotension, bone marrow suppression, electrolyte abnormalitiesTeratogenic – risk to staff?7.94*All ages4mg/kgmax 300mgADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/INF.0b013e318292f560", "ISSN" : "1532-0987", "PMID" : "23538522", "abstract" : "BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy.\n\nMETHODS: We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected.\n\nRESULTS: One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count >1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit.\n\nCONCLUSIONS: Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.", "author" : [ { "dropping-particle" : "", "family" : "DeMasi", "given" : "James M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Jennifer A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leonard", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koh", "given" : "Andrew Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aquino", "given" : "Victor M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Pediatric infectious disease journal", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "933-6", "title" : "Intravenous pentamidine is safe and effective as primary pneumocystis pneumonia prophylaxis in children and adolescents undergoing hematopoietic stem cell transplantation.", "type" : "article-journal", "volume" : "32" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(50)", "plainTextFormattedCitation" : "(50)", "previouslyFormattedCitation" : "(50)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(50)IntravenousOnce every 4 weeksRisk of cardiac arrest if given as rapid infusion (<60 minutes)Allergy: hives, tachypnoea, subjective shortness of breath and hypoxaemia (incidence 8.5%) ?4.24**DapsoneAge 1 month- 18y2mg/kgmax 100mgoralOnce dailyFever, rash, GI upset, methemoglobinemia (almost 20%), hemolytic anaemia (check for G6PD deficiency)?14.90***AtovaquoneNo recommended dose in BNF30mg/kg once daily (max 1500mg/day) used in a study from USA 30mg/kg daily recommended in UKALL2011 trial protocoloralOnce dailyGI intolerance due to diarrhoea, rash and headache found in trials for the treatment of PJP No treatment-limiting complications occurred in the 16 patients randomised to receive atovaquone as prophylaxis post SCT in a RCT in adults ?120.52*Does not include cost of nebulisation **If 300mg vials cannot be split and used for another patient, the cost would be ?7.94/week. Does not include cost of delivering IV infusion ***This is the cost for 100mg/day as the tablets come in only 50 and 100mg strengthsAppendix B – Guideline Development GroupGuideline Development Group MembersDr. Rebecca ProudfootPaediatric specialty registrar, Oxford John Radcliffe HospitalDr. Sophie Wilne, Consultant paediatric oncologist, University Hospitals Nottingham NHS TrustDr. Bob PhilipsSenior Clinical Academic,?Honorary Consultant in Paediatric Oncology,?University of YorkDr. Rachel CoxConsultant paediatric oncologist, Royal Bristol Children’s HospitalDisclosure of potential conflicts of interest:NoneAppendix C – MethodsHow this Guideline was Developed:This guideline was developed in accordance with the methods outlined in the CCLG guideline development standard operating procedure, version 5 which has been developed according to Institute of Medicine guidelines.Developing the Clinical Questions and OutcomesThe guideline objectives were broken down into several clinical questions structured in the PICO format (patient and problem, intervention, comparison, outcomes). See clinical questions were then circulated around the Guideline Development Group (GDG) for approval before using as a basis for a systematic search of the published literature. Due to a paucity of relevant studies the initial literature search was expanded to include adult data. In total 163 references were found. After discarding review articles, case reports, letters and irrelevant studies 34 titles were analysed (24 retrospective studies/reviews, 5 prospective surveys, 1 systematic review/meta-analysis (haematology patients only), 2 non-blinded RCTs (1 haematology patients only), 1 double blinded RCT (haematology and RMS patients only) and 1 unstructured prospective trial).Developing Recommendations and Stakeholder ReviewRecommendations were drawn from the GDG interpretation of the available evidence, taking into account the balance of benefits, harms and costs. When clinical evidence was of poor quality or absent, the GDG drafted recommendations based on their expert opinion. Recommendations based on expert opinion alone were peer reviewed by the CCLG members using a formal consensus process (Delphi process) alongside a link to the full draft guideline. See Appendix G. The considerations for making consensus-based recommendations include the balance between potential harms and benefits, economic or cost implications compared to the benefits, current practices and patient preferences.Updating the GuidelineA formal review by the CCLG will be undertaken in 3 years’ time to determine whether the evidence base has progressed significantly to alter the guideline recommendations and warrant an update. FundingProvided by the CCLG.Summary of Review Questions and OutcomesTopicStructured Clinical QuestionOutcomesBackground risk of PJP Patients: Children up to 19 years of age with solid malignancies Intervention: undergoing chemotherapy +/- radiotherapyOutcome: what is the risk of PJP?Control: compared to the normal populationPrevalence of PJP infection in children undergoing treatment for solid tumoursEffectiveness of PJP prophylaxisPatients: Children up to 19 years of age with solid malignancies undergoing chemotherapy +/- radiotherapyIntervention: Does PJP prophylaxis withco-trimoxazolepentamidineatovaquone ordapsoneOutcome: prevent PJP Control: compared with no prophylaxis.PJP infection in children receiving co-trimoxazole prophylaxis undergoing treatment for solid tumoursEffectiveness of pentamidine in preventing PJP infection in childrenEffectiveness of atovaquone in preventing PJP in paediatric patients Patients: Children up to 19 years' of age with solid malignancies undergoing chemotherapy +/- radiotherapyIntervention: Does PJP prophylaxis with twice weekly co-trimoxazoleOutcome: prevent PJP Control: compared with daily or thrice weekly co-trimoxazoleIncidence of PJP infection in children undergoing treatment for solid tumours receiving co-trimoxazole 3 days per week v 2 days per week v one day per weekBenefit v risk of PJP prophylaxisPatients: In children up to 19 years of age with solid malignancies undergoing chemotherapy+/- radiotherapy with a low risk of PJPIntervention: Does PJP prophylaxis withco-trimoxazoleaerosolized pentamidineatovaquone ordapsoneOutcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no parison of effectiveness of co-trimoxazole, dapsone, pentamidine and atovoquone in preventing PJP in paediatric patients undergoing treatment for solid tumoursside effects of dapsone (risk versus benefit) in the prevention of PJP in paediatric patients undergoing treatment for solid tumoursAtovaquone versus co-trimoxazole for the prevention of PJP in paediatric patients undergoing treatment for solid tumoursUse of lymphocyte/CD4 counts as a marker of riskPatients: In children up to 19 years of age with solid malignancies undergoing chemotherapy+/- radiotherapy Intervention: can lymphocyte and/or CD4 counts Outcome: predict risk of PJP? Use of CD4 or lymphocyte counts to predict risk of PJP in paediatric patients undergoing treatment for solid tumoursCorticosteroids and brain tumoursPatients: In children up to 19 years of age with brain tumours undergoing treatment with corticosteroidsIntervention: Does PJP prophylaxis Outcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxisRisk/benefit of PJP prophylaxis in children with brain tumours undergoing treatment with corticosteroidsTemozolomidePatients: In children up to 19 years of age with solid malignancies undergoing treatment with temozolomideIntervention: does PJP prophylaxis Outcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxis.Risk/benefit of PJP prophylaxis in children being treated with temozolomideRituximab and other immunomodulating agentsPatients: In children up to 19 years of age solid malignancies undergoing treatment with immunomodulating agentsIntervention: Does PJP prophylaxis Outcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxis.Risk/benefit of PJP prophylaxis in children undergoing treatment with rituximab and other immunomodulating agentsUnderlying lung pathologyPatients: In children up to 19 years of age with solid malignancies and underlying chronic lung diseaseIntervention: Undergoing chemotherapy +/- radiotherapyOutcome: What is the risk of PJP?Control: compared to children up to 19 years of age with solid malignancies but healthy lungsDoes underlying lung pathology increase the risk of PJP in paediatric patients undergoing treatment for solid tumours?Previous PJPPatients: In children up to 19 years of age with solid malignancies who have had previous PJP infection Intervention: undergoing chemotherapy +/- radiotherapyOutcome: What is the risk of PJP?Control: compared to children up to 19 years of age with solid malignancies who have had not had previous PJP infectionDoes previous PJP increase the risk of repeat infection?Myelosuppression with co-trimoxazolePatients: In children up to 19 years of age with malignancies undergoing chemotherapy +/- radiotherapyIntervention: Does PJP prophylaxis with co-trimoxazoleOutcome: cause clinically significant myelosuppression Control: compared with no prophylaxis.Myelosuppression with co-trimoxazolePatients: In children up to 19 years of age with malignancies undergoing chemotherapy +/- radiotherapyIntervention: Does PJP prophylaxis with twice weekly co-trimoxazoleOutcome: cause clinically significant myelosuppression Control: compared with thrice weekly or daily co-trimoxazoleMethotrexatePatients: In children up to 19 years of age with malignancies undergoing treatment with methotrexateIntervention: Does PJP prophylaxis with co-trimoxazoleOutcome: cause clinically significant increased rates of methotrexate toxicityControl: compared with no prophylaxis.Increased methotrexate toxicity with co-trimoxazolePotential for development of resistant isolatesPatients: In children up to 19 years of age with malignancies Intervention: Does PJP prophylaxis with co-trimoxazoleOutcome: cause an increase in resistant strains of PJPControl: compared with no prophylaxis.Emergence of PJP infections resistant to co-trimoxazoleG6PD deficiencyPatients: In children up to 19 years of age with malignancies and G6PD deficiency Intervention: Does PJP prophylaxis with co-trimoxazoleOutcome: cause haemolysisControl: compared with no prophylaxis.Haemolysis with co-trimoxazoleSearching for EvidenceAn information specialist (see acknowledgements) undertook the evidence search. Medline, Embase, Cochrane Library, TRIP & NHS Evidence were searched, no date limits were applied, language was limited to English, French, Spanish. Literature reviews, letters and editorials and unpublished studies were excluded. Some potentially relevant adult studies were included after repeating the literature search to encompass all ages due to a paucity of paediatric data. The search terms were generated from the structured clinical questions and are shown below.Note: Pneumocystis species demonstrate a high degree of host species specificity. Those infecting humans have been named P. jirovecii, whilst P. carinii refers to those infecting rats. Previously P. carinii was thought to infect humans and therefore to ensure identification of all relevant evidence both P. jirovecii and P. carinii were included as search terms. Search strategy:1. (infant? or infancy or baby or babies or child* or schoolchild* or boy? or girl? or p?ediatric? or teenage* or adolescen* or youth? or juvenile?).mp.2. Langerhans cell histiocytosis/3. neuroblastoma/4. exp glioma/5. retinoblastoma/6. nephroblastoma/7. exp sarcoma/8. Hodgkin disease/9. exp brain tumor/ or exp central nervous system tumor/10. bone cancer/11. solid tumor/12. (langerhans adj3 histiocytosis).ti,ab.13. (glioma* or neuroblastoma* or retinoblastoma* or nephroblastoma* or wilm* tumo?r? or medulloblastoma*).ti,ab.14. (rhabdomyosarcoma* or osteosarcoma* or sarcoma*).ti,ab.15. (hodgkin* adj3 (lymphoma* or disease)).ti,ab.16. ((brain or cerebral or cerebrovascular or cvs or central nervous system or cns) adj3 (tumo?r? or cancer? or neoplas? or malignan*)).ti,ab.17. (bone adj3 (tumo?r? or cancer? or neoplas? or malignan*)).ti,ab.18. (solid adj3 (tumo?r? or cancer? or neoplas? or malignan*)).ti,ab.19. 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 1820. 1 and 1921. ((infant? or infancy or baby or babies or child* or schoolchild* or boy? or girl? or p?ediatric? or teenage* or adolescen* or youth? or juvenile?) adj5 (tumo?r? or cancer? or neoplas? or malignan*)).ti,ab.22. ((infant? or infancy or baby or babies or child* or schoolchild* or boy? or girl? or p?ediatric? or teenage* or adolescen* or youth? or juvenile?) and (tumo?r? or cancer? or neoplas? or malignan*)).ti.23. childhood cancer/24. 20 or 21 or 22 or 2325. pneumocystis/ or Pneumocystis pneumonia/ or pneumocystis carinii/ or pneumocystis jiroveci/26. (pneumocystis adj3 (carinii or jiroveci)).ti,ab.27. (p carinii or p jiroveci).ti,ab.28. (pneumocystis adj5 pneumonia*).ti,ab.29. pneumocystis.ti.30. 25 or 26 or 27 or 28 or 2931. 24 and 3032. prophylaxis/ or prevention/ or infection prevention/33. (prophyla* or prevent*).ti,ab.34. 32 or 3335. 31 and 3436. Pneumocystis pneumonia/pc [Prevention]37. 24 and 3638. 35 or 3739. 31 not 38Evidence analysisThe lead author:Identified potentially relevant studies from the search results by reviewing titles, abstracts and full papersCritically appraised relevant studiesExtracted key outcomes into evidence tables Appendix D: Structured clinical questions and answers identified in literature reviewBackground risk of PJP (Pneumocystis jirovecii Pneumonia)Patients: Children up to 19 years of age with solid malignancies Intervention: undergoing chemotherapy +/- radiotherapyOutcome: what is the risk of PJP?Control: compared to the normal populationPJP attack rates in paediatric solid tumoursSee Table 1Prevalence studies of PJPPaperDesignStudy populationResultsSummaryADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Background: High-dose chemotherapy with autologous hematopoietic progenitor cell rescue (AuHPCR) for pediatric patients with brain tumors has become an important therapeutic modality to avoid or delay the long-term effects of cranial irradiation. Data on post-AuHPCR infectious complications in this population are lacking. This single institution retrospective review reports the prophylactic practices and infections in the first year following AuHPCR in pediatric patients with brain tumors. Procedure: The medical record of patients who underwent AuHPCR for the treatment of a malignant brain tumor at Children's Hospital Los Angeles between 1988 and 2010 were reviewed. Patients without prior irradiation who were free of disease at 1 year without additional chemotherapy were evaluated for all infectious disease complications occurring from time of neutrophil engraftment to 1 year post-AuHPCR. Results: Forty-three of the 115 eligible patients were included. The median time to neutrophil engraftment was 11 days (range: 8-43 days), and 20 Grade III/IV (no Grade V) infectious episodes developed in 15 patients (35%). Fourteen episodes of bacteremia (70%) were catheter-related, predominantly gram-negative (71%), and polymicrobial (50%). There were no fungal or pneumocystis infections and only 1 of 25 (4%) at-risk patients developed VZV reactivation. Conclusions: These data suggest patients with brain tumors undergoing AuHPCR have few late-occurring non-catheter-related post-transplant infections indicating that prophylaxis practices were sufficient. Central lines should be removed soon after engraftment, but those with central line infections should receive adequate treatment including gram-negative coverage. In addition, only at-risk patients who receive further irradiation may benefit from VZV reaction prophylaxis. Pediatr Blood Cancer 2013;60:2012-2017. 2013 Wiley Periodicals, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Brown", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahim", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wong", "given" : "K E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cooper", "given" : "R M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marachelian", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butturini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dhall", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Finlay", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric Blood and Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "2012-2017", "publisher-place" : "(Brown, Rahim, Marachelian, Dhall, Finlay) Neuro-Oncology Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, United States (Wong) Department of Radiation Oncology, Children's Hospital Los Angeles, L", "title" : "Infectious complications in the first year following autologous hematopoietic progenitor cell rescue for children with brain tumors", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(68)", "plainTextFormattedCitation" : "(68)", "previouslyFormattedCitation" : "(68)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(68) Brown et al 2013Single institution retrospective reviewPatients who underwent autologous SCR for malignant brain tumours at a Children’s Hospital between 1988-2010.Only those without prior irradiation who were free of disease at 1 year without additional chemotherapy were evaluated. N=43, age range 0.8-19.8y14 episodes of bacteraemiaNo fungal or pneumocystis infectionsAll patients were given PJP prophylaxis but duration and drug regimens varied. These included co-trimoxazole, dapsone, atavoquone or pentamidine (iv or aerosolized) and was started after day +42. Median length of post-transplantation PJP prophylaxis was 7.7 months (0.8-11.9 months; n=38) with 8 patients still on prophylaxis at the end of follow up at 1y. All patients received PJP prophylaxis but the duration and drug regimen varied. No details regarding drug doses and frequency given. There were no cases of PJP but the numbers in the study are too small and the prophylaxis regimes too varied to determine either the background risk of PJP or the efficacy of prophylaxis. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0031-3939", "PMID" : "6605512", "author" : [ { "dropping-particle" : "", "family" : "Cyklis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zieli\u0144ska", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatria polska", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1983", "4" ] ] }, "page" : "337-40", "title" : "[Pneumocystis carinii infection in children with acute leukemia and non-Hodgkin malignant lymphoma].", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(24)", "plainTextFormattedCitation" : "(24)", "previouslyFormattedCitation" : "(24)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(24)Cyklis & Zielinkska 1983Observational studyChildren aged 1-16y treated at Krakow haematology hospital Jan 1974- December 19807 out of 27 children (26%) with NHL were diagnosed with PCP. Results are combined with those of children with acute leukaemia, where 28 cases were diagnosed by clinical and radiological features plus cysts found in laryngeal swabs. However 8 cases of PCP were diagnosed by cysts in laryngeal swabs only and no clinical symptoms. Unknown number of cases within the NHL group with PCP diagnosed by throat swab only, and no clinical symptoms. This implies carriage and not disease therefore the study is unreliable and cannot be used to determine a PCP rate for NHL patients. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(26)", "plainTextFormattedCitation" : "(26)", "previouslyFormattedCitation" : "(26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(26)Henson et al 1991Retrospective reviewAll histologically documented episodes of PJP in adult patients ≥ 20y with primary brain tumours treated at Memorial Sloan-Kettering Cancer Centre 1981-1989PJP was histologically documented 11 times in 10 patients. During same period approx. 587 adults were seen at the centre for a brain tumour. At least 1.7% (10/587) developed PJP. 40% mortalityAll the patients with PJP were receiving dexamethasone with a median duration of 2.75 months (5-9.5 months) at the onset of infection. At the time of diagnosis the daily dose ranged from 2-60mgPJP attack rates in adults with brain tumours are approximately 1.7%. All cases of PJP received corticosteroid treatment. All paediatric patients excluded from the study because they were routinely treated with prophylactic co-trimoxazole during the study period. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-3476", "PMID" : "4572932", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "H K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coburn", "given" : "T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grigsby", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of pediatrics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1973", "3" ] ] }, "page" : "404-15", "title" : "Pneumocystis carinii pneumonitis in children with malignancies.", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(22)", "plainTextFormattedCitation" : "(22)", "previouslyFormattedCitation" : "(22)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(22)Hughes et al 1973Retrospective review51 cases PJP in children with malignancies, out of total 1251 children with malignancies who were admitted and treated at St Jude Children’s Research Hospital 1962-1971. Age of patients with PJP 4 months-19y, with median 6.2y. Malignancies in children with PJP included HD, NBL, reticulum cell sarcoma and Letterer-Siwe disease (LCH) (51 cases out of a total of 872 children with these diseases). PJP in 6.5% (45/684) of children with leukaemia, 1.3% (1/77) with HD, 3.8% (3/78) with NBL, 4% (1/26) with reticulum cell sarcoma and 14% (1/7) with Letterer-Siwe diseaseDiagnosis by identification of organisms in material removed by percutaneous transthoracic needle aspiration from infected lung. 41 patients were treated with pentamidine and 28 recovered (68%)Retrospective review in one institution of prevalence rates of PJP in paediatric oncology patients pre-prophylaxis. Rates for solid tumours are summarized in table 1 above but the numbers are small. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0008-543X", "PMID" : "1081905", "abstract" : "One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(13)", "plainTextFormattedCitation" : "(13)", "previouslyFormattedCitation" : "(13)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(13)Hughes et al 1975Surveillance study of effects of intensity of chemotherapyon incidence of PJPChildren with ALL randomized in a prospective study to receive gradations of chemotherapy agents, January 1972 – September 1974.All received treatment with prednisolone, vincristine and asparaginase and cranial irradiation plus intrathecal methotrexate. Following cranial irradiation the patients were randomized to receive 1 of 4 maintenance therapies for 2-3yPJP occurred in 29 (16%) of 180 patients. The 4 drug maintenance regimen was associated with an incidence of PJP 4.5 times that of the one drug regimen (methotrexate only). Incidences of PJP in the 2 and 3 drug regimens were not significantly different form the one drug regimen. The difference between the 3 and 4 drug regimen was the addition of cytarabine.However some patients with more extensive malignancy did not receive cytarabine, but mediastinal irradiation in addition to maintenance with 3 chemotherapy agents. This group had the highest incidence of PJP. Generally more intensive chemotherapy regimens are associated with higher risk of PJP. This study only included children with ALL and all were treated with cranial irradiation and protocols that vary from those used today. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuhn", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaudhary", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "George", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1977", "12", "29" ] ] }, "page" : "1419-26", "title" : "Successful chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "297" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(12)", "plainTextFormattedCitation" : "(12)", "previouslyFormattedCitation" : "(12)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(12)Hughes et al 1977Randomized double blind placebo controlled over 2y160 patients, 80 in each group.9 months-24yPatients selected as high risk for PJP (>15% attack rate) according to previous observational study.136 ALL17 with RMS7 ‘other’.Daily co-trimoxazole v placeboPJP developed in 17 (21%) of patients in placebo group and none of the patients in the treatment group.Diagnosis was by identification of organisms in fluid obtained by needle aspiration of the lung or at autopsy. P<0.01No difference in adverse events between 2 groupsRate of PJP in placebo group was 21% (17 out of 80 patients, 70 of whom had ALL, 7 RMS and 3 ‘other’ malignancies). The underlying diagnoses of the patients who contracted PJP are not described. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0098-7484 (Print) 0098-7484 (Linking)", "author" : [ { "dropping-particle" : "", "family" : "Perera", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Western", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "H D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "W W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Akers", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA", "edition" : "1970/11/09", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1970" ] ] }, "page" : "1074-1078", "title" : "Pneumocystis carinii pneumonia in a hospital for children. Epidemiologic aspects", "type" : "article-journal", "volume" : "214" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21)Perera et al 1970Retrospective review of hospital-associated outbreak of PJP Children <19y with malignancies at St. Jude’s Research Hospital, March 1968-August 1969 19 cases of PJP: 14 antemortem, 5 discovered postmortem. 14 had ALL, 2 NBL, 2 lymphosarcoma, 1 stage IV HD.All had been receiving cytotoxics +/- steroidsAged 19 months – 10y, mean 5.5yIn addition 301 consecutive postmortem specimens of lung tissue obtained since 1962 were stained for P. jirovecci organisms and a further 39 cases were identified in children with cancer, none of whom had clinically diagnosed PJP pre-death.Overall ‘attack rate’ PJP in children with malignant disease pre-prophylaxis 2.3%Clinical PJP was frequently associated with the more intensive chemotherapeutic protocols. Most of the cases of PJP occurred after these intensive protocols were introduced in 1968. No pattern of person-to–person spread was elucidated.PJP attack rates for solid tumours are given in table 1 Combined figures for clinically diagnosed and cases only discovered at autopsyAll were histologically confirmedSignificance of cases discovered at autopsy only is not clear. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9343 (Print) 0002-9343 (Linking)", "abstract" : "Between 1976 and 1983, 53 cases of Pneumocystis carinii pneumonia were documented at the Mayo Clinic. Underlying diseases included leukemia in 15 patients, lymphoma in nine, nonhematologic malignancies in five, acquired immune deficiency syndrome in two, an various inflammatory diseases treated by corticosteroids in 16 patients. Cytotoxic drugs with corticosteroids were used in 68 percent of patients, whereas 23 percent received corticosteroids alone. Clinical features consisted of progressive dyspnea (74 percent), cough (55 percent), and fever (62 percent), with normal findings on examination (43 percent), or crackles (53 percent). Arterial oxygen tension and oxygen saturation were 48.6 +/- 12.8 mm Hg and 81.2 +/- 6.5 percent, respectively. Chest roentgenographs exhibited diffuse alveolar and interstitial infiltrates with predominantly perihilar distribution. The diagnostic rates for open lung biopsy and bronchoscopy were 97 percent and 62 percent, respectively. Clinical improvement and survival following appropriate therapy were noted in 22 patients (41.5 percent), whereas the remaining 31 patients died within four weeks of hospitalization. When survivors were compared with nonsurvivors, there was no difference in mean age, leukocyte counts, arterial oxygen tension, or duration of symptoms before treatment. A coexisting pulmonary infection was identified more frequently in nonsurvivors (51.6 percent) than in survivors (22.7 percent, p = 0.01). The mortality from P. carinii pneumonia alone was 47 percent, whereas 76 percent of those with coexisting infection died. Despite antibiotic therapy and potentially effective chemoprophylaxis, P. carinii pneumonia remains a significant and life-threatening complication of diseases or treatments associated with immune suppression.", "author" : [ { "dropping-particle" : "", "family" : "Peters", "given" : "S G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prakash", "given" : "U B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Med", "edition" : "1987/01/01", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1987" ] ] }, "page" : "73-78", "title" : "Pneumocystis carinii pneumonia. Review of 53 cases", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(69)", "plainTextFormattedCitation" : "(69)", "previouslyFormattedCitation" : "(69)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(69)Peters & Prakash 1987Retrospective review All microbiologically confirmed cases of PJP seen at the Mayo Clinic and affiliated hospitals 1976-1983.N=53Average age 49y (9 months- 78y)Only 4 children <15yAll patients had underlying disease associated with defective immunity or were receiving treatment with corticosteroids or cytotoxic drugs. Largest group haematological malignanciesIncluded patients with HIV and auto-immune conditions. 12 patients (22.6%) received corticosteroids alonediagnoses for the 4 children not givenNo specific data on incidence rates or risks of PJP for children. No information on whether prophylaxis was used. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Sedaghatian", "given" : "M R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singer", "given" : "D B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1972" ] ] }, "page" : "772-777", "title" : "Pneumocystis carinii in children with malignant disease", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(70)", "plainTextFormattedCitation" : "(70)", "previouslyFormattedCitation" : "(70)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(70)Sedaghatian & Singer 1972Retrospective review of autopsies 267 children with cancer who were autopsied in Texas Children’s Hospital 1954-1969.195 leukaemias, 25 lymphomas, 29 NBL, 8 Wilm’s, 5 HD, 5 other malignant tumours.15 (5.6%) cases had PJP:9 (4.6%) with leukaemia, 4 lymphoma (16%), 1 Wilms (12.5%), 1 HD (20%). Aged 3.5-14y, nine were ≤ 8yIn 12 patients the infection was extensive but in the other 3 there were only a few isolated organisms without an associated inflammatory response.None of the patients were treated for PJP because the respiratory illness was not recognized clinically or was obscured by other prominent symtpoms. All the patients were treated with steroids and cytotoxic agents. The leukaemic patients were all in relapse at the time of death. Four patients with solid tumours also received irradiation and all had disseminated tumour at autopsy. Prevalance rates of PJP at autopsy given for children treated for cancer pre-prophylaxis (1954-1969). None were diagnosed with PJP pre-death and it is not clear from the data whether the patients died of PJP or of their primary malignant disease. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25)", "plainTextFormattedCitation" : "(25)", "previouslyFormattedCitation" : "(25)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25)Sepkowitz 199212 y retrospective review140 patients without HIV, constituting 142 cases with morphologically proved PJP1978-1989median age 43y (3 months – 80y)23 patients ≤ 18yLymphoma 27%Leukaemia 18%Solid tumour 31%BMT 18%25 cases (18%) diagnosed at autopsyCorticosteroid use in 87%Only 1 patient was receiving ‘adequate’ PJP prophylaxis at the time PJP was diagnosed (BMT recipient)Increase in PJP in solid tumours over the study period. Increase occurred specifically among patients with primary or metastatic brain neoplasm (including breast and lung primary only) with an attack rate of 1.3% during 1988 and 1989. PJP attack rate of 1.3% in patients with primary or metastatic brain neoplasms not on prophylaxis. Almost all of these patients were adults (exact numbers not given). 2. Effectiveness of PJP prophylaxisPatients: Children up to 19 years of age with solid malignancies undergoing chemotherapy +/- radiotherapyIntervention: does PJP prophylaxis withco-trimoxazoleaerosolized pentamidineatovaquone ordapsoneOutcome: prevent PJP Control: compared with no prophylaxis.Studies on PJP prophylaxis efficacyDrugPaperDesignStudy populationResultsSummaryCo-trimoxazoleADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM197712292972602", "ISSN" : "0028-4793", "PMID" : "412099", "abstract" : "In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuhn", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaudhary", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "George", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1977", "12", "29" ] ] }, "page" : "1419-26", "title" : "Successful chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "297" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(12)", "plainTextFormattedCitation" : "(12)", "previouslyFormattedCitation" : "(12)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(12)Hughes et al 1977Randomized double blind placebo controlled over 2y160 patients, 80 in each group.9 months-24yPatients selected as high risk for PJP (>15% attack rate) according to previous observational study.136 ALL17 with RMS7 ‘other’.Daily co-trimoxazole v placeboPJP developed in 17 (21%) of patients in placebo group and none of the patients in the treatment group.Diagnosis was by identification of organisms in fluid obtained by needle aspiration of the lung or at autopsy. P<0.01No difference in adverse events between 2 groupsDaily co-trimoxazole is highly effective in preventing PJP in patients <25y with ALL.The numbers of patients included in this study with other diagnoses are too small. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23)", "plainTextFormattedCitation" : "(23)", "previouslyFormattedCitation" : "(23)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23)Wilber et al 1980Prospective open study with unstructured delivery system.Adverse events related to prophylaxis collected from medical records retrospectively786 patients deemed by attending oncologist to be at sufficient risk for PJP over a 3 y period. Risk assessment based on age of patient, intensity of therapy and annual PJP attack rates by category of malignancy in the same institution over the period 1970-1975. Rate for leukaemia given as 6.6%, data for other tumours presented in table 1 above.618 of 786 (79%) patients in the trial had acute leukaemia, other tumour types as per table 1. Data on confirmed cases of PJP collected for all patients treated at the institution over the study period (n=3314). Daily dosing used. Upper age limit not specified but all data was on patients treated in a children’s hospital. 9 cases of PJP during the study period. 8 patients were in remission and on maintenance therapy and had stopped taking prophylaxis (6 ALL and 1 NHL). Only 1 case of PJP whilst on prophylaxis in a patient with ALL. No cases in patients excluded from defined population at risk. 43 (5.4%) with presumed adverse reactions. 24 mild skin rashes but relationship to co-trimoxazole unclear as rash resolved in all but 3 cases with no recurrence when drug reinstituted. 2 cases of erythema multiforme1 fatal case of Stevens Johnson’s syndrome 2 cases of vomiting14 of neutropaenia/anaemiaincluding 1 case of PJP in patient whose prophylaxis was stopped due to neutropaeniaUnstructured delivery of co-trimoxazole prophylaxis is feasible.Evidence of efficacy provided by continuing decline year by year of PJP rate at the same institution (1977, 1978, 1979: 0.3%, 0.45%, 0.08% of population deemed to be at risk) and comparison with historical attack rates (6.6% for leukaemia plus data in table 1). Generally well toleratedSupports argument for continuation of prophylaxis throughout the duration of anticancer chemotherapy (most of the PJP cases had discontinued prophylaxis in the maintenance phase of leukaemia therapy). Limitations:Most of the patients in this study had ALLData on adverse events collected retrospectively and in some cases by local physicians (not at primary treatment centre). ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19)Green et al 2007Cochrane review – meta-analysis of RCTs or quasi-RCTs1155 non-HIV immunocompromised patients (520 children)All the children had acute leukaemiaCompared to no treatment or treatment with fluoroquinolones there was a 91% reduction in occurrence of PJP, RR 0.09, 8 trials, 821 patientsOccurrence of leukopaenia, neutropaenia and their duration were not reported consistently. No significant adverse events seen comparing co-trimoxazole versus no treatment/placebo (4 trials, 470 patients)No severe adverse events recorded in paediatric patientsNo differences between once daily versus thrice weekly prophylaxis (2 trials, 207 patients)NNT to prevent one episode of PJP = 15Co-trimoxazole is effective in reducing PJP in paediatric patients with ALL.No difference in daily versus 3 days/week treatment. Trials with 2 days/week not included. No data on paediatric or adult patients with solid malignancies. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Owing to a 15% attack rate of Pneumocystis carinii pneumonitis (PCP) among the leukemic population at Riley Hospital, Indianapolis, a two-year study using continuous low-dosage sulfamethoxazole-trimethoprim to prevent PCP was started in January 1977. A total of 229 pediatric cancer patients considered at high risk for getting PCP received prophylaxis, while 19 additional low-risk cancer patients did not receive sulfamethoxazole-trimethoprim. None of these 248 patients contracted PCP. However, five cases of PCP did occur among ten additional high-risk patients who failed to receive this preparation for a variety of reasons. Complications of the continuous prophylaxis program included neutropenia, rash, and gastrointestinal complaints. This study confirms that continuous, low-dosage sulfamethoxazole-trimethoprim prophylaxis is effective in preventing PCP in susceptible immunosuppressed patients but is ineffective in eradicating the organism from the population at risk.", "author" : [ { "dropping-particle" : "", "family" : "Harris", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCallister", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "S A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "35-38", "publisher-place" : "(Harris, McCallister, Allen) Div. Ped. Hematol. Oncol., Dept. Ped., James Whitcomb Riley Hosp. Child., Indiana Univ. Sch. Med., Indianapolis, Ind. 46223 United States", "title" : "Prevention of Pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethoprim therapy", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(71)", "plainTextFormattedCitation" : "(71)", "previouslyFormattedCitation" : "(71)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(71)Harris et al 1980Prospective observational study. Not randomized. All children with a diagnosis of cancer included in study 1977-79. Only those who received chemotherapy or extensive radiation therapy were considered to be at high risk and received prophylaxis. ALL patients received prophylaxis with daily co-trimoxazole from day 28 for a minimum of one year. All other oncology patients started prophylaxis at the start of therapy and were continued for a period of 6 months after all cancer therapy had been stopped. Prophylaxis received by 229 patientsSolid tumours = 110ALL = 101Acute non-lymphocytic leukaemia (ANLL) = 18Solid tumours considered very low risk = 19, not given prophylaxisHigh risk patients inadventently not given prophylaxis = 10No cases of PJP among 229 who received daily prophylaxis with co-trimoxazole or among the 19 low-risk patients not given prophylaxis. Compared with previous attack rate of 15 +/- 7% in the same institution over the previous few years among patients with leukaemia. 5 cases PJP in the 10 high risk patients who failed to receive prophylaxis (3 with ALL, 1 with ALL, 1 with LCH)Incidence of rash associated with co-trimoxazole = 3.5%One case of Stevens-Johnson syndrome, which resolved. 3 cases of suspected nausea and vomiting associated with prophylaxis (1.5%). None experienced GI discomfort when rechallenged with co-trimoxazole at a later date. Neutropaenia well documented to be associated with co-trimoxazole in 5 patients (4.8%)Daily prophylaxis is highly effective in preventing PJP in children with leukaemia and is generally well tolerated.This study provides little insight into the risk/benefit for children with solid tumours. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198706253162604", "ISSN" : "0028-4793", "PMID" : "3495732", "abstract" : "We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera", "given" : "G K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schell", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lott", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1987", "6", "25" ] ] }, "page" : "1627-32", "title" : "Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(8)", "plainTextFormattedCitation" : "(8)", "previouslyFormattedCitation" : "(8)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(8)Hughes et al 1987See details under q 2b belowPentamidineADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/inf.0000000000000044", "ISSN" : "0891-3668", "abstract" : "Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.", "author" : [ { "dropping-particle" : "", "family" : "Orgel", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rushing", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Infect Dis J", "edition" : "2013/09/14", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "319-321", "publisher-place" : "From the *Jonathan Jaques Children's Cancer Center, Miller Children's Hospital Long Beach, Long Beach and daggerChildren's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA.", "title" : "Efficacy and tolerability of intravenous pentamidine isethionate for pneumocystis jiroveci prophylaxis in a pediatric oncology population", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(53)", "plainTextFormattedCitation" : "(53)", "previouslyFormattedCitation" : "(53)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(53)Orgel & Rushing 2014Retrospective cohort study of patients who received eitherintravenous or aerosolized pentamidine (IVP v AP) for over 2 consecutive months0.5-21y50% ALL27% brain tumours~5% othersn=312No clear difference in efficacy between IVP and AP.Only 3 cases of proven breakthrough infection, all in ALL patients on maintenance. Not statistically significant (nos too small)Adverse reactions AP =0.7%, IVP 8.5%IVP is a well-tolerated and effective alternative to AP in children unable to tolerate co-trimoxazole or aerosolized pentamidine. This paper does not specifically answer question 2. No cases of proven PJP in solid tumour patients. 2 ‘possible’ cases, 1 in neuroblastoma patient on palliative care and the other on treatment for high grade glioma. Both were diagnosed on clinical context and radiographic findings. No broncheoalveolar lavage was performed. No control group. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Background: Pneumocystis carnii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Although prophylaxis with trimethoprim-sulfamethoxazole has been shown to be effective in the prevention of PCP, the development of neutropenia limits its use in the early post-transplant period. Aerosolized pentamidine is a commonly used second line agent, but the need to have the drug administered via respiratory route may increase the risk of infection. Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy. A recent series studying the use of intravenous pentamidine as secondary prophylaxis in children with cancer receiving conventional chemotherapy reported a breakthrough rate of 1.3%. We evaluated the overall efficacy of intravenous pentamidine, toxicity profile, and overall impact in the prevention of PCP in HSCT recipients. Patients and Methods: Retrospective review of medical records of children who underwent HSCT from Jan 1, 2005 - October 1, 2011 who received intravenous pentamidine as first line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management, and outcome data was collected. Results: 170 consecutive pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was 6 months post-HSCT, had stable neutrophil recovery (ANC >1000 without growth factor support), had discontinued immunosuppression and did not have evidence of chronic graft versus host disease.). No cases of PCP were seen in this cohort. Ten (6%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (1%) had a grade IV reaction with anaphylaxis and hypotension requiring transfer to the intensive care unit for management. Conclusions: Our pediatric HSCT patients receiving pentamidine had no episodes of breakthrough PCP, and the incidence of side effects was low. Given the potential neutropenic effects of trimethoprim- sulfamethoxazole, compliance with drug administration, and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first line therapy in the prevention of PCP in children undergoing HSCT.", "author" : [ { "dropping-particle" : "", "family" : "DeMasi", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koh", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aquino", "given" : "V M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biology of Blood and Marrow Transplantation", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "S321", "publisher-place" : "(DeMasi, Koh, Aquino) Children's Medical Center Dallas, Dallas, TX, United States (Cox) Huntsville Hospital for Women and Children, Huntsville, AL, United States (Koh, Aquino) University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, United", "title" : "Safety and efficacy of intravenous pentamidine in children and adolescents undergoing hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "2)" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(72)", "plainTextFormattedCitation" : "(72)", "previouslyFormattedCitation" : "(72)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(72)DeMasi et al 2012Retrospective review of medical records of children who underwent HSCT during a 5.5y period who received iv pentamidine as first line PJP prophylaxis initiated at admission167 transplants in 137 paediatric HSCT recipients113 (68%) autologous stem cells received32 (19%) neuroblastoma24 (14%) other solid tumoursOthers were haematological malignancies, immunologic disorders and bone marrow failure syndromes. No cases of PJP.10 (7%) mild side effects (nausea/vomiting)2 (2%) anaphylaxis and hypotension, 1 required transfer to intensive care. IV pentamidine is safe and probably effective for prevention of PJP in paediatric HSCT patients.Potential advantage over co-trimoxazole as the latter drug may cause neutropaenia, although this is not a comparative or prospective study. Numbers are too small, especially for solid tumour patients, to determine efficacy. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21287", "ISSN" : "1545-5017", "PMID" : "17635000", "abstract" : "BACKGROUND: Pneumocystis jirovecii, formerly carinii, pneumonia (PCP) poses a life-threatening risk to oncology patients. The use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis virtually eliminates the risk of infection; however, many patients cannot tolerate TMP-SMZ. We performed a retrospective analysis to determine the PCP breakthrough rate in pediatric oncology patients receiving intravenous pentamidine as second line PCP prophylaxis.\n\nPROCEDURE: We conducted a retrospective chart review of pediatric oncology patients who received intravenous pentamidine from 2001 to 2006 at our institution. The diagnosis, age and bone marrow transplant (BMT) status were determined. A subset of patients had review of their records to determine the justification for discontinuing TMP-SMZ. Children who developed symptoms of pneumonia with a clinical suspicion of PCP underwent bronchoscopy, allowing for identification of Pneumocystis.\n\nRESULTS: A total of 232 patients received 1,706 doses of intravenous pentamidine and no toxicities were identified. The main reasons for discontinuing TMP-SMZ were bone marrow suppression and drug allergy. Three children developed PCP, equating to a breakthrough rate of 1.3%. Two of these children had undergone BMT (1.9% breakthrough rate) and both were under the age of two (6.5% breakthrough rate).\n\nCONCLUSIONS: The use of intravenous pentamidine as PCP prophylaxis results in a breakthrough rate of 1.3%. TMP-SMZ is the first choice for PCP prophylaxis. However, when necessary, the use of intravenous pentamidine has an acceptably low failure rate, even in high-risk BMT patients. Other options should be considered for children less than 2 years of age.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Su Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dabb", "given" : "Alix A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glenn", "given" : "Donald J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snyder", "given" : "Kristen M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chuk", "given" : "Meredith K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loeb", "given" : "David M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "779-83", "title" : "Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(51)", "plainTextFormattedCitation" : "(51)", "previouslyFormattedCitation" : "(51)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(51)Kim et al 2008Retrospective chart review of patients who received iv pentamidine as 2nd line prophylaxis over 5y period232 paediatric oncology patients who received at least 1 dose iv pentamidine50% leukaemiabrain tumours 11%sarcomas 10%lymphomas 6%other solid tumours 10%3 cases PJP (confirmed on BAL specimens)breakthrough rate 1.3%no significant toxicities related to iv pentamidine identified2 of proven cases were <2y. One had undergone 2nd unrelated BMT for recurrence of leukaemia and the other autologous BMT for stage 4 neuroblastoma. Use of iv pentamidine results in breakthrough rate of 1.3%.No comparison group, not prospective. Aerosolized pentamidine(AP)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0732-183X", "PMID" : "8113834", "abstract" : "PURPOSE: Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX.\n\nPATIENTS AND METHODS: AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25).\n\nRESULTS: Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP.\n\nCONCLUSION: AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.", "author" : [ { "dropping-particle" : "", "family" : "Mustafa", "given" : "M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pappo", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winick", "given" : "N J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchanan", "given" : "G R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1994", "2" ] ] }, "page" : "258-61", "title" : "Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(52)", "plainTextFormattedCitation" : "(52)", "previouslyFormattedCitation" : "(52)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(52)Mustafa et al 1994Observational study60 children aged 3-19y prescribed AP for allergy/ intolerance/ myelosuppression or non-compliance with co-trimoxazole. 1989-199346 ALL5 AML2 NHL7 solid tumours (osteosarcoma, Ewing’s & undifferentiated sarcoma)No cases of PJPTransient cough in 15% patients10% developed one or more episodes of bronchospasm, necessitating bronchodilator therapy5% discontinued AP because of toxicity (2 patients with bronchospasm and one with nausea, vomiting and cough)Study suggests AP is effective and safe for PJP prophylaxis in children ≥ 3yAssumptions made about incidence of PJP in solid tumours, citing a mean attack rate without of prophylaxis of 6% referencing .Numbers of children with solid malignancies in this study too small to show efficacy of AP for PJP prophylaxis Adverse events to AP, although frequent, are usually mild and seldom necessitate discontinuation. Co-trimoxazole dapsone, pentamidine & atovaquoneADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21202", "ISSN" : "1545-5017", "PMID" : "17458875", "abstract" : "Pneumocystis pneumonia (PCP) is a serious complication of chemotherapy-induced immunosuppression. Trimethoprim-sulfamethoxazole (TMP-SMZ) given twice daily, 3 days every week is considered the best form of prophylaxis for PCP. We evaluated PCP prophylaxis in all children up to 18 years of age undergoing cancer chemotherapy over a 2-year period. Four children were diagnosed with PCP over 24 months. Two of 12 children on intravenous pentamidine, 1 of 143 on TMP-SMZ and 1 of 36 on dapsone for PCP prophylaxis developed PCP. Intravenous pentamidine may not be as effective as previously considered and should be used with caution.", "author" : [ { "dropping-particle" : "", "family" : "Prasad", "given" : "Pinki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nania", "given" : "Joseph J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shankar", "given" : "Sadhna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "896-8", "title" : "Pneumocystis pneumonia in children receiving chemotherapy.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(55)", "plainTextFormattedCitation" : "(55)", "previouslyFormattedCitation" : "(55)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(55)Prasad et al 2008Retrospective review of children undergoing chemotherapy and receiving PJP prophylaxis223 children up to 18y HL 17 (7.6%)NHL 25 (11.2%)Other solid tumours 11 (4.9%) 143 given co-trimoxazole36 dapsone, 21 inhaled pentamidine, 12 iv pentamidine, 5 oral atovoquone, 6 no prophylaxis4 patients with confirmed PJP (demonstration of organisms on BAL specimen)2 died2 were on ALL maintenance, 1 RMS treated with steroids for radiation pneumonitis, 1 AML consolidation.Only one was taking co-trimoxazole. The other 3 were changed to alternative prophylaxis due to myelosuppresion (2) and hypersensitivity -2 out of 12 patients on iv pentamidine developed PJPonly 1 out of 143 on co-trimoxazole and 1 out of 36 on dapsoneIv pentamidine 4 weekly may be inferior to other forms of PJP prophylaxis.Results not statistically significant between dapsone and pentamidine. atovaquoneADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/cncr.22562", "ISSN" : "0008-543X", "PMID" : "17345613", "abstract" : "BACKGROUND: Despite extensive studies of atovaquone in human immunodeficiency virus (HIV)-infected patients, there is little information about its efficacy as a prophylactic agent for Pneumocystis carinii pneumonia (PCP) in pediatric patients with cancer. Therefore, a retrospective analysis was conducted to determine the incidence of PCP in pediatric patients who received prophylactic atovaquone during treatment for acute leukemia.\n\nMETHODS: We reviewed the medical records of all patients treated at our institution for acute lymphoblastic leukemia or acute myeloid leukemia between 1994 and 2004. Only patients who were intolerant of trimethoprim-sulfamethoxazole (TMP-SMZ) and received atovaquone prophylaxis were included in the analysis.\n\nRESULTS: Eighty-six patients were unable to tolerate TMP-SMZ and received daily atovaquone for PCP prophylaxis. PCP was not diagnosed in any patient who received atovaquone prophylaxis: the upper limit of the 95% confidence interval (CI) was 1.74 per 100 person-years.\n\nCONCLUSIONS: Atovaquone is an efficacious alternative for PCP prophylaxis in pediatric patients who have leukemia and are intolerant of TMP-SMZ.", "author" : [ { "dropping-particle" : "", "family" : "Madden", "given" : "Renee M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pui", "given" : "Ching-Hon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hughes", "given" : "Walter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flynn", "given" : "Patricia M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leung", "given" : "Wing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2007", "4", "15" ] ] }, "page" : "1654-8", "title" : "Prophylaxis of Pneumocystis carinii pneumonia with atovaquone in children with leukemia.", "type" : "article-journal", "volume" : "109" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(73)", "plainTextFormattedCitation" : "(73)", "previouslyFormattedCitation" : "(73)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(73)Madden et al 2007Retrospective analysis86 children treated for ALL or AML during 10y period who were intolerant of co-trimoxazole and received daily atovaquoneNo cases of PJPSuggests atovaquone is effective as PJP prophylaxis. Limited by retrospective non-comparative designNo info about side effectsdapsoneNo relevant studiesb)Patients: Children up to 19 years of age with solid malignancies undergoing chemotherapy +/- radiotherapyIntervention: does PJP prophylaxis with twice weekly co-trimoxazoleOutcome: prevent PJP Control: compared with daily or thrice weekly co-trimoxazoleStudies of different co-trimoxazole regimensRegimePaperDesignStudy populationResultsSummary3 d/week v dailyADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198706253162604", "ISSN" : "0028-4793", "PMID" : "3495732", "abstract" : "We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera", "given" : "G K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schell", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lott", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1987", "6", "25" ] ] }, "page" : "1627-32", "title" : "Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(8)", "plainTextFormattedCitation" : "(8)", "previouslyFormattedCitation" : "(8)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(8) Hughes et al 1987Prospective RCT. Not blinded (daily v 3/week allocated on basis of even v odd dates of birth)Patients with known allergy to sulfonamides were untreated controls167 patients with ALL enrolled consecutively in Total Therapy Study XI at St. Jude Children’s Research Hospital (ages not specified). Only 1 case of PJP (in the only patient who did not receive prophylaxis due previous history of allergy). Previous RCT by the same group in similar patient cohort showed PJP incidence of 21% in placebo group, versus none in treatment group. This study suggests that prophylaxis 3 d/week is equally as effective as daily prophylaxis as there were no cases of PJP in this treatment arm. This paper does not address the situation for children with solid malignancies. 3 d/week v 2 d/week v 1 d/weekADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jpeds.2013.10.021", "ISSN" : "0022-3476", "abstract" : "OBJECTIVE: To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN: A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS: The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION: A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.", "author" : [ { "dropping-particle" : "", "family" : "Caselli", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petris", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rondelli", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carraro", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colombini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muggeo", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ziino", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Melchionda", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pierani", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soncini", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desantis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zanazzo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barone", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cesaro", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cellini", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mura", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Milano", "given" : "G M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meazza", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cicalese", "given" : "M P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tropia", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masi", "given" : "S", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castagnola", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arico", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Pediatr", "edition" : "2013/11/21", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "389-392.e1", "publisher-place" : "Department of Pediatric Hematology-Oncology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Florence, Italy. Pediatric Hematology-Oncology, Padua, Italy. Pediatric Oncology and Hematology, Lalla Seragnoli Unit, University of Bologna, Bologna,", "title" : "Single-day trimethoprim/sulfamethoxazole prophylaxis for pneumocystis pneumonia in children with cancer", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(16)", "plainTextFormattedCitation" : "(16)", "previouslyFormattedCitation" : "(16)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(16)Caselli et al 2014Prospective surveyChildren (ages not specified) requiring chemotherapy for which PJP prophylaxis was considered indicated according to local policy (not specified)1093 solid tumours1371 leukaemia/lymphoma2 primary immunodeficiencies.20 centres in Italy participated. Each used varying co-trimoxazole regimens from 1 to 3 days per week. 2 cases (0.08%) of proven PJP during 2 year study period.One non-compliant with prophylaxis, the other discontinued due to side effects and was not given an alternative. Both were on 2 d/week regimen. Single day course of co-trimoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens.Study probably underpowered to detect an increase in PJP in the group receiving prophylaxis on only 1 day/week (n= 689, of whom 250 were solid tumours)2 non-consecutive days per weekADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21774", "ISSN" : "1545-5009", "abstract" : "Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.", "author" : [ { "dropping-particle" : "", "family" : "Ohata", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohta", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashii", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokimasa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ozono", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Blood Cancer", "edition" : "2008/09/27", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "142-144", "publisher-place" : "Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "title" : "Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(15)", "plainTextFormattedCitation" : "(15)", "previouslyFormattedCitation" : "(15)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(15)Ohata et al 2009Retrospective analysis181 children who received PJP prophylaxis during chemotherapy or HSCT during 5y period:147 received co-trimoxazole on 2 non-consecutive days/week34 received either iv or inhaled pentamidineincluded:48 brain tumours11 lymphomas43 other solid tumoursplus patients with leukaemia, myelodysplasia, histiocytosis, immunodeficiency and metablic disease. No cases of PJPOnly 1 patient discontinued co-trimoxazole due to myelosuppressionCo-trimoxazole on 2 non-consecutive days per week is probably as effective as more frequent dosing schedules and is likely to be associated with less side effects. This is not a comparative/controlled or prospective trial and the numbers are small. 2 consecutive days per weekADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14)", "plainTextFormattedCitation" : "(14)", "previouslyFormattedCitation" : "(14)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14)Lindemulder & Albano 2007Retrospective reviewAll paediatric patients with leukaemia & lymphoma diagnosed over a 9y period, n=529Of these 482 took co-trimoxazole 2 d/week (345 leukaemia137 lymphoma) and the rest took an alternative drug or alternative co-trimoxazole regimen238 patients with ALL/ lymphoblastic lymphoma on 2 d/week co-trimoxazole during maintenance therapy were compared with 13 on alternative medications for incidence of neutropaeniaNo cases PJP in compliant patients2 proven cases during study period, both had stopped taking prophylaxisPatients on co-trimoxazole experienced neutropaenia on 4.11% of maintenance days versus 2.17% on alternative drugs (p<0.001), but the proportion of patients with 0 neutropaenic days was not significantly different between the 2 groups. The statistical analysis here is difficult to comprehend. 2 consecutive days/week trimethoprim is an effective regime in paediatric patients with leukaemia and lymphoma.Not prospective or comparative but large number of patients studied over long period of time.No difference in neutropaenia during maintenance therapy between those treated with co-trimoxazole and an alternative (pentamidine or dapsone) but the number of patients treated with an alternative was very small (13). 3. Benefit v risk of PJP prophylaxisPatients: Children up to 19 years of age with solid malignancies undergoing chemotherapy+/- radiotherapy with a low risk of PJPIntervention: does PJP prophylaxis withco-trimoxazoleaerosolized pentamidineatovaquone ordapsoneOutcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxis/ alternative regimensStudies of alternatives to co-trimoxazoleDrug/RegimePaperDesignStudy populationResultsSummaryDapsoneADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing >20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P =.016), whereas methemoglobinemia risk was increased with dosing >20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P <.001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. 2011 American Cancer Society.", "author" : [ { "dropping-particle" : "", "family" : "Esbenshade", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ho", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shintani", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhao", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "L A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "3485-3492", "publisher-place" : "(Esbenshade, Ho, Smith, Friedman) Department of Pediatrics, Vanderbilt University Medical Center, Monroe Carell Jr Children's Hospital at Vanderbilt, 2200 Pierce Avenue, 397 PRB, Nashville, TN 37232, United States (Shintani, Zhao) Department of Biostatist", "title" : "Dapsone-induced methemoglobinemia: A dose-related occurrence?", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(56)", "plainTextFormattedCitation" : "(56)", "previouslyFormattedCitation" : "(56)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(56)Ebenshade et al 2011Retrospective review167 paediatric patients (≤22y) treated for haematological malignancies or aplastic anaemiaSymptomatic methemoglobinemia documented in 19.8% Higher dosing increased riskCytochrome b5 reductase activity did not differ by methemoglobinemia status. No patient developed PJPRisk of methemoglobinemia found exceeds likely risk of PJP in solid tumour patients.Study population was not solid tumours but underlying malignancy is unlikely to affect risk of drug side effect. Risk of methemoglobinemia was related to dapsone dosing but efficacy in preventing PJP was not (although numbers were too small to adequately assess the latter). Possible that less frequent dapsone dosing may be safer and equally as effective. Co-trimoxazole versus atovaquoneADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/sj.bmt.1702004", "ISSN" : "0268-3369", "PMID" : "10516703", "abstract" : "Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study dem\u2026", "author" : [ { "dropping-particle" : "", "family" : "Colby", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAfee", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sackstein", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Finkelstein", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fishman", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spitzer", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bone marrow transplantation", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1999", "10" ] ] }, "page" : "897-902", "title" : "A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(57)", "plainTextFormattedCitation" : "(57)", "previouslyFormattedCitation" : "(57)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(57)Colby et al 1999Prospective randomized trial.Prophylaxis given from day -5 to day -1 and then resumed on neutrophil count recovery.Both drugs given 3d/week post transplant. Not blinded. 39 adult patients undergoing PBSC for haematological and solid malignanciesHigh incidence of adverse effects in co-trimoxazole group (40%) led to early discontinuation of trialNone of 16 patients treated with atovaquone suffered adverse eventsNo PJP in either groupAtovaquone seemed to be well tolerated in the 16 adult patients undergoing PBSC in this study. High incidence of adverse reactions to co-trimoxazole. Rate of side effects to co-trimoxazole in adults known to be much higher than in children.Study not powered to look at efficacy of atovaquone versus co-trimoxazole, only the toxicity and safety of both treatments. Study is probably not relevant to children with solid malignancies, as the underlying diagnoses, treatment regimens and risk of adverse effects differ substantially. 4. Use of lymphocyte/CD4 counts as a marker of riskPatients: Children up to 19 years of age with solid malignancies undergoing chemotherapy+/- radiotherapy Intervention: can lymphocyte and/or CD4 counts Outcome: predict risk of PJP? Control: noneTable 6: CD4 counts and PJPPaperDesignStudy populationResultsSummaryADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1080/00365540601150497", "ISSN" : "0036-5548", "PMID" : "17577823", "abstract" : "A retrospective study was conducted to describe risk factors associated with Pneumocystis jiroveci pneumonia (PCP) among HIV-negative patients. During 2002-2004, 50 cases of PCP were identified at Rigshospitalet University Hospital on the basis of histology, PCR and clinical symptoms of PCP. Predisposing conditions included haematological malignancy (72%), inflammatory diseases (14%), solid organ transplantation (6%) and other conditions associated with immunodeficiency (8%). The most common treatment related risk factors were steroid usage (76%) and chemotherapy (72%). In 88% of patients who received steroids, dosage was either lowered or given as pulse-therapy in the 2 weeks preceding the onset of symptoms. Only 1 patient was on PCP prophylaxis at diagnosis and only 8 (16%) patients had previously been given PCP prophylaxis. At diagnosis, 78% of patients were lymphopenic. CD4 counts were available in 17 patients. Only 9 patients (52%) had CD4 count values below 300 cells/microl. The overall mortality attributable to PCP was 14% and was significantly associated with delayed diagnosis and treatment. Among immunocompromized HIV-negative patients, PCP should be particularly suspected in the context of steroid treatment and lymphopenia. Although low CD4 count is associated with a higher risk of PCP, the use of CD4 count as guidance for risk identification or prophylaxis among HIV-negative patients appears insufficient.", "author" : [ { "dropping-particle" : "", "family" : "Overgaard", "given" : "Ulrik M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helweg-Larsen", "given" : "Jannik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scandinavian journal of infectious diseases", "id" : "ITEM-1", "issue" : "6-7", "issued" : { "date-parts" : [ [ "2007", "1", "8" ] ] }, "language" : "en", "page" : "589-95", "publisher" : "Informa UK Ltd UK", "title" : "Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004.", "type" : "article-journal", "volume" : "39" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(32)", "plainTextFormattedCitation" : "(32)", "previouslyFormattedCitation" : "(32)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(32)Overgaard & Helweg-Larsen 2007Retrospective study to describe risk factors associated with PJP in HIV negative patients 50 cases of histologically and micoroscopy +/- PCR confirmed PJP identified in one institution over 3y period. Only 11 children 0-17yMajor predisposing factor was haematological malignancy, especially NHL (n=15) and ALL (n=6). All 6 ALL patients were not taking prophylaxis at the time. 76% patients had received steroids, median time of treatment 12 weeks. 72% received chemotherapy.Lymphocyte counts were available for all patients but CD4 counts for only 17 (34%).Lymphopaenia (<1 x 109 cells/litre) detected in 78% before onset or during initiation of PJP therapy.Median CD4 count 280 x 106/litre. Only 52% <300, and 70% <400. 3 patients had CD4 counts >500. All patients identified with PJP had established risk factors, including steroid therapy (76%), haematological malignancy and chemotherapy (72%). Relation between CD4 counts and risk of PJP is less obvious compared to HIV positive patients. Number of children included in this study (11) is too small to meaningfully address the clinical question above. Results have not been separated for adults and children. 5. Corticosteroids and brain tumoursPatients: Children up to 19 years of age with brain tumours undergoing treatment with corticosteroidsIntervention: does PJP prophylaxis Outcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxis.No directly relevant studies found. See table 1 for background risk of PJP in brain tumours.Henson et al 1991 & Sepkowitz 1992 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25,26)", "plainTextFormattedCitation" : "(25,26)", "previouslyFormattedCitation" : "(25,26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25,26) and Green et al 2007 – Cochrane review ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19) for side effects of co-trimoxazole in children.6. TemozolomidePatients: Children up to 19 years of age with solid malignancies undergoing treatment with temozolomideIntervention: does PJP prophylaxis Outcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxis.No relevant studies found7. Rituximab and other immunomodulating agentsPatients: Children up to 19 years of age with solid malignancies undergoing treatment with immunomodulating agentsIntervention: does PJP prophylaxis Outcome: offer more benefit (prevention of PJP) than risk (side effects/cost/inconvenience) Control: compared with no prophylaxis.No relevant studies found8. Underlying lung pathologyPatients: Children up to 19 years of age with solid malignancies and underlying chronic lung diseaseIntervention: undergoing chemotherapy +/- radiotherapyOutcome: what is the risk of PJP?Control: compared to children up to 19 years of age with solid malignancies but healthy lungsStudies of PJP and underlying lung pathologyPaperDesignStudy populationResultsSummaryADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3201/eid1903.121151", "ISSN" : "1080-6059", "PMID" : "23622345", "abstract" : "After an increase in the number of reported cases of Pneumocystis jirovecii pneumonia in England, we investigated data from 2000-2010 to verify the increase. We analyzed national databases for microbiological and clinical diagnoses of P. jirovecii pneumonia and associated deaths. We found that laboratory-confirmed cases in England had increased an average of 7% per year and that death certifications and hospital admissions also increased. Hospital admissions indicated increased P. jirovecii pneumonia diagnoses among patients not infected with HIV, particularly among those who had received a transplant or had a hematologic malignancy. A new risk was identified: preexisting lung disease. Infection rates among HIV-positive adults decreased. The results confirm that diagnoses of potentially preventable P. jirovecii pneumonia among persons outside the known risk group of persons with HIV infection have increased. This finding warrants further characterization of risk groups and a review of P. jirovecii pneumonia prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Maini", "given" : "Rishma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Katherine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sheridan", "given" : "Elizabeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lamagni", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nichols", "given" : "Gordon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delpech", "given" : "Valerie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phin", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Emerging infectious diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "386-92", "title" : "Increasing Pneumocystis pneumonia, England, UK, 2000-2010.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(10)", "plainTextFormattedCitation" : "(10)", "previouslyFormattedCitation" : "(10)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(10)Maini et al 2013Retrospective analysis of multiple national data sourcesAll inpatient admissions to NHS hospitals in England where PJP infection was coded between 2000-2010. HIV infected patients excluded. Laboratory confirmed cases extracted from LabBase2 (HPA’s national communicable diseases database for England, Wales and N Ireland). Death certificate data where PJP coded as cause or contributory cause of deathNumber of inpatient admissions where PJP coded increased from 157 to 352/year over the study period, an average annual increase of 9% (p<0.001).Most (40.6%) had a haematologic malignancy17.5% had pre-existing lung disease (included TB, COPD, CF, bronchiectasis, asthma and interstitial lung disease). There was also an increasing trend in rates of microbiologically confirmed cases. However hospital admission data yielded 2258 cases but LabBase2 found only 765. This difference may reflect underreporting by laboratories, or diagnosis by clinical and radiological findings or by immunofluorescence in the cytology department without microbiological confirmation. Unable to say whether increased number of cases is due to increased testing as the laboratory surveillance system captures positive samples only, not the total number of samples submitted. Increased incidence of PJP in HIV negative patients between the years 2000-2010. Observed across all age groups, but especially in over 60s. Identification of a new group at risk for PJP: patients with pre-existing lung disease. Age range of this sub-group not given.Does not provide information on severity of lung disease.NB – Does mild asthma increase the risk of PJP?9. Previous PJPPatients: Children up to 19 years of age with solid malignancies who have had previous PJP infection Intervention: undergoing chemotherapy +/- radiotherapyOutcome: what is the risk of PJP?Control: compared to children up to 19 years of age with solid malignancies who have had not had previous PJP infectionNo relevant studies found10. Myelosuppression with co-trimoxazolea)Patients: Children up to 19 years of age with malignancies undergoing chemotherapy +/- radiotherapyIntervention: does PJP prophylaxis with co-trimoxazoleOutcome: cause clinically significant myelosuppression Control: compared with no prophylaxis.b)Patients: Children up to 19 years of age with malignancies undergoing chemotherapy +/- radiotherapyIntervention: does PJP prophylaxis with twice weekly co-trimoxazoleOutcome: cause clinically significant myelosuppression Control: compared with thrice weekly or daily co-trimoxazole.See also under q 2 references ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "Owing to a 15% attack rate of Pneumocystis carinii pneumonitis (PCP) among the leukemic population at Riley Hospital, Indianapolis, a two-year study using continuous low-dosage sulfamethoxazole-trimethoprim to prevent PCP was started in January 1977. A total of 229 pediatric cancer patients considered at high risk for getting PCP received prophylaxis, while 19 additional low-risk cancer patients did not receive sulfamethoxazole-trimethoprim. None of these 248 patients contracted PCP. However, five cases of PCP did occur among ten additional high-risk patients who failed to receive this preparation for a variety of reasons. Complications of the continuous prophylaxis program included neutropenia, rash, and gastrointestinal complaints. This study confirms that continuous, low-dosage sulfamethoxazole-trimethoprim prophylaxis is effective in preventing PCP in susceptible immunosuppressed patients but is ineffective in eradicating the organism from the population at risk.", "author" : [ { "dropping-particle" : "", "family" : "Harris", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCallister", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "S A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "35-38", "publisher-place" : "(Harris, McCallister, Allen) Div. Ped. Hematol. Oncol., Dept. Ped., James Whitcomb Riley Hosp. Child., Indiana Univ. Sch. Med., Indianapolis, Ind. 46223 United States", "title" : "Prevention of Pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethoprim therapy", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14,23,71)", "plainTextFormattedCitation" : "(14,23,71)", "previouslyFormattedCitation" : "(14,23,71)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14,23,71) Studies on PJP prophylaxis efficacy and Studies of different co-trimoxazole regimensPaperDesignStudy populationresultsSummaryADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/bmt.2010.285", "ISSN" : "1476-5365", "PMID" : "21102496", "author" : [ { "dropping-particle" : "", "family" : "Fontanet", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chalandon", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roosnek", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mohty", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Passweg", "given" : "J R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bone marrow transplantation", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2011", "9" ] ] }, "page" : "1272-3", "publisher" : "Macmillan Publishers Limited", "title" : "Cotrimoxazole myelotoxicity in hematopoietic SCT recipients: time for reappraisal.", "title-short" : "Bone Marrow Transplant", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(60)", "plainTextFormattedCitation" : "(60)", "previouslyFormattedCitation" : "(60)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(60)Fontanet et al 2011Retrospective case control17 adult patients undergoing HSCT receiving continuous prophylaxis with co-trimoxazole compared with 49 matched controlled who received interrupted prophylaxisNo differences in time to neutrophil and platelet engraftment found (p= 0.9 and 0.6 respectively). No cases of PJP infectionNo differences observed in speed of myeloid and platelet engraftment on comparing patients receiving continued with those receiving interrupted prophylaxisInsufficiently powered study to detect small differences11. Methotrexate (mtx)Patients: Children up to 19 years of age with malignancies undergoing treatment with methotrexateIntervention: does PJP prophylaxis with co-trimoxazoleOutcome: cause clinically significant increased rates of methotrexate toxicityControl: compared with no prophylaxis.Studies of methotrexate and co-trimoxazolePaperDesignStudy populationresultsSummaryADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0022-3476(05)83351-7", "ISSN" : "00223476", "author" : [ { "dropping-particle" : "", "family" : "Ferrazzini", "given" : "Gianmario", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "Julla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sulh", "given" : "Hassan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chung", "given" : "Derrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griesbrecht", "given" : "Esther", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koren", "given" : "Gideon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Pediatrics", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "1990", "11" ] ] }, "page" : "823-826", "title" : "Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(58)", "plainTextFormattedCitation" : "(58)", "previouslyFormattedCitation" : "(58)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(58)Ferrazzini et al 1990Pharmacokinetic study of mtx given iv or orally, once with and once without co-trimoxazole. 9 children (2-11y) with ALL on maintenance therapy. Increase in free mtx fraction in the serum during co-trimoxazole therapy in all patients from 37.4 +/- 11% to 52.2 +/- 6.4% (p<0.01)Plasma clearance of total mtx before and during co-trimoxazole administration did not change significantly but there was a significant decrease in the plasma clearance of free mtx. Consistent decrease in renal clearance of free mtx with co-trimoxazole (p<0.05)Elimination half life of free mtx was not significantly different without or without the antibioticElimination half life of free mtx in the oral studies did not differ from that in during iv therapyCorrelation between serum concentrations of co-trimoxazole and percentage of decrease in renal clearance of free mtx (r=0.91, p<0.05)No changes in creatinine clearance. Mean 66% increase in systemic exposure to free mtx when co-administered with co-trimoxazole. Since the free mtx fraction enters cells and exerts the antileukaemic and toxic effects, children exposed to both drugs may be at risk of increased mtx toxicity, including myelosuppression. However this study did not assess myelosuppression directly. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Relling", "given" : "MV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fairclough", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ayers", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crom", "given" : "WR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodman", "given" : "JH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pui", "given" : "CH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "WE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J. Clin. Oncol.", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1994", "8", "1" ] ] }, "page" : "1667-1672", "title" : "Patient characteristics associated with high-risk methotrexate concentrations and toxicity", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(59)", "plainTextFormattedCitation" : "(59)", "previouslyFormattedCitation" : "(59)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(59)Relling et al 1994Retrospective analysis of clinical and pharmacokinetic variables associated with high-risk mtx concentrations 134 children entrolled on the St. Jude Total Therapy Study XII for newly diagnosed ALL.Data analysed for 66 patients with high risk mtx levels at 42h after high dose mtxMost important covariates of high risk mtx concentrations were mtx area under the curve (or end of infusion concentration), low urine pH and occurrence of emesis during mtx infusion.The concurrent use of co-trimoxazole did not correlate with high risk mtx levels. All patients were treated with co-trimoxazole 3 days/week (mon, tues, wed). Estimated approximately half the children in the study received co-trimoxazole on the same day at high dose mtx but all would have received it within the same week. Small numbers of patients may mean that significant correlations between toxic mtx levels and concurrent use of co-trimoxazole may have been missed.Current doses of high dose mtx used in ALL and osteosarcoma protocols are much higher (5g/m2 and 12g/m2 respectively compared to 0.9-3.7g/m2 used in this study)12. Potential for development of resistant isolatesPatients: Children up to 19 years of age with malignancies Intervention: does PJP prophylaxis with co-trimoxazoleOutcome: cause increased rates of resistant strains of PJPControl: compared with no prophylaxis.No relevant studies found 13. G6PD deficiencyPatients: Children up to 19 years of age with malignancies and G6PD deficiency Intervention: does PJP prophylaxis with co-trimoxazoleOutcome: cause haemolysisControl: compared with no prophylaxis.No relevant studies foundAppendix E: Grading the Quality of EvidenceAssessing the quality of the identified evidenceThe lead author assessed the quality of the evidence for each outcome identified in the literature review using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. GRADE Profiles/ Grading the Quality of EvidenceThe main criteria considered in the rating of the evidence are summarized below. The ratings for each component were summed to obtain an overall assessment for each outcome. Description of quality elements in GRADE profile (Source: Adapted from BMJ 2008 diagnostic GRADE ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Gordon H Guyatt, professor1, Andrew D Oxman, researcher2, Gunn E Vist, researcher2, Regina Kunz, associate professor3, Yngve Falck-Ytter, assistant professor4, Pablo Alonso-Coello, researcher5, Holger J Sch\u00fcnemann, professor6 for the GRADE Working Group 1Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z52Norwegian Knowledge Centre for the Health Services, PO Box 7004, St Olavs Plass, 0130 Oslo, Norway3Basel Institute of Clinical Epidemiology, University Hospital Basel, Hebelstrasse 10, 4031 Basel, Switzerland4Division of Gastroenterology, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA5Iberoamerican Cochrane Center, Servicio de Epidemiolog\u00eda Cl\u00ednica y Salud P\u00fablica (Universidad Aut\u00f3noma de Barcelona), Hospital de Sant Pau, Barcelona 08041, Spain 6Department of Epidemiology, Italian National Cancer Institute Regina Elena, Rome, ItalyCorrespondence to: G H Guyatt, CLARITY Research Group, Department of Clinical Epidemiology and Biostatistics, Room 2C12, 1200 Main Street, West Hamilton, ON, Canada L8N 3Z5 guyatt{at}mcmaster.caGuidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide Summary points Failure to consider the quality of evidence can lead to misguided recommendations; hormone replacement therapy for post-menopausal women provides an instructive example High quality evidence that an intervention\u2019s desirable effects are clearly greater than its undesirable effects, or are clearly not, warrants a strong recommendationUncertainty about the trade-offs (because of low quality evidence or because the desirable and undesirable effects are closely balanced) warrants a weak recommendationGuidelines should inform clinicians what the quality of the underlying evidence is and whether recommendations are strong or weakThe Grading of Recommendations Assessment, Development and Evaluation (GRADE ) approach provides a system for rating quality of evidence and strength of recommendations that is explicit, comprehensive, transparent, and pragmatic and is increasingly being adopted by organisations worldwideGuideline developers around the world are inconsistent in how they rate quality of evidence and grade strength of recommendations. As a result, guideline users face challenges in understanding the messages that gr\u2026", "author" : [ { "dropping-particle" : "", "family" : "Guyatt", "given" : "Gordon H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oxman", "given" : "Andrew D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vist", "given" : "Gunn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kunz", "given" : "Regina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falck-Ytter", "given" : "Yngve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alonso-Coello", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sch\u00fcnemann", "given" : "Holger J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMJ", "id" : "ITEM-1", "issue" : "7650", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "924-926", "title" : "GRADE: an emerging consensus on rating quality of evidence and strength of recommendations", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "Gordon H Guyatt, professor1, Andrew D Oxman, researcher2, Regina Kunz, associate professor3, Gunn E Vist, researcher2, Yngve Falck-Ytter, assistant professor4, Holger J Sch\u00fcnemann, associate professor5 for the GRADE Working Group1Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z52Norwegian Knowledge Centre for the Health Services, PO Box 7004, St Olavs plass, 0130 Oslo, Norway3Basel Institute of Clinical Epidemiology, University Hospital Basel, Hebelstrasse 10, 4031 Basel, Switzerland4Division of Gastroenterology, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA5Department of Epidemiology, CLARITY Research Group, Italian National Cancer Institute Regina Elena, Rome, ItalyCorrespondence to: G H Guyatt, CLARITY Research Group, Department of Clinical Epidemiology &amp;amp; Biostatistics, Room 2C12, 1200 Main Street West Hamilton, ON, Canada L8N 3Z5 guyatt{at}mcmaster.caGuideline developers use a bewildering variety of systems to rate the quality of the evidence underlying their recommendations. Some are facile, some confused, and others sophisticated but complexIn 2004 the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group presented its initial proposal for patient management.1 In this second of a series of five articles focusing on the GRADE approach to developing and presenting recommendations we show how GRADE has built on previous systems to create a highly structured, transparent, and informative system for rating quality of evidence.Summary pointsA guideline\u2019s formulation should include a clear question with specification of all outcomes of importance to patientsGRADE offers four levels of evidence quality: high, moderate, low, and very lowRandomised trials begin as high quality evidence and observational studies as low quality evidenceQuality may be downgraded as a result of limitations in study design or implementation, imprecision of estimates (wide confidence intervals), variability in results, indirectness of evidence, or publication biasQuality may be upgraded because of a very large magnitude of effect, a dose-response gradient, and if all plausible biases would reduce an apparent treatment effectCritical outcomes determine the overall quality of evidenceEvidence profiles provide simple, transparent summariesA guideline\u2019s formulation should include a clear questionAny question addressing clinical management has four componen\u2026", "author" : [ { "dropping-particle" : "", "family" : "Guyatt", "given" : "Gordon H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oxman", "given" : "Andrew D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kunz", "given" : "Regina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vist", "given" : "Gunn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falck-Ytter", "given" : "Yngve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sch\u00fcnemann", "given" : "Holger J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMJ", "id" : "ITEM-2", "issue" : "7651", "issued" : { "date-parts" : [ [ "2008", "5" ] ] }, "page" : "995-998", "title" : "What is \u201cquality of evidence\u201d and why is it important to clinicians?", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1136/bmj.39493.646875.AE", "ISSN" : "0959-8138", "abstract" : "The GRADE system classifies recommendations made in guidelines as either strong or weak. This article explores the meaning of these descriptions and their implications for patients, clinicians, and policy makers ", "author" : [ { "dropping-particle" : "", "family" : "Guyatt", "given" : "Gordon H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oxman", "given" : "Andrew D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kunz", "given" : "Regina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falck-Ytter", "given" : "Yngve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vist", "given" : "Gunn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liberati", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sch\u00fcnemann", "given" : "Holger J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMJ : British Medical Journal", "id" : "ITEM-3", "issue" : "7652", "issued" : { "date-parts" : [ [ "2008", "5" ] ] }, "page" : "1049-1051", "publisher" : "BMJ Publishing Group Ltd.", "title" : "Going from evidence to recommendations", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(74\u201376)", "plainTextFormattedCitation" : "(74\u201376)", "previouslyFormattedCitation" : "(74\u201376)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(74–76) )Quality elementDescriptionStudy limitations/ risk of biasLimitations in the study design and implementation may bias the estimates of the treatment effect. Major limitations in studies decrease the confidence in the estimate of the effect.InconsistencyUnexplained heterogeneity of resultsIndirectnessDifferences in study population, intervention, comparator and outcomes between the available evidence and the review question, or recommendation made.ImprecisionStudies include relatively few patients and few events and thus have wide confidence intervals around the estimate of the effect relative to the clinically important threshold.Publication BiasSystematic underestimate or overestimate of the underlying beneficial or harmful effect due to the selective publication of studies.Large EffectLarge effect size may increase the quality level of evidencePlausible confoundingMay reduce the effect or suggest a spurious effectDose Response GradientPresence of such a gradient increases confidence in the findings and should raise the rating of the quality of evidence. ?Levels of quality elements in GRADELevelDescriptionNoneThere are no serious issues with the evidenceSeriousThe issues are serious enough to downgrade the outcome evidence by one levelVery seriousThe issues are serious enough to downgrade the outcome evidence by 2 levels Overall quality of outcome evidence in GRADE?LevelDescriptionHighFurther research is very unlikely to change our confidence in the estimate of effectModerateFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimateLowFurther research in very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimateVery lowAny estimate of effect is very uncertainGrading the quality of clinical evidenceThe overall quality of evidence for each outcome was considered. The following procedure was adopted when using GRADE:A quality rating was assigned, based on the study design. RCTs, prospective diagnostic cross sectional or cohort studies start HIGH and observational studies as LOW, uncontrolled case series as LOW or VERY LOW. The rating was then downgraded or upgraded for the specified criteria: Study limitations, inconsistency, indirectness, imprecision and reporting bias. Observational studies were upgraded if there was: a large magnitude of effect, dose-response gradient, and if all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results showed no effect. Each quality element considered to have “serious” or “very serious” risk of bias were rated down -1 or -2 points respectively. The downgraded/upgraded marks were then summed and the overall quality rating was revised. For example, all RCTs started as HIGH and the overall quality became MODERATE, LOW or VERY LOW if 1, 2 or 3 points were deducted respectively. The reasons or criteria used for downgrading were specified in the footnotes. Appendix F: GRADE profiles for outcomes identified from the literature review:1. Outcome: PJP infection in children receiving co-trimoxazole prophylaxis undergoing treatment for solid tumoursRefNo. of studiesStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasCochrane systematic review 2007ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19) 4RCTSerious:not all studies clear allocation concelamentNot seriousSerious:studies in adults and children being treated for Leukaemia not seriousundetectedHarris et al 1980ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Owing to a 15% attack rate of Pneumocystis carinii pneumonitis (PCP) among the leukemic population at Riley Hospital, Indianapolis, a two-year study using continuous low-dosage sulfamethoxazole-trimethoprim to prevent PCP was started in January 1977. A total of 229 pediatric cancer patients considered at high risk for getting PCP received prophylaxis, while 19 additional low-risk cancer patients did not receive sulfamethoxazole-trimethoprim. None of these 248 patients contracted PCP. However, five cases of PCP did occur among ten additional high-risk patients who failed to receive this preparation for a variety of reasons. Complications of the continuous prophylaxis program included neutropenia, rash, and gastrointestinal complaints. This study confirms that continuous, low-dosage sulfamethoxazole-trimethoprim prophylaxis is effective in preventing PCP in susceptible immunosuppressed patients but is ineffective in eradicating the organism from the population at risk.", "author" : [ { "dropping-particle" : "", "family" : "Harris", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCallister", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "S A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "35-38", "publisher-place" : "(Harris, McCallister, Allen) Div. Ped. Hematol. Oncol., Dept. Ped., James Whitcomb Riley Hosp. Child., Indiana Univ. Sch. Med., Indianapolis, Ind. 46223 United States", "title" : "Prevention of Pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethoprim therapy", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(71)", "plainTextFormattedCitation" : "(71)", "previouslyFormattedCitation" : "(71)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(71) 1cohortvery serious:observational not randomised or concealednot seriousSerious:included ALL patientsnot serious:calculated confidence interval 0-1.6% proportion of PJP cases on prophylaxis (binomial exact model)undetectedWilber et al 1980 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23)", "plainTextFormattedCitation" : "(23)", "previouslyFormattedCitation" : "(23)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23)1cohortvery seriousnot serious:not randomised or controlled. Prophylaxis given at attending oncologists discretion.Serious:most patients in the study had ALL, not solid tumoursSerious:evidence of efficacy provided by decline in yearly PJP rate at the same institution and comparison with historical data. ImpreciseundetectedOutcome: PJP infection in children receiving co-trimoxazole prophylaxis undergoing treatment for solid tumours – continuedRefLarge effectPlausible confoundingDose response gradientSummary of FindingsQualityCotrimoxazole eventsNo. of patientsPlacebo/ no prophylaxis eventsNo. of patientsPooled effectCochrane systematic review 2007ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD005590.pub2", "ISSN" : "1469-493X", "PMID" : "17636808", "abstract" : "Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cochrane database of systematic reviews (Online)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "CD005590", "title" : "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(19)", "plainTextFormattedCitation" : "(19)", "previouslyFormattedCitation" : "(19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(19) very largenono0276262520.08 (0.02-0.38)highHarris et al 1980ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Owing to a 15% attack rate of Pneumocystis carinii pneumonitis (PCP) among the leukemic population at Riley Hospital, Indianapolis, a two-year study using continuous low-dosage sulfamethoxazole-trimethoprim to prevent PCP was started in January 1977. A total of 229 pediatric cancer patients considered at high risk for getting PCP received prophylaxis, while 19 additional low-risk cancer patients did not receive sulfamethoxazole-trimethoprim. None of these 248 patients contracted PCP. However, five cases of PCP did occur among ten additional high-risk patients who failed to receive this preparation for a variety of reasons. Complications of the continuous prophylaxis program included neutropenia, rash, and gastrointestinal complaints. This study confirms that continuous, low-dosage sulfamethoxazole-trimethoprim prophylaxis is effective in preventing PCP in susceptible immunosuppressed patients but is ineffective in eradicating the organism from the population at risk.", "author" : [ { "dropping-particle" : "", "family" : "Harris", "given" : "R E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCallister", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "S A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "35-38", "publisher-place" : "(Harris, McCallister, Allen) Div. Ped. Hematol. Oncol., Dept. Ped., James Whitcomb Riley Hosp. Child., Indiana Univ. Sch. Med., Indianapolis, Ind. 46223 United States", "title" : "Prevention of Pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethoprim therapy", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(71)", "plainTextFormattedCitation" : "(71)", "previouslyFormattedCitation" : "(71)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(71) largenono0229510n/alowWilber et al 1980 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23)", "plainTextFormattedCitation" : "(23)", "previouslyFormattedCitation" : "(23)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23)largenono1786n/an/an/alow2. Outcome: Prevalence of PJP infection in children undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionBrown et al 2013 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Background: High-dose chemotherapy with autologous hematopoietic progenitor cell rescue (AuHPCR) for pediatric patients with brain tumors has become an important therapeutic modality to avoid or delay the long-term effects of cranial irradiation. Data on post-AuHPCR infectious complications in this population are lacking. This single institution retrospective review reports the prophylactic practices and infections in the first year following AuHPCR in pediatric patients with brain tumors. Procedure: The medical record of patients who underwent AuHPCR for the treatment of a malignant brain tumor at Children's Hospital Los Angeles between 1988 and 2010 were reviewed. Patients without prior irradiation who were free of disease at 1 year without additional chemotherapy were evaluated for all infectious disease complications occurring from time of neutrophil engraftment to 1 year post-AuHPCR. Results: Forty-three of the 115 eligible patients were included. The median time to neutrophil engraftment was 11 days (range: 8-43 days), and 20 Grade III/IV (no Grade V) infectious episodes developed in 15 patients (35%). Fourteen episodes of bacteremia (70%) were catheter-related, predominantly gram-negative (71%), and polymicrobial (50%). There were no fungal or pneumocystis infections and only 1 of 25 (4%) at-risk patients developed VZV reactivation. Conclusions: These data suggest patients with brain tumors undergoing AuHPCR have few late-occurring non-catheter-related post-transplant infections indicating that prophylaxis practices were sufficient. Central lines should be removed soon after engraftment, but those with central line infections should receive adequate treatment including gram-negative coverage. In addition, only at-risk patients who receive further irradiation may benefit from VZV reaction prophylaxis. Pediatr Blood Cancer 2013;60:2012-2017. 2013 Wiley Periodicals, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Brown", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahim", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wong", "given" : "K E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cooper", "given" : "R M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marachelian", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butturini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dhall", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Finlay", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric Blood and Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "2012-2017", "publisher-place" : "(Brown, Rahim, Marachelian, Dhall, Finlay) Neuro-Oncology Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, United States (Wong) Department of Radiation Oncology, Children's Hospital Los Angeles, L", "title" : "Infectious complications in the first year following autologous hematopoietic progenitor cell rescue for children with brain tumors", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(68)", "plainTextFormattedCitation" : "(68)", "previouslyFormattedCitation" : "(68)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(68)cohortvery serious:observational, not randomisedvery serious:all patients given prophylaxis but duration and drug regimens variednot seriousnot seriousCyklis & Zielinska 1983 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0031-3939", "PMID" : "6605512", "author" : [ { "dropping-particle" : "", "family" : "Cyklis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zieli\u0144ska", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatria polska", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1983", "4" ] ] }, "page" : "337-40", "title" : "[Pneumocystis carinii infection in children with acute leukemia and non-Hodgkin malignant lymphoma].", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(24)", "plainTextFormattedCitation" : "(24)", "previouslyFormattedCitation" : "(24)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(24)cohortvery serious:some diagnoses of PCP were made by cysts on throat swab only and no clinical symptoms (Ie carriage only). Unknown number within NHL patients in this group.very serious:some cases diagnosed on clinical and radiological grounds, plus cysts on throat swab. Others diagnosed by throat swab alone.Serious:historical population given historical treatment protocolsvery serious:diagnosis of PCP very impreciseHenson et al 1991 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(26)", "plainTextFormattedCitation" : "(26)", "previouslyFormattedCitation" : "(26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(26)cohortSerious:incomplete follow up of patients. Some cases of PJP may have been missednot seriousvery serious:Only adults >20 yearsSerious:Incomplete follow up, uncertain denominatorhughes et al 1973ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-3476", "PMID" : "4572932", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "H K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coburn", "given" : "T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grigsby", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of pediatrics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1973", "3" ] ] }, "page" : "404-15", "title" : "Pneumocystis carinii pneumonitis in children with malignancies.", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(22)", "plainTextFormattedCitation" : "(22)", "previouslyFormattedCitation" : "(22)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(22) cohortSerious:unknown if the study population is representative of the paediatric oncology as a whole and if cases were missednot seriousSerious:historical population given historical treatment protocolsnot seriousHughes et al 1975 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0008-543X", "PMID" : "1081905", "abstract" : "One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(13)", "plainTextFormattedCitation" : "(13)", "previouslyFormattedCitation" : "(13)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(13)cohortnot seriousnot seriousSerious:Only children with ALL. All were treated with cranial irradiation and on protocols that vary from those used todaynot serious2. Outcome: Prevalence of PJP infection in children undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPerera et al 1970 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0098-7484 (Print) 0098-7484 (Linking)", "author" : [ { "dropping-particle" : "", "family" : "Perera", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Western", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "H D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "W W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Akers", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA", "edition" : "1970/11/09", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1970" ] ] }, "page" : "1074-1078", "title" : "Pneumocystis carinii pneumonia in a hospital for children. Epidemiologic aspects", "type" : "article-journal", "volume" : "214" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21)cohortSerious:Significance of cases discovered at autopsy only not clearnot seriousSerious:Historical study, children treated with protocols that vary from those used todaynot seriousPeters & Prakash 1987 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9343 (Print) 0002-9343 (Linking)", "abstract" : "Between 1976 and 1983, 53 cases of Pneumocystis carinii pneumonia were documented at the Mayo Clinic. Underlying diseases included leukemia in 15 patients, lymphoma in nine, nonhematologic malignancies in five, acquired immune deficiency syndrome in two, an various inflammatory diseases treated by corticosteroids in 16 patients. Cytotoxic drugs with corticosteroids were used in 68 percent of patients, whereas 23 percent received corticosteroids alone. Clinical features consisted of progressive dyspnea (74 percent), cough (55 percent), and fever (62 percent), with normal findings on examination (43 percent), or crackles (53 percent). Arterial oxygen tension and oxygen saturation were 48.6 +/- 12.8 mm Hg and 81.2 +/- 6.5 percent, respectively. Chest roentgenographs exhibited diffuse alveolar and interstitial infiltrates with predominantly perihilar distribution. The diagnostic rates for open lung biopsy and bronchoscopy were 97 percent and 62 percent, respectively. Clinical improvement and survival following appropriate therapy were noted in 22 patients (41.5 percent), whereas the remaining 31 patients died within four weeks of hospitalization. When survivors were compared with nonsurvivors, there was no difference in mean age, leukocyte counts, arterial oxygen tension, or duration of symptoms before treatment. A coexisting pulmonary infection was identified more frequently in nonsurvivors (51.6 percent) than in survivors (22.7 percent, p = 0.01). The mortality from P. carinii pneumonia alone was 47 percent, whereas 76 percent of those with coexisting infection died. Despite antibiotic therapy and potentially effective chemoprophylaxis, P. carinii pneumonia remains a significant and life-threatening complication of diseases or treatments associated with immune suppression.", "author" : [ { "dropping-particle" : "", "family" : "Peters", "given" : "S G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prakash", "given" : "U B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Med", "edition" : "1987/01/01", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1987" ] ] }, "page" : "73-78", "title" : "Pneumocystis carinii pneumonia. Review of 53 cases", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(69)", "plainTextFormattedCitation" : "(69)", "previouslyFormattedCitation" : "(69)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(69)CohortNot seriousNot seriousVery serious:Only 4 children included in the study, for whom the underlying diagnoses were not givenVery serious:No specific data on incidence or risks of PJP for children. No information on whether prophylaxis was used. Sedaghatian & Singer 1972 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Sedaghatian", "given" : "M R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singer", "given" : "D B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1972" ] ] }, "page" : "772-777", "title" : "Pneumocystis carinii in children with malignant disease", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(70)", "plainTextFormattedCitation" : "(70)", "previouslyFormattedCitation" : "(70)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(70)CohortSerious:Indication for autopsy and autopsy rates not givenNot seriousVery serious:includes some patients with leukaemia. Includes some patients with only a few isolated organisms found at autopsy of unknown clinical significance. None of the patients were diagnosed or treated for PJP pre-death. All the solid tumour patients had disseminated tumour at autopsy.Very serious:Not clear whether the patients died of PJP or their primary malignant disease. Prevalence rates for children undergoing autopsy, not for all patients treated for malignancy or dying of malignancy and its associated complications. Indications for autopsy not given.Sepkowitz 1992 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25)", "plainTextFormattedCitation" : "(25)", "previouslyFormattedCitation" : "(25)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25)CohortNot seriousNot seriousVery serious:most patients in the study were adults. Within the PJP attack rate for brain tumours the number of children included is not given.Not serious2. Outcome: Prevalence of PJP infection in children undergoing treatment for solid tumoursRefPublication biasLarge effectPlausible confoundingDose response gradientQualityBrown et al 2013 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Background: High-dose chemotherapy with autologous hematopoietic progenitor cell rescue (AuHPCR) for pediatric patients with brain tumors has become an important therapeutic modality to avoid or delay the long-term effects of cranial irradiation. Data on post-AuHPCR infectious complications in this population are lacking. This single institution retrospective review reports the prophylactic practices and infections in the first year following AuHPCR in pediatric patients with brain tumors. Procedure: The medical record of patients who underwent AuHPCR for the treatment of a malignant brain tumor at Children's Hospital Los Angeles between 1988 and 2010 were reviewed. Patients without prior irradiation who were free of disease at 1 year without additional chemotherapy were evaluated for all infectious disease complications occurring from time of neutrophil engraftment to 1 year post-AuHPCR. Results: Forty-three of the 115 eligible patients were included. The median time to neutrophil engraftment was 11 days (range: 8-43 days), and 20 Grade III/IV (no Grade V) infectious episodes developed in 15 patients (35%). Fourteen episodes of bacteremia (70%) were catheter-related, predominantly gram-negative (71%), and polymicrobial (50%). There were no fungal or pneumocystis infections and only 1 of 25 (4%) at-risk patients developed VZV reactivation. Conclusions: These data suggest patients with brain tumors undergoing AuHPCR have few late-occurring non-catheter-related post-transplant infections indicating that prophylaxis practices were sufficient. Central lines should be removed soon after engraftment, but those with central line infections should receive adequate treatment including gram-negative coverage. In addition, only at-risk patients who receive further irradiation may benefit from VZV reaction prophylaxis. Pediatr Blood Cancer 2013;60:2012-2017. 2013 Wiley Periodicals, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Brown", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahim", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wong", "given" : "K E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cooper", "given" : "R M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marachelian", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butturini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dhall", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Finlay", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric Blood and Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "2012-2017", "publisher-place" : "(Brown, Rahim, Marachelian, Dhall, Finlay) Neuro-Oncology Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, United States (Wong) Department of Radiation Oncology, Children's Hospital Los Angeles, L", "title" : "Infectious complications in the first year following autologous hematopoietic progenitor cell rescue for children with brain tumors", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(68)", "plainTextFormattedCitation" : "(68)", "previouslyFormattedCitation" : "(68)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(68)undetectedn/anon/aVery lowCyklis & Zielinska 1983 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0031-3939", "PMID" : "6605512", "author" : [ { "dropping-particle" : "", "family" : "Cyklis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zieli\u0144ska", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatria polska", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1983", "4" ] ] }, "page" : "337-40", "title" : "[Pneumocystis carinii infection in children with acute leukemia and non-Hodgkin malignant lymphoma].", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(24)", "plainTextFormattedCitation" : "(24)", "previouslyFormattedCitation" : "(24)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(24)undetectedn/awould reduce demonstrated effect:inclusion of PCP carriers (throat swab positive only)n/aVery lowHenson et al 1991 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2012515", "abstract" : "All histologically documented episodes of Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors, especially during tapering of steroid therapy.", "author" : [ { "dropping-particle" : "", "family" : "Henson", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalaj", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "R W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stover", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fels", "given" : "A O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1991", "4" ] ] }, "page" : "406-9", "title" : "Pneumocystis carinii pneumonia in patients with primary brain tumors.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(26)", "plainTextFormattedCitation" : "(26)", "previouslyFormattedCitation" : "(26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(26)undetectedn/awould reduce demonstrated effect:incomplete follow up may have some missed some cases of PJPn/aVery lowhughes et al 1973ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-3476", "PMID" : "4572932", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "H K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coburn", "given" : "T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grigsby", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of pediatrics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1973", "3" ] ] }, "page" : "404-15", "title" : "Pneumocystis carinii pneumonitis in children with malignancies.", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(22)", "plainTextFormattedCitation" : "(22)", "previouslyFormattedCitation" : "(22)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(22) undetectedn/anon/aVery lowHughes et al 1975 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0008-543X", "PMID" : "1081905", "abstract" : "One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aur", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verzosa", "given" : "M S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hustu", "given" : "H O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Simone", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1975", "12" ] ] }, "page" : "2004-9", "title" : "Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(13)", "plainTextFormattedCitation" : "(13)", "previouslyFormattedCitation" : "(13)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(13)undetectedlargenoYes:more intensive chemotherapy regimens are associated with higher risk of PJPmoderatePerera et al 1970 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0098-7484 (Print) 0098-7484 (Linking)", "author" : [ { "dropping-particle" : "", "family" : "Perera", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Western", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "H D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "W W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Akers", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA", "edition" : "1970/11/09", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1970" ] ] }, "page" : "1074-1078", "title" : "Pneumocystis carinii pneumonia in a hospital for children. Epidemiologic aspects", "type" : "article-journal", "volume" : "214" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21)undetectedn/aWould reduce demonstrated effect:Unclear significance of cases discovered at autopsy onlyn/amoderatePeters & Prakash 1987 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9343 (Print) 0002-9343 (Linking)", "abstract" : "Between 1976 and 1983, 53 cases of Pneumocystis carinii pneumonia were documented at the Mayo Clinic. Underlying diseases included leukemia in 15 patients, lymphoma in nine, nonhematologic malignancies in five, acquired immune deficiency syndrome in two, an various inflammatory diseases treated by corticosteroids in 16 patients. Cytotoxic drugs with corticosteroids were used in 68 percent of patients, whereas 23 percent received corticosteroids alone. Clinical features consisted of progressive dyspnea (74 percent), cough (55 percent), and fever (62 percent), with normal findings on examination (43 percent), or crackles (53 percent). Arterial oxygen tension and oxygen saturation were 48.6 +/- 12.8 mm Hg and 81.2 +/- 6.5 percent, respectively. Chest roentgenographs exhibited diffuse alveolar and interstitial infiltrates with predominantly perihilar distribution. The diagnostic rates for open lung biopsy and bronchoscopy were 97 percent and 62 percent, respectively. Clinical improvement and survival following appropriate therapy were noted in 22 patients (41.5 percent), whereas the remaining 31 patients died within four weeks of hospitalization. When survivors were compared with nonsurvivors, there was no difference in mean age, leukocyte counts, arterial oxygen tension, or duration of symptoms before treatment. A coexisting pulmonary infection was identified more frequently in nonsurvivors (51.6 percent) than in survivors (22.7 percent, p = 0.01). The mortality from P. carinii pneumonia alone was 47 percent, whereas 76 percent of those with coexisting infection died. Despite antibiotic therapy and potentially effective chemoprophylaxis, P. carinii pneumonia remains a significant and life-threatening complication of diseases or treatments associated with immune suppression.", "author" : [ { "dropping-particle" : "", "family" : "Peters", "given" : "S G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prakash", "given" : "U B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Med", "edition" : "1987/01/01", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1987" ] ] }, "page" : "73-78", "title" : "Pneumocystis carinii pneumonia. Review of 53 cases", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(69)", "plainTextFormattedCitation" : "(69)", "previouslyFormattedCitation" : "(69)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(69)Undetectedn/aWould reduced demonstrated effect:Not known if prophylaxis was given to any of the groups of patientsn/aVery low2. Outcome: Prevalence of PJP infection in children undergoing treatment for solid tumoursRefPublication biasLarge effectPlausible confoundingDose response gradientQualitySedaghatian & Singer 1972 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Sedaghatian", "given" : "M R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singer", "given" : "D B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1972" ] ] }, "page" : "772-777", "title" : "Pneumocystis carinii in children with malignant disease", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(70)", "plainTextFormattedCitation" : "(70)", "previouslyFormattedCitation" : "(70)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(70)Undetectedn/aWould reduce demonstrated effect:Possible that those children referred for autopsy may have had higher rates of PJP.n/aVery lowSepkowitz 1992 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/jama.1992.03480060078034", "ISSN" : "0098-7484", "author" : [ { "dropping-particle" : "", "family" : "Sepkowitz", "given" : "Kent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA: The Journal of the American Medical Association", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1992", "2", "12" ] ] }, "page" : "832", "publisher" : "American Medical Association", "title" : "Pneumocystis carinii Pneumonia Among Patients Without AIDS at a Cancer Hospital", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25)", "plainTextFormattedCitation" : "(25)", "previouslyFormattedCitation" : "(25)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25)Undetectedn/aWould reduce demonstrated effectn/aLow3. Outcome: Incidence of PJP infection in children undergoing treatment for solid tumours receiving co-trimoxazole 3 days per week v 2 days per week v one day per weekRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityCaselli et al 2004ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jpeds.2013.10.021", "ISSN" : "0022-3476", "abstract" : "OBJECTIVE: To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN: A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS: The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION: A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.", "author" : [ { "dropping-particle" : "", "family" : "Caselli", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petris", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rondelli", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carraro", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colombini", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muggeo", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ziino", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Melchionda", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pierani", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soncini", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desantis", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zanazzo", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barone", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cesaro", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cellini", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mura", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Milano", "given" : "G M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meazza", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cicalese", "given" : "M P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tropia", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masi", "given" : "S", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castagnola", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arico", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Pediatr", "edition" : "2013/11/21", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "389-392.e1", "publisher-place" : "Department of Pediatric Hematology-Oncology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Florence, Italy. Pediatric Hematology-Oncology, Padua, Italy. Pediatric Oncology and Hematology, Lalla Seragnoli Unit, University of Bologna, Bologna,", "title" : "Single-day trimethoprim/sulfamethoxazole prophylaxis for pneumocystis pneumonia in children with cancer", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(16)", "plainTextFormattedCitation" : "(16)", "previouslyFormattedCitation" : "(16)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(16)CohortVery serious:Lack of randomisation and lack of concealment allocationNot seriousSerious:Includes large number of haematological malignanciesNot serious:Calculated confidence interval for the once weekly group = 0-0.5%Undetectedn/aNoNoVery lowHughes et al 1987 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM198706253162604", "ISSN" : "0028-4793", "PMID" : "3495732", "abstract" : "We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "W T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera", "given" : "G K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schell", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lott", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "1987", "6", "25" ] ] }, "page" : "1627-32", "title" : "Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(8)", "plainTextFormattedCitation" : "(8)", "previouslyFormattedCitation" : "(8)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(8)RCT, not blindedNot seriousNot seriousSerious:All patients with ALL, not solid malignanciesNot seriousUndetectedLargeNon/ahighLindemulder & albano 2007 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14)", "plainTextFormattedCitation" : "(14)", "previouslyFormattedCitation" : "(14)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14)CohortSerious:Mixed, small (n=13) control group. No randomisationNot seriousSerious:Most of the patients in the study had leukaemiaNot seriousUndetectedVery largeNo n/aHighOhata et al 2009 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21774", "ISSN" : "1545-5009", "abstract" : "Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.", "author" : [ { "dropping-particle" : "", "family" : "Ohata", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohta", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashii", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokimasa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ozono", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Blood Cancer", "edition" : "2008/09/27", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "142-144", "publisher-place" : "Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "title" : "Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(15)", "plainTextFormattedCitation" : "(15)", "previouslyFormattedCitation" : "(15)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(15)CohortSerious:Not comparative or controlled, small numbersNot seriousSerious:Included patients with haematological malignancies, histiocytosis, immunodeficiency and metabolic disease and patients undergoing HSCT. Only 102 solid tumour patients (53%)SeriousSmall numbers, n=181UndetectedNoNo n/alow4. Outcome: Effectiveness of pentamidine in preventing PJP infection in children undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionDeMasi et al 2013 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/INF.0b013e318292f560", "ISSN" : "1532-0987", "PMID" : "23538522", "abstract" : "BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy.\n\nMETHODS: We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected.\n\nRESULTS: One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count >1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit.\n\nCONCLUSIONS: Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.", "author" : [ { "dropping-particle" : "", "family" : "DeMasi", "given" : "James M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Jennifer A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leonard", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koh", "given" : "Andrew Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aquino", "given" : "Victor M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Pediatric infectious disease journal", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "933-6", "title" : "Intravenous pentamidine is safe and effective as primary pneumocystis pneumonia prophylaxis in children and adolescents undergoing hematopoietic stem cell transplantation.", "type" : "article-journal", "volume" : "32" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(50)", "plainTextFormattedCitation" : "(50)", "previouslyFormattedCitation" : "(50)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(50)CohortSerious:Not comparative or controlled, Data collected retrospectivelyNot seriousSerious:Only 33% of paitents had a solid malignancySeriousSmall numbers, n=137Kim et al 2008 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21287", "ISSN" : "1545-5017", "PMID" : "17635000", "abstract" : "BACKGROUND: Pneumocystis jirovecii, formerly carinii, pneumonia (PCP) poses a life-threatening risk to oncology patients. The use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis virtually eliminates the risk of infection; however, many patients cannot tolerate TMP-SMZ. We performed a retrospective analysis to determine the PCP breakthrough rate in pediatric oncology patients receiving intravenous pentamidine as second line PCP prophylaxis.\n\nPROCEDURE: We conducted a retrospective chart review of pediatric oncology patients who received intravenous pentamidine from 2001 to 2006 at our institution. The diagnosis, age and bone marrow transplant (BMT) status were determined. A subset of patients had review of their records to determine the justification for discontinuing TMP-SMZ. Children who developed symptoms of pneumonia with a clinical suspicion of PCP underwent bronchoscopy, allowing for identification of Pneumocystis.\n\nRESULTS: A total of 232 patients received 1,706 doses of intravenous pentamidine and no toxicities were identified. The main reasons for discontinuing TMP-SMZ were bone marrow suppression and drug allergy. Three children developed PCP, equating to a breakthrough rate of 1.3%. Two of these children had undergone BMT (1.9% breakthrough rate) and both were under the age of two (6.5% breakthrough rate).\n\nCONCLUSIONS: The use of intravenous pentamidine as PCP prophylaxis results in a breakthrough rate of 1.3%. TMP-SMZ is the first choice for PCP prophylaxis. However, when necessary, the use of intravenous pentamidine has an acceptably low failure rate, even in high-risk BMT patients. Other options should be considered for children less than 2 years of age.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Su Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dabb", "given" : "Alix A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glenn", "given" : "Donald J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snyder", "given" : "Kristen M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chuk", "given" : "Meredith K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loeb", "given" : "David M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "779-83", "title" : "Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(51)", "plainTextFormattedCitation" : "(51)", "previouslyFormattedCitation" : "(51)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(51)cohortSerious:Not comparative or controlled. Data collected retrospectivelynot seriousSerious:50% patients leukaemia, 50% solid tumoursnot seriousMustafa et al 1994ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0732-183X", "PMID" : "8113834", "abstract" : "PURPOSE: Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX.\n\nPATIENTS AND METHODS: AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25).\n\nRESULTS: Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP.\n\nCONCLUSION: AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.", "author" : [ { "dropping-particle" : "", "family" : "Mustafa", "given" : "M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pappo", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winick", "given" : "N J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchanan", "given" : "G R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1994", "2" ] ] }, "page" : "258-61", "title" : "Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(52)", "plainTextFormattedCitation" : "(52)", "previouslyFormattedCitation" : "(52)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(52) CohortSerious:Historical controls only. Small numbersNot seriousSerious:Included only 9 patients with solid tumours (15%). Only children >3ySerious:Small numbers, n=60Orgel & Rushing 2014 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/inf.0000000000000044", "ISSN" : "0891-3668", "abstract" : "Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.", "author" : [ { "dropping-particle" : "", "family" : "Orgel", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rushing", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Infect Dis J", "edition" : "2013/09/14", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "319-321", "publisher-place" : "From the *Jonathan Jaques Children's Cancer Center, Miller Children's Hospital Long Beach, Long Beach and daggerChildren's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA.", "title" : "Efficacy and tolerability of intravenous pentamidine isethionate for pneumocystis jiroveci prophylaxis in a pediatric oncology population", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(53)", "plainTextFormattedCitation" : "(53)", "previouslyFormattedCitation" : "(53)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(53)CohortVery serious:not comparative or controlled. Younger patients more likely to be given iv pentamidine. Choice of therapy was by practioner preference then midway through the study period an institutional practice guideline was implementedNot seriousSerious:Half the cohort had ALLSerious:Scarcity of events preluded statistical power to perform a direct comparisonOrgel & Rushing 2014 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/inf.0000000000000044", "ISSN" : "0891-3668", "abstract" : "Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.", "author" : [ { "dropping-particle" : "", "family" : "Orgel", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rushing", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Infect Dis J", "edition" : "2013/09/14", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "319-321", "publisher-place" : "From the *Jonathan Jaques Children's Cancer Center, Miller Children's Hospital Long Beach, Long Beach and daggerChildren's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA.", "title" : "Efficacy and tolerability of intravenous pentamidine isethionate for pneumocystis jiroveci prophylaxis in a pediatric oncology population", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(53)", "plainTextFormattedCitation" : "(53)", "previouslyFormattedCitation" : "(53)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(53)CohortVery serious:not comparative or controlled. Younger patients more likely to be given iv pentamidine. Choice of therapy was by practioner preference then midway through the study period an institutional practice guideline was implementedNot seriousSerious:Half the cohort had ALLSerious:Scarcity of events preluded statistical power to perform a direct comparison4. Outcome: Effectiveness of pentamidine in preventing PJP infection in children undergoing treatment for solid tumoursRefPublication biasLarge effectPlausible confoundingDose response gradientQualityDeMasi et al 2013 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/INF.0b013e318292f560", "ISSN" : "1532-0987", "PMID" : "23538522", "abstract" : "BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy.\n\nMETHODS: We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected.\n\nRESULTS: One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count >1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit.\n\nCONCLUSIONS: Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.", "author" : [ { "dropping-particle" : "", "family" : "DeMasi", "given" : "James M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Jennifer A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leonard", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koh", "given" : "Andrew Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aquino", "given" : "Victor M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Pediatric infectious disease journal", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "9" ] ] }, "page" : "933-6", "title" : "Intravenous pentamidine is safe and effective as primary pneumocystis pneumonia prophylaxis in children and adolescents undergoing hematopoietic stem cell transplantation.", "type" : "article-journal", "volume" : "32" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(50)", "plainTextFormattedCitation" : "(50)", "previouslyFormattedCitation" : "(50)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(50)UndetectedNoNon/alowKim et al 2008 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21287", "ISSN" : "1545-5017", "PMID" : "17635000", "abstract" : "BACKGROUND: Pneumocystis jirovecii, formerly carinii, pneumonia (PCP) poses a life-threatening risk to oncology patients. The use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis virtually eliminates the risk of infection; however, many patients cannot tolerate TMP-SMZ. We performed a retrospective analysis to determine the PCP breakthrough rate in pediatric oncology patients receiving intravenous pentamidine as second line PCP prophylaxis.\n\nPROCEDURE: We conducted a retrospective chart review of pediatric oncology patients who received intravenous pentamidine from 2001 to 2006 at our institution. The diagnosis, age and bone marrow transplant (BMT) status were determined. A subset of patients had review of their records to determine the justification for discontinuing TMP-SMZ. Children who developed symptoms of pneumonia with a clinical suspicion of PCP underwent bronchoscopy, allowing for identification of Pneumocystis.\n\nRESULTS: A total of 232 patients received 1,706 doses of intravenous pentamidine and no toxicities were identified. The main reasons for discontinuing TMP-SMZ were bone marrow suppression and drug allergy. Three children developed PCP, equating to a breakthrough rate of 1.3%. Two of these children had undergone BMT (1.9% breakthrough rate) and both were under the age of two (6.5% breakthrough rate).\n\nCONCLUSIONS: The use of intravenous pentamidine as PCP prophylaxis results in a breakthrough rate of 1.3%. TMP-SMZ is the first choice for PCP prophylaxis. However, when necessary, the use of intravenous pentamidine has an acceptably low failure rate, even in high-risk BMT patients. Other options should be considered for children less than 2 years of age.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Su Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dabb", "given" : "Alix A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glenn", "given" : "Donald J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snyder", "given" : "Kristen M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chuk", "given" : "Meredith K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loeb", "given" : "David M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "779-83", "title" : "Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(51)", "plainTextFormattedCitation" : "(51)", "previouslyFormattedCitation" : "(51)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(51)Undetectednonon/a lowMustafa et al 1994ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0732-183X", "PMID" : "8113834", "abstract" : "PURPOSE: Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX.\n\nPATIENTS AND METHODS: AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25).\n\nRESULTS: Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP.\n\nCONCLUSION: AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.", "author" : [ { "dropping-particle" : "", "family" : "Mustafa", "given" : "M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pappo", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winick", "given" : "N J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchanan", "given" : "G R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1994", "2" ] ] }, "page" : "258-61", "title" : "Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(52)", "plainTextFormattedCitation" : "(52)", "previouslyFormattedCitation" : "(52)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(52) UndetectedNoNon/aVery lowOrgel & Rushing 2014 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/inf.0000000000000044", "ISSN" : "0891-3668", "abstract" : "Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.", "author" : [ { "dropping-particle" : "", "family" : "Orgel", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rushing", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Infect Dis J", "edition" : "2013/09/14", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "319-321", "publisher-place" : "From the *Jonathan Jaques Children's Cancer Center, Miller Children's Hospital Long Beach, Long Beach and daggerChildren's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA.", "title" : "Efficacy and tolerability of intravenous pentamidine isethionate for pneumocystis jiroveci prophylaxis in a pediatric oncology population", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(53)", "plainTextFormattedCitation" : "(53)", "previouslyFormattedCitation" : "(53)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(53)undectectedNo:Very few patients experienced breakthrough PJP infection but there was no control group for comparisonn/an/alow5. Outcome: Effectiveness of atovaquone in preventing PJP in paediatric patients undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityMadden et al 2007 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/cncr.22562", "ISSN" : "0008-543X", "PMID" : "17345613", "abstract" : "BACKGROUND: Despite extensive studies of atovaquone in human immunodeficiency virus (HIV)-infected patients, there is little information about its efficacy as a prophylactic agent for Pneumocystis carinii pneumonia (PCP) in pediatric patients with cancer. Therefore, a retrospective analysis was conducted to determine the incidence of PCP in pediatric patients who received prophylactic atovaquone during treatment for acute leukemia.\n\nMETHODS: We reviewed the medical records of all patients treated at our institution for acute lymphoblastic leukemia or acute myeloid leukemia between 1994 and 2004. Only patients who were intolerant of trimethoprim-sulfamethoxazole (TMP-SMZ) and received atovaquone prophylaxis were included in the analysis.\n\nRESULTS: Eighty-six patients were unable to tolerate TMP-SMZ and received daily atovaquone for PCP prophylaxis. PCP was not diagnosed in any patient who received atovaquone prophylaxis: the upper limit of the 95% confidence interval (CI) was 1.74 per 100 person-years.\n\nCONCLUSIONS: Atovaquone is an efficacious alternative for PCP prophylaxis in pediatric patients who have leukemia and are intolerant of TMP-SMZ.", "author" : [ { "dropping-particle" : "", "family" : "Madden", "given" : "Renee M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pui", "given" : "Ching-Hon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hughes", "given" : "Walter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flynn", "given" : "Patricia M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leung", "given" : "Wing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2007", "4", "15" ] ] }, "page" : "1654-8", "title" : "Prophylaxis of Pneumocystis carinii pneumonia with atovaquone in children with leukemia.", "type" : "article-journal", "volume" : "109" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(73)", "plainTextFormattedCitation" : "(73)", "previouslyFormattedCitation" : "(73)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(73)CohortSerious:Retrospective, not comparative or controlledNot seriousSerious:Only patients with AML or ALLSerious:Small numbers, n=86. incidence of PJP = 0 (95% CI 0-1.74 per 100 person-years by Poisson exact statistics)UndetectedLarge:if compared to historical controls (Hughes et al 1977), where 21% patients receiving placebo developed PJP, this is a large effect.Would increase demonstrated effect:more intensive treatment given to this cohort of patients than to historical control so effect may be greater as background risk of PJP may be highern/amoderate6. Outcome: Comparison of effectiveness of co-trimoxazole, dapsone, pentamidine and atovoquone in preventing PJP in paediatric patients undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityPrasad et al 2008 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21202", "ISSN" : "1545-5017", "PMID" : "17458875", "abstract" : "Pneumocystis pneumonia (PCP) is a serious complication of chemotherapy-induced immunosuppression. Trimethoprim-sulfamethoxazole (TMP-SMZ) given twice daily, 3 days every week is considered the best form of prophylaxis for PCP. We evaluated PCP prophylaxis in all children up to 18 years of age undergoing cancer chemotherapy over a 2-year period. Four children were diagnosed with PCP over 24 months. Two of 12 children on intravenous pentamidine, 1 of 143 on TMP-SMZ and 1 of 36 on dapsone for PCP prophylaxis developed PCP. Intravenous pentamidine may not be as effective as previously considered and should be used with caution.", "author" : [ { "dropping-particle" : "", "family" : "Prasad", "given" : "Pinki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nania", "given" : "Joseph J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shankar", "given" : "Sadhna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric blood & cancer", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "896-8", "title" : "Pneumocystis pneumonia in children receiving chemotherapy.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(55)", "plainTextFormattedCitation" : "(55)", "previouslyFormattedCitation" : "(55)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(55)CohortSerious:Retrospective, not comparative, controlled or randomisedNot seriousSerious:Most patients had haematological malignancies (72.6%)Serious:Results not statistically significant for dapsone and pentamidine, especiallly the latter. The rate of PCP was lowest for patients receiving TMP-SMZ (rate, 95% confidence interval: 0.004/person–year, [ 0.004, 0.012]), and was significantly lower than dapsone (0.03/person–year, [ 0.03, 0.08]) and intravenous pentamidine (0.17/person–year, [ 0.04, 0.38]).UndetectedNo Would suggest spurious effect:Numbers are small in the dapsone, pentamidine and atovaquone groups so incidence of PJP may differ due to difference in underlying diagnosis and treatment intensity rather than prophylactic regimenn/alow7. Outcome: Side effects of dapsone (risk versus benefit) in the prevention of PJP in paediatric patients undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityEsbenshade et al 2011 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing >20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P =.016), whereas methemoglobinemia risk was increased with dosing >20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P <.001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. 2011 American Cancer Society.", "author" : [ { "dropping-particle" : "", "family" : "Esbenshade", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ho", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shintani", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhao", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "L A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "3485-3492", "publisher-place" : "(Esbenshade, Ho, Smith, Friedman) Department of Pediatrics, Vanderbilt University Medical Center, Monroe Carell Jr Children's Hospital at Vanderbilt, 2200 Pierce Avenue, 397 PRB, Nashville, TN 37232, United States (Shintani, Zhao) Department of Biostatist", "title" : "Dapsone-induced methemoglobinemia: A dose-related occurrence?", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(56)", "plainTextFormattedCitation" : "(56)", "previouslyFormattedCitation" : "(56)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(56)cohortNot seriousNot seriousNot serious:although patients in the study had haematological malignancies, the underlying diagnosis is unlikely to affect the risk of the side effect (methemoglobinemia) being assessed in this studyNot seriousundetectedLarge:19.8% patients treated with dapsone suffered confirmed methemoglobinemia. This is likely to exceed the background risk of PJP in paediatric solid tumour patients. Dapsone is probably effective since none of the patients developed PJP. However there was no control group.NoYes:risk of methemoglobinaemia was related to increased dapsone levels. Efficacy was not affected by drug levels.moderate8. Outcome: Atovaquone versus co-trimoxazole for the prevention of PJP in paediatric patients undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityColby et al 1999 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/sj.bmt.1702004", "ISSN" : "0268-3369", "PMID" : "10516703", "abstract" : "Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study dem\u2026", "author" : [ { "dropping-particle" : "", "family" : "Colby", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAfee", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sackstein", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Finkelstein", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fishman", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spitzer", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bone marrow transplantation", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1999", "10" ] ] }, "page" : "897-902", "title" : "A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(57)", "plainTextFormattedCitation" : "(57)", "previouslyFormattedCitation" : "(57)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(57)RCT:Prospective but not blindedSerious:Treatment allocation not blindedNot seriousVery serious:all adult patients undergoing autologous peripheral blood stem cell transplantation. Study discontinued early because of high incidence of side effects due to co-trimoxazole. Co-trimoxazole is known to be better tolerated in children (Cochrane review 2007ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4065/82.9.1052", "ISSN" : "0025-6196 (Print) 0025-6196", "abstract" : "OBJECTIVE: To assess the efficacy of prophylaxis for Pneumocystis pneumonia (PCP), caused by Pneumocystis jirovecii (formerly Pneumocystis carinii), for immunocompromised non-HIV-infected patients by conducting a systematic review and meta-analysis. METHODS: We searched for randomized controlled trials that compared prophylaxis using antibiotics effective against P jirovecii, given orally or intravenously, vs placebo, no intervention, or antibiotics with no activity against P jirovecii. In addition, we included trials that compared different PCP prophylactic regimens or administration schedules. The search included the Cochrane Central Register of Controlled Trials, PubMed, Latin American and Caribbean Health Sciences Literature, and conference proceedings. No language, year, or publication restrictions were applied. Two reviewers (H.G. and M.P.) independently searched, selected trials, extracted data, and performed methodological quality assessment. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis was performed using the random-effects model. RESULTS: Twelve randomized trials were identified, including 1245 patients (50% children) who had undergone autologous bone marrow or solid organ transplant or who had hematologic cancer. When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity. Pneumocystis pneumonia-related mortality was significantly reduced (RR, 0.17; 95% CI, 0.03-0.94), whereas all-cause mortality did not differ significantly (RR, 0.79; 95% CI, 0.18-3.46). Adverse events that required discontinuation occurred in 3.1% of adults and none of the children, and all were reversible. No differences between once-daily and thrice-weekly administration schedules were found. CONCLUSION: Balanced against severe adverse events, PCP prophylaxis is warranted when the risk for PCP is higher than 3.5% for adults. Adverse events are less frequent in children, for whom prophylaxis might be warranted at lower PCP incidence rates.", "author" : [ { "dropping-particle" : "", "family" : "Green", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vidal", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leibovici", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Mayo Clin Proc", "edition" : "2007/09/07", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2007" ] ] }, "language" : "eng", "note" : "Green, Hefziba\nPaul, Mical\nVidal, Liat\nLeibovici, Leonard\nJournal Article\nMeta-Analysis\nReview\nUnited States\nMayo Clin Proc. 2007 Sep;82(9):1052-9.", "page" : "1052-1059", "publisher-place" : "Unit of Infectious Diseases, Rabin Medical Centre, Beilison Hospital, Petah-Tikva 49100, Israel.", "title" : "Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(77)", "plainTextFormattedCitation" : "(77)", "previouslyFormattedCitation" : "(77)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(77))Serious:small numbers of patients as study discontinued early, n=39. Study not powered to look at efficacy of atovaquone, only toxicity and safety.UndetectedNoNonolow9. Outcome: Use of CD4 or lymphocyte counts to predict risk of PJP in paediatric patients undergoing treatment for solid tumoursRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityOvergaard & Helweg-Larsen 2007 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1080/00365540601150497", "ISSN" : "0036-5548", "PMID" : "17577823", "abstract" : "A retrospective study was conducted to describe risk factors associated with Pneumocystis jiroveci pneumonia (PCP) among HIV-negative patients. During 2002-2004, 50 cases of PCP were identified at Rigshospitalet University Hospital on the basis of histology, PCR and clinical symptoms of PCP. Predisposing conditions included haematological malignancy (72%), inflammatory diseases (14%), solid organ transplantation (6%) and other conditions associated with immunodeficiency (8%). The most common treatment related risk factors were steroid usage (76%) and chemotherapy (72%). In 88% of patients who received steroids, dosage was either lowered or given as pulse-therapy in the 2 weeks preceding the onset of symptoms. Only 1 patient was on PCP prophylaxis at diagnosis and only 8 (16%) patients had previously been given PCP prophylaxis. At diagnosis, 78% of patients were lymphopenic. CD4 counts were available in 17 patients. Only 9 patients (52%) had CD4 count values below 300 cells/microl. The overall mortality attributable to PCP was 14% and was significantly associated with delayed diagnosis and treatment. Among immunocompromized HIV-negative patients, PCP should be particularly suspected in the context of steroid treatment and lymphopenia. Although low CD4 count is associated with a higher risk of PCP, the use of CD4 count as guidance for risk identification or prophylaxis among HIV-negative patients appears insufficient.", "author" : [ { "dropping-particle" : "", "family" : "Overgaard", "given" : "Ulrik M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helweg-Larsen", "given" : "Jannik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scandinavian journal of infectious diseases", "id" : "ITEM-1", "issue" : "6-7", "issued" : { "date-parts" : [ [ "2007", "1", "8" ] ] }, "language" : "en", "page" : "589-95", "publisher" : "Informa UK Ltd UK", "title" : "Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004.", "type" : "article-journal", "volume" : "39" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(32)", "plainTextFormattedCitation" : "(32)", "previouslyFormattedCitation" : "(32)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(32)CohortSerious:Retrospective, not comparative, controlled or randomised. Not seriousVery serious:only 11 (22%) patients included were children. Most diagnoses were of haematological maligancies. Inflammatory diseases, organ transplants and other non-malignant diagnoses were included.Serious:no control group or denominator given. CD4 counts only available for 17 (34%) of total cohort, Not known how many of these were children.UndetectedNo Would suggest spurious effect:Underlying diagnoses and treatments were hugely variedNolow10. Does underlying lung pathology increase the risk of PJP in paediatric patients undergoing treatment for solid tumours?RefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientqualityMaini et al 2013ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3201/eid1903.121151", "ISSN" : "1080-6059", "PMID" : "23622345", "abstract" : "After an increase in the number of reported cases of Pneumocystis jirovecii pneumonia in England, we investigated data from 2000-2010 to verify the increase. We analyzed national databases for microbiological and clinical diagnoses of P. jirovecii pneumonia and associated deaths. We found that laboratory-confirmed cases in England had increased an average of 7% per year and that death certifications and hospital admissions also increased. Hospital admissions indicated increased P. jirovecii pneumonia diagnoses among patients not infected with HIV, particularly among those who had received a transplant or had a hematologic malignancy. A new risk was identified: preexisting lung disease. Infection rates among HIV-positive adults decreased. The results confirm that diagnoses of potentially preventable P. jirovecii pneumonia among persons outside the known risk group of persons with HIV infection have increased. This finding warrants further characterization of risk groups and a review of P. jirovecii pneumonia prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Maini", "given" : "Rishma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Katherine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sheridan", "given" : "Elizabeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lamagni", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nichols", "given" : "Gordon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delpech", "given" : "Valerie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phin", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Emerging infectious diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "386-92", "title" : "Increasing Pneumocystis pneumonia, England, UK, 2000-2010.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(10)", "plainTextFormattedCitation" : "(10)", "previouslyFormattedCitation" : "(10)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(10) CohortSerious:retrospective analysis of data. Increased number of PJP cases identified may be due to increased testing. Total number of samples sent to labs for possible PJP not known. Paediatric population at risk may not be identified as they are already taking prophylaxis.Serious:Hospital admission data yielded many more cases than laboratory confirmed data (2258 versus 765). Not known how many cases may have been confirmed by cytology or by clinical and radiological findings as this data was not collected.Serious:patients with pre-existing lung disease identified as a group at risk for PJP but the age range for this group is not given.Very serious:no information on the severity of the lung disease. Not known whether increased risk applies to children with mild asthma for example.UndetectedLarge:17.5% of patients identified with PJP had pre-existing lung disease.Would increase demonstrated effect:Paediatric population at risk may not be identified as they may already be taking prophylaxisn/alow11. Outcome: Myelosuppression with co-trimoxazoleRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientQualityLindemulder & Albano 2007ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2006-1360", "ISSN" : "1098-4275", "PMID" : "17606548", "abstract" : "OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.\n\nMETHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.\n\nRESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.\n\nCONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.", "author" : [ { "dropping-particle" : "", "family" : "Lindemulder", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albano", "given" : "Edythe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "7", "1" ] ] }, "page" : "e47-51", "title" : "Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.", "type" : "article-journal", "volume" : "120" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14)", "plainTextFormattedCitation" : "(14)", "previouslyFormattedCitation" : "(14)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14)CohortSerious:Mixed, small (n=13) control group. No randomisationNot seriousSerious:only the subgroup of patients with ALL or lymphoblastic lymphoma were assessed for neutropaenia on maintenance therapy daysSerious:numbers in the group given an alternative to co-trimoxazole small (n=13) and not uniform (pentamidine or dapsone). No control group.UndetectedNoNon/aLowOhata et al 2009 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/pbc.21774", "ISSN" : "1545-5009", "abstract" : "Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.", "author" : [ { "dropping-particle" : "", "family" : "Ohata", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohta", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashii", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokimasa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ozono", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatr Blood Cancer", "edition" : "2008/09/27", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "142-144", "publisher-place" : "Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.", "title" : "Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(15)", "plainTextFormattedCitation" : "(15)", "previouslyFormattedCitation" : "(15)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(15)CohortSerious:Not comparative or controlled, small numbersNot seriousSerious:included patients with haematological malignancies, histiocytosis, immunodeficiency and metabolic disease patients undergoing HSCT. Only 102 solid tumour patients (53%). Myelosuppression as an outcome not directly or prospectively measured, only recorded as a reason for discontinuing co-trimoxazole.Serious:small number of patients, n=181. Only 1 discontinued co-trimoxazole due to myelosuppression, with no information regarding the certainty that the drug was the cause of the myelosuppression. In addition reasons for discontinuing co-trimoxazole were not clearly documented in 10 cases. Myelosuppression not directly or prospectively measured.UndetectedNo Would suggest spurious effect:no information regarding the certainty that the drug was the cause of the myelosuppression. In addition reasons for discontinuing co-trimoxazole were not clearly documented in 10 cases.n/aVery low11. Outcome: Myelosuppression with co-trimoxazoleRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionPublication biasLarge effectPlausible confoundingDose response gradientqualityWilber et al 1980 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.", "author" : [ { "dropping-particle" : "", "family" : "Wilber", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malone", "given" : "W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Diseases of Children", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1980" ] ] }, "page" : "643-648", "publisher-place" : "(Wilber, Feldman, Malone) Infect. Dis. Serv., St Jude Child. Res. Hosp., Memphis, Tenn. 38101 United States", "title" : "Chemoprophylaxis for Pneumocystis carinii pneumonitis. Outcome of unstructured delivery", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23)", "plainTextFormattedCitation" : "(23)", "previouslyFormattedCitation" : "(23)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23)CohortVery serious:not randomised or controlled. Prophylaxis given at attending oncologists discretion. Adverse events recorded by attending physician, not verified.Not seriousSerious:most patients in the study had ALL, not solid tumours. Daily prophylaxis with co-trimoxazole given.Serious:Detection of adverse reactions depended on the assessment recorded by the attending physician. Relationship between haematological abnormalities and cotrimoxazole not verified.UndetectedLargeWould suggest spurious effect:data not prospectively collected. Review of medical records may have missed cases with myelosuppression. Many other drugs given concurrently with cotrimoxazole. Detection of adverse reactions depended on the assessment recorded by the attending physician.n/aVery low12. Outcome: Increased methotrexate toxicity with co-trimoxazoleRefStudy DesignRisk of biasInconsistencyIndirectnessImprecisionFerrazzini et al 1990 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0022-3476(05)83351-7", "ISSN" : "00223476", "author" : [ { "dropping-particle" : "", "family" : "Ferrazzini", "given" : "Gianmario", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "Julla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sulh", "given" : "Hassan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chung", "given" : "Derrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griesbrecht", "given" : "Esther", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koren", "given" : "Gideon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Pediatrics", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "1990", "11" ] ] }, "page" : "823-826", "title" : "Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(58)", "plainTextFormattedCitation" : "(58)", "previouslyFormattedCitation" : "(58)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(58)CohortNot seriousNot seriousSerious:ALL patients on maintenance only. Showed increase in systemic exposure to free methotrexate when co-administered with co-trimoxazole but did not assess consequent toxicity or myelosuppression.Not serious:Increase in free mtx fraction in the serum during co-trimoxazole therapy in all patients from 37.4 +/- 11% to 52.2 +/- 6.4% (p<0.01)Relling et al 1994 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Relling", "given" : "MV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fairclough", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ayers", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crom", "given" : "WR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodman", "given" : "JH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pui", "given" : "CH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "WE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J. Clin. Oncol.", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1994", "8", "1" ] ] }, "page" : "1667-1672", "title" : "Patient characteristics associated with high-risk methotrexate concentrations and toxicity", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(59)", "plainTextFormattedCitation" : "(59)", "previouslyFormattedCitation" : "(59)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(59)CohortSerious:RetrospectiveNot seriousSerious:ALL patients undergoing high dose methotrexate. Current doses of mtx used in ALL and osteosarcoma protocols are much higher (5g/m2 and 12g/m2 respectively compared to 0.9-3.7g/m2 used in this study)Serious:small numbers of patients (n=66) may mean that significant correlations between toxic mtx levels and concurrent use of cotrimoxazole may have been missed. Concurrent use of contrimoxazole was estimated as it was prescribed 3 days/week (mon, tues, wed) so it was supposed that was that half the children received cotrimoxazole on the same day as high dose mtx but this may not be true.12. 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Clin. Oncol.", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1994", "8", "1" ] ] }, "page" : "1667-1672", "title" : "Patient characteristics associated with high-risk methotrexate concentrations and toxicity", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(59)", "plainTextFormattedCitation" : "(59)", "previouslyFormattedCitation" : "(59)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(59)UndetectedNo Would suggest spurious effect:Concurrent use of contrimoxazole was estimated as it was prescribed 3 days/week (mon, tues, wed) so it was supposed that was that half the children received cotrimoxazole on the same day as high dose mtx but this may not be true. Nonetheless all patients would have received cotrimoxazole within the same week and there may not be any difference in the increased mtx toxicity afforded by the antibiotic whether it is given on the same day or, for example, the day before.NolowAppendix G: Consensus Survey & ResultsThe following six statements were circulated to all members of the CCLG and the GDG and 55 responses were received. Respondents included paediatric oncologists, a paediatric infectious disease physician, a medical microbiologist, a paediatric advanced nurse practioner and paediatric pharmacists.Respondents were asked to choose between the following choices for each statement:I support the statementI would support the statement with modification*I do not support the statement*I do not have the experience in this area to be able to comment*If you have answered ‘I would support the statement with modification’ or ‘I do not support the statement’ please add comments below:Results:1. PJP prophylaxis should be offered to all solid tumour patients undergoing treatment that is likely to render them lymphopaenic, unless there are clear contraindications*.*For example allergy and concurrent high dose methotrexateAnswer choicesResponsesI support the statement4276.4%I would support the statement with modification*59%I do not support the statement*35.5%I do not have the experience in this area to be able to comment59%Total552. For patients intolerant of co-trimoxazole the need for any prophylaxis at all should be re-evaluated on an individual basis because alternatives are associated with increased toxicity and expense.Answer choicesResponsesI support the statement4480%I would support the statement with modification*47.3%I do not support the statement*59%I do not have the experience in this area to be able to comment23.6%Total553. Where 2nd line prophylaxis is required intravenous or inhaled pentamidine is recommended.Answer choicesResponses%I support the statement2648.2%I would support the statement with modification*916.7%I do not support the statement*1018.5%I do not have the experience in this area to be able to comment916.7%Total544. In children undergoing autologous stem cell transplant, recommence co-trimoxazole prophylaxis once neutrophil count is >1 x109/litreAnswer choicesResponses%I support the statement2953.7%I would support the statement with modification*713%I do not support the statement*59.3%I do not have the experience in this area to be able to comment1324.1%Total545. In children undergoing autologous stem cell transplant continue prophylaxis until 6 months post stem cell transplantAnswer choicesResponses%I support the statement3563.6%I would support the statement with modification*916.4%I do not support the statement*23.6%I do not have the experience in this area to be able to comment916.4%Total556. Children who are immunocompromised due to treatment for a solid malignancy should receive prophylaxis against PJP from the start of treatment until 3 months after the end of treatment as long as lymphocyte count has returned to normal.Answer choicesResponses%I support the statement3361.1%I would support the statement with modification*1018.5%I do not support the statement*35.6%I do not have the experience in this area to be able to comment814.8%Total5411. ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Edman JC, Kovacs JA, Masur H, Santi D V, Elwood HJ, Sogin ML. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. 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