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AppendixContents TOC \o "1-3" \h \z \u Table S1. Retrieval strategy and search results in PubMed PAGEREF _Toc37002819 \h 2Table S2. Retrieval strategy and search results in Embase PAGEREF _Toc37002820 \h 2Table S3. Retrieval strategy and search results in the Cochrane Library PAGEREF _Toc37002821 \h 2Table S4. The list of excluded studies in the process of full text screening PAGEREF _Toc37002822 \h 3Table S5. Basic characteristics of all included studies PAGEREF _Toc37002823 \h 6Table S6. Risk of bias assessment for randomized controlled trial PAGEREF _Toc37002824 \h 12Table S7. Quality assessment for cohort studies PAGEREF _Toc37002825 \h 12Table S8. Risk of bias assessment for case series studies PAGEREF _Toc37002826 \h 13Table S9. Quality assessment of pharmacokinetic studies using ClinPK Statement PAGEREF _Toc37002827 \h 14Table S1. Retrieval strategy and search results in PubMedSearch termsNumber of documents1(VANCOMYCIN[MeSH Terms]) OR vancomycin[Text Word]302722neutropenia[MeSH Terms] OR neutropeni*[Text Word]619163(Hematologic neoplasms[MeSH Terms]) OR ((hematologic*[Text Word] OR haematologic*[Text Word] OR blood[Text Word]) AND (malignanc*[Text Word] OR neoplasm*[Text Word] OR cancer[Text Word]))4025724#2 OR #34540505#1 AND #41062Table S2. Retrieval strategy and search results in EmbaseSearch termsNumber of documents 1'hematologic malignancy'/exp OR 'hematologic neoplasms'/exp2,413,0982(hematologic*:ti,ab,kw OR haematologic*:ti,ab,kw OR blood:ti,ab,kw) AND (malignanc*:ti,ab,kw OR neoplasm*:ti,ab,kw OR cancer:ti,ab,kw)263,2093#1 OR #22,570,5494'neutropenia'/exp OR neutropenia:ab,ti,kw OR neutropenic:ab,ti,kw128,7085#3 OR #42,575,9006vancomycin:ab,ti,kw39,6067#5 AND #75,162Table S3. Retrieval strategy and search results in the Cochrane LibrarySearch termsNumber of documents 1MeSH descriptor: [Hematologic Neoplasms] explode all trees5442(hematologic*:ti,ab,kw OR haematologic*:ti,ab,kw OR blood:ti,ab,kw) AND (malignanc*:ti,ab,kw OR neoplasm*:ti,ab,kw OR cancer:ti,ab,kw) (Word variations have been searched)339873MeSH descriptor: [Neutropenia] explode all trees17034Neutropeni*:ti,ab,kw (Word variations have been searched)130905MeSH descriptor: [Vancomycin] explode all trees7916vancomycin:ti,ab,kw (Word variations have been searched)19877#1 or #2 or #3 or #4436398#5 or #619879#7 and #8180Table S4. The list of excluded studies in the process of full text screeningNo.Author (year)TitleJournalReason for exclusionNote1Kremery 1997Monitoring vancomycin serum concentrations in cancer patients undergoing cytotoxic chemotherapyPediatr Infect Dis JPatients did not meet the inclusion criteriaCancer patients not specified to hematological malignancy2Haeseker 2016Evaluation of Vancomycin Prediction Methods Based on Estimated Creatinine Clearance or Trough LevelsTher Drug MonitPatients did not meet the inclusion criteriaNeither hematological malignancy nor neutropenia3Omote 2009A retrospective analysis of vancomycin pharmacokinetics in Japanese cancer and non-cancer patients based on routine trough monitoring dataBiol Pharm BullPatients did not meet the inclusion criteriaSolid cancer4Bauters 2019Augmented Renal Clearance Associated with Vancomycin Clearance in Pediatric Hemato-Oncology and Stem Cell Transplantation PatientsBiology of Blood and Marrow TransplantationPatients did not meet the inclusion criteriapediatrics5Soto 1992[Initial dosage of vancomycin in neutropenic hematologic patients]Sangre (Barc)Already reportedContents in duplicate with Soto 19936Kergueris 1994Application of USC*PACK clinical programs to vancomycin in neutropenic patientsInt J Biomed ComputAlready reportedSame data and same objective from Le Normand7Jasic 2006Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancerClin Infect DisNot relevant to vancomycin dosing regimen8Monnier 2014Generic vancomycin products: Analysis of serum concentrations in patients with acute myeloid leukemiaAnnales pharmaceutiques fran?aisesNot relevant to vancomycin dosing regimen9Vergoulidou 2009Comparative evaluation of daptomycin and pharmakocinetically-guided vancomycin therapy in patients with prolonged neutropenia or haematopoietic stem cell transplantationClinical Microbiology and InfectionNot relevant to vancomycin dosing regimen10Libuit 2014Empiric vancomycin use in febrile neutropenic oncology patientsOpen Forum Infect DisNot relevant to vancomycin dosing regimen11Tattevin 2006What can we learn from studies comparing linezolid with vancomycin in neutropenic patients when vancomycin dosages are not optimized?Clin Infect DisNot relevant to vancomycin dosing regimen12Mae 2013Acute kidney injury after myeloablative cord blood transplantation in adults: The efficacy of strict monitoring of vancomycin serum trough concentrationsTransplant Infectious DiseaseNot relevant to vancomycin dosing regimen13Caroline 2012Prospective vancomycine audit in a regional centre of fight against cancerInternational Journal of Clinical PharmacyNot relevant to vancomycin dosing regimen14Hayatshahi 2010Drug utilization review of Vancomycin in febrile neutropenic patients hospitalized at a bone marrow transplantation centerInternational Journal of Hematology-Oncology and Stem Cell ResearchNot relevant to vancomycin dosing regimen15Junior 2007Analysis of vancomycin use and associated risk factors in a university teaching hospital: a prospective cohort studyBMC Infect DisNot relevant to vancomycin dosing regimen16Fernandez 1994Individualizing vancomycin dosing regimens: an evaluation of two pharmacokinetic dosing programs in critically ill patientsPharmacotherapyNot relevant to vancomycin dosing regimen17Tatsuzawa 2019Pharmacokinetic assessment of vancomycin for the management of febrile neutropenia in patients with hematologic malignancy and its difficulty:-Case reportsJapanese Pharmacology and TherapeuticsIneligible study typeCase reports18Lee 2013Individualized dosing of anti-MRSA antibiotics based on PK/PDInternational Journal of Antimicrobial AgentsIneligible study typereview19Lortholary 1997Using glycopeptides in febrile neutropenic adultsMedecine et Maladies InfectieusesIneligible study typereview20Pea 2000Optimisation of vancomycin regimen in neutropenic haematological patients with normal renal function. Multiple daily doses may be preferableClinical Drug InvestigationInsufficient clinical dataFull-text was not available and abstract couldn’t provide adequate information21Fernandez 1993Vancomycin pharmacokinetics and dosage requirements in hematologic malignanciesClin PharmInsufficient clinical dataFull-text, abstract and the corresponding author were not available22Molas 2012Vancomycin dose adjustment in oncologic and haematologic patientsInternational Journal of Clinical PharmacyInsufficient clinical dataConference abstract provides insufficient information23Toro 2017Acute renal injury and vancomycin levels in patients undergoing autologous hematopoietic stem cell transplantationBiology of Blood and Marrow TransplantationInsufficient clinical dataConference abstract provides insufficient informationTable S5. Basic characteristics of all included studies StudyCountry Study designCharacteristics of patients includedPatients with neutropenia (%)Sample sizeAge(years)Gender(M/F)Weight(kg)Renal functionGroupingType of study aGroup AGroup BHochart 2011Francesingle-center retrospective study (case series)acute myeloid leukemia patients with febrile neutropenia100%54 (67 vancomycin treatment courses, VTCs)50 ± 13.627/2773 ± 18.1 107.5 ± 35.4 ml/min NANA1O'Donnell 2011 (conference abstract)UKsingle-center retrospective study (case series)bone marrow transplant patients who experienced an episode of febrile neutropenia100%12NRNRNRNRNANA1Donovan 2012 (conference abstract)United statesretrospective study (case series)neutropenic adult patients 100%198NRNRNRNRNANA1Vazin 2012 Iranprospective study (case series)Patients in a hematology-oncology ward who received at least 3 successive doses of vancomycin and had serum vancomycin concentrations at steady state88%5836.58 ± 14.3344/1468.05 ± 12.6157/58（98.2%）bNANA1Ghehi 2013 Taghizadeh-Ghehi 2015Iransingle-center prospective study (case series)Adults receiving vancomycin for neutropenic fever after HSCT 100%4632.9 ± 12.4530/1674.8 ± 16.6102.5 ± 35.33 ml/minNANA1, 3, 5Luo 2014 CanadaSingle-center prospective study (case series)Leukemia/bonemarrow transplant outpatients (at least two doses of vancomycin)21 (42%)4854.5 (median)24/24NR77 μmol/L (median)cNANA1Vermis 2014 (conference abstract)Belgiumsingle-center retrospective study (case series)Patients with hematological malignancies72 %96 (112 VTCs)NRNRNRNRNANA1Haeseker 2014NetherlandsSingle-center prospective studyAdults received vancomycin intravenously and had at least two plasma samplesNA17159 ± 14104/67NR109 ± 72 ml/minNeutropenia (< 500/mm3): n=56Non-neutropenia:n=1152, 4, 5Choi 2017KoreaSingle-center retrospective studyadults receiving routine TDM of vancomycinNA1307Median is 54 and 56 in 2 groups728/579Median is 62.0 and 60.0 in 2 groupsMedian is 53.0 and 61.9 μmol/LNeutropenia (< 500/mm3)n=162Non-neutropenia:n=11452Al-Kofide 2009Saudi ArabiaSingle-center retrospective studyAdults receiving vancomycin therapyNA3146.4 ± 20.8NR68.0 ± 15.197.8 ± 50.8 mL/mincancer patients (proportion of patients with hematological malignanacies was 88.9%): n=18patients without cancer: n=132, 5Bury 2019The NetherlandsRetrospective matched cohort studyintravenous vancomycin therapy for ≥ 2 days and at least one available vancomycin concentration26.7%11661.4 ± 13.467/49NRMedian 92.7 mL/minNANA3, 5Izumisawa 2019Japanretrospective cohort studyAdults receiving > 3 days of vancomycin therapyNR52266.4 ±15.3 321/20155.6 ± 11.775.6 ± 32.4hematologic malignancy patients: n=261non-malignancy patients: n=2612Kureishi 1990CanadaSingle-center prospective studypatients with acute leukemia and had absolute granulocyte below 500/mm3 100%25NRNRNRNRNANA3Le Normand 1994FranceSingle-center prospective studypatients with hematologic malignancies who were neutropenic (100/mm3)100%1036.2 (range:18-50)4/664.6±10.4141.2 ± 36.2 ml/minNANA3, 4Jarkowski 2011United statesSingle-center prospective studyacute myeloid leukemia patients receiving vancomycin NR2559.12±16.2617/886.05±19.42 85.72±37.28 ml/min/1.73m2NANA3Buelga 2005SpainSingle-center retrospective studyAdult inpatients with an underlying hematological malignancy43.7%21551.5±15.9119/9664.7±11.389.4±39.2 ml/minNANA3Okada 2018JapanSingle-center retrospective studypatients undergoing allo-HSCT who received preventive treatment with vancomycinNR7549 (range: 17–69)49/2659.4 (range: 39.4–104.5)113 (range: 47–253) ml/minNANA3, 5Hirai 2016JapanSingle-center retrospective study (case series)Adults receiving intravenous vancomycin11.3%29272.0 (62.8 – 82.0) d185/10752.8 (44.6–60.6) d79.5 (57.0–110.4) d mL/minNANA4Soto 1993SpainCase seriesNeutropenic (<1000/mm3) hematological patients100%4543 ± 1821/2463 ± 1284.7 ± 32 mL/minNANA4Fernandez 2009Spainpharmacokinetic/pharmacodynamic analyses using monte carlo simulationpatients with malignant haematological diseaseNANANANANANANANA5Suzuki 2015JapanSingle-center retrospective study (case series)Hospitalized patients with hematological malignancy treated with vancomycin for febrile neutropenia100%6350.9 ± 14.243/2055.6 ± 7.9113.1 ± 40.6 ml/minNANA6Fernandez 1996SpainRandomized controlled trialImmunocompromised febrile adults with hematologic malignancies and received vancomycin100%7753.1 ± 16.750/2063.7 ± 11.675.7 ± 25.0 μmol/LA one-compartment pharmacokinetic model was used for pharmacokinetic interpretation of serum vancomycin concentrationsInitial: a published nomagramDose adjustment: Non-intervention6Abbreviations: NA, not applicable; NR, not reported; HSCT, hematopoietic stem cell transplantation; VTC, vancomycin treatment coursea Type of study: 1. Clinical audit of vancomycin dosing; 2. Comparative pharmacokinetic studies; 3. Development of pharmacokinetic/population pharmacokinetic models; 4. The potential effect of neutropenia on creatinine clearance calculated by Cockroft-Gault formula; 5. Optimization of initial vancomycin dosage regimen; 6. Evaluation and implementation of vancomycin TDMb, Proportion of patients with normal renal functionc, the median of serum creatinine;d, median (interquartile range)Table S6. Risk of bias assessment for randomized controlled trialRandom sequence generationAllocation concealmentBlinding of participants and personnelBlinding of outcome assessmentIncomplete outcome dataSelective reportingOther biasFernandez 1996Low riskLow riskHigh riskHigh riskLow riskUnclearUnclearTable S7. Quality assessment for cohort studiesStudySelectionComparabilityOutcomeRepresentativeness of the exposed cohortSelection of the non exposed cohortAscertainment of exposureDemonstration that outcome of interest was not present at start of study aComparability of cohorts on the basis of the design or analysisAssessment of outcomeWas follow-up long enough for outcomes to occur aAdequacy of follow up of cohortsHaeseker 2014☆☆☆☆☆☆☆☆8Choi 2017☆☆☆☆0☆☆☆7AI-Kofide 2009☆☆☆☆00☆☆6Izumisawa 2019☆☆☆☆☆☆☆☆8a The outcome of these studies is pharmacokinetic parameter, which will not be affected by the item.Table S8. Risk of bias assessment for case series studiesStudyQ1Q2Q3Q4Q5Q6Q7Q8Q9Quality ratingHochart 2011YesYesYesYesYesNoYesNAYesFairVazin 2012YesYesYesNoNoYesYesNAYesFairGhehi 2013,Ghehi 2015YesYesYesYesYesYesYesYesYesGoodLuo 2014YesYesYesNoYesYesNRNAYesFairHirai 2016YesYesYesNoNoYesYesYesYesFairSoto 1993YesCDYesYesYesYesYesYesYesGoodSuzuki 2015YesYesYesYesNoYesYesYesYesFairAbbreviations: CD, cannot determine; NA, not applicable; NR, not reportedQ1. Was the study question or objective clearly stated?Q2. Was the study population clearly and fully described, including a case definition?Q3. Were the cases consecutive?Q4. Were the subjects comparable?Q5. Was the intervention clearly described?Q6. Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants?Q7. Was the length of follow-up adequate?Q8. Were the statistical methods well-described?Q9. Were the results well-described?Table S9. Quality assessment of pharmacokinetic studies using ClinPK StatementChecklist ItemGhehi 2013Kureishi 1990Le Normand 1994Jarkowski 2011Buelga 2005Okada 2018Bury 2019Title/Abstract1. The title identifies the drug(s) and patient population(s) studied.YesYesYesYesYesYesYes2. The abstract minimally includes the name of the drug(s) studied, the route of administration, the population in whom it was studied, and the results of the primary objective and major clinical pharmacokinetic findings.YesPartiallyYesYesYesYesPartiallyBackground3. Pharmacokinetic data (i.e., absorption, distribution, metabolism, excretion) that is known and relevant to the drugs being studied is describedYesNoNoYesYesYesYes4. An explanation of the study rationale is providedYesYesYesYesYesYesYes5. Specific objectives or hypotheses is providedYesYesYesYesYesYesYesMethods6. Eligibility criteria of study participants are describedYesYesYesYesYesYesYes7. Co-administration (or lack thereof) of study drug(s) with other potentially interacting drugs or food within this study is described.NANANANANANANA8. Drug preparation and administration characteristics including dose, route, formulation, infusion duration (if applicable) and frequency are described.PartiallyYesYesYesYesYesPartially9. Body fluid or tissue sampling (timing, frequency and storage) for quantitative drug measurement is described.YesYesYesYesYesYesNo10. Validation of quantitative bioanalytical methods used in the study are referenced or described if applicable.YesYesYesYesYesYesYes11. Pharmacokinetic modeling methods and software used are described, including assumptions made regarding the number of compartments and order of kinetics (zero, first or mixed order).YesYesYesYesYesYesYes12. For population pharmacokinetic studies, covariates incorporated into pharmacokinetic models are identified and described.NANANANAYesYesYes13. Formulas for calculated variables (such as creatinine clearance, body surface area, AUC, and adjusted body weight) are provided or referenced.YesYesYesYesYesYesYes14. The specific body weight used in drug dosing and pharmacokinetic calculations are reported (i.e., ideal body weight vs. actual body weight vs. adjusted body weight)NoYesYesYesYesYesYes15. Statistical methods including software used are describedNANAYesYesYesYesYesResults16. Study withdrawals or subjects lost to follow- up (or lack thereof) are reported.YesNoYesYesYesYesYes17. Quantification of missing or excluded data is provided if applicable.YesNoYesYesYesYesYes18. All relevant variables that may explain inter- and intra-patient pharmacokinetic variability (including: age, sex, end-organ function, ethnicity, weight or BMI, health status or severity of illness, and pertinent co-morbidities) are provided with appropriate measures of variance.YesNoYesYesYesYesYes19. Results of pharmacokinetic analyses are reported with appropriate measures of precision (such as range or 95% confidence intervals)YesYesYesYesYesYesYes20. Studies in patients receiving extracorporeal drug removal (i.e., dialysis) should report the mode of drug removal, type of filters used, duration of therapy and relevant flow rates.NANANANANANANA21. In studies of drug bioavailability comparing two formulations of the same drug, F (bioavailability), AUC, Cmax (maximal concentration) and Tmax (time to maximal concentration) should be reported. NANANANANANANADiscussion/Conclusion22. Study limitations describing potential sources of bias and imprecision where relevant should be describedYesNoNoNoNoYesYes23. The relevance of study findings (applicability, external validity) is describedYesNoNoYesYesYesYesOther Information24. Funding sources and conflicts of interest for the authors are disclosed.NoNoNoNoNoYesNoNA, not applicable ................
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