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TitleINDIVIDUALIZING DURATION OF ANTIBIOTIC THERAPY IN COMMUNITY-ACQUIRED PNEUMONIASUPPLEMENTARY MATERIALData CollectionPatients’ management, laboratory analyses, and antibiotic therapy (including switch from intravenous to oral route) were performed according to the current standard of care for community-acquired pneumonia (CAP) patients and following local standard operating procedures [1]. Patients were daily assessed during their hospital stay. The following information was collected: demographics, comorbidity, radiographic, microbiological and laboratory results, as well as signs and symptoms on admission and during hospitalization, antibiotic treatment, outcomes during hospitalization and after discharge. At the follow-up visit after 30 days from the CAP diagnosis, a chest radiograph and an electrocardiogram (EKG) were performed, and blood samples were collected. A phone call was performed by one blinded investigator in each study centre 90 days after the diagnosis of CAP to assess patients’ clinical conditions.Outcome definitionsSecondary outcomes were: 1) Pneumonia-related early failure, as composite index due to pneumonia occurring within 30 days following the diagnosis of pneumonia and including any of the following criteria: a) pneumonia-related complications; b) clinical failure due to pneumonia occurring during hospitalization; c) a new antibiotic course after discontinuation of antibiotic therapy given for the pneumonia for a pneumonia relapse; d) re-hospitalization due to a pneumonia relapse; e) death due to pneumonia. 2) Days of antibiotic exposure at 30-day follow-up, including intravenous and oral antibiotic therapy given for any reason. 3) Late failure, as composite outcome occurring within 90 days following the diagnosis of pneumonia and including the following criteria: a) a new antibiotic course for any reason after discontinuation of antibiotic therapy for pneumonia; b) re-hospitalization for any reason; c) death for any reason. 4) Length of hospital stay. 5) Adverse events associated with the antibiotic treatment given for the episode of pneumonia at both 30- and 90-day follow-up after the diagnosis of pneumonia. Outcome assessmentEarly failure was assessed during the hospital stay by the blinded board if the patient was still hospitalised at day 30. Early failure was assessed by the blinded board during a follow-up visit at day 30 after the diagnosis of pneumonia with blood exams for full blood count, liver and renal function tests, and EKG if patients were discharged before day 30. Late failure was assessed with a phone call by a blinded study investigator.Other study definitionsPneumonia was defined as the evidence of a new pulmonary infiltrate seen on either CXR or computed tomography of the chest within 48 hours after hospitalization plus at least two of the following criteria: 1) new or increased cough with/without sputum production and/or purulent respiratory secretions; 2) fever (documented temperature -rectal or oral- ≥37.8 °C) or hypothermia (documented temperature –rectal or oral- <36o C); 3) deterioration of oxygen saturation; 4) evidence of systemic inflammation (such as abnormal white blood cell count -either leukocytosis (WBC >10,000/cm3) or leukopenia (WBC <4,000/cm3) - or increased C-reactive protein (CRP) or procalcitonin (PCT) values above the local upper limit of normality. CAP was defined as pneumonia occurring in any patient admitted to the hospital coming from the community and who were not hospitalised in the previous 14 days [1].Immunodeficiency was defined as the presence of at least one of the following criteria: chemotherapy or radiotherapy in the previous 12 months, transplantation, immunosuppressive treatment, haematology malignancy, HIV/AIDS with a CD4 cell count <200/mmc, asplenia.Empiric antibiotic therapy for the pneumonia was considered appropriate if prescribed within 24 hours after admission to the hospital and if was in accordance with local and/or international guidelines [1]. The following antibiotics were used in the present study: amikacin, amoxicillin/clavulanate, ampicillin/sulbactam, azithromycin, cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, claritromycin, clindamycin, imipenem/cilastatin, levofloxacin, linezolid, meropenem, metronidazole, piperacillin/tazobactam, teicoplanin, vancomycin.Severe sepsis was defined as sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following thought to be due to the infection): sepsis-induced hypotension; lactate greater than the upper limits of normal laboratory results; urine output <0.5 mL/kg hr for <2 hours, despite adequate fluid resuscitation; acute lung injury with PaO2/FiO2 <200; creatinine <2.0 mg/dL; bilirubin <2 mg/dL; platelet count <100,000; coagulopathy (INR>15) [2]. Septic shock was defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation. Sepsis induced tissue hypoperfusion was defined as either septic shock, an elevated lactate, or oliguria [2].Severe CAP was defined as the presence of 3 among the minor criteria or one among the major criteria [3]. Minor criteria: respiratory rate >30 breaths/min, PaO2/FiO2 ratio <250; multilobar infiltrates; confusion/disorientation; uremia (BUN level, >20 mg/dL); leukopenia (WBC count <4,000 cells/mm3); thrombocytopenia (platelet count <100,000 cells/mm3); hypothermia (core temperature <36 °C); hypotension requiring aggressive fluid resuscitation; hypoglycemia (in non-diabetic patients); acute alcoholism / alcoholic withdrawal; hyponatremia; unexplained metabolic acidosis or elevated lactate level; cirrhosis; asplenia. Major criteria: septic shock requiring vasopressors or acute respiratory failure requiring intubation and mechanical ventilation.Definition of clinical failureOnce the patient reached clinical stability and was enrolled in the study, his “clinical status” was defined. The presence of clinical failure was evaluated after enrolment of the patient in the study, and during hospitalization [4]. Clinical failure was identified by the presence of at least one of the following in comparison to his “clinical status” or the previous day:1) acute pulmonary deterioration with the need of either non-invasive or invasive mechanical ventilation (defined as: use of accessory muscles or paradoxical movement during breathing plus respiratory rate > 30 b/m plus PaO2/FiO2 ratio < 250 or a reduction of ≥30% of the basal PaO2/FiO2 ratio value or acute respiratory acidosis or increase of 20% of PaCO2 value if prior PaCO2 value was ≥40mmHg) or leading to either non-invasive or invasive mechanical ventilation.2) acute hemodynamic deterioration with the need of aggressive fluid resuscitation (over 40 ml/kg of colloids or crystalloids in 4-6 hours), vasopressors or invasive procedures (e.g.: pericardial drainage, electrical cardioversion).Definition of clinical failure due to pneumoniaEach failure case was presented to a clinical review committee of the single centre to examine the etiology of clinical failure. The blinded review committee was composed by at least three respiratory or infectious diseases or intensivist physicians with clinical and research experience with CAP. The members of the committee was asked to propose and discuss the cause of clinical failure. Final assignment of the cause of failure and the role of CAP in causing failure was based on the consensus of the review committee. Failure was considered related to pneumonia, if the etiology of failure was considered directly related to the pulmonary infection and its systemic inflammatory response. Failure was considered as unrelated to pneumonia, if the etiology of failure was not considered related to the pulmonary infection and its systemic inflammatory response, as previously published [4].Definition of relapse of pneumoniaRelapse of pneumonia was considered to occur when clinically stable patients after enrolment in the trial regained clinical instability (temperature >37.8 ?C; heart rate >100 beats/min; respiratory rate >24 breaths/min; systolic blood pressure <90 mm Hg; or oxygen saturation of <90% or arterial oxygen partial pressure of <60 mm Hg on room air) and developed or worsen one or more clinical manifestations of respiratory infection, not attributable to alternative causes. Definition of death due to pneumoniaDeath was considered as due to pneumonia if the etiology of death was directly related to the pulmonary infection and its systemic inflammatory response, and pneumonia was an immediate or underlying cause of death or if it played a major role in the patient’s death, as previously published [4].The underlying cause of death was defined as the disease or injury that initiate the cascade of morbid events leading directly to death. The immediate cause of death was defined as the disease process, injury, or complication immediately preceding death. If pneumonia was not considered to be the underlying or immediate cause of death, then the blinded review committee was asked to determine whether pneumonia played a major role in patient’s death. Pneumonia was judged as playing a major role if death would not have occurred if the patient did not have pneumonia but another condition was present that also contributed.Microbiological work upBased on local standard operating procedures, within 24 hours after admission and before empirical antibiotic therapy the following samples were taken: Two blood cultures at 30 minutes distance from two different sites; Sputum (Sputum was Gram-stained. Representative sputum originated from the lower respiratory tract was defined as that containing >25 polymorphonuclear cells and <10 squamous epithelial cells per low power field microscopic view (100x). Validated sputum was cultured; microorganisms were identified according to standards methods); BAS or BAL culture; Pleural effusion culture; Urinary antigens (Pneumococcal antigen detected in urine -i.e: Binax Now Streptococcus pneumoniae urinary antigen Test; Binax Inc., Portland, ME, USA-; Legionella pneumophila serogroup 1 antigen detected in urine -i.e: Binax Now Legionella antigen Test; Binax Inc., Portland, ME, USA-); Nasopharyngeal swabs (two nasopharyngeal swabs were collected from each patient, then they were diluted in physiological solution and kept at –70 °C until processing. Chromosomal DNA was extracted by a commercial kit (i.e. Roche diagnostics, Germany). PCR amplification: to confirm the extraction, each DNA sample was tested for its ability to be amplified with B-globin specific primers. Chlamydia pneumoniae. for the detection of C. Pneumoniae by nested PCR , primers that amplify 207-bp fragment of the major outer membrane protein genes (ompA) were used. Mycoplasma pneumoniae. Primers that amplify 104 bp fragment P1 protein antigen were used for the detection of Mycoplasma p. by nested PCR. Legionella pneumophila. For the detection of Legionella p. by nested PCR, primers that amplify 403-bp fragment of the macrophage infectivity potentiator protein (mip) were used. After amplification, 4% agarose gel electrophoresis and sybr safe DNA stain were used to visualise the PCR products. Specimens were also stored for microbiological analysis on viruses, including H1N1 influenza virus); Serology (Chlamydia pneumoniae: the presence of serum antibodies (IgG, IgA, IgM) was determined by the ANI Labsystems? microimmunofluorescence (MIF) test. The serum samples were considered positive when there were titers of? >1:64 for IgG antibodies and >1:16 for IgA and IgM. Mycoplasma pneumoniae: the detection of serum antibodies (IgG, IgM) was determined by an enzyme-linked immunosorbent assay (ELISA)? (Viro-Immun Labor –Diagnostika GmbH). REFERENCESWoodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, Ortqvist A, Schaberg T, Torres A, van der Heijden G, Read R, Verheij TJ; Joint Taskforce of the European Respiratory Society and European Society for Clinical Microbiology and Infectious Diseases. Guidelines for the management of adult lower respiratory tract infections. Clin Microbiol Infect 2011;17 Suppl 6:E1-59.Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296–327.Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44 Suppl 2:S27-72.Aliberti S, Amir A, Peyrani P, Mirsaeidi M, Allen M, Moffett BK, Myers J, Shaib F, Cirino M, Bordon J, Blasi F, Ramirez JA. Incidence, etiology, timing, and risk factors for clinical failure in hospitalized patients with community-acquired pneumonia. Chest 2008;134:955-62. ................
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