title: Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis.
abstract: BACKGROUND
  Nebulized antibiotics are a promising new treatment option for ventilator-associated pneumonia. However, more evidence of the benefit of this therapy is required.
  
  
  METHODS
  The Medline, Scopus, EMBASE, Biological Abstracts, CAB Abstracts, Food Science and Technology Abstracts, CENTRAL, Scielo and Lilacs databases were searched to identify randomized controlled trials or matched observational studies that compared nebulized antibiotics with or without intravenous antibiotics to intravenous antibiotics alone for ventilator-associated pneumonia treatment. Two reviewers independently collected data and assessed outcomes and risk of bias. The primary outcome was clinical cure. Secondary outcomes were microbiological cure, ICU and hospital mortality, duration of mechanical ventilation, ICU length of stay and adverse events. A mixed-effect model meta-analysis was performed. Trial sequential analysis was used for the main outcome of interest.
  
  
  RESULTS
  Twelve studies were analyzed, including six randomized controlled trials. For the main outcome analysis, 812 patients were included. Nebulized antibiotics were associated with higher rates of clinical cure (risk ratio (RR) = 1.23; 95% confidence interval (CI), 1.05 to 1.43; I(2) = 34%; D(2) = 45%). Nebulized antibiotics were not associated with microbiological cure (RR = 1.24; 95% CI, 0.95 to 1.62; I(2) = 62.5), mortality (RR = 0.90; CI 95%, 0.76 to 1.08; I(2) = 0%), duration of mechanical ventilation (standardized mean difference = -0.10 days; 95% CI, -1.22 to 1.00; I(2) = 96.5%), ICU length of stay (standardized mean difference = 0.14 days; 95% CI, -0.46 to 0.73; I(2) = 89.2%) or renal toxicity (RR = 1.05; 95% CI, 0.70 to 1.57; I(2) = 15.6%). Regarding the primary outcome, the number of patients included was below the information size required for a definitive conclusion by trial sequential analysis; therefore, our results regarding this parameter are inconclusive.
  
  
  CONCLUSIONS
  Nebulized antibiotics seem to be associated with higher rates of clinical cure in the treatment of ventilator-associated pneumonia. However, the apparent benefit in the clinical cure rate observed by traditional meta-analysis does not persist after trial sequential analysis. Additional high-quality studies on this subject are highly warranted.
  
  
  BACKGROUND
  CRD42014009116 . Registered 29 March 2014.
authors.affiliation: Cooperative Network for Research - AMIB-Net, Associação de Medicina Intensiva Brasileira, São Paulo, Brazil. fgzampieri@gmail.com.|Emergency Medicine Discipline, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. fgzampieri@gmail.com.|Intensive Care Unit, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil. fgzampieri@gmail.com.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Zampieri
authors.affiliation: Cooperative Network for Research - AMIB-Net, Associação de Medicina Intensiva Brasileira, São Paulo, Brazil. paulo_nassar@yahoo.com.br.|Emergency Medicine Discipline, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. paulo_nassar@yahoo.com.br.|Adult Intensive Care Unit, A.C. Camargo Cancer Center, São Paulo, Brazil. paulo_nassar@yahoo.com.br.
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Nassar
authors.affiliation: Cooperative Network for Research - AMIB-Net, Associação de Medicina Intensiva Brasileira, São Paulo, Brazil. dimitrigusmao@gmail.com.|Intensive Care Unit, University Hospital Prof. Edgar Santos, Universidade Federal da Bahia, Rua Augusto Viana, Salvador, 40110-910, Brazil. dimitrigusmao@gmail.com.|Programa de Pós-graduação em Medicina e Saúde (PPgMS) - Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil. dimitrigusmao@gmail.com.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Gusmao-Flores
authors.affiliation: Emergency Medicine Discipline, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. leandro.taniguchi@gmail.com.|Research and Education Institute (IEP), Hospital Sirio-Libanes, São Paulo, Brazil. leandro.taniguchi@gmail.com.
authors.forename: Leandro U
authors.initials: LU
authors.lastname: Taniguchi
authors.affiliation: Institut Clinic de Pneumologia i Cirurgia Toràcica, Servei de Pneumologia, UVIR, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Spain. atorres@clinic.ub.es.
authors.forename: Antoni
authors.initials: A
authors.lastname: Torres
authors.affiliation: Cooperative Network for Research - AMIB-Net, Associação de Medicina Intensiva Brasileira, São Paulo, Brazil. otavioranzani@yahoo.com.br.|Institut Clinic de Pneumologia i Cirurgia Toràcica, Servei de Pneumologia, UVIR, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Spain. otavioranzani@yahoo.com.br.|Amil Critical Care Group, Hospital Paulistano, São Paulo, Brazil. otavioranzani@yahoo.com.br.|Respiratory Intensive Care Unit, Pulmonary Division, Heart Institute, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil. otavioranzani@yahoo.com.br.
authors.forename: Otavio T
authors.initials: OT
authors.lastname: Ranzani
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D006801:Humans; D009330:Nebulizers and Vaporizers; D053717:Pneumonia, Ventilator-Associated / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D000900:Anti-Bacterial Agents