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Meta-Analysis
. 2016 Oct 20;10(10):CD004267.
doi: 10.1002/14651858.CD004267.pub4.

Antibiotics for ventilator-associated pneumonia

Lauren E Arthur  1 , Russell S Kizor, Adrian G Selim, Mieke L van Driel, Leonardo Seoane
Affiliations
Meta-Analysis

Antibiotics for ventilator-associated pneumonia

Lauren E Arthur et al. Cochrane Database Syst Rev. .

Abstract

Background: Ventilator-associated pneumonia (VAP) is a significant cause of morbidity and mortality, complicating the medical course of approximately 10% of mechanically-ventilated patients, with an estimated attributable mortality of 13%. To treat VAP empirically, the American Thoracic Society currently recommends antibiotic therapy based on the patients' risk of colonisation by an organism with multidrug resistance. The selection of initial antibiotic therapy in VAP is important, as inappropriate initial antimicrobial treatment is associated with higher mortality and longer hospital stay in intensive care unit (ICU) patients.While guidelines exist for the antibiotic treatment of hospital-acquired pneumonia (HAP) from the American Thoracic Society and the British Society for Antimicrobial Chemotherapy, there are many limitations in the quality of available evidence. This systematic review aimed to summarise the results of all randomised controlled trials (RCTs) that compare empirical antibiotic regimens for VAP.

Objectives: The primary objective of this review was to assess the effect of different empirical antimicrobial therapies on the survival and clinical cure of adult patients with ventilator-associated pneumonia (VAP). Secondary objectives included reporting the incidence of adverse events, new superinfections, length of hospital stay, and length of intensive care unit (ICU) stay associated with these therapies.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CINAHL and Web of Science to December 2015; we searched ClinicalTrials.gov to September 2016.

Selection criteria: Two review authors independently assessed RCTs comparing empirical antibiotic treatments of VAP in adult patients, where VAP was defined as new-onset pneumonia that developed more than 48 hours after endotracheal intubation. Physicians and researchers were not required to be blinded for inclusion in this review.

Data collection and analysis: Two review authors independently extracted study data. We pooled studies and analysed them in two ways. We examined monotherapy, or a single experimental antimicrobial drug, versus combination therapy, or multiple experimental antimicrobial drugs. We also examined carbapenem therapy versus non-carbapenem therapy.

Main results: We included 12 studies with 3571 participants. All included studies examined the empiric use of one antimicrobial regimen versus another for the treatment of adults with VAP, but the particular drug regimens examined by each study varied. There was potential for bias because some studies did not report outcomes for all participants. All but one study reported sources of funding or author affiliations with pharmaceutical companies.We found no statistical difference in all-cause mortality between monotherapy and combination therapy (N = 4; odds ratio (OR) monotherapy versus combination 0.97, 95% confidence interval (CI) 0.73 to 1.30), clinical cure (N = 2; OR monotherapy versus combination 0.88, 95% CI 0.56 to 1.36), length of stay in ICU (mean difference (MD) 0.65, 95% CI 0.07 to 1.23) or adverse events (N = 2; OR monotherapy versus combination 0.93, 95% CI 0.68 to 1.26). We downgraded the quality of evidence for all-cause mortality, adverse events, and length of ICU stay to moderate for this comparison. We determined clinical cure for this comparison to be of very low-quality evidence.For our second comparison of combination therapy with optional adjunctives only one meta-analysis could be performed due to a lack of trials comparing the same antibiotic regimens. Two studies compared tigecycline versus imipenem-cilastatin for clinical cure in the clinically evaluable population and there was a statistically significant increase in clinical cure for imipenem-cilastatin (N = 2; OR tigecycline versus imipenem-cilastatin 0.44, 95% CI 0.23 to 0.84). Of importance, this effect was due to a single study.We found no statistical difference in all-cause mortality between carbapenem and non-carbapenem therapies (N = 1; OR carbapenem versus non-carbapenem 0.59, 95% CI 0.30 to 1.19) or adverse events (N = 3; OR carbapenem versus non-carbapenem 0.78, 95% CI 0.56 to 1.09), but we found that carbapenems are associated with a statistically significant increase in the clinical cure (N = 3; OR carbapenem versus non-carbapenem 1.53, 95% CI 1.11 to 2.12 for intention-to-treat (ITT) analysis and N = 2; OR carbapenem versus non-carbapenem 2.29, 95% CI 1.19 to 4.43 for clinically evaluable patients analysis). For this comparison we downgraded the quality of evidence for mortality, and clinical cure (ITT and clinically evaluable populations) to moderate. We determined the quality of evidence for adverse events to be low.

Authors' conclusions: We did not find a difference between monotherapy and combination therapy for the treatment of people with VAP. Since studies did not identify patients with increased risk for multidrug-resistant bacteria, these data may not be generalisable to all patient groups. However, this is the largest meta-analysis comparing monotherapy to multiple antibiotic therapies for VAP and contributes further evidence to the safety of using effective monotherapy for the empiric treatment of VAP.Due to lack of studies, we could not evaluate the best antibiotic choice for VAP, but carbapenems as a class may result in better clinical cure than other tested antibiotics.

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Conflict of interest statement

Lauren E Arthur: none known. Russell S Kizor: none known. Adrian G Selim: none known. Mieke L van Driel: none known. Leonardo Seoane: none known.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 2 Clinical cure (ITT).
1.3
1.3. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 3 Clinical cure (CE).
1.4
1.4. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 4 Adverse events.
1.5
1.5. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 5 Superinfection.
1.6
1.6. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 6 Length of ICU stay.
2.1
2.1. Analysis
Comparison 2 Combination therapy with optional adjunctives, Outcome 1 All‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Combination therapy with optional adjunctives, Outcome 2 Clinical cure (ITT).
2.3
2.3. Analysis
Comparison 2 Combination therapy with optional adjunctives, Outcome 3 Clinical cure (CE).
2.4
2.4. Analysis
Comparison 2 Combination therapy with optional adjunctives, Outcome 4 Adverse events.
2.5
2.5. Analysis
Comparison 2 Combination therapy with optional adjunctives, Outcome 5 Superinfections.
3.1
3.1. Analysis
Comparison 3 Carbapenem versus non‐carbapenem, Outcome 1 All‐cause mortality.
3.2
3.2. Analysis
Comparison 3 Carbapenem versus non‐carbapenem, Outcome 2 Clinical cure (ITT).
3.3
3.3. Analysis
Comparison 3 Carbapenem versus non‐carbapenem, Outcome 3 Clinical cure (CE).
3.4
3.4. Analysis
Comparison 3 Carbapenem versus non‐carbapenem, Outcome 4 Adverse events.
3.5
3.5. Analysis
Comparison 3 Carbapenem versus non‐carbapenem, Outcome 5 Superinfections.
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References

References to studies included in this review

Alvarez Lerma 2001 {published data only (unpublished sought but not used)}
    1. Alvarez Lerma F, Serious Infections Study Group. Efficacy of meropenem as monotherapy in the treatment of ventilator‐associated pneumonia. Journal of Chemotherapy 2001;13(1):70‐81. - PubMed
Awad 2014 {published data only}
    1. Awad SS, Rodriguez AH, Chuang YC, Marjanek Z, Pareigis AJ, Reis G, et al. A phase 3 randomized double‐blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital‐acquired pneumonia. Clinical Infectious Diseases 2014;59(1):51‐61. - PMC - PubMed
Beaucaire 1999 {published data only}
    1. Beaucaire G, Nicolas MH, Martin C, Offenstadt G, Philippon A, Holzapfel L, et al. Comparative study of the association cefepime‐amikacin versus the association ceftazidime‐amikacin in the treatment of nosocomial pneumonias in ventilated patients [Etude comparative de l'association céfépime‐amikacine versus ceftazidime en association avec l'amikacine dans le traitement des pneumonies nosocomiales chez les patients ventilés]. Annales Françaises d'Anesthésie et de Réanimation 1999;18:186‐95. - PubMed
Brun‐Buisson 1998 {published data only}
    1. Brun‐Buisson C, Sollet JP, Schweich H, Brière S, Petit C. Treatment of ventilator‐associated pneumonia with piperacillin‐tazobactam/amikacin versus ceftazidime/amikacin: a multicenter, randomized controlled trial. Clinical Infectious Diseases 1998;26:346‐54. - PubMed
Damas 2006 {published data only}
    1. Damas P, Garweg C, Monchi M, Nys M, Canivet JL, Ledoux D, et al. Combination therapy versus monotherapy: a randomised pilot study on the evolution of inflammatory parameters after ventilator associated pneumonia [ISRCTN31976779]. Critical Care 2006;10(2):R52. - PMC - PubMed
Freire 2010 {published data only}
    1. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital‐acquired pneumonia. Diagnostic Microbiology and Infectious Disease 2010;68(2):140‐51. - PubMed
Heyland 2008 {published data only}
    1. Heyland DK, Dodek P, Muscedere J, Day A, Cook D, Canadian Critical Care Trials Group. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator‐associated pneumonia. Critical Care Medicine 2008;36(3):737‐44. - PubMed
Kollef 2004 {published and unpublished data}
    1. Kollef MH, Rello J, Cammarata SK, Croos‐Dabrera RV, Wunderink RG. Clinical cure and survival in Gram‐positive ventilator‐associated pneumonia: retrospective analysis of two double‐blind studies comparing linezolid with vancomycin. Intensive Care Medicine 2004;30(3):388‐94. - PubMed
    1. Rubinstein E, Cammarata S, Oliphant T, Wunderink R, Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU‐100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double‐blind, multicenter study. Clinical Infectious Diseases 2001;32(3):402‐12. - PubMed
    1. Wunderink RG, Cammarata SK, Oliphant TH, Kollef MH, Linezolid Nosocomial Pneumonia Study Group. Continuation of a randomized, double‐blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clinical Therapeutics 2003;25(3):980‐92. - PubMed
Kollef 2012 {published data only}
    1. Kollef MH, Chastre J, Clavel M, Restrepo MI, Michiels B, Kaniga K, et al. A randomized trial of 7‐day doripenem versus 10‐day imipenem‐cilastatin for ventilator‐associated pneumonia. Critical Care 2012;16(6):R218. - PMC - PubMed
Ramirez 2013 {published data only}
    1. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth‐Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high‐dosage tigecycline regimens versus imipenem‐cilastatin for treatment of hospital‐acquired pneumonia. Antimicrobial Agents and Chemotherapy 2013;57(4):1756‐62. - PMC - PubMed
Rea‐Neto 2008 {published data only (unpublished sought but not used)}
    1. Réa‐Neto A, Niederman M, Lobo SM, Schroeder E, Lee M, Kaniga K, et al. Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open‐label, multicenter study. Current Medical Research and Opinion 2008;24(7):2113‐26. - PubMed
Shorr 2005 {published data only}
    1. Shorr AF, Zadeikis N, Jackson WL, Ramage AS, Wu SC, Tennenberg AM, et al. Levofloxacin for treatment of ventilator‐associated pneumonia: a subgroup analysis from a randomized trial. Clinical Infectious Diseases 2005;40(Suppl):123‐9. - PubMed
    1. West M, Boulanger BR, Fogarty C, Tennenberg A, Wiesinger B, Oross M, et al. Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open‐label study. Clinical Therapeutics 2003;25(2):485‐506. - PubMed

References to studies excluded from this review

Amonova 2011 {published data only}
    1. Amonova DS, Ibadova DN. Clinical and bacteriological efficiency of two modes of ceftazidim and aminkacin dosing in patients with ventilator‐associated pneumonia. Likars'ka Sprava / Ministerstvo Okhorony Zdorov'ia Ukrainy 2011;1‐2:110‐7. - PubMed
Barriere 2014 {published data only}
    1. Barriere SL. The ATTAIN trials: efficacy and safety of telavancin compared with vancomycin for the treatment of hospital‐acquired and ventilator‐associated bacterial pneumonia. Future Microbiology 2014;9(3):281‐9. - PubMed
Bassetti 2007 {published data only}
    1. Bassetti M, Righi E, Fasce R, Molinari MP, Rosso R, Biagio A, et al. Efficacy of ertapenem in the treatment of early ventilator‐associated pneumonia caused by extended‐spectrum beta‐lactamase‐producing organisms in an intensive care unit. Journal of Antimicrobial Chemotherapy 2007;60(2):433‐5. - PubMed
Chastre 2008 {published data only}
    1. Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland I. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator‐associated pneumonia: a multicenter, randomized study. Critical Care Medicine 2008;36(4):1089‐96. - PubMed
Giamerellos‐Bourboulis 2008 {published data only}
    1. Giamerellos‐Bourboulis E, Pechere J, Routsi C, Plachouras D, Kollias S, Raftogiannis M, et al. Effect of clarithromycin in patients with sepsis and ventilator‐associated pneumonia. Clinical Infectious Diseases 2005;46(8):1157‐64. - PubMed
Iakovlev 2006 {published data only}
    1. Iakovlev SV, Beloborodov VB, Sidorenko SV, Iakovlev VP, Grigor'ev KB, Eliseeva EV, et al. Multicentre study of comparative efficacy of meropenem and combined regimens for empirical antibacterial therapy of severe nosocomial infections: results of clinical and pharmacoeconomic analysis. Antibiotiki i Khimioterapiia 2006;51(7):15‐27. - PubMed
Klapdor 2014 {published data only}
    1. Klapdor B, Ewig S. Ventilator associated pneumonia [Ventilator‐assoziierte Pneumonie]. Deutsche Medizinische Wochenschrift 2014;139:251‐4. - PubMed
Polk Jr 1997 {published data only}
    1. Polk HC Jr, Livingston DH, Fry DE, Malangoni MA, Fabian T, Trachtenberg LS, et al. Treatment of pneumonia in mechanically ventilated trauma patients. Results of a prospective trial. Archives of Surgery 1997;132(10):1086‐92. - PubMed

References to ongoing studies

NCT01808092 {unpublished data only}
    1. NCT01808092. A study comparing ceftazidime‐avibactam versus meropenem in hospitalized adults with nosocomial pneumonia [A phase III, randomized, multicentre, double‐blind, double‐dummy, parallel‐group comparative study to determine the efficacy, safety and tolerability of ceftazidime‐avibactam versus meropenem in the treatment of nosocomial pneumonia including ventilator‐associated pneumonia in hospitalized adults]. clinicaltrials.gov/ct2/show/NCT01808092 (first received 28 February 2013).

Additional references

Alvarez‐Lerma 1996
    1. Alvarez‐Lerma F. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU‐Acquired Pneumonia Study Group. Intensive Care Medicine 1996;22(5):387‐94. - PubMed
Atkins 2004
    1. Atkins D, Best D, Briss PA, Eccles M, Falck‐Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490. - PMC - PubMed
ATS 2005
    1. American Thoracic Society. Guidelines for the management of adults with hospital‐acquired, ventilator‐associated, and healthcare‐associated pneumonia. American Journal of Respiratory and Critical Care Medicine 2005;171(4):388‐416. - PubMed
ATS 2016
    1. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital‐acquired and ventilator‐associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Disease Society of America and the American Thoracic Society. Clinical Infectious Diseases 2016;63(5):e61‐e111. [DOI: 10.1093/cdi/ciw353] - DOI - PMC - PubMed
Chastre 2002
    1. Chastre J, Fagon JY. Ventilator‐associated pneumonia. American Journal of Respiratory and Critical Care Medicine 2002;165(7):867‐903. - PubMed
Fagon 2006
    1. Fagon JY, Rello J. Targeted antibiotic management of ventilator‐associated pneumonia. Clinical Microbiology and Infection 2006;12(Suppl 9):17‐22.
Garnacho‐Montero 2007
    1. Garnacho‐Montero J, Sa‐Borges M, Sole‐Violan J, Barcenilla F, Escoresca‐Ortega A, Ochoa M, et al. Optimal management therapy for Pseudomonas aeruginosa ventilator‐associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Critical Care Medicine 2007;35(8):1888‐95. - PubMed
GRADEpro GDT 2015 [Computer program]
    1. GRADE Working Group, McMaster University. GRADEpro GDT. Version accessed prior to 7 October 2016. Hamilton (ON): GRADE Working Group, McMaster University, 2015.
Higgins 2011
    1. Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org. Chichester: Wiley‐Blackwell.
Hozo 2005
    1. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Medical Research Methodology 2005;5:13. [http://vassarstats.net/median_range.html] - PMC - PubMed
Iregui 2002
    1. Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator‐associated pneumonia. Chest 2002;122(1):262‐8. - PubMed
Kim 1989
    1. Kim JH, Gallis HA. Observations on spiraling empiricism: its causes, allure, and perils, with particular reference to antibiotic therapy. American Journal of Medicine 1989;87(2):201‐6. - PubMed
Kollef 2005
    1. Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS. Epidemiology and outcomes of health‐care associated pneumonia: results from a large US database of culture‐positive pneumonia. Chest 2005;128(6):3854‐62. - PubMed
Kuti 2008
    1. Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator‐associated pneumonia and blood stream infection: a meta‐analysis. Journal of Critcal Care 2008;23(1):91‐100. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org. Chichester: Wiley‐Blackwell.
Liberati 2009
    1. Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD000022.pub2] - DOI - PMC - PubMed
Magill 2014
    1. Magill SS, Edwards JR, Beldavs ZG, Dumyati G, Janelle SJ, Kainer MA, et al. Prevalence of antimicrobial use in US acute care hospitals, May‐September 2011. JAMA 2014;312(14):1438‐46. - PMC - PubMed
Masterton 2008
    1. Masterton RG, Galloway A, French G, Street M, Armstrong J, Brown E, et al. Guidelines for the management of hospital‐acquired pneumonia in the UK: Report of the Working Party on Hospital‐Acquired Pneumonia of the British Society for Antimicrobial Chemotherapy. Journal of Antimicrobial Chemotherapy 2008;62(1):5‐34. - PMC - PubMed
Meslen 2013
    1. Meslen WG, Rovers MM, Groenwold R, Bergmans D, Camus C, Bauer TT, et al. Attributable mortality of ventilator‐associated pneumonia: a meta‐analysis of individual patient data from randomised prevention studies. Lancet Infectious Disease 2013;13:665‐71. - PubMed
Rello 2007
    1. Rello J. Importance of appropriate initial antibiotic therapy and de‐escalation in the treatment of nosocomial pneumonia. European Respiratory Review 2007;16:33‐9.
RevMan 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Rubinstein 2001
    1. Rubinstein E, Cammarata S, Oliphant T, Wunderink R. Linezolid (PNU‐100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double‐blind, multicenter study. Clinical Infectious Diseases 2001;32(3):402‐12. - PubMed
Schreiber 2010
    1. Schreiber MP, Chan CM, Shorr AF. Resistant pathogens in non‐nosocomial pneumonia and respiratory failure: is it time to refine the definition of health‐care‐associated pneumonia?. Chest 2010;137(6):1283‐8. - PubMed
Torres 2001
    1. Torres A, Carlet J, European Task Force on ventilator‐associated pneumonia. Ventilator‐associated pneumonia. European Respiratory Journal 2001;17(5):1034‐45. - PubMed
West 2003
    1. West M, Boulanger B, Fogarty C, Tennenberg A, Wiesinger B, Oross M, et al. Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open‐label study. Clinical Therapeutics 2003;25(2):485‐506. - PubMed
Wunderink 2003
    1. Wunderink RG, Cammarata S, Oliphant T, Kollef M. Continuation of a randomized, double‐blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clinical Therapeutics 2003;25(3):980‐92. - PubMed

References to other published versions of this review

Aarts 2003
    1. Aarts MW, Hancock JN, Heyland DK, Marshall JC. Antibiotics for ventilator‐associated pneumonia. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD004267] - DOI
Selim 2010
    1. Selim AG, Balalis G, Bhaskar B, Driel ML. Antibiotics for ventilator‐associated pneumonia. Cochrane Database of Systematic Reviews 2010, Issue 4. [DOI: 10.1002/14651858.CD004267.pub3] - DOI - PMC - PubMed

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