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Alternatives to carbapenems in ventilator-associated pneumonia due to ESBL-producing Enterobacteriaceae

2016; Elsevier BV; Volume: 73; Issue: 3 Linguagem: Inglês

10.1016/j.jinf.2016.06.006

1532-2742

Anne Boucher, Agnès Meybeck, Pierre Patoz, M. Valette, Damien Thellier, P Delannoy, Arnaud Chiche, Nicolas Boussekey, Hugues Georges, Olivier Leroy,

Antibiotic Use and Resistance

We read with interest the study recently published by Martin-Loeches et al. demonstrating the prognosis impact of multidrug-resistance in patients with ICU-acquired pneumonia.1Martin-Loeches I. Torres A. Rinaudo M. Terraneo S. de Rosa F. Ramirez P. et al.Resistance patterns and outcomes in intensive care unit (ICU)-acquired pneumonia. Validation of European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) classification of multidrug resistant organisms.J Infect. 2015; 70: 213-222Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar They reported higher ICU-mortality, and lower rate of appropriate antibiotic therapy in case of infections due to multidrug-resistant organisms despite higher carbapenem use. Wide empirical use of carbapenems justified by the increase of infections caused by extended spectrum betalactamase-producing Enterobacteriaceae (ESBL-PE) has resulted in the rapid emergence of carbapenem resistance in nosocomial gram-negative pathogens.2Melsen W.G. Rovers M.M. Groenwold R.H.H. Bergmans D.C.J.J. Camus C. Bauer T.T. et al.Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies.Lancet Infect Dis. 2013; 13: 665-671Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar In 2010, the European Committee on Antimicrobial Susceptibility Testing changed their recommendations for the interpretation of antibiograms of ESBL-PE.3Nordmann P. Naas T. Poirel L. Global spread of carbapenemase-producing enterobacteriaceae.Emerg Infect Dis. 2011; 17 (European Committee on Antimicrobial Susceptibility Testing (EUCAST 2012). Breakpoint tables for interpretation of MICs and zone diameters. Version 2.0. Available at:): 1791-1798http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST-files/Breakpoint-tables/Breakpoint-table-v-2.0-120221.pdfCrossref PubMed Scopus (1696) Google Scholar The presence of an ESBL did not influence the definition of susce.ptibility any longer, allowing treatment of infections due to ESBL-PE with betalactams. We conducted a retrospective observational study in the 16-bed ICU of the Dron Hospital in Tourcoing over a period of 5 years (1 January 2010 through 1 January 2015) in adults who have ESBL-PE ventilator-associated pneumonia (VAP) to evaluate the frequency and factors associated with the prescription of alternatives to carbapenems, define as third generation cephalosporins (3GC) or betalactam/betalactamase inhibitor (BLBLI) combinations. During the study period, 56 patients with ESBL-PE VAP were included. Table 1 shows characteristics and outcome of our patients depending on empirical antibiotic treatment. Our patients were predominantly male (71%), with median age of 62.5 years (IQR: 54–72). Forty-seven (84%) patients were colonized with ESBL-PE. Causative ESBL-PE were Klebsiella pneumoniae (n = 27), Enterobacter cloacae (n = 18), Escherichia coli (n = 9), other ESBL-PE (n = 2). All the 56 isolates displayed in vitro sensitivity to imipenem. Sixteen (29%) isolates were sensitive to at least one alternative antibiotic. Fifty patients (89%) experienced clinical cure. A relapse occurred in 5 (9%) patients. ICU-mortality rate was 39%. The outcome was not different depending on empirical treatment.Table 1Characteristics and outcome of our patients depending on empirical antibiotic treatment.Alternative empirical treatment n = 23Carbapenem empirical treatment n = 33pCharacteristics at ICU admissionMale sex (%)15 (65%)25 (76%)0.55Age (years)70.0 (41–83)61.0 (33–78)0.03Immunodepression5 (22%)7 (21%)0.99SAPS II, median (IQR)44.0 (21–60)47 (17–89)0.4SOFA, median (IQR)6.0 (0–16)8.0 (0–15)0.26Characteristics upon PAVM onsetDuration of mechanical ventilation (days), median (IQR)12.0 (2–34)16.0 (2–55)0.28Prior antibiotics, n (%)23 (100%)31 (96%)0.51SAPS II, median (IQR)39.5 (22–79)39.0 (24–115)0.64SOFA, median (IQR)5.5 (1–12)7.0 (1–19)0.39Shock15 (65%)20 (61%)0.78Prior antibiotic treatment10 (43%)14 (42%)0.99Microbiological dataPrior ESBL-PE colonization16 (70%)31 (94%)0.03Bacteremia3 (13%)5 (15%)0.99Polymicrobial infection9 (39%)12 (36%)0.99Type of Enterobacteriaceae E. coli5 (22%)4 (12%)0.46 K. pneumoniae8 (35%)19 (58%)0.11 Enterobacter sp.10 (43%)9 (27%)0.26 Citrobacter freundii01 (3%)0.99Clinical evolution after VAP Clinical cure21 (91%)29 (88%)0.99 Duration of ICU stay (days), median (IQR)15 (1–79)17 (1–96)0.3 Duration of mechanical ventilation (days), median (IQR)12 (11–79)11 (1–69)0.10 Death in ICU11 (48%)11 (33%)0.41 Acute respiratory distress syndrome2 (9%)6 (18%)0.44Microbiological evolution Surinfection3 (13%)4 (12%)0.99 Colonization10 (43%)13 (39%)0.61 Relapse3 (13%)2 (6%)0.39 Open table in a new tab The antibiotic regimens are shown in Table 2. Thirty-three patients (59%) received empirically carbapenems and 23 (41%) alternatives. Empirical antibiotic treatment was appropriate in 46 patients (82%), 33 (100%) treated with a carbapenem and 13 (57%) with an alternative (p < 0.001). Four patients died before the culture results were available. Fifty-two patients received a definitive treatment, with a carbapenem (n = 37) or an alternative (n = 15). De-escalation from carbapenem to alternative prescription was applied in 4 out of 11 patients (36%) treated empirically with carbapenems and infected with alternative-susceptible ESBL-PE. By multivariate analysis, monomicrobial infection (HR: 23.7, 95% IC: 2.51–223.7; p = 0.05), absence of ESBL-PE susceptibility to at least one alternative (HR: 17.2, 95% IC: 1.95–151.8; p = 0.01) and absence of ESBL-PE bacteremia (HR: 13.7, 95% IC: 1.42–131.9; p = 0.02) were independently associated with definitive prescription of a carbapenem. While, empirical prescription of an alternative (HR: 0.03, 95% IC: 0.00–0.3; p = 0.002) was independently associated with definitive prescription of an alternative.Table 2Empirical and definitive antibiotic treatment.Total n = 56Alternative empirical treatment n = 23Carbapenem empirical treatment n = 33Empirical antibiotherapyGuided by previous endotracheal aspirate33 (77%)15 (65%)28 (85%)Appropriate initial therapy46 (82%)13 (57%)33 (100%)Type of empirical antibiotherapy Empirical monotherapy27 (48%)14 (61%)13 (39%) Empirical combination therapy29 (52%)9 (39%)20 (61%)With aminoglycoside22814With fluoroquinolone202With colistin514Anti-staphylococcal antibiotherapy23 (41%)8 (35%)15 (45%)Definitive antibiotherapyn = 52n = 21n = 31Delay of antibiotics adjustment (days), mean (range)3 (1–6)3 (1–5)3 (1–6)De-escalation De-escalation to monotherapy20 (38%)8 (38%)12 (39%) Switch to narrow spectrum5 (10%)05 (16%)Type of definitive antibiotherapy Definitive monotherapy42 (81%)17 (81%)25 (76%)Alternative monotherapy13103Carbapenem monotherapy29722 Definitive bitherapy10 (19%)4 (19%)6 (24%)Alternative + colistin211Carbapenem with aminoglycoside330Carbapenem with fluoroquinolone101Carbapenem with colistin404 Open table in a new tab In our cohort, choice of empirical antibiotherapy had no impact on mortality and clinical cure rate. Several studies have previously evaluated efficacy of non-carbapenem alternatives for the treatment of bacteremia due to ESBL-PE. Rodriguez-Bano J et al. found no association between empirical therapy with BLBLI combination and increased mortality.4Rodriguez-Bano J. Navarro M.D. Retamar P. Picon E. Pascual A. The Extended-Spectrum Beta-Lactamases-Red Espanola de Investigacion en Patologia Infecciosa/Grupo de Estudio de Infeccion Hospitalaria Groupß-Lactam/ß-Lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum ß-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts.Clin Infect Dis. 2012; 54: 167-174Crossref PubMed Scopus (294) Google Scholar Their results were confirmed by a systematic review and meta-analysis.5Vardakas K.Z. Tansarli G.S. Rafailidis P.I. Falagas M.E. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to enterobacteriaceae producing extended-spectrum ß-lactamases: a systematic review and meta-analysis.J Antimicrob Chemother. 2012; 67: 2793-2803Crossref PubMed Scopus (277) Google Scholar On the opposite, Tamma et al. reported increased risk of mortality in blood stream infections caused by ESBL-PE treated with non-carbapenem alternatives.6Tamma P.D. Han J.H. Rock C. Harris A.D. Lautnebach E. Hsu A.J. et al.Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum beta-lactamase bacteremia.Clin Infect Dis. 2015; 60: 1319-1325Crossref PubMed Scopus (233) Google Scholar These contrasting findings can be explained by differences in term of etiological Enterobacteriaceae, in vitro susceptibilities to alternatives, and infection sources. In their conclusion, Rodriguez-Bano J et al. underlined the need for complementary data concerning difficult-to-treat infections, such as pneumonia, or infections caused by other Enterobacteriaceae than E. coli.4Rodriguez-Bano J. Navarro M.D. Retamar P. Picon E. Pascual A. The Extended-Spectrum Beta-Lactamases-Red Espanola de Investigacion en Patologia Infecciosa/Grupo de Estudio de Infeccion Hospitalaria Groupß-Lactam/ß-Lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum ß-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts.Clin Infect Dis. 2012; 54: 167-174Crossref PubMed Scopus (294) Google Scholar In the course of pneumonia, the inoculum effect induced by the high bacterial load may reduce the efficacy of BLBLI combinations. In our ICU, BLBLI combination and 3GC were administered at high doses by continuous infusion after a loading dose to improve pharmacodynamics. We found no significant impact of empirical treatment on the outcome, but the proportion of inappropriate initial treatment was significantly higher in case of empirical alternative prescription. Our study might lack sufficient statistical power to properly assess prognosis impact of empirical alternative prescription. In our cohort, definitive treatment was an alternative in 29%. After identification of ESBL-PE prescribers showed no reluctance to pursue a microbiologically or clinically effective treatment with an alternative. Moreover, de-escalation from carbapenem to alternative prescription was applied in more than one third of patients treated empirically with carbapenems and infected with alternative-susceptible ESBL-PE. De-escalation therapy has been previously evaluated in patients with VAP. The overall de-escalation rate has been reported to be 22–32%.7Kollef M.H. Morrow L.E. Niederman M.S. Leeper K.V. Anzueto A. Benz-Scott L. et al.Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia.Chest. 2006; 129: 1210-1218Crossref PubMed Scopus (246) Google Scholar, 8Joung M.K. Lee J.A. Moon S.Y. Cheong H.S. Joo E.J. Ha Y.E. et al.Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia.Crit Care. 2011; 15: R79Crossref PubMed Scopus (75) Google Scholar It was significantly lower in patients infected with resistant organisms. No previous study has specifically evaluated de-escalation rate from carbapenem to alternative in case of VAP due to ESBL-PE. But, in patients suffering from various ESBL-PE infections, de-escalation was applied in 34–48% cases.9Pilmis B. Delory T. Groh M. Weiss E. Emirian A. Lecuyer H. et al.Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) infections: are carbapenem alternatives achievable in daily practice?.Int J Infect Dis. 2015; 39: 62-67Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 10Gauzit R. Pean Y. Alfandari S. Bru J.-P. Bedos J.-P. Rabaud C. et al.Carbapenem use in French hospitals: a nationwide survey at the patient level.Int J Antimicrob Agents. 2015; 46: 707-712Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In our cohort, monomicrobial infection, lack of ESBL-PE susceptibility to alternatives and absence of bacteremia were independently associated with definitive prescription of a carbapenem. While, empirical prescription of an alternative was independently associated with definitive prescription of an alternative. Previous studies regarding the use of non-carbapenem alternatives as definitive therapy for ESBL-PE infections have also identified lack of susceptibility to alternatives, and efficiency of initial carbapenem treatment as factors associated with maintenance of carbapenem.9Pilmis B. Delory T. Groh M. Weiss E. Emirian A. Lecuyer H. et al.Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) infections: are carbapenem alternatives achievable in daily practice?.Int J Infect Dis. 2015; 39: 62-67Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 10Gauzit R. Pean Y. Alfandari S. Bru J.-P. Bedos J.-P. Rabaud C. et al.Carbapenem use in French hospitals: a nationwide survey at the patient level.Int J Antimicrob Agents. 2015; 46: 707-712Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In our cohort, the association between ESBL-PE bacteremia and definitive prescription of an alternative could be explain by stronger evidence concerning the clinical efficacy of alternatives in case of ESBL-PE blood stream infections.5Vardakas K.Z. Tansarli G.S. Rafailidis P.I. Falagas M.E. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to enterobacteriaceae producing extended-spectrum ß-lactamases: a systematic review and meta-analysis.J Antimicrob Chemother. 2012; 67: 2793-2803Crossref PubMed Scopus (277) Google Scholar, 6Tamma P.D. Han J.H. Rock C. Harris A.D. Lautnebach E. Hsu A.J. et al.Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum beta-lactamase bacteremia.Clin Infect Dis. 2015; 60: 1319-1325Crossref PubMed Scopus (233) Google Scholar Our study is the first specifically assessing the prescription of non-carbapenem alternatives in adults who suffer from ESBL-PE VAP. Despite, small sample size and retrospective design, our study suggests that empirical prescription of alternatives should be avoid in patients at risk of ESBL-PE VAP because it exposed to high proportion of inappropriate initial antibiotic therapy. But, after determination of ESBL-PE susceptibility pattern, prescription of definitive alternatives seems achievable in daily practice. Large prospective studies designed to evaluate the implementation of de-escalation strategies are needed to determine prognosis impact of definitive alternative prescription in patients with ESBL-PE VAP. All authors deny any potential conflicts of interest relevant to this article.