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ESCMID Online Lecture Library © by Author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Treatment of ESBL Producers David© by Paterson author Brisbane, Australia ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Effects of ESBL producers on outcome • Meta-analysis of 16 studies – Increased mortality in patients with bacteremia due to ESBL producing bacteria (RR 1.85; 95% Cis 1.39-2.47) – Increased incidence in delay of effective treatment (RR ©5.56; by 95% author Cis 2.9-10.5) • No increase in mortality for UTI ESCMID Online Lecture Library [Schwaber & Carmeli 2007; Hyle 2005] Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Treatment Outcomes • Multivariate analysis showed that use of a carbapenem due to an ESBL-producing organism was independently associated with lower mortality. • 28 day mortality: – Carbapenems 4% (1/27) – Quinolones © by36 %author (4/11) – Cephalosporins 40% (2/5) ESCMID– BLBLIC Online 5 0Lecture% (2/4) Library Australasian Society for Infectious Diseases Clinical Research Network Carbapenems • Not inactivated by ESBLs • Lower MICs compared to other classes • Not subject to the inoculum effect • No RCTs • In no observational© by study author has the outcome been significantly better with other antibiotic ESCMIDclasses Online Lecture Library • Predominantly meropenem and imipenem Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Doripenem – Data from RCTs involving doripenem – All studies combined; all Enterobacteriaceae combined – cure rates for doripenem 73% (16/22) versus comparators 72% (21/29) – Comparators were levofloxacin (for complicated UTI); meropenem (for complicated IAI); piperacillin- tazobactam (for ©nosocomial by author pneumonia) and imipenem (also for nosocomial pneumonia) ESCMID– Doripenem (6/Online8; 75% cured) Lecture vs pip-tazo Library (13/17; 76.5%) for nosocomial pneumonia Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Ertapenem for ESBL producers? – Detroit 2005-2010 – 261 patients with BSI due to ESBL producers – In multi-variate analysis, in-hospital mortality was significantly lower among patients who received carbapenems as their consolidative therapy (14.9% vs 30%; p=0.04) versus those who received other therapy – Empiric therapy –in-hospital mortality 12% in those treated with ertapenem vs 20.4% in those treated empirically with other carbapenems (not significantly different) – Consolidative therapy© - byIn-ho spitalauthor mortality – ertapenem (6.1%; 3/49) versus other carbapenems (20/109; 18.3%) p=0.05 – Ertapenem receiving patients were more likely to have E. coli ESCMIDand be less sick Online Lecture Library [Collins 2012] Australasian Society for Infectious Diseases Clinical Research Network Ertapenem for ESBL producers? – ESBL producing E. coli BSI in Taiwan; 2005-2007 – 97 patients; 71 with monomicrobial BSI – 9 died in the first 3 days leaving 62 able to receive definitive therapy – Definitive therapy with a carbapenem was associated with lower mortality – 30 day mortality for patients treated with ertapenem was 7.4% and for those treated with meropenem/imipenem© by wasauthor 31.8%. However, ertapenem treated patients were less likely to be immunosuppressed or in septic shock at onset of ESCMIDinfection Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Ertapenem for ESBLs (3) – ESBL E. coli or Klebsiella BSI – A total of 244 patients, including 73 (29.9%) treated by ertapenem and 171 (70.1%) by either imipenem or meropenem, were included and analyzed. – 30 day mortality rates not significantly different: 17.6% for imipenem/meropenem and 16.4% for ertapenem © by author – Unlike other evaluations, ertapenem treated patients ESCMIDjust as sick andOnline not more Lecture likely to have Library E. coli [Lee 2011] Australasian Society for Infectious Diseases Clinical Research Network Ertapenem (4) – 251 patients with bacteremia caused by ESBL- producing Escherichia coli and Klebsiella pneumoniae isolates treated by a carbapenem were identified. – Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs ≤ 0.25 mg/l) were 83.8% for E. coli and 76.4% for Klebsiella – Patients infected by ertapenem-susceptible organisms (MICs ≤ 0.25 mg/l) and treated by ertapenem had a lower sepsis-related© by mortality author than those infected by ertapenem-nonsusceptible (5.3% [3/57] versus 33.3% [6/18]; P = 0.002) ESCMID Online Lecture Library [Lee 2012] Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Webster DP, Gaulton D, Woodford N, Pike R, Turton J, Perry C, Bowler ICJW © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Ertapenem - conclusions • Ertapenem is generally effective as treatment of ESBL producers, even bloodstream infections • The ertapenem MIC matters • Likely a higher rate of breakthrough infection than with other© carbapenems by author • Once daily therapy makes it suitable for ESCMIDoutpatient intravenous Online Lecture therapy Library Australasian Society for Infectious Diseases Clinical Research Network Role of cephalosporins © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Cefepime (1) • Death by Empirical therapy – cefepime alone (17/43 – 40%); cefepime alone or in combination (26/69 – 38%); carbapenem alone (5/14 – 36%); carbapenem alone or in combination 15/40 (38%) • In multivariate analysis, which included severity of illness indicators, empiric use of cefepime was associated with non-significant trend to increased mortality while empiric© by use author of carbapenem was associated with non-significant trend to decreased ESCMIDmortality Online Lecture Library [Chopra 2012] Australasian Society for Infectious Diseases Clinical Research Network Cefepime (2) • Patients who received cefepime (n = 17) as definitive therapy were more likely to have a clinical failure (odds ratio [OR] 6.2; 95% confidence interval [CI], 1.7–22.5; P = .002), microbiological failure (OR 5.5; 95% CI, 1.3–25.6; P = .04), and 30-day mortality (OR 7.1; 95% CI, 2.5–20.3; P < .001) than those who received carbapenem therapy (n = 161). • Multivariate regression revealed that a critical illness, a rapidly fatal underlying© by authordisease and definitive cefepime therapy (OR 9.9; 95% CI, 2.8–31.9; P < .001) were independently associated with 30-day crude ESCMIDmortality. Online Lecture Library [Lee 2013] Australasian Society for Infectious Diseases Clinical Research Network Cephamycins • Unlike third generation cephalosporins, the cephamycins (cefoxitin, cefotetan, cefmetazole, flomoxef etc) are not inactivated by ESBLs • A number of case© reportsby author have shown breakthrough infection with OMP deficient ESCMIDstrains Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network © by author ESCMID Online Lecture Library Australasian Society for Infectious Diseases Clinical Research Network Flomoxef • Lee 2006: 7 patients treated with flomoxef and 20 with a carbapenem: no difference in outcome • Yang 2012: 42 dialysis patients with ESBL producers in blood • Multivariate analyses revealed that flomoxef use was independently© associatedby author with increased mortality (OR, 3.52; 95% CI, 1.19–58.17) • ESCMIDRisk of compromising Online carbapenem Lecture Librarytherapy by selection of OMP deficient mutants Australasian
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