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A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia.

ABSTRACT: The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0).Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome.ClinicalTrials.gov: NCT00589693.

SUBMITTER: Kollef MH

PROVIDER: S-EPMC3672596 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia.

Kollef Marin H MH Chastre Jean J Clavel Marc M Restrepo Marcos I MI Michiels Bart B Kaniga Koné K Cirillo Iolanda I Kimko Holly H Redman Rebecca R

Critical care (London, England) 20121113 6

<h4>Introduction</h4>The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.<h4>Methods</h4>This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).< ...[more]

PMID: 23148736

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Project description:BackgroundImipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP).MethodsThis was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population.ResultsOf 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively.ConclusionsImipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients.Clinical trials registrationNCT02493764.

Project description:IntroductionVentilator-associated pneumonia (VAP) is associated with increased medical resource utilization, but few randomized studies have been conducted to evaluate the effect of initial antibiotic therapy. To assess medical resource utilization in patients with VAP, we conducted a pooled analysis of two prospective, randomized, open-label, multicenter, phase III studies, which also showed that doripenem was clinically noninferior to comparators.MethodsWe assessed durations of mechanical ventilation, intensive care unit (ICU) stay, and hospitalization in patients with VAP who received at least 1 dose of doripenem or a comparator in the phase III studies. Comparators were piperacillin/tazobactam (study 1) and imipenem (study 2). We analyzed between-group differences in medical resource utilization endpoints by comparison of Kaplan-Meier curves with generalized Wilcoxon test and in microbiologic eradication rates by two-sided Fisher's exact test.Results625 patients with VAP were evaluated and received at least 1 dose of doripenem (n = 312) or a comparator (n = 313). Median durations of mechanical ventilation (7 versus 10 days; P = 0.008) and hospitalization (22 versus 26 days; P = 0.010) were shorter for doripenem than comparators; corresponding ICU stays were 12 and 13 days (P = 0.065). All-cause, overall mortality rates were similar (51/312 [16%] versus 47/313 [15%]; P = 0.648). MIC90 values against Pseudomonas aeruginosa for doripenem versus imipenem were 4 versus 16 microg/mL in study 2. P. aeruginosa was eradicated from 16/24 (67%) doripenem recipients and 10/24 (42%) comparator recipients (P = 0.147). In patients with P. aeruginosa at baseline, median durations of mechanical ventilation (7 versus 13 days; P = 0.031) and ICU stay (13 versus 21 days; P = 0.027) were shorter for doripenem; corresponding hospital stays were 24 and 35 days (P = 0.129).ConclusionsDoripenem was associated with lower medical resource utilization than comparators. Differences in antipseudomonal activity may have contributed to these findings.Trial registrationClinicalTrials.gov number NCT00211003 (study 1) and NCT00211016 (study 2).

Project description:The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).

Project description:BackgroundTigecycline, a first-in-class broad-spectrum glycylcycline antibiotic, has broad-spectrum in vitro activity against bacteria commonly encountered in complicated intra-abdominal infections (cIAIs), including aerobic and facultative Gram-positive and Gram-negative bacteria and anaerobic bacteria. In the current trial, tigecycline was evaluated for safety and efficacy vs. imipenem/cilastatin in hospitalized Chinese patients with cIAIs.MethodsIn this phase 3, multicenter, open-label study, patients were randomly assigned to receive IV tigecycline or imipenem/cilastatin for </=2 weeks. The primary efficacy endpoints were clinical response at the test-of-cure visit (12-37 days after therapy) for the microbiologic modified intent-to-treat and microbiologically evaluable populations. Because the study was not powered to demonstrate non-inferiority between tigecycline and imipenem/cilastatin, no formal statistical analysis was performed. Two-sided 95% confidence intervals (CIs) were calculated for the response rates in each treatment group and for differences between treatment groups for descriptive purposes.ResultsOne hundred ninety-nine patients received >/=1 dose of study drug and comprised the modified intent-to-treat population. In the microbiologically evaluable population, 86.5% (45 of 52) of tigecycline- and 97.9% (47 of 48) of imipenem/cilastatin-treated patients were cured at the test-of-cure assessment (12-37 days after therapy); in the microbiologic modified intent-to-treat population, cure rates were 81.7% (49 of 60) and 90.9% (50 of 55), respectively. The overall incidence of treatment-emergent adverse events was 80.4% for tigecycline vs. 53.9% after imipenem/cilastatin therapy (P < 0.001), primarily due to gastrointestinal-related events, especially nausea (21.6% vs. 3.9%; P < 0.001) and vomiting (12.4% vs. 2.0%; P = 0.005).ConclusionsClinical cure rates for tigecycline were consistent with those found in global cIAI studies. The overall safety profile was also consistent with that observed in global studies of tigecycline for treatment of cIAI, as well as that observed in analyses of Chinese patients in those studies; no novel trends were observed.Trial registrationClinicalTrials.gov NCT00136201.

Project description:Abstract Background Clinical trials of new antibacterial agents in patients with carbapenem-resistant infections are critical but challenging to conduct. One challenge is identifying the study population by microbiological (micro) criteria; patients need to be identified locally to initiate effective treatment rapidly, but data standardization requires central laboratory confirmation. REL is a novel ?-lactamase inhibitor that can restore imipenem activity against many imipenem-NS Gram-negative pathogens. Here we compare a supplemental analysis population based on local microbiology data (SmMITT eligibility) with the primary analysis population (mMITT) from the RESTORE-IMI 1 trial (NCT02452047) of IMI/REL vs. IMI+CST. Methods Randomized, active-controlled, double-blind, phase 3 trial enrolled adults with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI). Patients were mMITT-eligible if pathogens were imipenem-NS (but CST- and IMI/REL-susceptible) based on central laboratory minimum inhibitory concentration (MIC). SmMITT comprised mMITT plus all patients who met inclusion criteria only based on local laboratory MIC. Results The SmMITT population (n = 41 [28 IMI/REL; 13 IMI+CST]) comprised 31 from mMITT plus 10 based on local MIC; 12/41 (29%) had HABP/VABP, 8/41 (20%) cIAI, and 21/41 (51%) cUTI. The majority of differences in central vs. local MIC were 1–2 dilutions; similar numbers of patients were excluded from mMITT due to imipenem susceptibility (n = 5) or IMI/REL-NS (n = 4); 1 patient was CST-NS. Baseline characteristics, including infecting pathogens, were comparable in SmMITT and mMITT (SmMITT: 68% male; 46% ?65 y; 24% APACHE II score >15; 22% creatinine clearance <60 mL/minute). Rates of efficacy outcomes (overall response, day 28 clinical response, day 28 mortality) were comparable between populations, except that response rates in patients with cIAI were higher in SmMITT (table). Conclusion Consistency of results was demonstrated across two analysis populations in a trial of resistant pathogens. This analysis provides results supportive of expected future clinical use of IMI/REL when treatment decisions will be made based on local laboratory results. Disclosures K. Kaye, Merck & Co., Inc.: Consultant and Research Contractor, Research grant. Melinta, Achaogen, Allergan: Consultant, Consulting fee. T. File, Bio Merieux, Curetis, Melinta, Merck, MotifBio, Nabriva, Paratek, Pfizer: Consultant, Consulting fee. H. W. Boucher, Merck & Co., Inc.: Scientific Advisor, Consulting fee. M. Brown, Merck & Co., Inc.: Employee, Salary. A. Aggrey, Merck & Co., Inc.: Employee, Salary. I. Khan, Merck & Co., Inc.: Employee, Salary. H. K. Joeng, Merck & Co., Inc.: Employee, Salary. R. Tipping, Merck & Co., Inc.: Employee, Salary. J. Du, Merck & Co., Inc.: Employee, Salary. K. Young, Merck & Co., Inc.: Employee, Salary and Stock options. J. Butterton, Merck & Co., Inc.: Employee, Salary and Stock. N. A. Kartsonis, Merck & Co., Inc.: Employee, Salary and Stocks. A. Paschke, Merck & Co., Inc.: Employee and Shareholder, Salary.

Dataset Information

A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia.

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A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia.

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