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A multicenter, double-blind, randomized, comparison study of the efficacy and safety of tigecycline to imipenem/cilastatin to treat complicated intra-abdominal infections in hospitalized subjects in China.

ABSTRACT: Purpose:To assess the efficacy and safety of tigecycline in treating complicated intra-abdominal infections (cIAIs) in hospitalized patients in China. Patients and methods:A Phase IV, multicenter, randomized, double-blinded, active-controlled, non-inferiority study was conducted. Hospitalized cIAI patients ?18 years of age were randomized (1:1) to receive intravenous tigecycline (initial dose 100 mg, then 50 mg q12h) or imipenem/cilastatin (500 mg/500 mg or adjusted for renal dysfunction, q6h) for 5-14 days. The primary end point was clinical response for clinically evaluable (CE) subjects at test-of-cure (TOC) assessment. Results:Four hundred and seventy subjects were randomized; 232 in the tigecycline and 231 in the imipenem/cilastatin group were treated. Tigecycline was non-inferior to imipenem/cilastatin with respect to clinical response at TOC for all CE subjects, ie, the lower bound of the two-sided 95% CI (-12.0%, -1.4%) for the treatment difference in cure rate, tigecycline (89.9%) minus imipenem/cilastatin (96.6%), was >-15%. As non-inferiority was concluded in the CE population, superiority of tigecycline over imipenem/cilastatin and superiority of imipenem/cilastatin over tigecycline were tested on the CE and the modified intent-to-treat (mITT) populations according to pre-specified statistical criteria, and neither could be demonstrated (the cure rate was 82.8% vs 88.7%, difference -6.0% [-12.8%, 0.8%], for the mITT population). The subject-level microbiological response rate at TOC for the microbiologically evaluable population was 88.0% (110/125) vs 95.3% (102/107, difference -7.3% [-15.2%, 0.5%]). Nausea, drug ineffectiveness, postoperative wound infection, vomiting, and pyrexia were the most common adverse events in tigecycline-treated subjects; pyrexia, nausea, vomiting, and increased alanine aminotransferase and aspartate aminotransferase levels were most common in imipenem/cilastatin-treated subjects; none were unanticipated. Conclusion:Tigecycline was non-inferior to imipenem/cilastatin in treating hospitalized adult patients with cIAI. Superiority of tigecycline over imipenem/cilastatin or imipenem/cilastatin over tigecycline could not be demonstrated. Safety was consistent with the known profile for tigecycline. ClinicalTrialsgov identifier:NCT01721408.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6281154 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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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:BackgroundThe prognostic role of what a surgeon observes in the abdomen of patients with complicated intra-abdominal infection (cIAI) is largely unknown. The aim of this prospective study was to systemically analyze components of the intra-abdominal view (IAV) and their association to severe complicated intra-abdominal sepsis (SCIAS) or mortality.MethodsThe study cohort consisted of adult patients with cIAI. The operating surgeon filled a paper form describing the intra-abdominal view. Demographics, operative details, and preoperative physiological status were collected. Descriptive, univariate, and multivariate statistical analyses were performed, and a new score was developed based on regression coefficients. The primary outcome was a composite outcome of SCIAS or 30-day mortality, in which SCIAS was defined as organ dysfunctions requiring intensive care unit admission.ResultsA total of 283 patients were analyzed. The primary outcome was encountered in 71 (25%) patients. In the IAV, independent risk factors for the primary outcome were fecal or bile as exudate (odds ratio (OR) 1.98, 95% confidence interval 1.05-3.73), diffuse peritonitis (OR 2.15, 1.02-4.55), diffuse substantial redness of the peritoneum (OR 5.73, 2.12-15.44), and a non-appendiceal source of cIAI (OR 11.20, 4.11-30.54). Based on these factors, an IAV score was developed and its performance analyzed. The area under the receiver operating characteristic for the IAV score was 0.81. The IAV score also correlated significantly with several outcomes and organ dysfunctions.ConclusionsThe extent of peritonitis, diffuse substantial redness of the peritoneum, type of exudate, and source of infection associate independently with SCIAS or mortality. A high IAV score associates with mortality and organ dysfunctions, yet it needs further external validation. Combining components of IAV into comprehensive scoring systems for cIAI patients may provide additional value compared to the current scoring systems.Trial registrationThe study protocol was retrospectively registered on April 4, 2016, right after the first enrolled patient at Clinicaltrials.gov database (NCT02726932).

Project description:BACKGROUND:Complicated intra-abdominal infections (cIAIs) are common in clinical practice, caused by a mixture of aerobic and anaerobic bacteria, increase the risk of mortality. Carbapenems and tigecycline (TGC) are recommended for antimicrobial therapies for cIAIs. OBJECTIVE:To compare the effectiveness and safety of different carbapenems vs TGC for the treatment of cIAIs. METHODS:PubMed, Embase, Medline (via Ovid SP) and Cochrane library databases were systematically searched. We included randomized controlled trials (RCTs) comparing different carbapenems vs TGC for the treatment of cIAIs. The pooled odds ratio (OR) with 95% credible interval (CrI) was calculated by Markov chain Monte Carlo methods. We estimated summary ORs using pairwise and network meta-analysis with random effects. RESULTS:Fifteen studies involving 6745 participants were included in the analysis. Five different carbapenems and TGC were ultimately evaluated in this study. Although, the efficacy of carbapenems and TGC by ORs with corresponding 95% CrIs had not yet reached statistical differences, the cumulative rank probability indicated that clinical treatment success from best to worst was doripenem (DOPM), meropenem (MEPM), imipenem/cilastatin (IC), biapenem (BAPM), TGC and imipenem/cilastatin/relebactam (ICRB); microbiological treatment success from best to worst was DOPM, MEPM, IC, BAPM, ICRB and TGC. As for the risk of adverse events (AEs), TGC showed higher risk of AEs compared with IC (OR = 1.53, 95% CrI = 1.02-2.41), the remain antibiotic agents from lower to higher was MEPM, IC, BAPM, DOPM, ICRB and TGC. The risk of mortality from lower to higher was BAPM, DOPM, MEPM, IC, TGC and ICRB. CONCLUSION:No differences in clinical and microbiological outcomes were observed between different carbapenems and TGC. Balancing the evidence for drug efficacy and side effects, DOPM appears to be the best available treatment for cIAIs. Therefore, it is reasonable to consider that DOPM is one of the best carbapenem monotherapy for cIAIs. MEPM and IC was also associated with higher rates of clinical and microbiological treatment success following DOPM. Empiric antimicrobial treatment of patients with cIAIs should be selected in light of the local bacterial epidemiology and patterns of resistance.

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.

Project description:BackgroundsTigecycline has a broad spectrum of antimicrobial activity and has been approved for the treatment of complicated intra-abdominal infections. However, it is debatable whether tigecycline should be used alone or in combination. This study aimed to investigate whether tigecycline plus β-lactam antibiotics (combination therapy [CT] group) are superior to tigecycline alone (monotherapy [MT] group) in non-critically ill intra-abdominal infection patients after tumor surgery.MethodsThis was a multicenter, retrospective cohort study. The primary outcome was mortality during the hospital stay. Secondary outcomes were clinical success rate, microbial eradication rate, relapse rate within one week, course of treatment, and adverse effects. Propensity score matching (PSM) was used to adjust the degree of infection before medication between the MT and CT groups. Univariate comparisons were performed using the chi-squared test for qualitative variables and Student's t-test or the Mann-Whitney U-test for continuous variables, as appropriate. Multivariate logistic regression analysis was performed to examine the relationship between antimicrobial treatments and mortality during hospitalization. The paired samples Wilcoxon test was used to compare the parameters before and after medication.ResultsIn total, 291 patients were included in the final analysis: 128 in MT group and 163 in CT group. Mortality rate was 6.25% in the MT group and 6.13% in the CT group (P = 0.97). Multivariate logistic regression model showed that carbapenem-resistant organisms (OR: 4.35, 95% CI: 2.36 ~ 61.70) and age > 65 (OR: 1.32, 95% CI:1.19 ~ 3.01) were independent risk factors for death. CT group had a shorter defervescence time (P < 0.05), with less likelihood of relapse (P < 0.05) but had a more significant effect on activated partial thromboplastin and prothrombin time.ConclusionsTigecycline plus β-lactam wasn't superior to tigecycline monotherapy for the treatment of non-critically ill patients with intra-abdominal infection. But for advanced age patients with cancer, tigecycline combination therapy maybe a better choice in terms of mortality.

Dataset Information

A multicenter, double-blind, randomized, comparison study of the efficacy and safety of tigecycline to imipenem/cilastatin to treat complicated intra-abdominal infections in hospitalized subjects in China.

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