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A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date.

ABSTRACT: Imipenem-relebactam (I-R) is a novel beta-lactam/beta-lactamase inhibitor combination given with cilastatin. It is indicated for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and hospital-acquired or ventilator-associated bacterial pneumonia. A literature search was completed to evaluate the evidence to date of I-R. I-R has in vitro activity against multidrug-resistant organisms including carbapenem-resistant Pseudomonas aeruginosa and extended-spectrum beta-lactamase and carbapenem-resistant Enterobacterales. It was granted FDA approval following the promising results of two phase II clinical trials in patients with complicated urinary tract infections and complicated intra-abdominal infections. The most common adverse drug events associated with I-R were nausea (6%), diarrhea (6%), and headache (4%). I-R is a new beta-lactam/beta-lactamase inhibitor combination that will be most likely used for patients with multidrug-resistant gram-negative infections in which there are limited or no available alternative treatment options.

SUBMITTER: Campanella TA

PROVIDER: S-EPMC7701153 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date.

Campanella Toni A TA Gallagher Jason C JC

Infection and drug resistance 20201125

Imipenem-relebactam (I-R) is a novel beta-lactam/beta-lactamase inhibitor combination given with cilastatin. It is indicated for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and hospital-acquired or ventilator-associated bacterial pneumonia. A literature search was completed to evaluate the evidence to date of I-R. I-R has in vitro activity against multidrug-resistant organisms including carbapenem-resistant <i>Pseudomonas aeruginosa</i> and exte ...[more]

PMID: 33268997

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Project description:Pseudomonas aeruginosa is an opportunistic human pathogen and a major cause of nosocomial infections. The global spread of carbapenem-resistant strains is growing rapidly and has become a major public health challenge. Imipenem-relebactam (I/R) is a novel carbapenem-beta-lactamase inhibitor combination that can overcome carbapenem resistance. In this study, we aimed to understand the mechanism underlying resistance to imipenem and imipenem-relebactam. For this purpose, we performed a genomic comparison of 40 new clinical P. aeruginosa strains with different antibiotic sensitivity patterns as well as the presence/absence of carbapenemases. Results indicated the presence of a reduced flexible genome (15% total) mostly represented by phages and defense mechanisms against them, showing an important role in evolution and pathogenicity. We found a high diversity of antibiotic resistance genes grouped in small clusters mobilized via integrative and conjugative elements and facilitated by the high homologous recombination detected. Ortholog genes were found in several pathogenic strains from distantly related taxa in different mobile elements with a global distribution. The microdiversity found in those strains without carbapenemases did not reveal a clear pattern that could be associated with carbapenem resistance, suggesting multiple mechanisms of resistance in the core genome. Our results provide new insight into the dynamics and high genomic plasticity by which clinical strains of P. aeruginosa acquire resistance. This knowledge can be applied to other multidrug-resistant microbes to create predictive frameworks for assessing common molecular mechanisms of antibiotic resistance and integrated into new strategies for their prevention. IMPORTANCE The growing emergence and spread of carbapenem-resistant pathogens worldwide exacerbate the clinical challenge of treating these infections. Given the importance of carbapenems for the treatment of infections caused by Pseudomonas aeruginosa, this study aimed to investigate the underlying genomic properties of the clinical isolates that exhibited resistance to imipenem and imipenem-relebactam. This information will enhance our ability to forecast traits of resistant strains and design reliable treatments against this important threat. Our results provide new insight into the dynamics and high genomic plasticity by which clinical strains of P. aeruginosa acquire resistance as well as offers a methodology that can be applied to many other opportunistic pathogens with broad antibiotic resistance.

Project description:The role of novel β-lactam/β-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS) Pseudomonas aeruginosa has not been fully elucidated. This study evaluated the in vitro activity of novel β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa clinical isolates, determined how avibactam restored ceftazidime activity, and compared the activity of ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) against KPC-producing P. aeruginosa. Similar high susceptibility rates for CZA, IMR, and ceftolozane-tazobactam (88.9% to 89.8%) were found for 596 P. aeruginosa clinical isolates from 11 hospitals in China, and a higher susceptibility rate to ceftazidime than imipenem was observed (73.5% versus 63.1%). For CAZ-NS and IPM-NS isolates, susceptibility rates for CZA, ceftolozane-tazobactam, and IMR were 61.5% (75/122), 54.9% (67/122), and 51.6% (63/122), respectively. For CAZ-NS, IPM-NS but CZA-susceptible isolates, 34.7% (26/75) harbored acquired β-lactamases with KPC-2 predominant (n = 19), and 45.3% (34/75) presented overexpression of chromosomal β-lactamase ampC. Among 22 isolates carrying KPC-2 carbapenemase alone, susceptibility rates to CZA and IMR were 86.4% (19/22) and 9.1% (2/22), respectively. Notably, 95% (19/20) of IMR-nonsusceptible isolates had an inactivating mutation of oprD gene. In conclusion, CZA, ceftolozane-tazobactam, and IMR exhibit high activity against P. aeruginosa, and CZA is more active than IMR against CAZ-NS and IPM-NS isolates as well as KPC-producing P. aeruginosa. Avibactam overcomes ceftazidime resistance engendered by KPC-2 enzyme and overexpressed AmpC. IMPORTANCE The emergence of antimicrobial resistance poses a particular challenge globally, and the concept of P. aeruginosa with "difficult-to-treat" resistance (DTR-P. aeruginosa) was proposed. Here, P. aeruginosa clinical isolates were highly susceptible to three β-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The combination of KPC-2 enzyme and nonfunctional porin OprD contributed to IMR resistance in P. aeruginosa, and CZA was more active than IMR in fighting against KPC-2-producing P. aeruginosa. CZA also showed good activity against CAZ-NS and IPM-NS P. aeruginosa, primarily by inhibiting KPC-2 enzyme and overproduced AmpC, supporting the clinical use of CZA in the treatment of infections caused by DTR-P. aeruginosa.

Project description:BACKGROUND:The ?-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. METHODS:Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5-21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ?1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ?1 dose study treatment. RESULTS:Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ?65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, -27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, -46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. CONCLUSIONS:Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections. CLINICAL TRIALS REGISTRATION:NCT02452047.

Dataset Information

A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date.

Publications

A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date.

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