mk-7655 and Intraabdominal-Infections

On 16 July, 2019, the US Food and Drug Administration approved imipenem-cilastatin/relebactam (Recarbrio™) for the treatment of adults with complicated urinary tract infections and complicated intra-abdominal infections. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work, and is an important step forward in the management of these debilitating conditions. This article provides an overview of the body of research associated with imipenem-cilastatin/relebactam, beginning with an examination of the fundamental underpinnings of the pharmacokinetic/pharmacodynamic index. This is followed by the pharmacokinetic/pharmacodynamic work that led to the approval of this novel drug combination, including data derived from checkerboard and hollow fiber infection studies, as well as large, multi-center, phase III clinical trials known as RESTORE-IMI 1 and RESTORE-IMI 2. The article also explores how this important new antibiotic may be used to treat other infections in the years to come, including hospital-acquired bacterial pneumonia and ventilator-associated pneumonia attributed to imipenem-non-susceptible pathogens and certain atypical mycobacterial infections.

Topics: Adult; Anti-Bacterial Agents; Azabicyclo Compounds; Cilastatin, Imipenem Drug Combination; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Humans; Intraabdominal Infections

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Boronic Acids; Drug Combinations; Drug Resistance, Bacterial; Heterocyclic Compounds, 1-Ring; Humans; Imipenem; Intraabdominal Infections; Meropenem; Molecular Structure; Structure-Activity Relationship; Thienamycins

Relebactam, a novel class A/C β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin, restores imipenem activity against imipenem-nonsusceptible gram-negative pathogens.. This phase 3, multicenter, open-label, noncomparative study (NCT03293485) evaluated relebactam/imipenem/cilastatin (250 mg/500 mg/500 mg) dosed every 6 h for 5-14 days in Japanese patients with complicated intra-abdominal infections (cIAIs) or complicated urinary tract infections (cUTIs), including those with secondary sepsis. Sepsis was defined as an infection-induced systemic inflammatory response syndrome, with a documented positive blood culture; patients meeting these protocol-defined criteria were evaluated for efficacy against sepsis.. Of 83 patients enrolled, 81 patients (cIAI, n = 37; cUTI, n = 44) received ≥1 dose of study treatment. Escherichia coli was the most common baseline pathogen isolated in both patients with cIAI and cUTI. Adverse events (AEs) were reported in 74.1% (n = 60/81) of patients, and drug-related AEs occurred in 18.5% (n = 15/81). The most common AEs were diarrhea and nausea (8.6%). Serious AEs occurred in nine patients, including one death, but none were considered treatment related. The primary efficacy endpoint for patients with cIAI was clinical response at end of treatment (EOT) in the microbiologically evaluable (ME) population, and for patients with cUTI was microbiological response at EOT in the ME population. The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis (cIAI, n = 1; cUTI, n = 5) achieved a favorable composite clinical and microbiological response at EOT.. A favorable safety and efficacy profile for relebactam/imipenem/cilastatin was observed in Japanese patients with cIAI and cUTI.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cilastatin; Cilastatin, Imipenem Drug Combination; Humans; Imipenem; Intraabdominal Infections; Japan; Urinary Tract Infections

Relebactam (REL [MK-7655]) is a novel class A/C β-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were ≥18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Humans; Imipenem; Intraabdominal Infections; Male; Middle Aged; Treatment Outcome; Young Adult

β-lactam- and multi-drug-resistant (MDR) Gram-negative bacilli frequently cause lower respiratory tract infections (LRTIs) in patients housed in intensive care units (ICUs). Relebactam, a novel diazabicyclooctane inhibitor of Ambler class A and C β-lactamases, in combination with imipenem-cilastatin was approved by the US Food and Drug Administration in July 2019 for the treatment of adults with complicated intra-abdominal infections and complicated urinary tract infections. A phase III study of imipenem/relebactam for the treatment of patients with respiratory tract infections, including antimicrobial-resistant Gram-negative infections, has also been completed. The Clinical and Laboratory Standards Institute's broth microdilution methodology was used to determine minimum inhibitory concentrations against non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa collected from ICU patients with LRTIs at 26 US hospitals in 2015-2017. Percent susceptibilities to imipenem/relebactam were 97.0%, 66.4% and 98.1%, respectively, for all NPE (n=1298), imipenem-non-susceptible NPE (n=113, of which 71% were Serratia marcescens) and MDR NPE (n=206), and 92.2%, 77.2% and 79.6%, respectively, for all P. aeruginosa (n=638), imipenem-non-susceptible P. aeruginosa (n=219) and MDR P. aeruginosa (n=225). Percent susceptibilities to imipenem/relebactam were 98.0-98.6% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible NPE and 77.8-82.5% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible P. aeruginosa. Generally, only slight variations in susceptibility were observed across US census regions. Imipenem/relebactam may provide a valuable therapeutic option for the treatment of ICU patients with LRTI caused by Gram-negative bacilli resistant to commonly used β-lactams, as it demonstrated potent in-vitro activity against the majority of tested β-lactam-non-susceptible and MDR Gram-negative bacilli from ICU patients with LRTIs in US hospitals.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Enterobacteriaceae; Gram-Negative Bacteria; Humans; Imipenem; Intensive Care Units; Intraabdominal Infections; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Respiratory Tract Infections; United States; Young Adult

Imipenem/cilastatin sodium/relebactam is a combination of imipenem/cilastatin, a U.S. Food and Drug Administration (FDA)-approved antibiotic, and β-lactamase inhibitor relebactam which has been developed for the treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) due to drug-resistant bacterial pathogens. The combination (Recarbrio) has been designated as a qualified infectious disease product (QIDP) and obtained FDA approval in 2019 for the treatment of cUTI and cIAI caused by susceptible Gram-negative microorganisms in adult patients with limited or no alternative treatment options. The product was also approved by the European Medicines Agency (EMA) in 2020 for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.

Topics: Adult; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Cilastatin, Imipenem Drug Combination; Humans; Intraabdominal Infections; Urinary Tract Infections

Considering the increasing incidence of carbapenem-resistant Enterobacteriaceae in China, this study aimed to establish the in vitro effectiveness of imipenem/relebactam (IMI/REL) on clinical Enterobacteriaceae isolates derived from intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs) in China between 2015 and 2018.. In total, 8781 Enterobacteriaceae isolates from IAI, RTI, and UTI samples were collected from 22 hospitals across 7 geographic regions of China. Susceptibility to antimicrobial drugs was tested using the Clinical and Laboratory Standards Institute broth microdilution and breakpoints, and IMI/REL activity was assessed using United States Food and Drug Administration guidelines.. In 2015-2018, the most frequently identified Enterobacteriaceae species was Escherichia coli (n = 4676 [53.3%]), followed by Klebsiella pneumoniae (n = 2949 [33.6%]) and Enterobacter cloacae (n = 542 [6.2%]). The Enterobacteriaceae isolates showed 95.2% overall susceptibility to IMI/REL, of which the susceptibility rates in isolates from IAI, RTI, and UTI were 95.8%, 91.4%, and 96.6%, respectively. Overall, the susceptibilities of both intensive care unit (ICU) and non-ICU Enterobacteriaceae isolates to colistin were 92.9%, followed by IMI/REL (90.7% [95.9%]) and amikacin (83.3% [92.3%]). In addition, IMI/REL restored 66.3% susceptibility in imipenem-nonsusceptible Enterobacteriaceae.. Given their high in vitro susceptibility, Enterobacteriaceae infections in China should be considered for IMI/REL treatment, especially with isolates that are not susceptible to carbapenems.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; China; Drug Resistance, Bacterial; Enterobacteriaceae; Humans; Imipenem; Intraabdominal Infections; Microbial Sensitivity Tests; Respiratory System; United States; Urinary Tract Infections