cilastatin--imipenem-drug-combination 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

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

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

The Study for Monitoring Antimicrobial Resistance Trends (SMART) follows trends in resistance among aerobic and facultative anaerobic gram-negative bacilli (GNB) isolated from complicated intra-abdominal infections (cIAIs) in patients around the world.. During 2004-2009, three centralized clinical microbiology laboratories serving 59 private hospitals in three large South African cities collected 1,218 GNB from complicated intra-abdominal infections (cIAIs) and tested them for susceptibility to 12 antibiotics according to the 2011 Clinical Laboratory Standards Institute (CLSI) guidelines.. Enterobacteriaceae comprised 83.7% of the isolates. Escherichia coli was the species isolated most commonly (46.4%), and 7.6% of these were extended-spectrum β-lactamase (ESBL)-positive. The highest ESBL rate was documented for Klebsiella pneumoniae (41.2%). Overall, ertapenem was the antibiotic most active against susceptible species for which it has breakpoints (94.6%) followed by amikacin (91.9%), piperacillin-tazobactam (89.3%), and imipenem-cilastatin (87.1%), whereas rates of resistance to ceftriaxone, cefotaxime, ciprofloxacin, and levofloxacin were documented to be 29.7%, 28.7%, 22.5%, and 21.1%, respectively. Multi-drug resistance (MDR), defined as resistance to three or more antibiotic classes, was significantly more common in K. pneumoniae (27.9%) than in E. coli (4.9%; p<0.0001) or Proteus mirabilis (4.1%; p<0.05). Applying the new CLSI breakpoints for carbapenems, susceptibility to ertapenem was reduced significantly in ESBL-positive E. coli compared with ESBL-negative isolates (91% vs. 98%; p<0.05), but this did not apply to imipenem-cilastatin (95% vs. 99%; p=0.0928). A large disparity between imipenem-cilastatin and ertapenem susceptibility in P. mirabilis and Morganella morganii was documented (24% vs. 96% and 15% vs. 92%, respectively), as most isolates of these two species had imipenem-cilastatin minimum inhibitory concentrations in the 2-4 mcg/mL range, which is no longer regarded as susceptible.. This study documented substantial resistance to standard antimicrobial therapy among GNB commonly isolated from cIAIs in South Africa. With the application of the new CLSI carbapenem breakpoints, discrepancies were noted between ertapenem and imipenem-cilastatin with regard to the changes in their individual susceptibilities. Longitudinal surveillance of susceptibility patterns is useful to guide recommendations for empiric antibiotic use in cIAIs.

Topics: Anti-Bacterial Agents; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Imipenem; Intraabdominal Infections; Microbial Sensitivity Tests; Prevalence; South Africa