mk-7655 and Enterobacteriaceae-Infections

Broth microdilution was used to determine the in vitro activities of imipenem-relebactam and comparators versus 4260 Enterobacterales and 1324 Pseudomonas aeruginosa clinical isolates. Excluding Serratia marcescens, 96.7% to 100% of Enterobacterales species were susceptible to imipenem-relebactam. Susceptibility of P. aeruginosa isolates to imipenem-relebactam and imipenem was 91.3% and 59.1%, respectively.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Canada; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Genotype; Humans; Imipenem; Microbial Sensitivity Tests; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections

To evaluate the potential clinical in vitro efficacy of novel β-lactam/β-lactamase-inhibitor combinations - including imipenem-relebactam (IPM-REL) and cefepime-AAI101 (enmetazobactam) (FEP-AAI) - against contemporary multidrug-resistant (MDR) Enterobacteriaceae.. Agar-based MIC screening against MDR Enterobacteriaceae (n = 264) was used to evaluate the in vitro efficacy of IPM-REL and FEP-AAI, to compare the results with established combinations, and to investigate alternative β-lactam partners for relebactam (REL) and enmetazobactam (AAI). The inhibition activities of REL, AAI and the comparators avibactam (AVI) and tazobactam, against isolated recombinant β-lactamases covering representatives from all four Ambler classes of β-lactamases, were tested using a fluorescence-based assay.. Using recombinant proteins, all four inhibitors were highly active against the tested class A serine β-lactamases (SBLs). REL and AVI showed moderate activity against the Class C AmpC from Pseudomonas aeruginosa and the Class D OXA-10/-48 SBLs, but outperformed tazobactam and AAI. All tested inhibitors lacked activity against Class B metallo-β-lactamases (MBLs). In the presence of REL and IPM, but not AAI, susceptibility increased against Klebsiella pnuemoniae carbapenemase (KPC)-positive and OXA-48-positive isolates. Both aztreonam-AVI and ceftolozane-tazobactam were more effective than IPM-REL. In all the tested combinations, AAI was a more effective inhibitor of class A β-lactamases (ESBLs) than the established inhibitors.. The results lead to the proposal of alternative combination therapies involving REL and AAI to potentiate the use of β-lactams against clinical Gram-negative isolates expressing a variety of lactamases. They highlight the potential of novel combinations for combating strains not covered by existing therapies.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Cefepime; Drug Combinations; Enterobacteriaceae Infections; Humans; Imipenem; Microbial Sensitivity Tests; Tazobactam; Triazoles

Imipenem/relebactam, an investigational β-lactam/β-lactamase inhibitor combination for treatment of Gram-negative infections, and comparators including ceftazidime/avibactam, piperacillin/tazobactam and colistin were tested for activity against representative carbapenemase-producing Enterobacteriaceae (CPE) isolates.. MICs of the antimicrobial agents were determined using standard broth microdilution methodology for CPE isolates collected from Indiana patients, primarily during the time frame of 2013-17 (n = 199 of a total of 200 isolates). Inhibitors were tested at 4 mg/L in all combinations.. Of the CPE in the study, 199 produced plasmid-encoded KPC class A carbapenemases; 1 Serratia marcescens isolate produced the SME-1 chromosomal class A carbapenemase. MIC50/MIC90 values of imipenem/relebactam were ≤0.25/0.5 mg/L, whereas MIC50/MIC90 values of ceftazidime/avibactam were 1/2 mg/L. Resistance to colistin was observed in 54% (n = 97) of 180 non-Serratia isolates tested (MIC50 of 4 mg/L). Colistin resistance mechanisms included production of a plasmid-encoded mcr-1-like gene (n = 2) or an inactivated mgrB gene.. Imipenem/relebactam was the most potent agent tested against CPE in this study and may be a useful addition to the antimicrobial armamentarium to treat infections caused by these pathogens.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Indiana; Microbial Sensitivity Tests

Carbapenem-resistant

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacteremia; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Drug Combinations; Enterobacteriaceae Infections; Humans; Imipenem; Klebsiella pneumoniae; Microbial Sensitivity Tests

Carbapenem-resistant Enterobacteriaceae (CRE) cause significant mortality and are resistant to most antimicrobial agents. Imipenem/relebactam, a novel beta-lactam/beta-lactamase inhibitor combination, and 16 other antimicrobials were evaluated against non-metallo-beta-lactamase-producing carbapenem-resistant Enterobacteriaceae clinical isolates from a United States tertiary academic medical center.. To evaluate imipenem/relebactam and other commonly utilised antimicrobial agents against carbapenem-resistant Enterobacteriaceae.. Clinical isolates (n  = 96) resistant to ertapenem or meropenem by BD Phoenix (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and negative for metallo-beta-lactamase-production by an EDTA (Sigma-Aldrich Corp., St. Louis, MO, USA)/phenylboronic acid (Sigma-Aldrich Corp., St. Louis, MO, USA) disk diffusion assay were identified and collected from January 2012 to January 2017. In vitro susceptibility by broth microdilution was performed according to CLSI guidelines using CLSI susceptibility breakpoints for 17 antimicrobials (Sigma-Aldrich Corp., St. Louis, MO, USA).. CRE primarily produced Klebsiella pneumoniae carbapenemase (KPC) and consisted primarily of K. pneumoniae (55%) and Enterobacter spp. (25%), followed by Citrobacter spp. (10%), Escherichia coli (5%), and others (5%). CRE were most susceptible to imipenem/relebactam (100%), followed by amikacin (85%), tigecycline (82%), and polymyxin B/colistin (65%). The median reduction of imipenem minimum inhibitory concentrations (MICs) of non-MBL-producing CRE was 16-fold but ranged from 0.5 to >512-fold. The MIC50, MIC90 and MIC range of imipenem/relebactam was 0.5/4, 1/4 and 0.06/4-1/4 mg/L, respectively.. Imipenem/relebactam exhibits excellent activity against CRE that produce KPC.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Carbapenem-Resistant Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Microbial Sensitivity Tests; Tertiary Care Centers; United States

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Resistance, Microbial; Enterobacteriaceae Infections; Humans; Imipenem; Pseudomonas Infections

The β-lactamase inhibitor relebactam inactivates class A β-lactamases, including KPC-type carbapenemases, and class C β-lactamases. Relebactam combined with imipenem is in clinical development for several indications, including hospital-acquired and ventilator-associated pneumonia. Employing CLSI-defined broth microdilution methodology, we evaluated the activities of imipenem-relebactam (using imipenem MIC breakpoints) and comparators against non-Proteeae Enterobacteriaceae (n=853) and Pseudomonas aeruginosa (n=598) isolated from lower respiratory tract infection samples in 20 hospital laboratories in the United States participating in the 2015 SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Imipenem-relebactam and imipenem susceptibilities were 97.2% and 91.6% for non-Proteeae Enterobacteriaceae and 93.1% and 68.1% for P. aeruginosa. Relebactam restored imipenem susceptibility to 66.7% and 78.5% of imipenem-non-susceptible non-Proteeae Enterobacteriaceae isolates (n=72) and P. aeruginosa (n=191), respectively. Further development of imipenem-relebactam as therapy for lower respiratory tract infections is warranted given relebactam's ability to restore activity to imipenem against non-susceptible non-Proteeae Enterobacteriaceae and P. aeruginosa.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; United States