Cefepime

Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase (ESBL) inhibitor. The combination of enmetazobactam with cefepime has entered clinical trials to assess safety and efficacy in patients with complicated urinary tract infections. Here, the in vitro activity of cefepime-enmetazobactam was determined for 1,993 clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa collected in the United States and Europe during 2014 and 2015. Enmetazobactam at a fixed concentration of 8 μg/ml lowered the cefepime MIC90 from 16 to 0.12 μg/ml for Escherichia coli, from >64 to 0.5 μg/ml for Klebsiella pneumoniae, from 16 to 1 μg/ml for Enterobacter cloacae, and from 0.5 to 0.25 μg/ml for Enterobacter aerogenes Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa Applying the Clinical and Laboratory Standards Institute susceptible-dose-dependent (SDD) breakpoint of 8 μg/ml to cefepime-enmetazobactam for comparative purposes resulted in cumulative inhibitions of 99.9% for E. coli, 96.4% for K. pneumoniae, 97.0% for E. cloacae, 100% for E. aerogenes, 98.1% for all Enterobacteriaceae assessed, and 82.8% for P. aeruginosa Comparator susceptibilities for all Enterobacteriaceae were 99.7% for ceftazidime-avibactam, 96.2% for meropenem, 90.7% for ceftolozane-tazobactam, 87% for cefepime (SDD breakpoint), 85.7% for piperacillin-tazobactam, and 81.2% for ceftazidime. For the subset of ESBL-producing K. pneumoniae isolates, the addition of 8 μg/ml enmetazobactam to cefepime lowered the MIC90 from >64 to 1 μg/ml, whereas the shift for 8 μg/ml tazobactam was from >64 to 8 μg/ml. Cefepime-enmetazobactam may represent a novel carbapenem-sparing option for empirical treatment of serious Gram-negative infections in settings where ESBL-producing Enterobacteriaceae are expected.

IntroductionIn the last years the rapid expansion of multidrug-resistant A. baumannii strains have become a major health problem. Efflux pumps are a group of transport proteins that contribute to the development of antibiotic resistance. The aim of this study was to evaluate the effect of the efflux pump inhibitor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on the antimicrobial action of imipenem and cefepime on clinical strains of A. baumannii.Materials and methodsA total of 49 non-duplicate clinical samples were collected during January through December of 2018 from patients hospitalized in the Hospital Regional Docente de Cajamarca. Of the 49 samples obtained, the confirmatory identification of A. baumannii was performed on 47 samples by molecular methods. The amplification of the blaOXA-51-like gene was carried out by polymerase chain reaction (PCR). The determination of the minimum inhibitory concentration (MIC) was calculated using the microdilution method in culture broth. The susceptibility to both antibiotics (cefepime and imipenem) was evaluated in the presence and absence of the inhibitor carbonyl cyanide 3-chlorophenylhydrazone (CCCP).ResultsA total of 47 strains of A. baumannii were isolated: 97.87% (46/47) were resistant to Imipenem, 2.13% (1/47) of them were classified as intermediate and none of these strains were susceptible. On the other hand, 51.06% (24/47) of isolates were resistant to cefepime; 19.15% (9/47) intermediate and 29.79% (14/47) susceptible. We considered a significant difference in antibiotic susceptibility if the MIC changed at least 4 dilutions, after the addition of the inhibitor. In the case of CCCP in addition to imipenem, 2.1% (1/47) had a significant change of 4 or more reductions in MIC, 59.6% (28/47) achieved a change equal or less than 3 dilutions and 17.0% (8/47) did not have any change. In the case of CCCP with cefepime the percentage of strains with the significant change of MIC was 8.5% (4/47). On the other hand, 53.2% (24/47) presented a reduction equal or less than 3 dilutions and 12.8% (6/47) did not show changes.ConclusionIn conclusion, our results demonstrate that the use of CCCP may improve the antibiotic effect of imipenem and cefepime on clinical strains of A. baumannii. The relevance of this study is that it provides evidence that this efflux pump inhibitor may be an alternative treatment against multidrug-resistant A. baumannii.

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized β-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried β-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes.Clinical trialsThis study is registered with ClinicalTrials.gov as NCT03840148.

We evaluated the activity of aztreonam-avibactam and comparators tested against 490 MBL-producing Enterobacterales isolates collected in 27 countries during 2019-2022. The most common MBL was NDM-1, which was detected among 307 isolates. The genes encoding NDM-5 and VIM-1 were detected among 68 and 53 isolates, respectively. Other 14 MBL-encoding genes or combinations were detected among 62 isolates. Mexico, Turkey, and Greece had the highest number of isolates (60, 59, and 57, respectively). All isolates were susceptible to aztreonam-avibactam (MIC50/90, 0.12/0.5 mg/L) when applying the EUCAST or FDA recently approved breakpoints (≤4 mg/L susceptible). Cefiderocol inhibited 66.7%/90.8% of the isolates when using EUCAST/FDA breakpoints. Cefepime-taniborbactam was active against 36.7%/55.5% of the isolates using the cefepime breakpoint for comparison purposes. Tigecycline and colistin inhibited 94.1% and 76.6% of the isolates (FDA and EUCAST breakpoints, respectively). The analysis of resistance mechanisms and genetic background of the MBL-producing isolates demonstrated genetic diversity among main species and presence of multiple resistance mechanisms including other β-lactamases, porin changes, and disruptions of efflux pump repressors. Aztreonam-avibactam was active despite the presence of these additional resistance mechanisms, but cefiderocol and cefepime-taniborbactam displayed variable activity. PBP3 YRIN and YRIK insertions were observed among 30 MBL-producing E. coli isolates. Aztreonam-avibactam MIC values ranged from 0.03 to 4 mg/L for these isolates, including an isolate carrying blaNDM-7, blaCMY-42, and porin changes. MBL-producing organisms are still considered an unmet medical need. Aztreonam-avibactam was active against this large collection of MBL-producing isolates that had elevated MIC values for many comparator agents.