piperidines and avibactam

Zidebactam, a bicyclo-acyl hydrazide β-lactam 'enhancer' antibiotic, in combination with cefepime (WCK 5222) is under clinical development for the treatment of resistant Gram-negative infections.. To evaluate the in vitro activity of cefepime/zidebactam and comparators against 24 220 Gram-negative bacteria.. Organisms were consecutively collected in 2018-19 from 137 medical centres located in the USA (n = 9140), Western Europe (W-EU; n = 5929), Eastern Europe (E-EU; n = 3036), the Asia-Pacific region (APAC; n = 3791) and Latin America (LATAM; n = 2324). The isolates were susceptibility tested using the broth microdilution method as part of the SENTRY Program. Cefepime/zidebactam was tested at a 1:1 ratio.. Cefepime/zidebactam was highly active against Enterobacterales (MIC50/90 0.03/0.25 mg/L; 99.9% inhibited at ≤8 mg/L) and retained potent activity against carbapenem-resistant Enterobacterales (CRE) isolates (97.8% inhibited at ≤8 mg/L). CRE rates varied widely from 1.1% in the USA to 1.9% in W-EU, 3.6% in APAC and 14.6% in E-EU (3.9% overall). The most common carbapenemase genes observed overall were blaKPC (37.6% of CRE), blaOXA-48-like (30.0%) and blaNDM (23.8%). Resistance to ceftazidime/avibactam among CRE was elevated in APAC (64.8%), E-EU (25.5%) and LATAM (20.7%). Against Pseudomonas aeruginosa, cefepime/zidebactam inhibited 99.2% of isolates at ≤8 mg/L and susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam was lowest in E-EU (83.9% and 82.0%, respectively). Cefepime/zidebactam exhibited good activity against Stenotrophomonas maltophilia (80.0% inhibited at ≤8 mg/L) and Burkholderia cepacia (89.4% inhibited at ≤8 mg/L).. Cefepime/zidebactam demonstrated potent in vitro activity against a large worldwide collection of contemporary clinical isolates of Gram-negative bacteria.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Cefepime; Ceftazidime; Cephalosporins; Cyclooctanes; Enterobacteriaceae; Gram-Negative Bacteria; Hydrazines; Lactams; Microbial Sensitivity Tests; Piperidines; Pseudomonas aeruginosa; Tazobactam

To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants.. The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies.. For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes.. Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Borinic Acids; Carboxylic Acids; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Cyclooctanes; Humans; Imipenem; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To investigate the susceptibility of imipenem-non-susceptible Escherichia coli (INS-EC), Klebsiella pneumoniae (INS-KP), Acinetobacter baumannii (INS-AB) and Pseudomonas aeruginosa (INS-PA) to novel antibiotics.. MICs were determined using the broth microdilution method. Carbapenemase and ESBL phenotypic testing and PCR for genes encoding ESBLs, AmpCs and carbapenemases were performed.. Zidebactam, avibactam and relebactam increased the respective susceptibility rates to cefepime, ceftazidime and imipenem of 17 INS-EC by 58.8%, 58.8% and 70.6%, of 163 INS-KP by 77.9%, 88.3% and 76.1% and of 81 INS-PA by 45.7%, 38.3% and 85.2%, respectively. Vaborbactam increased the meropenem susceptibility of INS-EC by 41.2% and of INS-KP by 54%. Combinations of β-lactams and novel β-lactamase inhibitors or β-lactam enhancers (BLI-BLE) were inactive against 136 INS-AB. In 58 INS-EC and INS-KP with exclusively blaKPC-like genes, zidebactam, avibactam, relebactam and vaborbactam increased the susceptibility of the partner β-lactams by 100%, 96.6%, 84.5% and 75.9%, respectively. In the presence of avibactam, ceftazidime was active in an additional 85% of 20 INS-EC and INS-KP with exclusively blaOXA-48-like genes while with zidebactam, cefepime was active in an additional 75%. INS-EC and INS-KP with MBL genes were susceptible only to cefepime/zidebactam. The β-lactam/BLI-BLE combinations were active against INS-EC and INS-KP without detectable carbapenemases. For INS-EC, INS-KP and INS-AB, tigecycline was more active than omadacycline and eravacycline but eravacycline had a lower MIC distribution. Lascufloxacin and delafloxacin were active in <35% of these INS isolates.. β-Lactam/BLI-BLE combinations were active in a higher proportion of INS-EC, INS-KP and INS-PA. The susceptibility of novel fluoroquinolones and tetracyclines was not superior to that of old ones.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Boronic Acids; Cefepime; Ceftazidime; Cyclooctanes; Drug Combinations; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Piperidines; Taiwan

The new diazabicyclooctane-based β-lactamase inhibitors avibactam and relebactam improve the

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactams; Cefepime; Cyclooctanes; Microbial Sensitivity Tests; Mycobacterium abscessus; Piperidines