Activity of ertapenem/zidebactam (WCK 6777) against problem Enterobacterales.

BACKGROUND: Secondary healthcare will remain pressured for some years, both because SARS-CoV-2 will circulate as a nosocomial pathogen, and owing to backlogs of patients awaiting delayed elective procedures. These stresses will drive the use of Outpatient Parenteral Antibiotic Therapy (OPAT), which will need to cover increasingly resistant Gram-negative opportunists. We evaluated the activity of ertapenem/zidebactam, proposed for 2 + 2 g q24h administration. MATERIALS AND METHODS: MICs were determined, by BSAC agar dilution, for 1632 Enterobacterales submitted to the UK national reference laboratory for investigation of antimicrobial resistance. RESULTS: Over 90% of Escherichia coli with AmpC, ESBLs, KPC, metallo- or OXA-48 carbapenemases were inhibited by ertapenem/zidebactam 1:1 at ertapenem's current 0.5 mg/L breakpoint. For other major Enterobacterales, the proportions inhibited by ertapenem/zidebactam 1:1 at 0.5 mg/L were mostly 65% to 90% but were lower for Klebsiella pneumoniae/oxytoca with metallo- or OXA-48 ß-lactamases. However, animal studies support an 8 mg/L breakpoint for ertapenem/zidebactam, based on a shortened T>MIC being needed compared with ertapenem alone. On this basis ertapenem/zidebactam would count as active against 90%-100% of isolates in all groups except K. pneumoniae/oxytoca with MBLs (±OXA-48), where MICs and percent susceptibility vary substantially even with inocula within the BSAC acceptable range. CONCLUSIONS: Ertapenem/zidebactam has a proposed once-daily regimen well suited to OPAT. Even on highly conservative breakpoint projections, it has potential against MDR E. coli, including metallo-carbapenemase producers. If trial data sustain the 8 mg/L breakpoint indicated by animal experiments, its potential will extend widely across infections due to ESBL-, AmpC- and carbapenemase-producing Enterobacterales.

Activity of cefepime/zidebactam (WCK 5222) against 'problem' antibiotic-resistant Gram-negative bacteria sent to a national reference laboratory.

BACKGROUND: Triple-action diazabicyclooctanes, e.g. zidebactam, combine ß-lactamase inhibition, antibacterial activity, and 'enhancement' of PBP3-targeted ß-lactams. OBJECTIVES: To examine the activity of cefepime/zidebactam against consecutive 'problem' Gram-negative bacteria referred to the UK national reference laboratory. METHODS: MICs were determined by BSAC agar dilution for 1632 Enterobacterales, 745 Pseudomonas aeruginosa and 450 other non-fermenters, categorized by carbapenemase detection and interpretive reading. RESULTS: Universal susceptibility to cefepime/zidebactam 8 + 8 mg/L was seen for otherwise multidrug-resistant Enterobacterales with AmpC, extended-spectrum, K1, KPC and OXA-48-like ß-lactamases, or with impermeability and 'unassigned' mechanisms. Unlike ceftazidime/avibactam and all other comparators, cefepime/zidebactam 8 + 8 mg/L also inhibited most (190/210, 90.5%) Enterobacterales with MBLs. Resistance in the remaining minority of MBL producers, and in 13/24 with both NDM MBLs and OXA-48-like enzymes, was associated with Klebsiella pneumoniae ST14. For Pseudomonas aeruginosa, MICs of cefepime/zidebactam rose with efflux grade, but exceeded 8 + 8 mg/L for only 11/85 isolates even in the highly-raised efflux group. Among 103 P. aeruginosa with ESBLs or MBLs, 97 (94.5%) were inhibited by cefepime/zidebactam 8 + 8 mg/L whereas fewer than 15% were susceptible to any comparator. MICs for Acinetobacter baumannii with acquired OXA carbapenemases clustered around 8 + 8 to 32 + 32 mg/L, with higher values for MBL producers. A strong enhancer effect augmented activity against many isolates that were highly resistant to cefepime and zidebactam alone and which had mechanisms not inhibited by zidebactam. CONCLUSIONS: Assuming successful clinical trials, cefepime/zidebactam has scope to widely overcome critical resistances in both Enterobacterales and non-fermenters.

Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria.

OBJECTIVES: Piperacillin/tazobactam has long been a broad-spectrum 'workhorse' antibiotic; however, it is compromised by resistance. One response is to re-partner tazobactam with cefepime, which is easier to protect, being less ß-lactamase labile, and to use a high-dose and prolonged infusion. On this basis, Wockhardt are developing cefepime/tazobactam (WCK 4282) as a 2+2 g q8h combination with a 90-min infusion. METHODS: The activity of cc cefepime/tazobactam was assessed, with other tazobactam combinations as comparators, against 1632 Enterobacterales, 745 Pseudomonas aeruginosa and 450 other non-fermenters, as submitted to the UK National Reference Laboratory. These were categorised by carbapenemase-gene detection and interpretive reading of phenotypes, with MICs determined by British Society for Antimicrobial Chemotherapy agar dilution. RESULTS: Although higher breakpoints may be justifiable, based on the pharmacodynamics, the results were reviewed against current cefepime criteria. On this basis, cefepime/tazobactam was broadly active against Enterobacterales with AmpC enzymes and extended-spectrum ß-lactamases (ESBLs), even when they had ertapenem resistance, suggesting porin loss. At 8+8 mg/L, activity extended to > 90% of Enterobacterales with OXA-48 and KPC carbapenemases, although the MICs for KPC producers belonging to the international Klebsiella pneumoniae ST258 lineage were higher; metallo-ß-lactamase producers remained resistant. Cefepime/tazobactam was less active than ceftolozane/tazobactam against Pseudomonas aeruginosa with AmpC de-repression or high-level efflux but achieved wider antipseudomonal coverage than piperacillin/tazobactam. Activity against other non-fermenters was species-specific. CONCLUSION: Overall, cefepime/tazobactam had a spectrum exceeding those of piperacillin/tazobactam and ceftolozane/tazobactam and resembling or exceeding that of carbapenems. Used as a 'new-combination of old-agents' it has genuine potential to be 'carbapenem-sparing'.