In vitro potency of novel ertapenem/zidebactam combination (WCK 6777) against carbapenemase-producing Enterobacterales collected across India

Background and objectives Ertapenem is well suited for outpatient parenteral antimicrobial therapy (OPAT) due to its once-daily dosing and favourable safety profile; however, increasing enzyme-mediated resistance limits its clinical utility. Ertapenem/zidebactam (WCK 6777) is a novel β-lactam/β-lactam enhancer combination in which zidebactam exhibits high-affinity binding to penicillin-binding protein 2 (PBP2), augmenting ertapenem activity and overcoming β-lactamase-mediated resistance. We evaluated the in vitro activity of ertapenem/zidebactam against carbapenem-resistant Escherichia coli and Klebsiella pneumoniae clinical isolates from India. Methods MICs of ertapenem/zidebactam and comparator agents (carbapenems, imipenem/relebactam, ceftazidime/avibactam and aztreonam/avibactam) were determined by broth microdilution method. Carbapenemase genes and PBP3 insertions were identified using PCR. Results Ertapenem/zidebactam demonstrated potent activity against E. coli, inhibiting 99.5% of isolates at the PK/PD breakpoint of ≤8 mg/L (MIC90, 0.5 mg/L), including NDM producers with PBP3 insertions. Against K. pneumoniae, susceptibility reached 93.6% among NDM producers and 88.5% among dual carbapenemase producers at the same breakpoint. Comparator agents showed variable activity, with limited efficacy against metallo-β-lactamase producers. Conclusions The enhanced activity of ertapenem/zidebactam is attributed to zidebactam’s dual mechanism, β-lactamase inhibition and high-affinity PBP2 binding, enabling effective coverage despite complex resistance mechanisms. Its once-daily dosing supports its potential as an OPAT-enabling therapeutic option and warrant further clinical development.