1081. Antimicrobial Activity of Ceftibuten-Avibactam against Clinical Isolates of Enterobacterales Producing Clinically Relevant Beta-Lactamases

Abstract

Background. Ceftibuten (CTB) is an oral cephalosporin active against Enterobacterales approved by the US Food and Drug Administration in 1995. Avibactam (AVI) is a potent inhibitor of extended-spectrum β-lactamases (ESBLs), serine carbapenemases and AmpC that can be administered orally. We evaluated the in vitro activity of CTB-AVI against molecularly characterized Enterobacterales that produced the most common β-lactamases (BLs) and assessed the AVI concentration to be combined with CTB for susceptibility testing. Methods. The organism collection (n=71) included Enterobacterales producing ESBLs (28; CTX-M, SHV, and TEM), KPCs (8), MBLs (7; NDM, VIM, and IMP), AmpC derepressed (3), plasmid AmpC (3), OXA-48-like (2), and SME (2) as well as isolates with porin alterations (5) and wild-type organisms (13). Resistance mechanisms were evaluated by whole genome sequencing. MIC values were determined by broth microdilution of CTB with fixed concentrations (2, 4, and 8 mg/L) and ratios (1:1 and 2:1) of AVI. Results. The fixed AVI concentration of 4 mg/L best separated CTB-AVIsusceptible from CTB-AVI-resistant isolates. CTB-AVI (fixed 4 mg/L) was very active against Enterobacterales producing ESBL (MIC50/90, 0.03/0.12 mg/L), including CTXM-15 (MIC50/90, 0.03/0.12 mg/L), KPC (MIC50, 0.06 mg/L), derepressed AmpC (MIC range, 1-2 mg/L), plasmidic AmpC (MIC range, 0.12-0.5 mg/L), SME (MIC range, 0.06-0.12 mg/L), and OXA-48-like (MIC range, 0.5-4 mg/L), but it showed limited activity against MBL-producers (MIC50, >128 mg/L) and isolates with porin alterations (MIC50, 32 mg/L; Table). CTB was very active against SME-producers (MIC, 0.12-0.25 mg/L) and showed some activity against KPC-producers (MIC50, 4 mg/L; MIC range, 2-16 mg/L) and ESBL-producers (MIC50/90, 4/64 mg/L), but it exhibited very limited activity against MBL, AmpC derepressed, plasmidic AmpC, and OXA-48-like producers (MIC50 values of 128 to >128 mg/L). Conclusion. CTB-AVI showed potent in vitro activity against Enterobacterales producing most clinically relevant BLs, including ESBLs, KPCs, OXA-48-like, and AmpC, for which limited oral treatment options are available. These in vitro results support further clinical development of CTB-AVI.