In Vitro Activity of Ceftibuten-Avibactam against β-Lactamase-Positive Enterobacterales from the ATLAS Global Surveillance Program

Abstract

Ceftibuten is an established, oral, third-generation cephalosporin in early clinical development in combination with an oral prodrug of avibactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. We evaluated the in vitro activity of ceftibuten-avibactam against 1,165 Enterobacterales isolates selected from the 2016-2020 ATLAS global surveillance program based upon their β-lactamase genotype, β-lactam-susceptible phenotype, species identification, and specimen source (95.8% urine). MICs were determined by CLSI broth microdilution. Avibactam was tested at a fixed concentration of 4 μg/mL. Molecular methods were used to identify β-lactamase genes. Ceftibuten-avibactam inhibited 90% (MIC₉₀) of ESBL-producing (n = 645), KPC-producing (n = 60), chromosomal AmpC-positive (n = 100), OXA-48-like-producing (n = 50), and acquired AmpC-producing (n = 110) isolates at concentrations of 0.12, 0.5, 1, 2, and 4 μg/mL, respectively. At concentrations of ≤1 and ≤8 μg/mL, ceftibuten-avibactam inhibited 98.4 and 99.2% of ESBL-positive isolates; 96.7 and 100% of KPC-positive isolates; 91.0 and 99.0% of chromosomal AmpC-positive isolates; 86.0 and 96.0% of OXA-48-like-positive isolates; and 85.5 and 91.8% of acquired AmpC-positive isolates. Against ESBL-producing, KPC-producing, chromosomal AmpC-positive, OXA-48-like-producing, and acquired AmpC-producing isolates, ceftibuten-avibactam was 256-, 128-, >64-, >32-, and > 16-fold more potent than ceftibuten alone. The potency of ceftibuten-avibactam was 4-fold greater than ceftazidime-avibactam against ESBL-producing (ceftibuten-avibactam MIC₉₀, 0.12 μg/mL; ceftazidime-avibactam MIC₉₀, 0.5 μg/mL) and KPC-producing (0.5 μg/mL; 2 μg/mL) isolates, equivalent to ceftazidime-avibactam (MIC₉₀, 2 μg/mL) against OXA-48-like-producing isolates, 2-fold less active than ceftazidime-avibactam (1 μg/mL; 0.5 μg/mL) against chromosomal AmpC-positive isolates, and 4-fold less active than ceftazidime-avibactam (4 μg/mL; 1 μg/mL) against acquired AmpC-producing isolates. Continued development of ceftibuten-avibactam appears justified.

Keywords: Enterobacterales; avibactam; ceftibuten; oral therapy; urinary tract infection.

FIG 1

Ceftibuten-avibactam (gray bars) and ceftibuten (black bars) MIC distributions for 200 wild-type Enterobacterales isolates.

FIG 2

Ceftibuten-avibactam (gray bars) and ceftibuten (black bars) MIC distributions for 645 ESBL-positive Enterobacterales isolates (excludes isolates with chromosomal AmpC and those carrying acquired AmpCs, serine carbapenemases, and metallo-β-lactamases).

FIG 3

Ceftibuten-avibactam (gray bars) and ceftibuten (black bars) MIC distributions for 60 KPC-positive Enterobacterales (excludes isolates carrying OXA-48-like carbapenemases and metallo-β-lactamases).

FIG 4

Ceftibuten-avibactam (gray bars) and ceftibuten (black bars) MIC distributions for 50 OXA-48-like-positive Enterobacterales isolates (includes isolates with or without ESBLs and excludes isolates carrying KPCs and metallo-β-lactamases).

FIG 5

Ceftibuten-avibactam (gray bars) and ceftibuten (black bars) MIC distributions for 100 chromosomal AmpC-producing Enterobacterales isolates (includes isolates with or without ESBLs and excludes isolates carrying serine carbapenemases and metallo-β-lactamases).

FIG 6

Ceftibuten-avibactam (gray bars) and ceftibuten (black bars) MIC distributions for 110 acquired AmpC-producing Enterobacterales isolates (includes isolates with or without ESBLs and excludes isolates carrying serine carbapenemases and metallo-β-lactamases).