In Vitro and In Vivo Activity of Amoxicillin–Clavulanate Combined with Ceftibuten or Cefpodoxime Against Extended-Spectrum β-Lactamase–Producing Escherichia coli and Klebsiella pneumoniae

Infections due to extended-spectrum β-lactamase (ESBL)–producing Enterobacterales are an increasingly common problem. For many of these infections, no oral treatment options are available. The activity of amoxicillin–clavulanate combined with ceftibuten or cefpodoxime was evaluated against a group of Escherichia coli and Klebsiella pneumoniae clinical isolates possessing a variety of CTX-M- and SHV-type ESBLs; some possessed bla TEM1 as well. In time-kill studies, the combination of subinhibitory concentrations of amoxicillin–clavulanate with ceftibuten was bactericidal and synergistic for all strains with an amoxicillin–clavulanate MIC ≤32 μg/mL, regardless of the type of ESBL and the cephalosporin minimal inhibitory concentration (MIC). The combination with cefpodoxime was also bactericidal and synergistic against all but one of these strains. These combinations were further tested against two strains of K. pneumoniae and one E. coli in a sepsis model using Galleria mellonella larvae. The combination of amoxicillin–clavulanate with ceftibuten demonstrated a synergistic survival benefit against all three strains. The combination with cefpodoxime also improved survival against the two K. pneumoniae strains, but not the E. coli strain. These findings support combining amoxicillin–clavulanate with ceftibuten, and possibly cefpodoxime, for the treatment of infections due to ESBL producers and suggest that having an amoxicillin–clavulanate MIC of 32 μg/mL or less may predict activity at clinically achievable concentrations. Clinical studies are warranted to further evaluate this therapeutic approach.