In vitro efficacy of humanized regimen of flomoxef against extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae

This study compared the efficacy of flomoxef with other β-lactam antibiotics against extended-spectrum β-lactamases (ESBL)-producing bacteria of clinical relevance. First, the prevalence and β-lactamase genotypes of ESBL-producing strains among Escherichia coli and Klebsiella pneumoniae isolates collected in Japan from 2004 to 2018 were investigated. High MIC(90) values (>64 µg/mL) of ceftriaxone, cefepime, and ceftazidime and low MIC(90) values (≤0.06–2 µg/mL) of flomoxef, cefmetazole, and meropenem against both species were observed. Second, a chemostat model was used to analyze the efficacy of humanized regimens of three oxacephem/cephamycin antibiotics (flomoxef, cefmetazole, cefoxitin) and two other antibiotics (meropenem and piperacillin/tazobactam) in suppressing the growth of five ESBL-producing E. coli and two K. pneumoniae strains. Flomoxef, piperacillin/tazobactam, and meropenem showed good bactericidal effects with >4 log(10) CFU/mL reduction without bacterial regrowth at 24 h even when the MIC of test isolates was >MIC(90). Cefmetazole and cefoxitin resulted in regrowth of test isolates with MIC ≥MIC(90) at 24 h. Cefmetazole, cefoxitin, flomoxef, and meropenem showed increased MICs for regrown samples. A clear relationship between the proportion of time that the free drug concentration exceeded the MIC (%fT(>MIC)) and antibiotic efficacy was found for flomoxef, cefoxitin, and cefmetazole, and flomoxef had the highest %fT(>MIC), whereas discrepancies between Clinical and Laboratory Standards Institute breakpoint and bactericidal activity were observed for cefmetazole. Flomoxef was effective in preventing the growth of all ESBL-producing strains, even those with an MIC eight times the MIC(90). Thus, flomoxef may be a good alternative to meropenem in context of carbapenems sparing stewardship.