In vitro efficacyof humanized regimen of flomoxefagainst extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae

Abstract

This study compared the efficacyof flomoxefwith 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 MIC90 values (>64 μg/mL) of ceftriaxone, cefepime,and ceftazidime and low MIC90 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 efficacyof humanized regimens of three oxacephem/cephamycin antibiotics (flomoxef,cefmetazole, cefoxitin) and two other antibiotics (meropenem and piperacillin/tazobactam) in suppressing the growth of fiveESBL-producing E. coli and two K. pneumoniae strains. Flomoxef, piperacillin/tazobactam, and meropenem showed good bactericidal effects with >4 log10 CFU/mL reduction without bacterial regrowth at 24 heven when the MIC of test isolates was >MIC90. Cefmetazole and cefoxitin resulted in regrowth of test isolates with MIC ≥MIC90 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 efficacywas found for flomoxef,cefoxitin, and cefmetazole, and flomoxefhad the highest %fT>MIC, whereas discrepancies between Clinical and Laboratory Standards Institute breakpoint and bactericidal activity were observed for cefmetazole. Flomoxef was effectivein preventing the growth of all ESBL-producing strains, even those with an MIC eight times the MIC90. Thus, flomoxefmay be a good alternative to meropenem in context of carbapenems sparing stewardship.