Pharmacodynamic evaluation of piperacillin/tazobactam against extended-spectrum β-lactamase (ESBL)-producing versus non-ESBL-producing Escherichia coli in a hollow-fibre infection model.

Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are a global public-health concern. We evaluated the pharmacodynamic activity of piperacillin/tazobactam (TZP) dosing regimens against ESBL-producing versus non-ESBL-producing E. coli. Five E. coli clinical isolates were obtained from Bangladesh. Broth microdilution and whole-genome sequencing (WGS) were performed on the five studied isolates. Three TZP-susceptible ESBL-producing and two non-ESBL-producing E. coli were exposed to TZP regimens of 4.5 g every 6 h (q6h) and every 8 h (q8h) as a 30-min infusion in a dynamic hollow-fibre infection model over 7 days. The extent of bacterial killing was ∼4-5 log10 CFU/mL against ESBL-producing and non-ESBL-producing E. coli with TZP q6h and q8h regimens over the first 8 h. Bacterial killing was similar between two of three ESBL-producing (CTAP#168 and CTAP#169) and two non-ESBL-producing (CTAP#179 and CTAP#180) E. coli clinical isolates over the course of the experiment. ESBL-producing CTAP#173 E. coli was poorly killed (∼1 log) compared with two non-ESBL-producing E. coli over 168 h. WGS revealed that ESBL-producing E. coli isolates co-harboured multiple antimicrobial resistance genes such as blaCTX-M-15, blaEC, blaOXA-1, blaTEM-1 and aac(6')-Ib-cr5. Overall, TZP q6h and q8h dosing regimens attained >3 log bacterial kill against all ESBL-producing or non-ESBL-producing E. coli within 24 h and maintained and prevented the emergence of resistance through the end of the experiment. In conclusion, TZP standard regimens resulted in similar bacterial killing and prevented the emergence of resistance against CTX-M-15-type ESBL-producing and non-ESBL-producing E. coli clinical isolates.