Evaluating the efficacy of ceftazidime/avibactam plus amikacin combination therapy as a carbapenem-sparing agent against ceftazidime/avibactam-resistant Escherichia coli using a hollow fiber infection model: a proof-of-concept study.

Carbapenems, often regarded as the last line of defense in treatment of urinary tract infections and urosepsis caused by Escherichia coli, are under pressure from emerging resistance. Thus, it is necessary to investigate carbapenem-sparing agents to mitigate the dissemination of carbapenem resistance. In this study, we aimed to evaluate the efficacy of ceftazidime/avibactam plus amikacin combination therapy against two ceftazidime/avibactam-resistant E. coli clinical isolates harboring IMP-4 carbapenemase (CTAP #226 and CTAP #233). To achieve this, we used a hollow fiber infection model (HFIM) with clinically relevant regimens of amikacin (15 mg/kg q24h) and ceftazidime/avibactam (2 g ceftazidime/0.5 g avibactam q8h), which were administered to the HFIM either alone or in combination over a 7-day treatment course. Initial inoculum was ~1 × 107 CFU/mL. Both amikacin and ceftazidime/avibactam monotherapies resulted in bacterial killing (~4 log10 and ~3 log10, respectively) within the first 8 h; however, regrowth surpassing the baseline was observed over the following 7 days. Conversely, combination therapy resulted in bacterial killing to <the limit of quantification (102 CFU/mL) within the first 48 h, which was sustained for the entirety of the experiment. This study showed that the combination of amikacin and ceftazidime/avibactam was superior to both monotherapies and therefore presents a promising carbapenem-sparing option for the treatment of ceftazidime/avibactam-resistant E. coli. Further clinical studies are required to assess the suitability for use in vivo.