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

ABSTRACT 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 × 10 7 CFU/mL. Both amikacin and ceftazidime/avibactam monotherapies resulted in bacterial killing (~4 log 10 and ~3 log 10 , 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 (10 2 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 .