Assessment of sustained efficacy and resistance emergence under human-simulated exposure of cefiderocol against Acinetobacter baumannii using in vitro chemostat and in vivo murine infection models

OBJECTIVES: This study evaluated the sustained kill and potential for resistance development of Acinetobacter baumannii exposed to human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models. METHODS: Seven A. baumannii isolates with cefiderocol MICs of 0.12–2 mg/L were tested. The sustained bactericidal activity compared with the initial inoculum and the resistance appearance over 72 h treatment were evaluated in both an in vitro chemostat and an in vivo murine thigh infection model under the human-simulated exposure of cefiderocol (2 g every 8 h as 3 h infusion). RESULTS: In the in vitro model, regrowth was observed against all seven tested isolates and resistance emergence (>2 dilution MIC increase) was observed in five test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed in six of seven tested isolates in vivo. The mechanism of one resistant isolate that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. The resistance acquisition mechanisms of other isolates have not been identified. CONCLUSIONS: The discrepancy in the sustained efficacy and resistance emergence between in vitro and in vivo models was observed for A. baumannii. Although the resistance mechanisms in vitro have not been fully identified, sustained efficacy without resistance emergence was observed in vivo for six of seven isolates. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among A. baumannii evaluated under human-simulated exposures.