Activity of cefiderocol in combination with tetracycline analogues against carbapenem-resistant Acinetobacter baumannii

Abstract

Therapeutic options for carbapenem-resistant Acinetobacter baumannii (CA-AB) are quite limited. Cefiderocol, a novel siderophore cephalosporin, has shown potent in vitro activity against CR-AB, and new tetracycline analogues such as eravacycline and omadacycline have been available in recent years. However, the synergism of cefiderocol with tetracycline analogues against CR-AB has not been well investigated. In this study, we evaluated the in vitro synergistic activity of cefiderocol in combination with tetracycline analogues (minocycline, tigecycline, eravacycline and omadacycline) against 48 clinical isolates of CR-AB by checkerboard methods and time-kill assays. Then we further verified the in vitro results with neutropenic murine thigh-infection models. Among 48 tested isolates tested with checkerboard methods, 35.4%, 33.3%, 50.0% and 37.5% showed synergistic interactions (FICI ≤ 0.5) in cefiderocol-minocycline combination, cefiderocol-tigecycline combination, cefiderocol-eravacycline combination and cefiderocol-omadacycline combination, respectively. None of the combinations exhibited any antagonistic interactions. In the time-kill assays, cefiderocol combined with tetracycline analogues showed synergistic effects in most isolates. Animal models found that combination therapy could reduce cell counts by nearly 2 log₁₀ CFU/thigh compared with the monotherapy in the AB-2 isolate who was susceptible to minocycline (MIC = 4 mg/l). But for the AB-26 who was resistant to minocycline, the decrease of bacterial cell counts was less than 1 log₁₀ CFU/thigh compared with cefiderocol monotherapy in the cefiderocol-minocycline, cefiderocol-tigecycline and cefiderocol-omadacycline therapies; while the cefiderocol-eravacycline combination could still reduce the bacterial cell counts nearly 2 log₁₀ CFU/thigh compared with the monotherapy. In summary, the cefiderocol-eravacycline combination seems to be a promising therapeutic strategy for treating CR-AB infections.