In vitro activity and in vivo efficacy of cefiderocol against Stenotrophomonas maltophilia

Abstract

Cefiderocol is a novel siderophore cephalosporin antibiotic with broad coverage against difficult-to-treat Gram-negative bacteria, including those resistant to carbapenems. Its activity against Stenotrophomonas maltophilia was investigated in vitro against clinical isolates and in lung infection models using strains either resistant (SR202006) or susceptible (SR201934, SR200614) to trimethoprim-sulfamethoxazole. Cefiderocol demonstrated potent in vitro activity against all 217 S. maltophilia clinical isolates tested (MIC50, 0.063μg/ml; MIC90, 0.25μg/ml). Cefiderocol also demonstrated low MICs against the trimethoprim-sulfamethoxazole-resistant S. maltophilia strains (i.e., SR202006; MIC, 0.125mg/ml). In a neutropenic mouse lung infection model, cefiderocol (30 mg/kg body weight and 100 mg/kg) demonstrated a significant, dose-dependent reduction in the lung viable bacteria cell count compared with untreated controls in S. maltophilia infection and was the only antibiotic tested to show a similar significant effect in a trimethoprim-sulfamethoxazole-resistant S. maltophilia infection. In immunocompetent rat lung infection models of S. maltophilia, humanized dosing of cefiderocol (2 g every 8 h) and meropenem (1 g every 8 h) revealed pharmacokinetic profiles similar to those in human subjects, and the humanized cefiderocol dosing significantly reduced the lung viable bacteria cell count compared with baseline controls, which received no intervention. Together, the results from these studies suggest that cefiderocol could provide an effective alternative treatment option for S. maltophilia infections in the lower respiratory tract, particularly strains resistant to empirical antibiotics, such as trimethoprim-sulfamethoxazole or minocycline.