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. maitophilia clinical isolates tested (MIC50, 0.063 mu g/ml; MIC90, 0.25 mu g/ml). Cefiderocol also demonstrated low MICs against the trimethoprim-sulfamethoxazole-resistant S. maltophilia strains (i.e., SR202006; MIC, 0.125 mu g/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. maitophilia 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 IV count compared with baseline controls, which received no intervention. Together, the results from these studies suggest that cefiderocol could provide an effective al- ternative treatment option for S. maltophilia infections in the lower respiratory tract, particularly strains resistant to empirical antibiotics, such as trimethoprim-sulfame- or thoxazole or minocycline.