Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits

Abstract

Stenotrophomonas maltophilia is an important cause of pneumonia in immunocompromised patients. Cefiderocol is a parenteral siderophore cephalosporin with potent in vitro activity against S. maltophilia. We evaluated the efficacy of cefiderocol in a neutropenic rabbit model of S. maltophilia pneumonia in comparison to trimethoprim-sulfamethoxazole (TMP-SMX). The cefiderocol area under the plasma drug concentration-time curve extrapolated to 8 h (AUC0-8) was lower (423.0 6 40.9 mg·h/mL versus 713.6 6 40.1 mg·h/mL) and clearance higher (252.77 6 38.9 mL/h/kg versus 142.6 6 32.9 mL/h/kg) in infected versus noninfected rabbits. We studied a clinical bloodstream S. maltophilia isolate with an MIC of 0.03 mg/mL of cefiderocol. Time spent above the MIC of cefiderocol for the majority of S. maltophilia isolates in rabbits recapitulated the plasma concentration-time profile observed in adult humans at the licensed dose of 2 g given intravenously (i.v.). Experimental groups consisted of 120 mg/kg cefiderocol i.v. every 8 hours (q8h); TMP-SMX, 5 mg/kg i.v. Q12h, and untreated controls (UCs). Treatment was administered for 10 days. Survival in cefiderocol-treated rabbits (87%) was greater than that in TMP-SMX-treated (25%; P, 0.05) and UC (0%; P, 0.05) groups. There was no residual bacterial burden in lung tissue or bronchoalveolar lavage (BAL) fluid in the cefiderocol group. Residual bacterial burden was present in lung tissue and BAL fluid in the TMP-SMX group but was decreased in comparison to UCs (P, 0.001). Lung weights (markers of pulmonary injury) were decreased in cefiderocol-treated versus TMP-SMX (P, 0.001) and UC (P, 0.001) groups. Cefiderocol is highly active in treatment of experimental S. maltophilia pneumonia, laying the foundation for future clinical investigations against this lethal infection in immunocompromised patients.