Abstract
Background
Stenotrophomonas maltophilia causes lethal pneumonia, bacteremia, and sepsis in immunocompromised patients. As a standard of care, trimethoprim-sulfamethoxazole (T/S) is considered to be the first-line therapy for Stenotrophomonas pneumonia. Cefiderocol (CFDC) is a new parenteral siderophore cephalosporin that is transported through the outer cell membrane as a siderophore mimic that then inhibits Gram-negative cell wall biosynthesis. CFDC has potent activity in vitro against S. maltophilia; however, little is known about its in vivo activity against Stenotrophomonas pneumonia in immunocompromised hosts. We therefore studied CFDC in comparison to TS in the persistently neutropenic rabbit model of Stenotrophomonas pneumonia. This rabbit model, in contrast to conventional murine models, reflects the human pattern of infection more accurately over time.
Methods
We initially studied the plasma pharmacokinetics of CFDC in non-infected and infected animals. Stenotrophomonas pneumonia was established by direct endotracheal inoculation of S. maltophilia 1×1010 CFUs for tracheobronchial colonization that evolved into bronchopneumonia. Experimental groups consisted of CFDC, T/S, and untreated controls (UC). Rabbits received CFDC at 120 mg/kg IV Q8h and T/S at 5 mg/kg IV Q12h. Profound persistent neutropenia was maintained with cytosine arabinoside. Treatment was continued for 10 days.
Results
There were no significant differences between non-infected and infected rabbits in CFDC pharmacokinetics. Rabbits treated with CFDC and T/S demonstrated significant decreases of residual pulmonary and BAL bacterial burden vs UC (p≤0.001). CFDC achieved full clearance of S. maltophilia from lung tissue and BAL. This antibacterial activity coincided with significant reduction of lung weights (marker of organism-mediated pulmonary injury) in the CFDC group vs T/S and UC (p< 0.01). Survival was prolonged in the CFDC treatment group with 87% survival in comparison to that of T/S (25%) and UC (0%) (p< 0.01).
Table 1. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistency Neutropenic Rabbits
Conclusion
Cefiderocol is highly active in treatment of experimental S. maltophilia pneumonia in persistently neutropenic rabbits, thus laying the foundation for future clinical investigations against this lethal infection.
Disclosures
Naoki Ishibashi, MD, Shionogi, Inc. (Employee) Benjamin Georgiades, n/a, Shionogi, Inc. (Consultant) Roger Echols, MD, Shionogi (Consultant) Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support) Yoshinori Yamano, PhD, Shionogi (Employee) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support)