Burkholderia pseudomallei Clinical Isolates Are Highly Susceptible <i>In Vitro</i> to Cefiderocol, a Siderophore Cephalosporin

Abstract

Cefiderocol is a cephalosporin designed to treat multidrug-resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater <i>in vitro</i> activity against many Gram-negative bacilli than currently used carbapenems, β-lactam/β-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the <i>in vitro</i> activity of cefiderocol against a total of 246 clinical isolates of <i>Burkholderia pseudomallei</i> from Queensland, Australia. The collection was composed primarily of bloodstream (56.1%), skin and soft tissue (16.3%), and respiratory (15.9%) isolates. MICs of cefiderocol ranged from ≤0.03 to 16 mg/liter, whereas the MIC₉₀ was 0.125 mg/liter. Based upon CLSI clinical breakpoints for cefiderocol against <i>Pseudomonas aeruginosa</i>, <i>Acinetobacter baumannii</i>, and <i>Stenotrophomonas maltophilia</i>, three isolates (1.2%) would be classified as nonsusceptible (MIC > 4 mg/liter). Using EUCAST non-species-specific (pharmacokinetic/pharmacodynamic [PK/PD]) clinical breakpoints or those set for <i>Pseudomonas aeruginosa</i>, four isolates (1.6%) would be resistant (MIC > 2 mg/liter). Further testing for coresistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, and doxycycline was performed on the four isolates with elevated cefiderocol MICs (>2 mg/liter); all isolates exhibited resistance to amoxicillin-clavulanic acid, while three isolates also displayed resistance to at least one other antimicrobial. Cefiderocol was found to be highly active <i>in vitro</i> against <i>B. pseudomallei</i> primary clinical isolates. This compound shows great potential for the treatment of melioidosis in countries of endemicity and should be explored further.