Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia

Abstract

The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of <i>Stenotrophomonas maltophilia</i> infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against <i>S. maltophilia</i>, but data on strains resistant to current first-line agents are limited, and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the <i>in vitro</i> activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, or trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical <i>S. maltophilia</i> isolates. For this purpose, the MICs of cefiderocol, ceftazidime, levofloxacin, minocycline, polymyxin B, and TMP-SMZ for 37 <i>S. maltophilia</i> isolates not susceptible to levofloxacin and/or TMP-SMZ were determined. Nine strains with various cefiderocol MICs were then tested in time-kill experiments with cefiderocol alone and in combination with comparators. The only agents for which susceptibility rates exceeded 40% were cefiderocol (100%) and minocycline (97.3%). Cefiderocol displayed the lowest MIC₅₀ and MIC₉₀ values (0.125 and 0.5 mg/liter, respectively). In time-kill experiments, synergy was observed when cefiderocol was combined with levofloxacin, minocycline, polymyxin B, or TMP-SMZ against 4/9 (44.4%), 6/9 (66.7%), 5/9 (55.5%), and 6/9 (66.7%) isolates, respectively. These data suggest that cefiderocol displays potent <i>in vitro</i> activity against <i>S. maltophilia</i>, including strains resistant to currently preferred agents. Future dynamic and <i>in vivo</i> studies of cefiderocol alone and in combination are warranted to further define cefiderocol's synergistic capabilities and its place in therapy for <i>S. maltophilia</i> infections.