Strategies to overcome intrinsic resistance in Stenotrophomonas maltophilia: In vitro activity of aztreonam/avibactam, cefiderocol, and cefepime–zidebactam

Purpose: To evaluate the in vitro activity of cefiderocol, aztreonam/avibactam, and cefepime/zidebactam against contemporary clinical Stenotrophomonas maltophilia isolates and to assess bactericidal activity using time-kill analyses. Methods: A total of 216 nonduplicate clinical S. maltophilia isolates collected between 2018 and 2024 from five tertiary care hospitals in India, were studied. MICs of trimethoprim/sulfamethoxazole (TMP-SMX), levofloxacin, minocycline, cefiderocol, aztreonam/avibactam, and cefepime/zidebactam were determined by broth microdilution according to CLSI guidelines. Cefiderocol was tested in iron-depleted cation-adjusted Mueller–Hinton broth. Aztreonam/avibactam was tested with avibactam at 4 mg/L, and cefepime/zidebactam at a 1:1 ratio. PK/PD breakpoints of ≤ 8 mg/L and ≤ 64 mg/L were applied for aztreonam/avibactam and cefepime/zidebactam, respectively. Time–kill assays were performed at 1× MIC against two representative isolates and ten additional isolates spanning cefepime/zidebactam MICs of 4–64 mg/L. Results: Cefiderocol inhibited 96.8% of isolates at MICs ≤ 1 mg/L (MIC50/MIC90 ≤ 0.12/1 mg/L). Susceptibility rates were 95.8% for aztreonam/avibactam and 99.5% for cefepime/zidebactam. TMP-SMX and levofloxacin each inhibited 91.7% of isolates, while minocycline susceptibility was 92.6%. The three novel agents retained activity against most isolates non-susceptible to comparators. In time–kill assays, cefiderocol, aztreonam/avibactam, and cefepime/zidebactam achieved ≥ 3-log10 CFU/mL reductions, including isolates with cefepime/zidebactam MICs up to 64 mg/L. Minocycline did not demonstrate bactericidal activity. Conclusions: Cefiderocol, aztreonam/avibactam, and cefepime/zidebactam demonstrated potent in vitro activity against contemporary S. maltophilia isolates. These findings support further PK/PD-informed clinical evaluation of these agents for difficult-to-treat S. maltophilia infections.