Paired In Vitro Susceptibility of Cefiderocol and Colistin in Colistin-Resistant, Extensively Drug-Resistant Gram-Negative Bacilli: A Single-Centre, MIC-Based Analysis of 236 Clinical Isolates

Extensively drug-resistant (XDR) Gram-negative bacilli increasingly exhaust therapeutic options, leaving colistin and cefiderocol as last-resort agents. We assessed whether cefiderocol retains in vitro activity against colistin-resistant isolates, without inferring clinical efficacy. We analysed 236 non-duplicate XDR Gram-negative isolates from 220 patients. Cefiderocol and colistin MICs were determined via reference broth microdilution with EUCAST-required quality control (iron-depleted broth for cefiderocol; mcr-1-positive Escherichia coli NCTC 13846 for colistin) and interpreted using species-specific EUCAST v16.1 (2026) breakpoints (cefiderocol: Enterobacterales S ≤ 2, I 4, R > 4 mg/L; Pseudomonas aeruginosa S ≤ 2, R > 2 mg/L; colistin: P. aeruginosa S ≤ 4 mg/L). Because EUCAST publishes no clinical cefiderocol breakpoint for Acinetobacter baumannii, the primary analysis comprised species with breakpoints for both agents (n = 150; 126 paired); A. baumannii is reported as an MIC distribution and the pooled 236-isolate comparison as secondary. In the primary analysis, 120/150 isolates (80.0%) were cefiderocol-susceptible at standard or increased exposure. Among paired isolates, cefiderocol covered 77.0% versus 43.7% for colistin; agreement was negligible (Cohen’s κ = 0.020), with 54 isolates favouring cefiderocol and 12 the reverse (McNemar p < 0.001). Conditional in vitro susceptibility among 71 colistin-resistant isolates was 76.1% (95% CI 65.0–84.5), giving 33.3 percentage points of incremental coverage and one additional cefiderocol-susceptible isolate per 2.3 matched isolates tested. Secondary analyses were directionally consistent (incremental coverage 21.8–33.3 points). These in vitro findings support paired testing of both agents to identify isolates retaining cefiderocol activity when colistin does not; clinical benefit was not assessed.