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Published on: September 9, 2015
In vitro activity of cefiderocol and sulbactam-durlobactam against clinical-isolated carbapenem-resistant
Yixin Zhang1, Mohan Ju1, Yumiao Guo2
1Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China.
Objectives:
This study aimed to evaluate the in vitro activity of cefiderocol and sulbactam-durlobactam against carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates from China and elucidate potential resistance mechanisms.
Methods:
A total of 281 non-duplicate CRAB isolates were collected (2017-2018) from nine tertiary hospitals across five Chinese provinces/municipalities. Minimum inhibitory concentrations (MICs) for cefiderocol, sulbactam-durlobactam, and comparators (including carbapenems, colistin, and tigecycline) were determined using broth microdilution according to Clinical and Laboratory Standards Institute guidelines. Whole-genome sequencing (Illumina) was performed to analyze homology, β-lactam resistance genes, mutations in siderophore receptors (pirA, piuA), and penicillin-binding proteins (PBPs).
Results:
Among 281 geographically diverse CRAB isolates, the majority were isolated from the lower respiratory tract. MLST analysis identified ST2 as the predominant type (270/281). Notably, 277 (98.6%) of these ST2 isolates carried the OXA-23 gene. Tigecycline and polymyxin demonstrated the highest susceptibility, with resistance rates of 0% and 0.7%, respectively. Both novel agents (cefiderocol and sulbactam-durlobactam) demonstrated potent in vitro activity. Cefiderocol exhibited 97.9% susceptibility (275/281 isolates), and sulbactam-durlobactam susceptibility reached 96.8% (272/281 isolates). Resistance analysis revealed that among six cefiderocol-resistant isolates (MIC ≥ 4 mg/L), three harbored PER-7 alongside OXA-23, while the remaining three exhibited amino acid substitutions in critical regions: PBP3 (A515V) and siderophore receptors. All nine sulbactam-durlobactam-non-susceptible isolates (MIC ≥ 8 mg/L) carried OXA-23/OXA-66 and displayed recurrent PBP3 substitutions (A515V in five isolates, T526S in three, N392T in one).
Conclusions:
Cefiderocol and sulbactam-durlobactam exhibit high in vitro efficacy against Chinese CRAB isolates. Although these agents were not yet approved for clinical use in China at the time of isolate collection, non-susceptibility to cefiderocol or sulbactam-durlobactam was already detected. Resistance to cefiderocol was potentially associated PER-7 β-lactamase and mutations in iron transporters/PBPs, while sulbactam-durlobactam non-susceptibility was potentially correlated with PBP3 substitutions. These findings underscore the need for ongoing surveillance and mechanistic studies to address emerging resistance in CRAB.