Cefiderocol and Moxifloxacin Have Additive and Synergistic Activity Against Pseudomonas aeruginosa Including an Isolate of the 2023 Keratitis Outbreak
Abstract
PURPOSE: The 2023 outbreak of Pseudomonas aeruginosa keratitis linked to contaminated artificial tears highlighted the need for new treatments targeting ocular infections caused by multi-drug-resistant and extensively drug-resistant bacteria. This study evaluated the in vitro efficacy and potential synergy of cefiderocol and moxifloxacin against P. aeruginosa keratitis isolates. The influence of quorum-sensing defects on antibiotic efficacy was also assessed because of the increase in lasR mutant keratitis isolates. Ceftazidime, which lacks the "Trojan Horse" iron-binding-mediated bacterial entry mechanism of cefiderocol, served as a comparator.
METHODS: Time-kill and epsilometer (E-test) assays were used to determine minimum inhibitory concentrations and drug interactions. Fractional inhibitory concentration indices were calculated to characterize drug interactions as antagonistic, indifferent, additive, or synergistic. Quorum-sensing defective strains were identified by a characteristic colony sheen phenotype associated with LasR system defects.
RESULTS: Time-kill studies demonstrated consistent synergistic interactions between cefiderocol and moxifloxacin against seven out of seven tested P. aeruginosa keratitis isolates, including one from the 2023 outbreak. E-test-based assays showed additive or synergistic activity against 79% of isolates, although this dropped to 60% among suspected quorum-sensing defective strains. In contrast, the ceftazidime and moxifloxacin…
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