Cefiderocol and Moxifloxacin Have Additive and Synergistic Activity Against Pseudomonas aeruginosa Including an Isolate of the 2023 Keratitis Outbreak.

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 combination was less effective, particularly sheen-positive strains. The cefiderocol-moxifloxacin combination showed indifferent effects against Serratia marcescens and Staphylococcus aureus, with each antibiotic retaining individual activity.

CONCLUSIONS

Cefiderocol and moxifloxacin exhibited synergy against most tested P. aeruginosa keratitis isolates in vitro, including those with suspected quorum-sensing defects. These findings support further investigation of this combination for treating highly drug-resistant ocular infections.