723. Synergistic Effect of Cefiderocol Combined With Other Antibiotics Against Cefiderocol High MIC Isolates From the Multi-National SIDERO-WT Studies

Abstract

BackgroundCefiderocol (CFDC) is a novel siderophore cephalosporin, which demonstrated potent activity at MICs of ≤4 µg/mL against ≥99% of the Gram-negative clinical isolates, including carbapenem-resistant Enterobacteriaceae spp. and nonfermenters in a multi-national SIDERO-WT study. In this study, we evaluated the synergistic effects of CFDC combined with other antibiotics against isolates with high CFDC MIC (i.e., ≥8 µg/mL).MethodsThe combination effects of CFDC and other antibiotics were evaluated by several Methods. (1) broth microdilution method in the presence of β-lactamase inhibitors avibactam and/or picolinic acid, (2) checkerboard method or time-kill assays in the presence of amikacin, meropenem, colistin, ceftazidime/avibactam or ceftolozane/tazobactam, (3) chemostat model reproducing humanized antibiotic exposures. Iron-depleted cation-adjusted Mueller–Hinton broth was used as the standard medium for CFDC as recommended by the Clinical Laboratory and Standard Institute (CLSI).ResultsA total of 39 CFDC nonsusceptible (NS) isolates were found among 9,205 isolates in the SIDERO-WT-2014 study. Among 28 CFDC-NS A. baumannii, 25 isolates were PER producers mainly from Russia and Turkey. Among 9 CFDC-NS Enterobacteriaceae, 5 isolates were NDM-producers from Turkey. Against all 34 non-NDM-producing isolates, the addition of avibactam significantly reduced CFDC MIC. The combination of CFDC with ceftazidime/avibactam and ceftolozane/tazobactam also showed strong synergy against these isolates, presumably due to the effect of β-lactamase inhibition. In addition, CFDC had synergistic effects with meropenem against 42.9% (9 of 21) of carbapenem NS isolates. Against the CFDC-NS isolates, including PER-producing A. baumannii, the combination of CFDC and meropenem under humanized drug exposures (chemostat model) showed synergistic effect leading to sustained eradication of bacteria over 24 hours.ConclusionEven against the non-NDM-producing CFDC-NS isolates, including PER-producing A. baumannii, the combinations of CFDC with ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem were effective due to synergistic effects. The mechanism of CFDC-meropenem synergy against A. baumannii is not known.Disclosures All authors: No reported disclosures.