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

BACKGROUND: Cefiderocol (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). METHODS: The 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). RESULTS: A 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. CONCLUSION: Even 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.