1626. Synergistic Effect of Cefiderocol with Other Antibiotics Against PER-Producing Acinetobacter baumannii Isolates from the Multinational SIDERO-WT Studies

Background Cefiderocol (CFDC), a novel siderophore cephalosporin, showed potent activity at minimum inhibitory concentrations (MICs) of ≤4 μg/mL against ≥99% of Gram-negative isolates in the multinational SIDERO-WT studies. PER-producing Acinetobacter baumannii, mainly from Russia, showed high CFDC MICs of 8– >64 μg/mL. This study evaluated the synergistic effects of CFDC combined with other antibiotics against PER-producing A. baumannii isolates with high CFDC MICs. Methods Two isolates of PER-producing A. baumannii with resistance to CFDC (MIC 16 μg/mL), meropenem (MEM; MIC 64 μg/mL), ceftazidime-avibactam (CZA; MIC 64/4 μg/mL), amikacin (AMK; MIC 32 or 64 μg/mL), and ciprofloxacin (CIP; MIC ≥64 μg/mL) were tested. Against ampicillin-sulbactam (SAM), one isolate was resistant (MIC 32/64 μg/mL) and another was susceptible (MIC 8/16 μg/mL). Effects of CFDC combined with other antibiotics were evaluated by checkerboard assay and chemostat model reproducing humanized antibiotic exposure. The checkerboard assay used a single agent (e.g. ceftazidime [CAZ], avibactam [AVI], ampicillin [AMP] or sulbactam [SUL]). Iron-depleted cation-adjusted Mueller‒Hinton broth was used as the standard medium for CFDC, as recommended by the Clinical Laboratory and Standards Institute. Results Against both isolates, synergy with CFDC was seen for two β-lactamase inhibitors, AVI and SUL, with a fractional inhibitory concentration (FIC) index of 0.026–0.033 and 0.26–0.27, respectively. A synergistic to additive effect was seen for MEM and AMK, with an FIC index of 0.53–0.75 and 0.25–0.52, respectively. In the chemostat model, regrowth during 24-h treatment was observed with single agents (CFDC 2 g, q8h, 3-h infusion; MEM 2 g, q8h, 1-h infusion; CZA 2 g, q8h, 2-h infusion; SAM 3 g, q8h, 3-h infusion; AMK 15 mg/kg, q8h, 3-h infusion) for both isolates, including the SAM-susceptible isolate. However, no regrowth was seen when CFDC was combined with CZA, MEM, SAM or AMK. Conclusion The most potent synergy was seen between CFDC and AVI against PER-producing A. baumannii with a decreased MIC to ≤1 µg/mL for all isolates, followed by SUL and MEM. Under humanized pharmacokinetic exposure, combination of CFDC and CZA, MEM, SAM or AMK is expected to be effective against PER-producing A. baumannii in spite of high CFDC MICs. Disclosures Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Naomi Anan, MSc, Shionogi & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)