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.