727. Potency of the β-Lactamase Inhibitor QPX7728 Is Minimally Affected by KPC Mutations that Reduce Potency of Ceftazidime–Avibactam

Background In the United States, carbapenem-resistant Enterobacteriaceae (CRE) are mainly represented by KPC-producing strains and ceftazidime–avibactam (C/A) is increasingly used to treat infections caused by KPC-producers. C/A resistant (C/A-R) mutants with mutations in blaKPC can be isolated in vitro and were reported in patients treated with C/A. QPX7728 (QPX) is a new ultra-broad-spectrum β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with a potent activity against serine and metallo-β-lactamases. QPX in combination with meropenem (MER), M/Q, or cefepime (FEP), F/Q, has potent activity against all types of CRE (KPC, MBLs and OXA-48). The objective of these studies was to evaluate the activity of QPX in combination with various antibiotics against KPC-producing strains with C/A-R due to mutations in blaKPC. Methods Ten strains of KPC-producing Klebsiella pneumoniae with C/A MIC varied from 0.5 µg/mL to 8 µg/mL were used in resistance studies using C/A at 2x–8x the MIC (with avibactam [AVI] fixed at 4 µg/mL). Mutations in blaKPC were identified by sequence analysis. Ceftazidime (CAZ), MER and FEP MIC alone and with AVI and QPX (both BLIs at 4 µg/mL) were determined using the reference broth microdilution method. Five C/A-R clinical isolates with mutations in blaKPC were also included in the panel. Results Mutations in blaKPC that result in C/A resistance were selected in all strains. Mutants had 4- to 64-fold (16-fold average) increase in C/A MIC that varied from 16 to 128 μg/mL. In contrast, there was a 2-fold increase for CAZ-QPX MICs (MICs between ≤0.125 to 2 μg/mL. Similarly, there was no more than 2-fold increase in MER/QPX and FEP/QPX MICs, and the majority of mutants did not have an increase in MER/QPX or FEP/QPX MICs (MICs varied from ≤0.125 to 1 µg/mL). For five clinical C/A-R isolates, C/A, M/Q and F/Q MIC varied from 16 to ≥128 μg/mL, ≤0.125 to 4 μg/mL, and ≤0.125 to 2 μg/mL, respectively. Conclusion These data indicate that KPC mutations that affect the potency of C/A have minimal effect on the potency of QPX7728 combinations with either CAZ, MER or FEP indicating the potential differences in binding sites for these inhibitors in KPC. Further studies of QPX combinations are in progress. Disclosures All authors: No reported disclosures.