685. An In Vitro Investigation of WCK 5222 (Cefepime/Zidebactam) and Currently Available Combination Antibiotic Regimens Against Enterobacteriaceae That Co-express Serine-β-Lactamase (SBL) and Metallo-β-Lactamase (MBL) Enzymes

Abstract

Background. Carbapenem-resistant Enterobacteriaceae (CRE) that simultaneously harbor SBLs and MBLs may demonstrate pan-drug resistance. Current therapeutic options include combinations of aztreonam (ATM), which is resistant to hydrolysis by MBLs, plus ceftazidime/avibactam (CZA) or meropenem/vaborbactam (M/V) for coverage of relevant SBLs. However, these selections add a level of complexity to clinical management compared with administration of a single antibiotic as monotherapy. Methods. Minimum inhibitory concentrations (MICs) of WCK 5222 (cefepime/ zidebactam), ATM, CZA, and M/V were determined with Liofilchem MIC Test Strips against SBL- and MBL-positive CRE (N = 15). The gradient diffusion strip (GDS) cross method was used to assess the activities of CZA+ATM and M/V+ATM. Additive interactions as defined by fractional inhibitory concentration indices ≤ 1 would be predicted based upon the known genotypic profiles; thus, the relative activities of the combination regimens were compared with the “zone of hope” (ZOH) test. The size of the ZOH (the zone of inhibited growth) was quantitated by multiplying the observed length of inhibited growth (in mm) adjacent to each GDS from the point of intersection. The Mann-Whitney rank-sum test was used to assess differences. Results. All isolates (N = 15) contained one MBL and ≥1 SBL, and were resistant to ATM, CZA, and M/V with the exception of one isolate intermediate to M/V (MIC=8 mg/L). The WCK 5222 MIC50 (range) was 1 (0.19-2) mg/L. The median (interquartile range) ZOH product for CZA+ATM and M/V+ATM was 75.4 (62.8-93.7) and 23.5 (14.1-60.4), respectively (P = 0.002). In strains that produced OXA-type carbapenemases (n = 6), the median ZOH product for CZA+ATM and M/V+ATM was 78.1 and 20.7, respectively (P = 0.004). In the remaining 9 strains with a single carbapenemase (i.e., the MBL),the median ZOH product for CZA+ATM and M/V+ATM was 73.8 and 25.6, respectively (P = 0.052). Conclusion. WCK 5222 displayed potent in vitro activity against SBL- and MBLpositive CRE, warranting further pre-clinical in vivo evaluation as a monotherapy option. When considering the co-expression of SBL and MBL, CZA+ATM appears to offer enhanced coverage compared with M/V+ATM.