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Background We previously reported the potent in vivo activity of ceftazidime/avibactam human-simulated regimen (HSR) against MBL-EB despite the observed resistance in vitro and the lack of avibactam MBL-inhibitory activity (AAC 2014 Nov;58(11):7007-9). Similar to avibactam, relebactam (REL) is a diazabicyclooctane that inhibits serine β-lactamases belonging to Classes A - C but not MBLs. In the current study, we examined the in vivo activity of cefepime (FEP)/REL combination HSR against MBL-EB in a murine thigh infection model. Methods Six clinical MBL-EB isolates expressing VIM, IMP or NDM and co-expressing at least one β-lactamase of Classes A - C (KPC, CTX-M, TEM, SHV, ACT, CMY) were utilized. MICs of FEP and FEP/REL combination (at fixed REL concentration of 4 mg/L) were determined using broth microdilution. FEP HSR (2 g q12h as 0.5 h infusion) alone and in combination with REL HSR (250 mg q6h as 0.5 h infusion) were established in the infection model. Thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 CFU/ml. Two hours later, mice were administered the FEP HSR or the FEP/REL HSR. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Results All isolates were FEP resistant (MIC ≥ 32 mg/L). Addition of REL had no impact on the MIC of the isolates. In in vivo studies, the average bacterial burden at 0 h was 5.84 ± 0.41 log10CFU/thigh. In accordance with the in vitro susceptibility, administration of FEP HSR was associated with net bacterial growth among all isolates ranging from 0.46 ± 0.60 to 2.97 ± 0.53 log10CFU/thigh. In contrast, FEP/REL combination HSR resulted in substantial bacterial reductions among all isolates ranging from -0.73 ± 0.13 to -1.72 ± 0.14 log10CFU/thigh, indicating that REL enhanced the FEP activity in vivo. Conclusion Despite the powerful β-lactam hydrolytic capability of MBLs in vitro, FEP inactivation in the murine model was attributed predominantly to the expression of the serine β-lactamases. The in vitro/in vivo discordance in β-lactam/β-lactamase activity against MBL-EB reveals a potential flaw in the currently utilized in vitro susceptibility testing methodologies and highlights a challenge encountered during the development of new agents against these isolates. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck &amp; Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

1312. Metallo-β-lactamase-Producing Enterobacterales (MBL-EB): Is it Time to Rethink Our Assessment Tools?