1410. Novel Framework to Compare the Effectiveness of Tazobactam, Relebactam and Avibactam Against Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae

BACKGROUND: Resistance mediated by extended-spectrum β-lactamases (ESBLs) presents a serious challenge in the treatment of Gram-negative pathogens. ESBLs confer resistance to most β-lactams which may be reversed with the addition of an active β-lactamase inhibitor (such as tazobactam, relebactam and avibactam). However, various ESBLs may display different susceptibilities to these inhibitors, which could impact efficacy. We propose a framework for comparing the efficacy of these inhibitors when combined with the same β-lactam. METHODS: Three clinical isolates of K. pneumoniae harboring CTX-M-15 and one E. coli with SHV-12 were used. The susceptibility of each isolate to piperacillin was determined by broth dilution using escalating concentrations of tazobactam, relebactam and avibactam. Similar experiments were subsequently conducted with ceftazidime. The resulting minimum inhibitory concentrations (MICs) were mapped as response to inhibitor concentration using an inhibitory E(max) model. The best-fit model parameters were compared for each isolate-inhibitor combination. RESULTS: In all scenarios, MIC reductions were observed in the presence of increasing inhibitor concentrations. The MIC reduction for each isolate was well fitted to inhibitor concentrations (r(2) ≥ 95%). IC(50) estimates reflected the sensitivity of the isolates to each inhibitor, while I(max) captured the maximum extent of MIC reduction. With piperacillin, IC(50) values ranged from 1.36 to 35.25µg/mL for tazobactam, 2.32–15.82 µg/mL for relebactam and 0.62–2.37 µg/mL for avibactam. I(max) values were 4.75–6.99, 6.56–9.77 and 7.83–11.22 for tazobactam, relebactam and avibactam, respectively. Similar trends in IC(50) and I(max) were observed with ceftazidime as the β-lactam. CONCLUSION: We illustrated a simple structural model capable of comparing the performance of different inhibitors. This platform may be used to identify the optimal pairing of various β-lactams and β-lactamase inhibitors for individual isolates. DISCLOSURES: V. Tam, European Union’s Seventh Framework Programme: Grant Investigator, Research grant.