Sulbactam Combined With the Novel β-lactamase Inhibitor ETX2514 for the Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Sarah McLeod, Adam Shapiro, Samir Moussa, Nicole Carter, Michele Johnstone, Robert McLaughlin, Boudewijn Dejonge, Ruben Tommasi, John Mueller, Alita Miller
2016 Open Forum Infectious Diseases  
Background. Multidrug-resistant (MDR) Acinetobacter baumannii infections are of great concern due to high mortality rates and limited number of treatment options. β-lactamase (BL) expression, especially class D, is an important resistance mechanism in this organism. The novel BL inhibitor ETX2514 has potent activity against class A, C, and D serine BLs. The MIC 90 of sulbactam (SUL) in the presence of ETX2514 is 4 mg/L against a large, globally diverse set of MDR A. baumannii clinical isolates
more » ... rom 2014. In this study, we investigate the mechanism of synergy of this combination alone or in the presence of imipenem (IPM) or meropenem (MEM), whose spectra of target inhibition vary across bacterial species Methods. MICs were performed according to CLSI guidelines. The frequency of resistance (FOR) to SUL/ETX2514 was determined in several clinical isolates of A. baumannii. Resistant mutants were analyzed by whole-genome sequencing. Morphological changes were examined by microscopy. PBP acylation rates were determined by competition with BOCILLIN FL in fluorescence polarization assays. Results. The MIC 50 and MIC 90 of relevant combinations against 598 contemporary isolates of A. baumannii are shown in the table.
doi:10.1093/ofid/ofw172.1794 fatcat:pzsyd4fpdbdfzc3tbbe3cxftji