In vitro activity of imipenem/relebactam plus aztreonam against metallo-,?-lactamase-producing, OprD-deficient Pseudomonas aeruginosa with varying levels of Pseudomonas-derived cephalosporinase production

Background: Treatment options for metallo- ,B-lactamase (MBL)-producing Pseudomonas aeruginosa infections are limited. Imipenem/relebactam (I/R) plus aztreonam (ATM) may be an option. Methods: Ten OprD(-) P. aeruginosa isolates (3 parent strains; 7 MBL-producers) were evaluated using checkerboard methodology and Fractional Inhibitory Concentration Index (FICI). Isolates exhibiting synergy in checkerboard studies (FICI <= 0.5) were evaluated using 24-h static concentration time-kill. Bacteria in late log-phase growth were diluted to 1 x 10 6 cfu/mL and incubated at 37 degrees C for 24 h. Samples were drawn at 0, 2, 4, 6 and 24 h. Physiological f C max , f C ss,avg and f C min of imipenem (26.7, 5.6, 0.5 mg/L), relebactam (REL; 13.1, 4, 0.8 mg/L) and ATM (62, 29, 8 mg/L) were used. Synergy in time-kill studies was defined as > 2 log 10 cfu/mL reduction compared with the most active individual agent.Results: Synergy was observed in five isolates in checkerboard studies, including three of seven MBLproducing isolates. Isolates that were OprD(-) and harbored inducible Pseudomonas-derived cephalosporinases (PDCs) did not show synergy as defined by FICI; however, ATM minimum inhibitory concentrations (MICs) were significantly reduced with the combination. In time-kill studies, ATM alone was as active as combination regimens for MBL-producing isolates with deleted or inducible PDC production. For strains exhibiting constitutive PDC production, I/R plus ATM was synergistic at f C ss,avg concentrations but exhibited similar activity to ATM at f C min and f C max concentrations.Conclusions: I/R plus ATM appears to exhibit synergy for some MBL-producing P. aeruginosa at physiological concentrations. Further study of the effect of dynamic concentrations is needed to fully understand the utility of this combination. (c) 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.