In vitro activity of imipenem/relebactam plus aztreonam against metallo-β-lactamase-producing, OprD-deficient Pseudomonas aeruginosa with varying levels of Pseudomonas-derived cephalosporinase production.
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Issue Date
6/1/2022
Authors
O'Donnell, J Nicholas
Putra, Vibert*
Belfiore, Gina M*
Maring, Brittney L
Young, Katherine
Lodise, Thomas P
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Abstract
Background: Treatment options for metallo-β-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 × 106 cfu/mL and incubated at 37°C for 24 h. Samples were drawn at 0, 2, 4, 6 and 24 h. Physiological fCmax, fCss,avg and fCmin 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 log10 cfu/mL reduction compared with the most active individual agent.
Results: Synergy was observed in five isolates in checkerboard studies, including three of seven MBL-producing 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 fCss,avg concentrations but exhibited similar activity to ATM at fCmin and fCmax 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.
Citation
O'Donnell JN, Putra V, Belfiore GM, Maring BL, Young K, Lodise TP. In vitro activity of imipenem/relebactam plus aztreonam against metallo-β-lactamase-producing, OprD-deficient Pseudomonas aeruginosa with varying levels of Pseudomonas-derived cephalosporinase production. Int J Antimicrob Agents. 2022 Jun;59(6):106595. doi: 10.1016/j.ijantimicag.2022.106595. Epub 2022 Apr 25. PMID: 35483625.
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