Determining the Activity of Imipenem/Relebactam Plus Aztreonam Against Constitutive Pseudomonas-Derived Cephalosporinase- and Metallo-β-Lactamase-Producing Pseudomonas aeruginosa in a Hollow Fiber Infection Model

Background Few treatment options exist for serious infections caused by metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa. This study evaluated imipenem/relebactam (I/R) plus aztreonam (ATM) against Pseudomonas-derived cephalosporinase (PDC)- and MBL-producing P. aeruginosa in a hollow fiber infection model, with ceftazidime/avibactam (CZA) plus ATM as a comparator. Methods Two isogenic PDC- and MBL-producing P. aeruginosa isolates (MB10480: IMP-1; MB10620: VIM-1) were studied at a starting inoculum of ∼8 log₁₀ CFU/mL over 96 hours. Humanized I/R exposures were evaluated alone and with extended-infusion ATM (1.5 g q6h; 2 g q8h; 2 g q6h), with CZA plus ATM (2 g q6h) as comparator. Combinations were tested in triplicate, and ATM/relebactam or ATM/avibactam MICs were assessed at 96 hours. Results For both MB10480 (ATM/relebactam MIC: 8/4 mg/L) and MB10620 (4/4 mg/L), monotherapy arms mirrored the growth control. Both I/R plus ATM and CZA plus ATM produced early synergy (≥2 log₁₀ CFU/mL reduction relative to the most active monotherapy) with >1 log₁₀ CFU/mL killing relative to the starting inoculum at 24 hours, followed by regrowth, with bacteriostasis observed at 96 hours across regimens. However, bacterial counts at 96 hours were lowest with I/R plus ATM 2 g every 6 hours. Two colony morphologies were recovered, and retested MICs were occasionally, but not consistently, elevated. Conclusions Both I/R plus ATM and CZA plus ATM showed early synergy against PDC- and MBL-producing P. aeruginosa, but regrowth occurred with all regimens. Higher-dose ATM with I/R provided more durable suppression, though persistence remained common, underscoring the need to better define dosing and mechanisms of regrowth.