Int J Antimicrob Agents. 2021 Jan 9:106278. doi: 10.1016/j.ijantimicag.2021.106278. Online ahead of print.
The emergence of Gram-negative resistance during antibacterial therapy yields worse clinical outcomes and increased antimicrobial resistance worldwide. We evaluated the emergence of nonsusceptibility to ceftolozane/tazobactam and meropenem among participants with Pseudomonas aeruginosa lower respiratory tract isolates from ASPECT-NP, a phase 3, randomized, double-blind, multicenter study that demonstrated the noninferiority of a ceftolozane/tazobactam 3-g dose q8h versus a meropenem 1-g dose q8h for treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia. Molecular resistance mechanisms among postbaseline nonsusceptible P. aeruginosa isolates and clinical outcomes associated with participants with emergence of nonsusceptibility were examined. Baseline susceptible and postbaseline nonsusceptible P. aeruginosa isolate pairs from the same participant underwent molecular typing. Emergence of nonsusceptibility was not observed among the 59 participants with baseline susceptible P. aeruginosa isolates in the ceftolozane/tazobactam arm. Among 58 participants with baseline susceptible P. aeruginosa isolates in the meropenem arm, emergence of nonsusceptibility was observed in 13 (22.4%). Among participants who received ceftolozane/tazobactam and meropenem, respectively, 5.1% and 3.4% had a new infection with a nonsusceptible strain. None of the isolates with emergence of nonsusceptibility to meropenem developed coresistance to ceftolozane/tazobactam. Molecular mechanisms associated with emergence of nonsusceptibility to meropenem were decreased expression or loss of OprD and overexpression of MexXY. Among participants with emergence of nonsusceptibility to meropenem, clinical outcomes were similar to overall clinical outcomes in the ASPECT-NP meropenem arm. Ceftolozane/tazobactam was more stable to emergence of nonsusceptibility versus meropenem; emergence of nonsusceptibility was not observed in any participants with baseline susceptible P. aeruginosa who received ceftolozane/tazobactam in ASPECT-NP.