Antimicrobial susceptibility and resistance mechanisms to antipseudomonal β-lactams in <i>Pseudomonas aeruginosa</i> isolates from blood

Bloodstream infection caused by <i>Pseudomonas aeruginosa</i> with antimicrobial resistance can be difficult to treat. Herein, we investigated antimicrobial susceptibility to major antipseudomonal β-lactams and analyzed the relationship between resistance mechanisms and susceptibilities in <i>P. aeruginosa</i> isolates from blood. A total of 97 isolates possessing no carbapenemase gene were included in this study. The susceptibility rates to piperacillin, piperacillin/tazobactam, ceftazidime, and cefepime were in the 80% range, while 74.2% and 80.4% of the isolates showed susceptibility to imipenem and meropenem, respectively. None of the isolates showed resistance to ceftolozane/tazobactam or cefiderocol, and only one isolate each showed intermediate resistance (susceptibility rate, 99.0% each). The susceptibility rate was lowest for aztreonam (71.1%). The most prevalent susceptibility pattern was susceptible to all agents (56 isolates), followed by not susceptible only to aztreonam (nine isolates) or imipenem (seven isolates), and susceptible only to both ceftolozane/tazobactam and cefiderocol (six isolates). Multivariate logistic regression analysis revealed significant correlations between decreased <i>oprD</i> expression and decreased susceptibility to carbapenems; between increased <i>ampC</i> expression and non-susceptibility to piperacillin, piperacillin/tazobactam, and ceftazidime; and between increased <i>mexA</i> expression and decreased susceptibility to piperacillin, piperacillin/tazobactam, cefepime, aztreonam, and meropenem. These findings highlight the correlations between the expression of AmpC β-lactamase, OprD porin, and efflux pumps and non-susceptibility to β-lactams in <i>P. aeruginosa</i> isolates from blood. In contrast to traditional β-lactams, the stability of ceftolozane/tazobactam and cefiderocol against the resistance mechanisms was confirmed.IMPORTANCE<i>Pseudomonas aeruginosa</i> is a significant pathogen in hospital-acquired bloodstream infection (BSI) whose treatment requires the appropriate antimicrobial selection in consideration of antimicrobial resistance and resistance mechanisms. Although antipseudomonal β-lactams are key antimicrobial agents, several molecular mechanisms, including β-lactamases, OprD porin, and efflux pumps, are known to be intricately involved in β-lactam resistance. This study evaluated susceptibility profiles of <i>P. aeruginosa</i> to antipseudomonal β-lactams and revealed the correlations between susceptibility and the expression of genes underlying the relevant resistance mechanisms. The results demonstrate the potent <i>in vitro</i> activity of two new agents, ceftolozane/tazobactam and cefiderocol, against <i>P. aeruginosa</i> showing resistance to traditional antipseudomonal β-lactams. This study provides insights into the mechanisms underlying antipseudomonal β-lactam resistance in <i>P. aeruginosa</i>, highlighting the potential of ceftolozane/tazobactam and cefiderocol for use against <i>P. aeruginosa</i> BSI.