Transcending the challenge of evolving resistance mechanisms in Pseudomonas aeruginosa through -lactam-enhancer-mechanism-based cefepime/zidebactam

Multi-drug resistant (MDR) Pseudomonas aeruginosa harbor a complex array of beta-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a beta-lactam/beta-lactam-enhancer, cefepime/zidebactam, and novel beta-lactam/beta-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of P. aeruginosa (n = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-beta-lactamases, serine beta-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and cefepime/taniborbactam demonstrated MIC(90)s of >128 mg/L, while cefepime/zidebactam MIC90 was 16 mg/L. In a neutropenic-murine lung infection model, a cefepime/zidebactam human epithelial-lining fluid-simulated regimen achieved or exceeded a translational end point of 1-log(10) kill for the isolates with elevated cefepime/zidebactam MICs (16-32 mg/L), harboring VIM-2 or KPC-2 and alterations in PBP2 and PBP3. In the same model, to assess the impact of zidebactam on the pharmacodynamic (PD) requirement of cefepime, dose-fractionation studies were undertaken employing cefepime-susceptible P. aeruginosa isolates. Administered alone, cefepime required 47%-68% fT >MIC for stasis to similar to 1 log(10) kill effect, while cefepime in the presence of zidebactam required just 8%-16% for >2 log(10) kill effect, thus, providing the pharmacokinetic/PD basis for in vivo efficacy of cefepime/zidebactam against isolates with MICs up to 32 mg/L. Unlike beta-lactam/beta-lactamase inhibitors, beta-lactam enhancer mechanism-based cefepime/zidebactam shows a potential to transcend the challenge of ever-evolving resistance mechanisms by targeting multiple PBPs and overcoming diverse beta-lactamases including carbapenemases in P. aeruginosa. IMPORTANCE Compared to other genera of Gram-negative pathogens, Pseudomonas is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed beta-lactam and beta-lactamase inhibitor combinations. This study shows that the novel beta-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of P. aeruginosa. This study highlights that the beta-lactam enhancer mechanism is a promising alternative to the conventional beta-lactam/beta-lactamase inhibitor approach in combating ever-evolving MDR P. aeruginosa.