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

• Published in: mBio 2023-12, Vol.14 (6), p.e0111823
• Main Authors: Hujer, Andrea M, Marshall, Steven H, Mack, Andrew R, Hujer, Kristine M, Bakthavatchalam, Yamuna Devi, Umarkar, Kushal, Palwe, Snehal R, Takalkar, Swapna, Joshi, Prashant R, Shrivastava, Rahul, Periasamy, Hariharan, Bhagwat, Sachin S, Patel, Mahesh V, Veeraraghavan, Balaji, Bonomo, Robert A
• Format: Article
• Language: English
• Subjects: antibiotic resistance; Antimicrobial Chemotherapy; cefepime; Pseudomonas aeruginosa; Research Article; zidebactam; ß-lactam enhancer; ß-lactamases
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.01118-23

Multi-drug resistant (MDR) harbor a complex array of β-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a β-lactam/β-lactam-enhancer, cefepime/zidebactam, and novel β-lactam/β-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of ( = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-β-lactamases, serine β-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and cefepime/taniborbactam demonstrated MIC s of >128 mg/L, while cefepime/zidebactam MIC 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 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 isolates. Administered alone, cefepime required 47%-68% T >MIC for stasis to ~1 log kill effect, while cefepime in the presence of zidebactam required just 8%-16% for >2 log 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 β-lactam/β-lactamase inhibitors, β-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 β-lactamases including carbapenemases in . Compared to other genera of Gram-negative pathogens, is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed β-lactam and β-lactamase inhibitor combinations. This study shows that the novel β-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of . This study highlights that the β-lactam enhancer mechanism is a promising alternative to the conventional β-lactam/β-lactamase inhibitor approach in combating ever-evolving MDR .