Comparison of In Vitro Activity of Ceftazidime-Avibactam and Imipenem-Relebactam against Clinical Isolates of Pseudomonas aeruginosa

The emergence of antimicrobial resistance poses a particular challenge globally, and the concept of P. aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) was proposed. Here, P. aeruginosa clinical isolates were highly susceptible to three beta-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The role of novel beta-lactam/beta-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS) Pseudomonas aeruginosa has not been fully elucidated. This study evaluated the in vitro activity of novel beta-lactam/beta-lactamase inhibitor combinations against Pseudomonas aeruginosa clinical isolates, determined how avibactam restored ceftazidime activity, and compared the activity of ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) against KPC-producing P. aeruginosa. Similar high susceptibility rates for CZA, IMR, and ceftolozane-tazobactam (88.9% to 89.8%) were found for 596 P. aeruginosa clinical isolates from 11 hospitals in China, and a higher susceptibility rate to ceftazidime than imipenem was observed (73.5% versus 63.1%). For CAZ-NS and IPM-NS isolates, susceptibility rates for CZA, ceftolozane-tazobactam, and IMR were 61.5% (75/122), 54.9% (67/122), and 51.6% (63/122), respectively. For CAZ-NS, IPM-NS but CZA-susceptible isolates, 34.7% (26/75) harbored acquired beta-lactamases with KPC-2 predominant (n = 19), and 45.3% (34/75) presented overexpression of chromosomal beta-lactamase ampC. Among 22 isolates carrying KPC-2 carbapenemase alone, susceptibility rates to CZA and IMR were 86.4% (19/22) and 9.1% (2/22), respectively. Notably, 95% (19/20) of IMR-nonsusceptible isolates had an inactivating mutation of oprD gene. In conclusion, CZA, ceftolozane-tazobactam, and IMR exhibit high activity against P. aeruginosa, and CZA is more active than IMR against CAZ-NS and IPM-NS isolates as well as KPC-producing P. aeruginosa. Avibactam overcomes ceftazidime resistance engendered by KPC-2 enzyme and overexpressed AmpC.IMPORTANCE The emergence of antimicrobial resistance poses a particular challenge globally, and the concept of P. aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) was proposed. Here, P. aeruginosa clinical isolates were highly susceptible to three beta-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The combination of KPC-2 enzyme and nonfunctional porin OprD contributed to IMR resistance in P. aeruginosa, and CZA was more active than IMR in fighting against KPC-2-producing P. aeruginosa. CZA also showed good activity against CAZ-NS and IPM-NS P. aeruginosa, primarily by inhibiting KPC-2 enzyme and overproduced AmpC, supporting the clinical use of CZA in the treatment of infections caused by DTR-P. aeruginosa.

Automated summary

The emergence of difficult-to-treat resistance in Pseudomonas aeruginosa is a global challenge. Three beta-lactamase inhibitor combinations (CZA, IMR, and ceftolozane-tazobactam) showed high susceptibility in clinical isolates of P. aeruginosa. CZA exhibited better activity against KPC-2-producing P. aeruginosa and also showed good efficacy against CAZ-NS and IPM-NS isolates.