Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Key Laboratory of Clinical Pharmacology of Antibiotics, National Heath Commission of People's Republic of China, Shanghai, China.
Microbiol Spectr. 2023 Jun 15;11(3):e0093223. doi: 10.1128/spectrum.00932-23. Epub 2023 May 18.
The role of novel β-lactam/β-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS) Pseudomonas aeruginosa has not been fully elucidated. This study evaluated the activity of novel β-lactam/β-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 β-lactamases with KPC-2 predominant ( = 19), and 45.3% (34/75) presented overexpression of chromosomal β-lactamase . 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 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. 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 β-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.
新型β-内酰胺/β-内酰胺酶抑制剂合剂在头孢他啶不敏感（CAZ-NS）和亚胺培南不敏感（IPM-NS）铜绿假单胞菌中的作用尚未完全阐明。本研究评估了新型β-内酰胺/β-内酰胺酶抑制剂合剂对铜绿假单胞菌临床分离株的活性，确定了阿维巴坦如何恢复头孢他啶的活性，并比较了头孢他啶-阿维巴坦（CZA）和亚胺培南-雷巴坦（IMR）对产 KPC 铜绿假单胞菌的活性。在中国 11 家医院的 596 株铜绿假单胞菌临床分离株中，发现 CZA、IMR 和头孢洛扎-他唑巴坦（88.9%至 89.8%）对 CZA、IMR 和头孢洛扎-他唑巴坦具有相似的高敏感性，且对头孢他啶的敏感性高于亚胺培南（73.5%比 63.1%）。对于 CAZ-NS 和 IPM-NS 分离株，CZA、头孢洛扎-他唑巴坦和 IMR 的敏感性分别为 61.5%（75/122）、54.9%（67/122）和 51.6%（63/122）。对于 CAZ-NS、IPM-NS 但 CZA 敏感的分离株，34.7%（26/75）携带以 KPC-2 为主的获得性β-内酰胺酶（ = 19），45.3%（34/75）表现出染色体β-内酰胺酶的过度表达。在 22 株仅携带 KPC-2 碳青霉烯酶的分离株中，CZA 和 IMR 的敏感性分别为 86.4%（19/22）和 9.1%（2/22）。值得注意的是，IMR 不敏感的 95%（19/20）分离株均存在基因的失活突变。总之，CZA、头孢洛扎-他唑巴坦和 IMR 对铜绿假单胞菌具有高活性，CZA 对 CAZ-NS 和 IPM-NS 分离株以及产 KPC 铜绿假单胞菌的活性均优于 IMR。阿维巴坦克服了 KPC-2 酶和过度表达的 AmpC 引起的头孢他啶耐药性。
全球抗菌药物耐药性的出现带来了特别的挑战，因此提出了“难治疗”铜绿假单胞菌（DTR-P. aeruginosa）的概念。在这里，铜绿假单胞菌临床分离株对三种β-内酰胺酶抑制剂合剂 CZA、IMR 和头孢洛扎-他唑巴坦高度敏感。KPC-2 酶和功能失调的孔蛋白 OprD 的组合导致铜绿假单胞菌对 IMR 耐药，CZA 在对抗产 KPC-2 的铜绿假单胞菌方面比 IMR 更有效。CZA 对 CAZ-NS 和 IPM-NS 铜绿假单胞菌也表现出良好的活性，主要通过抑制 KPC-2 酶和过度产生 AmpC，支持 CZA 在治疗 DTR-P. aeruginosa 引起的感染中的临床应用。
