Le Terrier Christophe, Raro Otávio Hallal Ferreira, Saad Alaaeldin Mohamed, Nordmann Patrice, Poirel Laurent
Emerging Antibiotic Resistance Unit, Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Chemin du Musée 18, Fribourg, CH-1700, Switzerland.
Division of Intensive Care Unit, University Hospitals of Geneva, Geneva, Switzerland.
Eur J Clin Microbiol Infect Dis. 2025 Feb;44(2):277-284. doi: 10.1007/s10096-024-04965-x. Epub 2024 Nov 26.
Overproduction of the intrinsic chromosomally-encoded AmpC β-lactamase is one of the main mechanisms responsible for broad-spectrum β-lactam resistance in Pseudomonas aeruginosa. Our study aimed to evaluate the in-vitro activity of anti-pseudomonal β-lactam molecules associated with the recently-developed and commercially-available β-lactamase inhibitors, namely avibactam, relebactam and vaborbactam, against P. aeruginosa isolates overproducing their AmpC.
MIC values of ceftazidime, cefepime, meropenem, imipenem and ceftolozane with or without β-lactam inhibitor were determined for 50 AmpC-overproducing P. aeruginosa clinical isolates. MIC breakpoints for resistance were retained at 8 mg/L for β-lactams and β-lactam/β-lactamase inhibitor combinations containing ceftazidime, cefepime and meropenem, while 4 mg/L was used for those containing imipenem and ceftolozane. The concentration of all β-lactamases inhibitors was fixed at 4 mg/L, except for vaborbactam (8 mg/L).
The rates of isolates not being resistant to ceftazidime, cefepime, meropenem, imipenem and ceftolozane were found at 12%, 22%, 34%, 8% and 74%, respectively. When combined with avibactam, those rates increased to 60%, 62%, 60%, 46%, and 80%, respectively. The highest rates were found with relebactam-based combinations, being 76%, 64%, 66%, 76% and 84%, respectively. By contrast, associations with vaborbactam did not lead to significantly increased "non-resistance" rates.
Our results showed that all combinations including relebactam led to higher "non-resistance" rates against AmpC-overproducing P. aeruginosa clinical isolates. The best activity was achieved by combining ceftolozane and relebactam, that might therefore be considered as an excellent clinical alternative against AmpC overproducers.
内在染色体编码的AmpCβ-内酰胺酶过度产生是铜绿假单胞菌对广谱β-内酰胺耐药的主要机制之一。我们的研究旨在评估与最近开发并上市的β-内酰胺酶抑制剂（即阿维巴坦、瑞巴坦和瓦博巴坦）联合使用的抗假单胞菌β-内酰胺分子对过度产生AmpC的铜绿假单胞菌分离株的体外活性。
测定了50株过度产生AmpC的铜绿假单胞菌临床分离株对头孢他啶、头孢吡肟、美罗培南、亚胺培南和头孢洛扎坦（有无β-内酰胺酶抑制剂）的最低抑菌浓度（MIC）值。含头孢他啶、头孢吡肟和美罗培南的β-内酰胺类及β-内酰胺/β-内酰胺酶抑制剂组合的耐药MIC折点保持在8mg/L，而含亚胺培南和头孢洛扎坦的组合则为4mg/L。除瓦博巴坦为8mg/L外，所有β-内酰胺酶抑制剂的浓度均固定为4mg/L。
未对头孢他啶、头孢吡肟、美罗培南、亚胺培南和头孢洛扎坦耐药的分离株比例分别为12%、22%、34%、8%和74%。与阿维巴坦联合使用时，这些比例分别增至60%、62%、60%、46%和80%。基于瑞巴坦的组合比例最高，分别为76%、64%、66%、76%和84%。相比之下，与瓦博巴坦联合使用并未导致“非耐药”比例显著增加。
我们的结果表明，所有含瑞巴坦的组合对过度产生AmpC的铜绿假单胞菌临床分离株的“非耐药”比例更高。头孢洛扎坦与瑞巴坦联合使用活性最佳，因此可能被视为针对AmpC过度产生菌的优秀临床替代方案。
