Servicio de Microbiología & Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
Servicio de Microbiología & Instituto de Investigación Sanitaria Illes Balears (IdISBa), Hospital Universitario Son Espases, Palma de Mallorca, Spain.
J Antimicrob Chemother. 2024 Oct 1;79(10):2591-2597. doi: 10.1093/jac/dkae263.
We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa.
We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to β-lactams. The other 43 constructs expressed transferable β-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution.
Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable β-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol.
Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged.
我们旨在比较新开发的β-内酰胺类药物（头孢地尔）和β-内酰胺/β-内酰胺酶抑制剂组合（头孢他啶/阿维巴坦、头孢唑肟/他唑巴坦、氨曲南/阿维巴坦、头孢吡肟/替坦博巴坦、头孢吡肟/齐多巴坦、亚胺培南/雷利巴坦、美罗培南/沃巴坦、美罗培南/那库巴坦和美罗培南/泽罗巴坦）对铜绿假单胞菌中最具临床相关性的突变和可转移β-内酰胺耐药机制的稳定性。
我们筛选了 61 株铜绿假单胞菌 PAO1 衍生物。18 株分离株对β-内酰胺的突变耐药机制表现出最相关的机制。其余 43 个构建体表达了来自 pUCP-24 克隆的可转移β-内酰胺酶。通过参考肉汤微量稀释法测定 MIC。
头孢地尔和亚胺培南/雷利巴坦对所有研究的突变耐药机制均表现出极好的体外活性。氨曲南/阿维巴坦、头孢吡肟/替坦博巴坦、头孢吡肟/齐多巴坦、美罗培南/沃巴坦、美罗培南/那库巴坦和美罗培南/泽罗巴坦对突变事件，尤其是外排操纵子的过度表达，证明更容易受到影响。对可转移β-内酰胺酶具有最广泛活性的药物是氨曲南/阿维巴坦和头孢吡肟/齐多巴坦，其次是头孢吡肟/替坦博巴坦、头孢地尔、美罗培南/泽罗巴坦和美罗培南/那库巴坦。然而，某些 MBL，特别是 NDM 酶，可能会影响它们的活性。某些酶（如 NDM-1）的联合产生，加上 MexAB-OprM 介导的外排增加和 OprD 缺乏，导致对几乎所有测试药物的耐药性，包括最后选择的药物，如氨曲南/阿维巴坦和头孢地尔。
头孢地尔和新型β-内酰胺/β-内酰胺酶抑制剂组合对铜绿假单胞菌突变和可转移β-内酰胺耐药性具有有前景且互补的体外活性。然而，外排泵、OprD 缺乏和高效β-内酰胺酶的联合作用仍可能导致所有治疗选择的丧失。鼓励进行耐药性监测、合理使用新药物和持续的药物开发工作。
