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Abstract：
Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to their emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent \"synergizer\". We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using five genetically different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10). Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolates except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.
摘要：
由产生KPC的肺炎克雷伯菌引起的感染由于其对新的抗微生物剂的新出现的抗性而继续构成重大的临床挑战。我们调查了两种药物之间的关联，这两种药物的作用已针对耐多药细菌重新利用：磷霉素和替莫西林。替莫西林对KPC酶表现出异常的稳定性，而磷霉素则是一种有效的“增效剂”。我们使用磷霉素和替莫西林的组合对100种产KPC的肺炎克雷伯菌的临床分离株进行了体外抗菌活性研究。结果表明在91%的分离物中具有协同活性。随后，我们使用五种基因不同的KPC-Kp分离株评估了对海绵状菌幼虫的影响。向替莫西林中添加磷霉素可将幼虫的存活率从73％提高到97％（Δ32％；分离株1），从93到100%(+Δ7%；隔离2)，从63%到86%(+Δ36%；隔离3)，从63%到90%(+Δ42%；隔离4)，从93到97%(+Δ4%；分离株10)。在产生耐替莫西林KPC的肺炎克雷伯菌分离株(24株)中，在除一个分离株之外的所有分离株中，磷霉素的添加将替莫西林的MIC值降至耐药断点以下。替莫西林与磷霉素联合使用，是对抗产生KPC的肺炎克雷伯菌的有希望的组合，需要进一步的临床评估。
