Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, NY 12208, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9255 Pharmacy Lane, La Jolla, CA, USA.
J Antimicrob Chemother. 2024 Oct 1;79(10):2421-2459. doi: 10.1093/jac/dkae253.
Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a β-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a β-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of β-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.
治疗由耐药革兰氏阴性菌引起的严重感染的患者仍然存在很大的问题，这促使临床医生以创新的方式使用现有的抗菌药物。一种越来越受到关注的治疗方法是联合静脉注射磷霉素治疗。本文综述了磷霉素治疗耐药革兰氏阴性菌引起的严重感染的临床前药代动力学/药效学（PK/PD）感染模型和临床数据。体外动态和动物感染模型研究数据以及针对高度耐药肠杆菌科和非乳糖发酵菌的研究数据均为阳性，表明磷霉素联合β-内酰胺类、多粘菌素或氨基糖苷类药物具有协同作用，其效果可与其他含氨基糖苷类或多粘菌素类药物的方案相媲美或超越。迄今为止开展的临床研究主要涉及肺炎和/或由肺炎克雷伯菌、铜绿假单胞菌或鲍曼不动杆菌引起的菌血症患者。总的来说，观察到的磷霉素联合方案的成功率与其他常用于治疗这些患者的联合方案报告的成功率一致。在可以直接进行治疗比较的研究中，结果表明接受磷霉素联合治疗的患者与其他治疗方法和联合治疗的患者的结果相似或改善，尤其是当与针对（1）PBP-3 和（2）在存在β-内酰胺酶时具有异常稳定性的β-内酰胺类药物联合使用时。总的来说，这些数据表明，对于抗生素耐药性革兰氏阴性感染的患者，当利大于弊时，联合静脉注射磷霉素治疗应被视为氨基糖苷类或多粘菌素类药物联合治疗的潜在替代方案。
