Jankeel Allen, Pérez-Parra Gabriel, Khetarpal Anuj K, Alvarado Ivan A, Nizet Victor, Sakoulas George, Ulloa Erlinda R
Department of Pediatrics, University of California, Irvine School of Medicine.
Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics.
J Infect Dis. 2025 Jul 30;232(1):181-190. doi: 10.1093/infdis/jiaf010.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high rates of treatment failure, even when antibiotics showing in vitro susceptibility are used. Early optimization of therapy is crucial to reduce morbidity and mortality. Building on our previous research on carbapenem therapy for methicillin-susceptible S aureus bacteremia, we examined the utility of adjunctive carbapenems (ertapenem or meropenem) to enhance the efficacy of ceftaroline or vancomycin for treatment of MRSA.
The effectiveness of combination therapy versus monotherapy against MRSA was assessed using checkerboard, time-kill, and human whole blood killing assays, as well as a murine bacteremia model. Additionally, we performed transcriptomic analysis and conducted human platelet and antimicrobial peptide killing assays on MRSA pretreated with subtherapeutic concentrations of ceftaroline and carbapenems. The supernatants from these MRSA isolates were used to treat platelets, and cytotoxicity was assessed via lactate dehydrogenase release assays.
Although not used for MRSA, we identified striking in vitro and in vivo synergy between carbapenems and ceftaroline or vancomycin. MRSA pretreated with subtherapeutic ceftaroline-carbapenem therapy revealed transcriptional shifts indicative of reduced antibiotic resistance, virulence, and host immune evasion. Supernatants from these MRSA isolates also caused less platelet injury compared to monotherapy. Furthermore, MRSA pretreated with ceftaroline and carbapenems demonstrated increased susceptibility to killing by human platelets and the antimicrobial peptide LL-37.
The therapeutic success of adjunctive carbapenems appears driven by multiple mechanisms, including direct drug-drug synergy with first-line anti-MRSA agents, attenuation of resistance and virulence factors, and enhancement of immune-mediated killing, each warranting further investigation.
耐甲氧西林金黄色葡萄球菌（MRSA）菌血症即使使用体外药敏显示敏感的抗生素，治疗失败率仍很高。早期优化治疗对于降低发病率和死亡率至关重要。基于我们之前关于碳青霉烯类药物治疗甲氧西林敏感金黄色葡萄球菌菌血症的研究，我们研究了辅助使用碳青霉烯类药物（厄他培南或美罗培南）增强头孢托罗或万古霉素治疗MRSA疗效的效用。
使用棋盘法、时间杀菌法、人全血杀菌试验以及小鼠菌血症模型评估联合治疗与单药治疗对MRSA的有效性。此外，我们进行了转录组分析，并对用亚治疗浓度的头孢托罗和碳青霉烯类药物预处理的MRSA进行了人血小板和抗菌肽杀菌试验。这些MRSA分离株的上清液用于处理血小板，并通过乳酸脱氢酶释放试验评估细胞毒性。
虽然未用于MRSA，但我们发现碳青霉烯类药物与头孢托罗或万古霉素之间在体外和体内均有显著协同作用。用亚治疗剂量的头孢托罗-碳青霉烯类药物预处理的MRSA显示出转录变化，表明抗生素耐药性、毒力和宿主免疫逃避降低。与单药治疗相比，这些MRSA分离株的上清液对血小板的损伤也更小。此外，用头孢托罗和碳青霉烯类药物预处理的MRSA对人血小板和抗菌肽LL-37的杀伤敏感性增加。
辅助使用碳青霉烯类药物的治疗成功似乎由多种机制驱动，包括与一线抗MRSA药物的直接药物协同作用、耐药性和毒力因子的减弱以及免疫介导杀伤作用的增强，每种机制都值得进一步研究。
