Sakoulas George, Moise Pamela A, Casapao Anthony M, Nonejuie Poochit, Olson Joshua, Okumura Cheryl Y M, Rybak Michael J, Kullar Ravina, Dhand Abhay, Rose Warren E, Goff Debra A, Bressler Adam M, Lee Yuman, Pogliano Joseph, Johns Scott, Kaatz Glenn W, Ebright John R, Nizet Victor
University of California San Diego School of Medicine, La Jolla, California.
Cubist Pharmaceuticals, Lexington, Massachusetts.
Clin Ther. 2014 Oct 1;36(10):1317-33. doi: 10.1016/j.clinthera.2014.05.061. Epub 2014 Jul 10.
Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin.
All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed.
Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model.
Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.
指南推荐达托霉素联合治疗作为万古霉素治疗失败后耐甲氧西林金黄色葡萄球菌（MRSA）菌血症的一种选择。近期数据表明，将达托霉素与β-内酰胺类药物联合使用可能具有独特的益处；然而，关于头孢洛林与达托霉素联合使用的临床数据非常有限。
纳入了2011年3月至2012年11月期间10个医疗中心使用头孢洛林加 达托霉素治疗确诊的难治性葡萄球菌菌血症的所有26例病例。还进行了体外（协同研究、结合试验、杀菌肽LL-37杀菌试验）和体内（使用小鼠皮下感染模型的毒力试验）研究，以考察头孢洛林与达托霉素联合使用的效果。
26例葡萄球菌菌血症患者使用了达托霉素加头孢洛林（20例MRSA、2例万古霉素中介金黄色葡萄球菌、2例甲氧西林敏感金黄色葡萄球菌[MSSA]、2例耐甲氧西林表皮葡萄球菌）。在先前的抗菌治疗中，菌血症持续的中位时间为10天（范围3 - 23天）。开始使用达托霉素加头孢洛林后，菌血症清除的中位时间为2天（范围1 - 6天）。体外研究表明头孢洛林对MRSA具有协同作用，并增强了杀菌肽LL-37和中性粒细胞对MRSA的杀灭作用。头孢洛林还在MSSA和MRSA中诱导达托霉素结合，其程度与萘夫西林相当。在亚抑菌浓度的头孢洛林环境中生长的MRSA在小鼠皮下感染模型中显示出毒力减弱。
头孢洛林加 达托霉素可能是加速难治性葡萄球菌菌血症清除的一种选择。头孢洛林通过与达托霉素协同作用以及对宿主天然防御肽杀菌肽LL37致敏发挥双重作用，这可能会减弱病原体的毒力。
