Efficacy of Daptomycin in Implant-Associated Infection Due to Methicillin-Resistant Staphylococcus aureus: Importance of Combination with Rifampin
Efficacy of Daptomycin in Implant-Associated Infection Due to Methicillin-Resistant Staphylococcus aureus: Importance of Combination with Rifampin
复制标题
DOI：
10.1128/aac.00047-09
复制
发表时间：
2009-07-01
影响因子：
4.9
通讯作者：
Trampuz, Andrej
中科院分区：
文献类型：
--
作者：
John, Anne-Kathrin;Baldoni, Daniela;Trampuz, Andrej
对于由耐甲氧西林金黄色葡萄球菌（MRSA）引起的植入物相关感染，可用的治疗选择有限。我们在豚鼠异物感染模型中比较了达托霉素（单独使用和与利福平[利福平]联合使用）与其他抗菌方案对MRSA ATCC 43300的活性。达托霉素对MRSA对数生长期和稳定生长期的MIC分别为0.625、0.625和20 μ g/ml。在时间杀灭研究中，达托霉素显示出对处于稳定生长期的MRSA的快速和浓度依赖性杀灭。当达托霉素浓度高于20 μ g/ml时，在2 ~ 4小时内可使菌落数减少>3 log（10）CFU/ml。在无菌笼液中，分别以20、30和40 mg/kg体重单次腹腔内给药后4 - 6 h达托霉素峰浓度达到23.1、46.3和53.7 μ g/ml。在治疗研究中，单独使用达托霉素可使耐甲氧西林MRSA计数降低0.3 log（10）CFU/ml，而与利福平联合使用时，观察到计数降低>6 log（10）CFU/ml。万古霉素和达托霉素（两种剂量）作为单药治疗时无法治愈任何笼相关感染，而利福平单独治疗治愈了33%笼的感染。与利福平联合使用时，达托霉素的治愈率为25%（20 mg/kg）和67%（30 mg/kg），万古霉素的治愈率为8%，利奈唑胺的治愈率为0%，左氧氟沙星的治愈率为58%。此外，高剂量（30 mg/kg）的达托霉素完全阻止了耐药和贴壁MRSA细胞中利福平耐药性的出现。高剂量达托霉素（相当于人体中6 mg/kg）与利福平联合治疗对耐甲氧西林和粘附性MRSA的活性最高。达托霉素加利福平是一种有前途的治疗选择植入物相关的MRSA感染。
Limited treatment options are available for implant-associated infections caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). We compared the activity of daptomycin (alone and with rifampin [rifampicin]) with the activities of other antimicrobial regimens against MRSA ATCC 43300 in the guinea pig foreign-body infection model. The daptomycin MIC and the minimum bactericidal concentration in logarithmic phase and stationary growth phase of MRSA were 0.625, 0.625, and 20 mu g/ml, respectively. In time-kill studies, daptomycin showed rapid and concentration-dependent killing of MRSA in stationary growth phase. At concentrations above 20 mu g/ml, daptomycin reduced the counts by >3 log(10) CFU/ml in 2 to 4 h. In sterile cage fluid, daptomycin peak concentrations of 23.1, 46.3, and 53.7 mu g/ml were reached 4 to 6 h after the administration of single intraperitoneal doses of 20, 30, and 40 mg/kg of body weight, respectively. In treatment studies, daptomycin alone reduced the planktonic MRSA counts by 0.3 log(10) CFU/ml, whereas in combination with rifampin, a reduction in the counts of >6 log(10) CFU/ml was observed. Vancomycin and daptomycin (at both doses) were unable to cure any cage-associated infection when they were given as monotherapy, whereas rifampin alone cured the infections in 33% of the cages. In combination with rifampin, daptomycin showed cure rates of 25% (at 20 mg/kg) and 67% (at 30 mg/kg), vancomycin showed a cure rate of 8%, linezolid showed a cure rate of 0%, and levofloxacin showed a cure rate of 58%. In addition, daptomycin at a high dose (30 mg/kg) completely prevented the emergence of rifampin resistance in planktonic and adherent MRSA cells. Daptomycin at a high dose, corresponding to 6 mg/kg in humans, in combination with rifampin showed the highest activity against planktonic and adherent MRSA. Daptomycin plus rifampin is a promising treatment option for implant-associated MRSA infections.