Département de Médecine Aiguë Spécialisée, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches Cedex, France.
Antimicrob Agents Chemother. 2011 Oct;55(10):4589-93. doi: 10.1128/AAC.00675-11. Epub 2011 Aug 8.
Daptomycin is an attractive option for treating prosthetic joint infection, but the 6-mg/kg of body weight/day dose was linked to clinical failure and emergence of resistance. Using a methicillin-resistant Staphylococcus aureus (MRSA) knee prosthesis infection in rabbits, we studied the efficacies of high-dose daptomycin (22 mg/kg given intravenously [i.v.] once daily [o.d.]; equivalent to 8 mg/kg/day in humans) or vancomycin (60 mg/kg given intramuscularly [i.m.] twice daily [b.i.d.]), both either alone or with adjunctive rifampin (10 mg/kg i.m. b.i.d.). After partial knee replacement with a silicone implant, 10(7) MRSA CFU was injected into the knees. Treatment started 7 days postinoculation and lasted 7 days. Positive cultures were screened for the emergence of mutant strains, defined as having 3-fold-increased MICs. Although in vivo mean log(10) CFU/g of daptomycin-treated (4.23 ± 1.44; n = 12) or vancomycin-treated (4.63 ± 1.08; n = 12) crushed bone was significantly lower than that of controls (5.93 ± 1.15; n = 9) (P < 0.01), neither treatment sterilized bone (2/12 and 0/12 rabbits with sterile bone, respectively). Daptomycin mutant strains were found in 6/12, 3/12, and 2/9 daptomycin-treated, vancomycin-treated, and control rabbits, respectively; no resistant strains emerged (MIC was always <1 mg/liter). Adjunctive rifampin with daptomycin (1.47 ± 0.04 CFU/g of bone [detection threshold]; 11/11 sterile bones) or vancomycin (1.5 ± 0.12 CFU/g of bone; 6/8 sterile bones) was significantly more effective than monotherapy (P < 0.01) and prevented the emergence of daptomycin mutant strains. In this MRSA joint prosthesis infection model, combining rifampin with daptomycin was highly effective. Daptomycin mutant strains were isolated in vivo even without treatment, but adjunctive rifampin prevented this phenomenon, previously found after monotherapy in humans.
达托霉素是治疗人工关节感染的一种有吸引力的选择，但 6 毫克/公斤/天的剂量与临床失败和耐药的出现有关。我们使用耐甲氧西林金黄色葡萄球菌（MRSA）兔膝关节假体感染模型，研究了高剂量达托霉素（22 毫克/公斤，静脉内[iv]，每天一次[od]；相当于人类的 8 毫克/公斤/天）或万古霉素（60 毫克/公斤，肌内[im]，每天两次[bid]）的疗效，两者均单独使用或与利福平（10 毫克/公斤，im，bid）联合使用。在膝关节硅胶植入物部分置换后，将 10（7）MRSA CFU 注入膝关节。治疗于接种后 7 天开始，持续 7 天。对阳性培养物进行了突变株的筛选，定义为 MIC 增加 3 倍。尽管达托霉素治疗组（4.23 ± 1.44；n = 12）或万古霉素治疗组（4.63 ± 1.08；n = 12）的体内平均 log（10）CFU/g 粉碎骨的数量明显低于对照组（5.93 ± 1.15；n = 9）（P < 0.01），但两种治疗方法都不能使骨无菌（分别有 2/12 和 0/12 只兔的骨无菌）。在 6/12、3/12 和 2/9 只接受达托霉素、万古霉素和对照组治疗的兔中分别发现了达托霉素突变株；未出现耐药株（MIC 始终<1 毫克/升）。达托霉素联合利福平（1.47 ± 0.04 CFU/g 骨[检测阈值]；11/11 只骨无菌）或万古霉素（1.5 ± 0.12 CFU/g 骨；6/8 只骨无菌）明显优于单药治疗（P < 0.01），并防止了达托霉素突变株的出现。在该耐甲氧西林金黄色葡萄球菌关节假体感染模型中，联合利福平的达托霉素非常有效。即使没有治疗，也会在体内分离出达托霉素突变株，但联合利福平可防止这种现象发生，这在人类单药治疗后曾有报道。
