Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
Antimicrob Agents Chemother. 2012 Nov;56(11):5709-14. doi: 10.1128/AAC.01185-12. Epub 2012 Aug 20.
Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (10(9) CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey's post hoc test. Daptomycin MICs were 4 μg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 μg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 μg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log(10) CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P < 0.05) and trimethoprim-sulfamethoxazole monotherapy (P < 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections.
耐达霉素不敏感（DNS）金黄色葡萄球菌存在于治疗困难的感染中，其最佳治疗方法尚不清楚。我们在模拟心内膜赘生物的体外药代动力学/药效动力学模型中，研究了高剂量（HD）达托霉素联合甲氧苄啶-磺胺甲恶唑降阶梯至 HD 达托霉素或甲氧苄啶-磺胺甲恶唑治疗 4 例临床 DNS 耐甲氧西林金黄色葡萄球菌（MRSA）分离株的活性（10（9）CFU/g）。模拟方案包括：HD 达托霉素 10mg/kg/天，连用 14 天；甲氧苄啶-磺胺甲恶唑 160/800mg 每 12 小时 1 次，连用 14 天；HD 达托霉素联合甲氧苄啶-磺胺甲恶唑连用 14 天；联合治疗 7 天后降阶梯至 HD 达托霉素 7 天，再降阶梯至甲氧苄啶-磺胺甲恶唑 7 天。通过方差分析（ANOVA）和 Tukey 事后检验评估 CFU/g（168 和 336 h）的差异。达托霉素 MIC 值分别为 4μg/ml（SA H9749-1，万古霉素中介金黄色葡萄球菌；R6212，异质性万古霉素中介金黄色葡萄球菌）和 2μg/ml（R5599 和 R5563）。甲氧苄啶-磺胺甲恶唑 MIC 值均≤0.06/1.19μg/ml。HD 达托霉素联合甲氧苄啶-磺胺甲恶唑对 SA H9749-1（7 小时）和 R6212（6 小时）具有快速杀菌活性，对 R5599（72 小时）和 R5563（36 小时）具有杀菌活性。所有菌株均观察到 HD 达托霉素联合甲氧苄啶-磺胺甲恶唑治疗后 CFU/g 下降≥8log10（48 至 144 h），在 336 h 时，HD 达托霉素或甲氧苄啶-磺胺甲恶唑降阶梯治疗仍能维持。14 天联合治疗和 7 天联合治疗降阶梯至 HD 达托霉素或甲氧苄啶-磺胺甲恶唑在 168 和 336 h 时均显著优于达托霉素单药治疗（P<0.05）和甲氧苄啶-磺胺甲恶唑单药治疗（P<0.05）。联合治疗后降阶梯治疗为高接种量、严重 DNS MRSA 感染提供了一种新的杀菌治疗选择。
