评价高剂量达托霉素联合复方磺胺甲噁唑治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的新型组合，该组合采用模拟心内膜赘生物的体外药代动力学/药效学模型。
Evaluation of the novel combination of high-dose daptomycin plus trimethoprim-sulfamethoxazole against daptomycin-nonsusceptible methicillin-resistant Staphylococcus aureus using an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations.
机构信息
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
出版信息
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。
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