Anti-Infective Research Laboratory, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Antimicrob Agents Chemother. 2011 Jul;55(7):3522-6. doi: 10.1128/AAC.00347-11. Epub 2011 May 16.
The objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) infections. Four clinical DNS MRSA strains, R5717, R5563, R5996 (heteroresistant vancomycin-intermediate S. aureus) and R5995 (vancomycin-intermediate S. aureus) were evaluated in a two-compartment hollow-fiber in vitro pharmacokinetic/pharmacodynamic model at a starting inoculum of 10(7) CFU/ml for 96 h. Simulated regimens were ceftaroline at 600 mg every 12 h (q12h) (maximum free-drug concentration [fC(max)], 15.2 μg/ml; serum half-life [t(1/2)], 2.3 h), daptomycin at 6 mg/kg q24h (fC(max), 7.9 μg/ml; t(1/2), 8 h), and daptomycin at 10 mg/kg q24h (fC(max), 15.2 μg/ml; t(1/2), 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a ≥3-log(10) CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 μg/ml, and the daptomycin MIC values were 2, 2, 4, and 4 μg/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, -3.1 log(10) CFU/ml; R5563, -2.5 log(10) CFU/ml; R5996, -5.77 log(10) CFU/ml; R5995, -6.38 log(10) CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains, P ≤ 0.008) and daptomycin at 10 mg/kg q24 h (3 strains, P ≤ 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.
本研究旨在探讨头孢洛林（一种新型广谱头孢菌素）作为治疗达托霉素不敏感（DNS）耐甲氧西林金黄色葡萄球菌（MRSA）感染的治疗选择的潜在作用。在起始接种量为 10(7)CFU/ml 的情况下，用 2 室中空纤维体外药代动力学/药效学模型评估了 4 株临床 DNS MRSA 菌株 R5717、R5563、R5996（异质万古霉素中介金黄色葡萄球菌）和 R5995（万古霉素中介金黄色葡萄球菌）。模拟方案为头孢洛林 600mg 每 12 小时（q12h）（最大游离药物浓度 [fC(max)]，15.2μg/ml；半衰期 [t(1/2)]，2.3h）、达托霉素 6mg/kg 每 24 小时（q24h）（fC(max)，7.9μg/ml；t(1/2)，8h）和达托霉素 10mg/kg 每 24 小时（q24h）（fC(max)，15.2μg/ml；t(1/2)，8h）。通过方差分析和 Tukey 事后检验评估 24 小时至 96 小时之间 CFU/ml 的差异。杀菌活性定义为从初始接种物减少 3 个对数（10）CFU/ml 的菌落计数。头孢洛林的 MIC 值分别为 0.25、0.5、0.5 和 0.5μg/ml，达托霉素的 MIC 值分别为 2、2、4 和 4μg/ml，用于 R5717、R5563、R5996 和 R5995。头孢洛林在 96 小时时对 4 株菌中的 3 株显示出持续的杀菌活性（R5717，-3.1 对数 CFU/ml；R5563，-2.5 对数 CFU/ml；R5996，-5.77 对数 CFU/ml；R5995，-6.38 对数 CFU/ml）。在达托霉素 6mg/kg q24h 方案（4 株菌）和达托霉素 10mg/kg q24h 方案（3 株菌）中观察到再生。在 96 小时时，头孢洛林的活性明显更高，导致 CFU/ml 计数低于达托霉素 6mg/kg q24h（4 株菌，P≤0.008）和达托霉素 10mg/kg q24h（3 株菌，P≤0.001）的计数。恢复了达托霉素 MIC 值增加（4 株菌均）但头孢洛林 MIC 值未增加的分离株。头孢洛林对测试的 4 株分离株有效，可能为治疗 DNS MRSA 感染提供临床选择。
