College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
St Boniface Hospital, Winnipeg, Manitoba, Canada.
J Antimicrob Chemother. 2018 Jul 1;73(7):1888-1894. doi: 10.1093/jac/dky120.
Despite the convenience of once-daily dosing, the use of ceftriaxone for Staphylococcus aureus infections has significant limitations, including scarce clinical evidence and increasingly questionable pharmacodynamic activity. Our goal was to conduct an integrated pharmacokinetic-pharmacodynamic analysis of the appropriateness of ceftriaxone compared with cefazolin for treating serious MSSA infections.
Ceftriaxone and cefazolin activity against five clinical MSSA isolates was characterized in an in vitro pharmacodynamic model. Monte Carlo simulations were then used to evaluate various dosing regimens of ceftriaxone and cefazolin based on relevant patient pharmacokinetic data, significant pharmacodynamic targets derived from the in vitro studies (55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill, 100%ƒT>MIC for ≥3 log10 bacterial kill) and MIC distributions for MSSA from national surveillance data.
Ceftriaxone at 1 g once daily had poor activity against MSSA with net bacterial growth predicted in 76% of simulated subjects. The standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in 54% of cases with bactericidal effects in only 17%. Cefazolin at 2 g once daily was notably similar to ceftriaxone in expected target attainments. Cefazolin at 2 g twice daily demonstrated maximal pharmacodynamic activity with bactericidal effects in 97% of simulated subjects.
Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risks of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly as optimal pharmacodynamics against MSSA may be achieved with twice-daily dosing in most patients.
尽管每日一次给药较为方便，但头孢曲松治疗金黄色葡萄球菌感染存在明显的局限性，包括临床证据不足和药效学活性越来越受到质疑。我们的目标是对头孢曲松与头孢唑林治疗金黄色葡萄球菌（MSSA）严重感染的适宜性进行综合药代动力学-药效学分析。
采用体外药效学模型对头孢曲松和头孢唑林对 5 株临床 MSSA 分离株的作用进行了描述。然后，根据相关患者药代动力学数据、从体外研究中得出的重要药效学目标（对细菌抑制的 55%ƒT>MIC，对 1 对数杀灭的 75%ƒT>MIC，对 ≥3 对数杀灭的 100%ƒT>MIC）和国家监测数据中 MSSA 的 MIC 分布，使用蒙特卡罗模拟评估头孢曲松和头孢唑林的各种给药方案。
头孢曲松 1 g 每日 1 次给药对 MSSA 的活性较差，预计 76%的模拟患者会出现净细菌生长。标准剂量的头孢曲松 2 g 每日 1 次给药，54%的情况下预计会出现细菌生长或抑菌作用，只有 17%的情况下会出现杀菌作用。头孢唑林 2 g 每日 1 次给药与头孢曲松在预期的目标达成方面非常相似。头孢唑林 2 g 每日 2 次给药显示出最大的药效学活性，97%的模拟患者均有杀菌作用。
鉴于头孢曲松对金黄色葡萄球菌的活性有限，特别是在需要杀菌时，对于严重感染，每日一次给药的便利性应与使用过于广泛、不理想的治疗方案的风险进行权衡。头孢唑林值得进一步考虑，特别是在大多数患者中，每日 2 次给药可能达到针对 MSSA 的最佳药效学作用。
