Objectives

The goal of this study is to assess, by means of pharmacokinetic/pharmacodynamic (PK/PD) analysis using the Monte Carlo simulation, the adequacy of oral cephalosporins cefuroxime axetil, cefixime and cefditoren at different dosing regimens as switch therapy after intravenous cephalosporin treatment in uncomplicated acute pyelonephritis.

Methods

The methodology included: (i) dosing regimen selection and acquisition of pharmacokinetic data; (ii) microbiological data acquisition; and (iii) Monte Carlo simulation to estimate the PTA (probability of PK/PD target attainment) and CFR (cumulative fraction of response), as indicators of treatment success.

Results

At the current susceptibility breakpoints defined by EUCAST and CLSI for either cefuroxime axetil or cefixime, the probability of bactericidal target attainment is zero for the dosage regimens simulated. Considering the bactericidal target %fT_>MIC > 70%, the likelihood of the cefuroxime 500-mg q8h regimen or the cefixime 200-mg q12h regimen producing this exposure or achieving this target is only above 90% for organisms yielding MICs ≤ 0.5 mg/l and MICs ≤ 0.25 mg/l, respectively. Cefditoren pivoxil 400 mg q12h provided probabilities of bactericidal target attainment of 80% or higher for MICs ≤ 0.03 mg/l, and ≤0.25 mg/l if considering total instead of free drug concentrations.

Conclusions

The results of the PK/PD target attainment analysis reveal that the likelihood of treatment success based upon the current breakpoints proposed by either EUCAST or CLSI is low. Of the three cephalosporins, cefixime 400 mg q12h prove to be the best option in oral APN treatment, although this regimen is currently off label.

中文翻译：

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从静脉治疗转换后，口服头孢呋辛酯、头孢克肟和头孢托仑酯是否足以治疗无并发症的急性肾盂肾炎？药代动力学/药效学观点。

目标

本研究的目的是通过使用蒙特卡罗模拟的药代动力学/药效学 (PK/PD) 分析来评估口服头孢菌素头孢呋辛酯、头孢克肟和头孢托仑在不同给药方案下作为静脉头孢菌素治疗后的转换疗法的充分性。无并发症的急性肾盂肾炎。

方法

该方法包括： (i) 给药方案选择和药代动力学数据的获取；(ii) 微生物数据采集；(iii) 蒙特卡罗模拟以估计 PTA（达到 PK/PD 目标的概率）和 CFR（反应的累积分数），作为治疗成功的指标。

结果

在 EUCAST 和 CLSI 为头孢呋辛酯或头孢克肟定义的当前敏感性断点处，模拟剂量方案达到杀菌目标的概率为零。考虑到杀菌目标 % f T _{> MIC}  > 70%，头孢呋辛 500-mg q8h 方案或头孢克肟 200-mg q12h 方案产生这种暴露或达到该目标的可能性仅高于 90% 对于产生 MIC ≤ 0.5 mg 的生物体/l 和 MICs 分别≤ 0.25 mg/l。Cefditoren pivoxil 400 mg q12h 为 MIC ≤ 0.03 mg/l 和 ≤ 0.25 mg/l 的 MIC 达到 80% 或更高的杀菌目标提供了可能性，如果考虑总浓度而不是游离药物浓度。

结论

PK/PD 目标实现分析的结果表明，基于 EUCAST 或 CLSI 提出的当前断点，治疗成功的可能性很低。在这三种头孢菌素中，头孢克肟 400 mg q12h 被证明是口服 APN 治疗的最佳选择，尽管该方案目前处于标签外。