Inserm U1070, Pôle Biologie Santé, 1 rue Georges Bonnet, Poitiers, France.
Université de Poitiers, UFR Médecine-Pharmacie, 6 rue de la milétrie, Poitiers, France.
J Antimicrob Chemother. 2019 Jan 1;74(1):117-125. doi: 10.1093/jac/dky374.
The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed.
Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets.
Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin.
Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.
本研究旨在描述不同程度肾功能损害的 ICU 感染患者中游离和总浓度的达托霉素的药代动力学特征。根据这些结果，评估了达到抗菌疗效的可能性和毒性风险。
招募了 24 名肾功能不同且需要达托霉素治疗复杂性皮肤和软组织感染、菌血症或心内膜炎的 ICU 患者。对于肌酐清除率（CLCR）≥30ml/min 的患者，每 24 小时给予达托霉素（Cubicin®）10mg/kg，对于 CLCR<30ml/min 的患者，每 48 小时给予达托霉素 10mg/kg。采用群体药代动力学方法同时分析达托霉素的总血浆浓度和游离血浆浓度及尿液浓度。进行模拟以估计达到疗效（游离 AUCu/MIC>40 或>80）或毒性（Cmin>24.3mg/L）目标的可能性。
当肾功能下降时，游离达托霉素的暴露增加，从而提高了达到疗效目标的可能性，但也增加了毒性风险。达托霉素游离分数（fu）的改变不影响游离达托霉素的药代动力学，但影响总达托霉素的药代动力学。
对于 CLCR≥30ml/min 的 ICU 患者，每 24 小时给予 10mg/kg 的达托霉素可达到疗效药代动力学/药效学目标。对于 CLCR<30ml/min 的患者，将药物给药频率减半，即每 48 小时给予 10mg/kg，足以达到这些目标。未观察到不良事件，但应进一步评估 10mg/kg 每 24 小时给药方案的毒性，特别是对于肾功能改变的患者。
