Canouï Etienne, Kerneis Solen, Morand Philippe, Enser Maya, Gauzit Rémy, Eyrolle Luc, Leclerc Philippe, Contejean Adrien, Zheng Yi, Anract Philippe, Hirt Deborah, Treluyer Jean Marc, Bouazza Naim, Benaboud Sihem
Université de Paris, Paris, France.
Equipe mobile d'infectiologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre-Cochin, F75014 Paris, France.
J Antimicrob Chemother. 2022 Apr 27;77(5):1344-1352. doi: 10.1093/jac/dkac031.
This study aimed at characterizing the pharmacokinetics (PK) of oral levofloxacin in adult patients in order to optimize dosing scheme and explore the PK/pharmacodynamics (PD) of levofloxacin in bone and joint infections (BJIs).
From November 2015 to December 2019, all patients hospitalized in Cochin Hospital, treated with levofloxacin and who had at least one dosage for therapeutic drug monitoring were included. PK was described using non-linear mixed-effect modelling. In a subgroup of patients with BJIs, the association between PK, MIC for the isolated pathogen and clinical outcome was investigated. Monte Carlo simulations investigated dosing regimens to achieve the PK/PD target (AUC/MIC ratio >100).
One hundred and two patients were included (199 measurements), including 32 treated for BJI. A one-compartment model with first-order absorption and elimination best described the data. Effects of estimated creatinine clearance (eCLCR) and age were significant on levofloxacin clearance. In BJI patients, no significant association was found between levofloxacin PK/microbiological parameters and either clinical outcome or adverse events. Based on our model, we proposed optimized oral levofloxacin dosing regimens according to renal function, to reach the PK/PD target AUC/MIC ratio >100 for three frequent causative pathogens (Staphylococcus aureus, Enterobacterales and Pseudomonas aeruginosa).
Our results reinforce the need of determining the MIC and using therapeutic drug monitoring in complex infections caused by P. aeruginosa.
本研究旨在描述成年患者口服左氧氟沙星的药代动力学（PK），以优化给药方案，并探索左氧氟沙星在骨与关节感染（BJI）中的PK/药效学（PD）。
2015年11月至2019年12月，纳入所有在科钦医院住院、接受左氧氟沙星治疗且至少有一次治疗药物监测剂量的患者。使用非线性混合效应模型描述PK。在BJI患者亚组中，研究PK、分离病原体的最低抑菌浓度（MIC）与临床结局之间的关联。蒙特卡洛模拟研究给药方案以实现PK/PD目标（AUC/MIC比值>100）。
纳入102例患者（199次测量），其中32例接受BJI治疗。具有一级吸收和消除的单室模型最能描述数据。估计的肌酐清除率（eCLCR）和年龄对左氧氟沙星清除率有显著影响。在BJI患者中，未发现左氧氟沙星PK/微生物学参数与临床结局或不良事件之间存在显著关联。基于我们的模型，我们根据肾功能提出了优化的口服左氧氟沙星给药方案，以达到三种常见病原体（金黄色葡萄球菌、肠杆菌科和铜绿假单胞菌）的PK/PD目标AUC/MIC比值>100。
我们的结果强化了在铜绿假单胞菌引起的复杂感染中确定MIC并使用治疗药物监测的必要性。
