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Impact of loading dose of caspofungin in PK/PD target attainment for severe candidiasis infections in ICU patients - the CASPOLOAD study.
Antimicrobial Agents and Chemotherapy ( IF 4.9 ) Pub Date : 2020-11-17 , DOI: 10.1128/aac.01545-20
Sébastien Bailly 1 , Elodie Gautier-Veyret 1, 2 , Minh P Lê 3, 4 , Lila Bouadma 5, 6 , Olivier Andremont 5 , Mathilde Neuville 5, 6 , Bruno Mourvillier 7, 8 , Romain Sonneville 5, 6, 7, 8, 9 , Eric Magalhaes 5 , Jordane Lebut 5 , Aguila Radjou 5 , Roland Smonig 5 , Michel Wolff 5, 6 , Laurent Massias 3, 4, 5, 6 , Claire Dupuis 10 , Jean-François Timsit 6, 11
Affiliation  

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0–24h) divided by the MIC (AUC0–24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0–24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.)

中文翻译:

卡泊芬净负荷量对ICU患者严重念珠菌感染的PK / PD目标达成率的影响-CASPOLOAD研究。

这项研究评估了重症监护病房(ICU)患者中高剂量卡泊芬净(CAS)对CAS药代动力学和药代动力学-药效学(PK-PD)目标达成的影响。前瞻性地要求接受CAS治疗的ICU患者接受140毫克负荷剂量的CAS。确定血浆CAS浓度(输注后0、2、3、5、7和24小时)以建立两室人口PK模型。使用先前发布的MIC进行了蒙特卡洛模拟,并计算了目标达成的概率(PTA)。PK-PD目标是浓度-时间曲线从0到24 h(AUC 0-24h)下的面积比除以MIC(AUC 0-24h / MIC)250、450和865以及最大浓度(Cmax)除以MIC(C max / MIC)分别为5、10、15和20。在13名患者中,CAS清除率为0.98±0.13升/小时,分布体积为V 1 = 9.0±1.2升和V 2 = 11.9±2.9升。在治疗的前24小时内,观察到的和模拟的CAS AUC 0-24h分别为79.1(IQR 55.2; 108.4)和81.3(IQR 63.8; 102.3)mg·h /升,与第3天在ICU患者中通常观察到的值相当或更高版本。考虑到AUC / MIC = 250和C max,MIC为0.19和0.5 mg / L的PTA> 90%/ MIC = 10作为PK-PD目标。因此,高剂量的CAS(140 mg)在治疗的前24小时内增加了CAS暴露,从而使大多数假丝酵母菌株的PK-PD目标得以尽早实现。尽管需要进一步研究以评估对临床结果的影响,但这种策略似乎可以提高治疗效果。(该研究已在ClinicalTrials.gov上注册,标识为NCT02413892。)
更新日期:2020-11-17
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