儿童侵袭性念珠菌感染的米卡芬净给药方案的优化

Optimal micafungin dosage regimens in pediatric patients with invasive candida infection

目的应用蒙特卡洛模拟优化米卡芬净治疗儿童侵袭性念珠菌感染的给药方案。方法结合米卡芬净在儿童患者中的药动学(PK)参数和药效学(PD)数据,以日剂量0.5、1、1.5、2、3、4 mg·kg^(-1)静脉滴注为给药方案,以AUC_(0-24)/MIC为米卡芬净的PK/PD模型。采用蒙特卡洛模拟法,设置抑菌达标靶值和杀菌达标靶值为f AUC/MIC≥10和20分别模拟5 000次,f为游离药物分数,米卡芬净f值为1%。计算米卡芬净不同给药方案治疗不同念珠菌感染的达标概率(PTA)和累积反应分数(CFR),以CFR>90%的最低剂量为最佳给药方案。结果米卡芬净不同给药方案治疗不同念珠菌感染的PTA和CFR值不同,抑菌指标下的PTA值和CFR值均大于杀菌指标下的PTA和CFR值。米卡芬净治疗儿童白色念珠菌、光滑念珠菌、热带念珠菌、克柔念珠菌和乳酒念珠菌侵袭性感染,达到CFR>90%的推荐抑菌日剂量分别为1、0.5、1.5、1.5、和1.5 mg·kg^(-1);推荐杀菌日剂量分别为1.5、1、3、3和3 mg·kg^(-1)。米卡芬净不同给药方案治疗儿童近平滑念珠菌和季也蒙念珠菌侵袭性感染,均未达到CFR>90%。结论米卡芬净治疗白色念珠菌、光滑念珠菌、热带念珠菌、克柔念珠菌和乳酒念珠菌引起的儿童侵袭性感染时,应根据不同菌种选择相应的给药方案;对于葡萄牙念珠菌、近平滑念珠菌和季也蒙念珠菌引起的感染,建议更换药物或进行药物联合治疗。本研究应用蒙特卡洛模拟的结果可为临床合理用药提供参考。

AIM To optimize micafungin regimens in pediatric patients with invasive fungal infection （IFI） by Monte Carlo simulations （MCS）. METHODS Consociating pharmacokinetic （PK） parameters of micafungin in pediatric patients and pharmacodynamic （PD） data by implying AUC0-24/MIC as PK/PD model of micafungin, and dosage regimens of 0.5, 1, 1.5, 2, 3 and 4 mg.kg^-1.d^-1 by intravenous drip were analyzed. MCS were performed each 5 000 times in terms of fungistatic target and fungicidal target setting f AUC/MIC ≥ 10 and ≥ 20 respectively, and the free-drug concentrations （f） of micafungin was 1%. The probabilities of target attainment （PTA） and cumulative fractions of response （CFR） of different dosage regimens against different Candida were calculated. The lomest daily dosage with the CFR expectation value of 〉 90% was optimal for a dosage regimen. RESULTS The PT＇A and CFR were different among different micafungin dosage regimens against different Candida. The PTA and CFR of fungistatic efficacy were larger than fungicidal efficacy. The recommended fungistatic daily doses of micafungin against Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei and Candida kefyr were 1, 0.5, 1.5, 1.5 and 1.5 mg .kg^-1 respectively, and fungicidal daily dosages were 1.5, 1, 3, 3 and 3 mg.kg^-1 respectively for pediatric patients infected with IFI in terms of CFR 〉 90%. None of dosage regimens of micafungin achieved CFR 〉 90% for infection caused by Candida parapsilosis and Candida guilliemondii in pediatric patients. CONCLUSION Corresponding dosage regimens of micafungin could be chosen when IFI caused by Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei and Candida kefyr in pediatric patients. Replacing antifungals or combination treatment should be recommended against Candida lusitaniae, Candida parapsilosis and Candida guiUiemondii. The results of this study by using MCS could provide a reference for rational use of medicines in clinic.