Current fluconazole treatment regimens result in under-dosing of critically ill adults during early therapy
Current fluconazole treatment regimens result in under-dosing of critically ill adults during early therapy
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DOI：
10.1007/s10096-021-04201-w
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发表时间：
2021-02
影响因子：
4.5
通讯作者：
I. Sandaradura;D. Marriott;R. Day;R. Norris;Edna Pang;S. Stocker;S. Reuter
中科院分区：
文献类型：
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作者：
I. Sandaradura;D. Marriott;R. Day;R. Norris;Edna Pang;S. Stocker;S. Reuter
目的评价成人危重病人氟康唑治疗方案的典型疗程。方法采用氟康唑治疗的30例危重患者的数据，建立人群药代动力学模型。通过对先前提出的四种治疗方案的模拟，确定了目标实现概率（PTA） （fAUC24/MIC bbb100）：(i) 400 mg每日一次，（ii） 800 mg负荷剂量，然后400 mg每日一次，（iii） 400 mg每日两次，以及（iv） 12 mg/kg负荷剂量，然后6 mg/kg每日一次。体重（40、70、120 kg）和肾功能的影响(持续肾替代治疗（CRRT）；评估20、60、120、180 mL/min肌酐清除率)对PTA的影响。结果氟康唑对最低抑菌浓度（MIC）为2 mg/L的感染，早期（0 ~ 48 h）的目标达到程度变化较大。体重不足（40公斤）患者的PTA负荷剂量最高，为800毫克/公斤，其余患者的负荷剂量为12毫克/公斤。治疗结束时，体重不足或正常的患者每日两次维持剂量为400 mg，超重（120 kg）患者维持剂量为6 mg/kg时，PTA最高。没有一种氟康唑方案可靠地达到mic≥4 mg/L的早期目标。结论目前的氟康唑给药方案在危重成人中不能达到足够的早期目标，特别是在超重、肌酐清除率较高或正在接受CRRT的患者中。目前的氟康唑给药策略通常不足以治疗MIC≥4mg /L的生物体。
PurposeTo evaluate current fluconazole treatment regimens in critically ill adults over the typical treatment course.MethodsData from critically ill adults treated with fluconazole (n=30) were used to develop a population pharmacokinetic model. Probability of target attainment (PTA) (fAUC24/MIC >100) was determined from simulations for four previously proposed treatment regimens: (i) 400 mg once daily, (ii) an 800 mg loading dose followed by 400 mg once daily, (iii) 400 mg twice daily, and (iv) a 12 mg/kg loading dose followed by 6 mg/kg once daily. The effect of body weight (40, 70, 120 kg) and renal function (continuous renal replacement therapy (CRRT); 20, 60, 120, 180 mL/min creatinine clearance) on PTA was assessed.ResultsEarly (0–48 h) fluconazole target attainment for infections with a minimum inhibitory concentration (MIC) of 2 mg/L was highly variable. PTA was highest with an 800 mg loading dose for underweight (40 kg) patients and with a 12 mg/kg loading dose for the remainder. End-of-treatment PTA was highest with the 400 mg twice daily maintenance dosing for patients who were under- or normal weight and 6 mg/kg maintenance dosing for overweight (120 kg) patients. None of the fluconazole regimens reliably attained early targets for MICs of ≥4 mg/L.ConclusionCurrent fluconazole dosing regimens do not achieve adequate early target attainment in critically ill adults, particularly in those who are overweight, have higher creatinine clearance, or are undergoing CRRT. Current fluconazole dosing strategies are generally inadequate to treat organisms with an MIC of ≥4 mg/L.