Dose Response Effect of High-Dose Fluconazole for HIV-Associated Cryptococcal Meningitis in Southwestern Uganda
Dose Response Effect of High-Dose Fluconazole for HIV-Associated Cryptococcal Meningitis in Southwestern Uganda
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DOI：
10.1086/593194
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发表时间：
2008-12-15
影响因子：
11.8
通讯作者：
Harrison, Thomas S.
中科院分区：
文献类型：
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作者：
Longley, Nicky;Muzoora, Conrad;Harrison, Thomas S.
背景在非洲的许多中心，人类免疫缺陷病毒（HIV）相关隐球菌脑膜炎的治疗是氟康唑，剂量为每天400-800 mg。然而，更高剂量的氟康唑已被用于治疗患者，而不会导致严重的毒性。药代动力学和药效学的考虑表明，更高的剂量可能与更大的疗效。在乌干达姆巴拉拉，60例HIV血清阳性、未接受过抗逆转录病毒治疗的首次发作隐球菌性脑膜炎患者接受氟康唑治疗：前30例患者每天接受800 mg，后30例患者每天接受1200 mg。2周后，剂量降至400 mg/天，再持续8周。主要结果指标是感染清除率或早期杀真菌活性，通过前2周内连续定量脑脊液隐球菌培养确定。次要结局指标为10周内的安全性和死亡率。47%的患者在就诊时意识水平降低。接受氟康唑1200 mg/天剂量的患者的早期杀真菌活性显著高于接受800 mg/天剂量的患者（早期杀真菌活性+/-标准差，-0.18 +/- 0.11 vs. -0.07 +/- 0.17 log菌落形成单位/mL/天; P = 0.007）。氟康唑1200 mg/天给药耐受性良好，未观察到肝功能障碍。两周和10周死亡率分别为30%和54%，两组之间无统计学显著差异。氟康唑以1200 mg/天的剂量给药时比以800 mg/天的剂量给药时更迅速地杀真菌。在资源有限的情况下，需要进行更多的研究来测试在高剂量氟康唑的基础上添加氟胞嘧啶或短疗程阿替霉素B，并测试有助于隐球菌脑膜炎患者早期表现、诊断和治疗的策略。
Background. Therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in many centers in Africa is fluconazole administered at a dosage of 400-800 mg per day. However, higher dosages of fluconazole have been used to treat patients without resulting in serious toxicity. Pharmacokinetic and pharmacodynamic considerations suggest that higher dosages might be associated with greater efficacy.Methods. Sixty HIV-seropositive, antiretroviral therapy-naive patients with first-episode cryptococcal meningitis in Mbarara, Uganda, were treated with fluconazole: the first 30 patients received 800 mg per day, and the second 30 patients received 1200 mg per day. After 2 weeks, the dosage was reduced to 400 mg per day for an additional 8 weeks. The primary outcome measure was rate of clearance of infection, or early fungicidal activity, as determined by serial quantitative cerebrospinal fluid cryptococcal cultures during the first 2 weeks. Secondary outcome measures were safety and mortality through 10 weeks.Results. Forty-seven percent of patients had a reduced level of consciousness at presentation. Early fungicidal activity was significantly greater for patients receiving fluconazole at a dosage of 1200 mg per day than it was for patients receiving 800 mg per day (early fungicidal activity +/- standard deviation, -0.18 +/- 0.11 vs. -0.07 +/- 0.17 log colony-forming units/mL per day; P = .007). Fluconazole administered at a dosage of 1200 mg per day appeared to be well tolerated, and no liver function disturbance was observed. Two-week and 10-week mortality were 30% and 54%, respectively, with no statistically significant difference between the groups.Conclusions. Fluconazole is more rapidly fungicidal when administered at a dosage of 1200 mg per day than when administered at a dosage of 800 mg per day. In resource-limited settings, additional studies are needed to test the addition of flucytosine or short-duration amphotericin B to high-dose fluconazole and to test strategies to facilitate earlier presentation, diagnosis, and treatment of patients with cryptococcal meningitis.