Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis
Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis
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DOI：
10.1128/aac.01698-15
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发表时间：
2015-12-01
影响因子：
4.9
通讯作者：
Jarvis, Joseph N.
中科院分区：
文献类型：
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作者：
Bicanic, Tihana;Bottomley, Christian;Jarvis, Joseph N.
两性霉素B脱氧胆酸盐（AmBd）是HIV相关隐球菌脑膜炎（CM）的推荐诱导治疗。它的使用受到毒性的阻碍，包括电解质异常，肾毒性和贫血。最大限度地减少毒性的方案没有得到一致的应用。在基于AmBD的CM诱导治疗的临床试验队列中，应用了预先水合和电解质补充的标准化方案。分析了14天内血细胞计数、电解质水平和肌酐水平的变化与AmBd剂量、治疗持续时间（5至7天的短期疗程或14天的标准疗程）、氟胞嘧啶（5 FC）添加和结局的关系。在研究的368例患者中，AmBd治疗7天后血红蛋白水平平均下降1.5 g/dl（95%置信区间[CI]，1.0至1.9 g/dl），14天后平均下降2.3 g/dl（95% CI，1.1至3.6 g/dl）。AmBd治疗第7天血清肌酐水平增加37 μ mol/L（95% CI，30至45 μ mol/L），第14天增加49 μ mol/L（95% CI，35至64 μ mol/L）。总体而言，33%的患者发生III/IV级贫血，5.6%的患者发生III级低钾血症，9.5%的患者肌酐水平超过220 μ mol，6%的患者提前停用AmBd。添加5 FC与贫血轻微增加相关，但与中性粒细胞减少无关。实验室检查异常在短期诱导的患者中在第二周稳定或逆转。III/IV级贫血（校正比值比[aOR]，2.2; 95%CI，1.1 - 4.3; P = 0.028）和肾毒性（aOR，4.5; 95%CI，1.8 - 11; P = 0.001）是10周死亡率的危险因素。总之，在基于AmBd的HIV相关CM诱导方案期间，常规静脉内盐水水合和预先电解质置换可最大限度地降低低钾血症和肾毒性的发生率。贫血仍然是一个令人担忧的不良反应。添加氟胞嘧啶与中性粒细胞减少症增加无关。AmBd疗程越短，毒性越小，可逆性越快。
Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 mu mol/liter (95% CI, 30 to 45 mu mol/liter) by day 7 and by 49 mu mol/liter (95% CI, 35 to 64 mu mol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 mu mol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.