Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Infectious Diseases Institute, Makerere University, Kampala, Uganda.
Clin Infect Dis. 2023 Dec 15;77(12):1659-1667. doi: 10.1093/cid/ciad440.
Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed.
In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA).
We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10 Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04).
This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin.
NCT04031833.
两性霉素 B 是治疗严重真菌感染的金标准治疗方法。现已开发出一种新的口服、毒性较低的两性霉素制剂。
在我们的随机临床试验中，我们在 4 个连续队列中测试了口服脂质纳米晶（LNC）两性霉素 B（MAT2203，Matinas Biopharma）与静脉内（IV）两性霉素治疗人类免疫缺陷病毒相关隐球菌性脑膜炎。两个试点队列评估了安全性和耐受性（各 10 例），两个队列评估了有/无 2 个 IV 负荷剂量的疗效（各 40 例）。实验组接受 1.8 g/d 口服 LNC 两性霉素，持续 2 周，同时每天给予 100 mg/kg 氟胞嘧啶，然后再接受 6 周 1.2 g/d LNC 两性霉素治疗。随机对照组（n = 41）接受 7 天 IV 两性霉素联合氟胞嘧啶，然后接受 7 天氟康唑 1200 mg/d。主要终点是脑脊液（CSF）早期杀菌活性（EFA）。
我们将 80 名参与者随机分为口服 LNC 两性霉素+氟胞嘧啶（n = 40）和无（n = 40）2 个 IV 负荷剂量组，以及 41 名对照组参与者静脉内两性霉素+氟胞嘧啶组。所有口服 LNC 两性霉素的平均 EFA 为 0.40 log10 菌落形成单位（CFU）/mL/d，口服 LNC 两性霉素联合 IV 负荷剂量的 EFA 为 0.42 log10 隐球菌 CFU/mL/d，IV 两性霉素对照组的 EFA 为 0.46 log10 CFU/mL/d。LNC 两性霉素组在 63%（70 例中的 44 例）达到 2 周 CSF 无菌，而对照组为 68%（34 例中的 23 例）。18 周的生存率为口服 LNC 两性霉素组 85%（40 例中的 34 例），口服 LNC 两性霉素联合 IV 负荷剂量组为 90%（40 例中的 36 例），IV 两性霉素组为 85%（41 例中的 35 例）。LNC 两性霉素组实验室不良事件 3-4 级发生率低于 IV 两性霉素组（41% vs 61%，P =.05），尤其是贫血（21% vs 44%；P =.01）和钾（5% vs 17%；P =.04）。
这种新的口服两性霉素 B LNC 制剂似乎对隐球菌性脑膜炎具有良好的抗真菌活性、相似的生存率和比 IV 两性霉素更低的毒性。
NCT04031833。
Zotero 插件