Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA, USA.
Astellas Pharma Global Development, Inc., Northbrook, IL, USA.
J Antimicrob Chemother. 2021 Sep 15;76(10):2636-2639. doi: 10.1093/jac/dkab233.
Liposomal amphotericin B (L-AMB) and isavuconazonium sulphate are commonly used antifungal drugs to treat mucormycosis. However, the efficacy of combination therapy of L-AMB/isavuconazonium sulphate versus monotherapy is unknown. We used an immunosuppressed mouse model of pulmonary mucormycosis to compare the efficacy of L-AMB/isavuconazonium sulphate versus either drug alone.
Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with L-AMB, isavuconazonium sulphate, or a combination of both started 8 h post-infection and continued through to Day +4. Placebo mice received vehicle control. Survival to Day +21 and tissue fungal burden (by conidial equivalent using quantitative PCR) on Day +4, served as primary and secondary endpoints, respectively.
For mice infected with R. delemar, L-AMB and isavuconazonium sulphate equally prolonged median survival time and enhanced survival versus placebo (an overall survival of 50% for either drug alone, versus 5% for placebo). Importantly, combination treatment resulted in an overall survival of 80%. Both antifungal drugs reduced tissue fungal burden of lungs and brain by ∼1.0-2.0 log versus placebo-treated mice. Treatment with combination therapy resulted in 2.0-3.5 log reduction in fungal burden of either organ versus placebo and 1.0 log reduction versus either drug alone. Similar treatment outcomes were obtained using mice infected with M. circinelloides.
The L-AMB/isavuconazonium sulphate combination demonstrated greater activity versus monotherapy in immunosuppressed mice infected with either of the two most common causes of mucormycosis. These studies warrant further investigation of L-AMB/isavuconazonium sulphate combination therapy as an optimal therapy of human mucormycosis.
两性霉素 B 脂质体（L-AMB）和硫酸伊曲康唑是治疗毛霉病常用的抗真菌药物。然而，L-AMB/硫酸伊曲康唑联合治疗与单药治疗的疗效尚不清楚。我们使用免疫抑制的肺毛霉病小鼠模型来比较 L-AMB/硫酸伊曲康唑联合治疗与单药治疗的疗效。
中性粒细胞减少症小鼠经气管内感染根毛霉或弯孢霉。L-AMB、硫酸伊曲康唑或两者联合治疗于感染后 8 小时开始，并持续至第 4 天。安慰剂组小鼠给予载体对照。第 21 天的生存情况和第 4 天的组织真菌负荷（通过定量 PCR 用分生孢子当量表示）分别作为主要和次要终点。
对于感染根毛霉的小鼠，L-AMB 和硫酸伊曲康唑同样延长了中位生存时间，并提高了与安慰剂相比的生存率（单独使用任一药物的总生存率为 50%，而安慰剂组为 5%）。重要的是，联合治疗的总生存率为 80%。两种抗真菌药物均使肺部和脑部组织的真菌负荷比安慰剂组降低了约 1.0-2.0 log。与安慰剂组相比，联合治疗组任一器官的真菌负荷降低了 2.0-3.5 log，与单独用药组相比降低了 1.0 log。用感染弯孢霉的小鼠进行的类似治疗也得到了类似的结果。
L-AMB/硫酸伊曲康唑联合治疗在感染两种最常见毛霉病病原体的免疫抑制小鼠中显示出比单药治疗更强的活性。这些研究支持进一步研究 L-AMB/硫酸伊曲康唑联合治疗作为人类毛霉病的最佳治疗方法。
