Giamberardino Charles D, Schell Wiley A, Tenor Jennifer L, Toffaletti Dena L, Perfect John R
Department of Medicine, Division of Infectious Diseases, School of Medicine, Duke University, Durham, NC 27710, USA.
J Fungi (Basel). 2024 Jul 26;10(8):520. doi: 10.3390/jof10080520.
Cryptococcal meningitis (CM) causes significant global morbidity and mortality. Current therapeutic strategies rely on deoxycholated or liposomal forms of the polyene amphotericin B. Nystatin is also a polyene with broad-spectrum antimicrobial activity. Treatment with systemic nystatin has been limited by toxicity, which is a consistent challenge with polyene therapeutics. One mechanism to improve the toxicity is usage of a liposomal form of the active agent. Previous data from a murine candidemia model indicated that liposomal nystatin may be an effective antifungal drug formulation. Since the rabbit model of CM is a highly predictive preclinical system for evaluating antifungal therapeutics, we tested the effectiveness of two doses of daily liposomal nystatin, 3 and 8 mg/kg in the rabbit model of CM. Treatment with liposomal nystatin in this model did not reduce the fungal burden in the cerebrospinal fluid. A subsequent clinical trial also did not find activity in a human population. These data indicate that liposomal nystatin in the current form and at the tested dosages is not an effective therapy for CM. The data provide further evidence for the predictive power of the rabbit model of CM as a vital preclinical system for testing novel antifungal therapeutics for CM.
隐球菌性脑膜炎（CM）在全球范围内导致了显著的发病率和死亡率。目前的治疗策略依赖于去氧胆酸盐或脂质体形式的多烯两性霉素B。制霉菌素也是一种具有广谱抗菌活性的多烯。全身使用制霉菌素一直受到毒性的限制，这是多烯疗法始终面临的挑战。改善毒性的一种机制是使用活性剂的脂质体形式。先前来自小鼠念珠菌血症模型的数据表明，脂质体制霉菌素可能是一种有效的抗真菌药物制剂。由于CM的兔模型是评估抗真菌治疗药物的高度预测性临床前系统，我们在CM的兔模型中测试了两种每日剂量的脂质体制霉菌素，即3和8mg/kg的有效性。在该模型中用脂质体制霉菌素治疗并未降低脑脊液中的真菌负荷。随后的一项临床试验在人群中也未发现其活性。这些数据表明，当前形式和测试剂量的脂质体制霉菌素不是CM的有效治疗方法。这些数据为CM的兔模型作为测试CM新型抗真菌治疗药物的重要临床前系统的预测能力提供了进一步的证据。
