Kuipers M E, de Vries H G, Eikelboom M C, Meijer D K, Swart P J
Section of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Studies, University Centre for Pharmacy, 9713 AV Groningen, The Netherlands.
Antimicrob Agents Chemother. 1999 Nov;43(11):2635-41. doi: 10.1128/AAC.43.11.2635.
Because of the rising incidence of failures in the treatment of oropharyngeal candidosis in the case of severely immunosuppressed patients (mostly human immunodeficiency virus [HIV]-infected patients), there is need for the development of new, more effective agents and/or compounds that support the activity of the common antifungal agents. Since lactoferrin is one of the nonspecific host defense factors present in saliva that exhibit antifungal activity, we studied the antifungal effects of human, bovine, and iron-depleted lactoferrin in combination with fluconazole, amphotericin B, and 5-fluorocytosine in vitro against clinical isolates of Candida species. Distinct antifungal activities of lactoferrin were observed against clinical isolates of Candida. The MICs generally were determined to be in the range of 0.5 to 100 mg. ml(-1). Interestingly, in the combination experiments we observed pronounced cooperative activity against the growth of Candida by using lactoferrin and the three antifungals tested. Only in a limited concentration range was minor antagonism detected. The use of lactoferrin and fluconazole appeared to be the most successful combination. Significant reductions in the minimal effective concentrations of fluconazole were found when it was combined with a relatively low lactoferrin concentration (1 mg/ml). Such combinations still resulted in complete growth inhibition, while synergy of up to 50% against several Candida species was observed. It is concluded that the combined use of lactoferrin and antifungals against severe infections with Candida is an attractive therapeutic option. Since fluconazole-resistant Candida species have frequently been reported, especially in HIV-infected patients, the addition of lactoferrin to the existing fluconazole therapy could postpone the occurrence of species resistance against fluconazole. Clinical studies to further elucidate the potential utility of this combination therapy have been initiated.
由于在严重免疫抑制患者（主要是人类免疫缺陷病毒[HIV]感染患者）中，口咽念珠菌病治疗失败的发生率不断上升，因此需要开发新的、更有效的药物和/或化合物来增强常用抗真菌药物的活性。乳铁蛋白是唾液中具有抗真菌活性的非特异性宿主防御因子之一，我们研究了人乳铁蛋白、牛乳铁蛋白和脱铁乳铁蛋白与氟康唑、两性霉素B和5-氟胞嘧啶联合使用时，对念珠菌临床分离株的体外抗真菌作用。观察到乳铁蛋白对念珠菌临床分离株具有明显的抗真菌活性。其最低抑菌浓度（MIC）一般在0.5至100mg/ml范围内。有趣的是，在联合实验中，我们观察到乳铁蛋白与所测试的三种抗真菌药物联合使用时，对念珠菌生长具有显著的协同活性。仅在有限的浓度范围内检测到轻微的拮抗作用。乳铁蛋白与氟康唑联合使用似乎是最成功的组合。当氟康唑与相对较低浓度的乳铁蛋白（1mg/ml）联合使用时，其最低有效浓度显著降低。这种联合使用仍能完全抑制生长，同时观察到对几种念珠菌的协同作用高达50%。得出的结论是，乳铁蛋白与抗真菌药物联合用于治疗严重念珠菌感染是一种有吸引力的治疗选择。由于经常报道出现对氟康唑耐药的念珠菌，尤其是在HIV感染患者中，在现有的氟康唑治疗中添加乳铁蛋白可能会推迟对氟康唑产生菌种耐药性的出现。目前已启动临床研究，以进一步阐明这种联合治疗的潜在效用。
