Synergistic Fungistatic Effects of Lactoferrin in Combination with Antifungal Drugs against Clinical Candida Isolates

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.

鉴于重度免疫抑制患者（多为人类免疫缺陷病毒[HIV]感染者）的口咽念珠菌病治疗失败率持续上升，亟需开发能够增强现有常用抗真菌药物活性的新型高效制剂或化合物。鉴于乳铁蛋白（lactoferrin）是唾液中具有抗真菌活性的非特异性宿主防御因子之一，本研究针对念珠菌属临床分离株，体外考察了人源、牛源以及脱铁乳铁蛋白与氟康唑、两性霉素B、5-氟胞嘧啶联合使用时的抗真菌效果。本研究观察到乳铁蛋白对念珠菌属临床分离株具有明确的抗真菌活性，其最低抑菌浓度（MIC）范围通常为0.5至100 mg·ml⁻¹。值得注意的是，联合用药实验结果显示，乳铁蛋白与本次测试的三种抗真菌药物联用，可对念珠菌生长产生显著的协同抑制效果；仅在极少数浓度范围内观察到轻微的拮抗作用。其中，乳铁蛋白与氟康唑的联合用药方案效果最为突出。当以较低浓度（1 mg/ml）的乳铁蛋白与氟康唑联用时，氟康唑的最低有效浓度可显著降低；此类联用方案仍可实现完全生长抑制，且针对多种念珠菌属菌株的协同效应最高可达50%。综上，乳铁蛋白与抗真菌药物联合用于重症念珠菌感染的治疗，是极具潜力的治疗方案。鉴于氟康唑耐药念珠菌属菌株的报道日益增多（尤其在HIV感染者中），在现有氟康唑治疗方案中添加乳铁蛋白，可延缓念珠菌对氟康唑耐药性的产生。目前，旨在进一步阐明该联合疗法临床应用价值的临床试验已正式启动。