Chapter 4 - Combination therapy against human infections caused by Candida species

Abstract

Candida species are opportunistic pathogens responsible for many superficial as well as systemic infections and are the cause of morbidity and mortality in burn, cancer, HIV, and organ transplant patients worldwide. Further, Candida species cause about 8% of the nosocomial bloodstream infections globally every year. Commonly, the five Candida species, namely C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei, are the causative agents for 60%–80% of total fungal infections. The pathogenesis of Candida species is poorly understood and varies significantly with geographical location. Azoles and triazoles are commonly used antifungal drugs in both treatment and prevention of Candida infection. For the past couple of years, due to widespread and prolonged use of antifungal drugs, the incidence of Candida species (i.e., C. albicans) acquiring resistance to azoles has increased considerably, which is posing serious problems for successful antifungal therapy. However, the molecular basis of antifungal resistance in fungi is not fully understood; evidence accumulated so far suggests that multidrug resistance is a multifactorial phenomena including a combination of several mechanisms. The major mechanism of antifungal resistance includes alternation in the ergosterol biosynthetic pathway, which leads to reduced affinity to many antifungal drugs (i.e., fluconazole). The reduced intracellular accumulation of antifungal drug due to overexpression of cell membrane transporters (i.e., Cdr1p and CaMdr1p) is another prominent mechanism of resistance in Candida cells. Further, the limited efficacy of the well-known antifungal drugs and also difficulties in introducing new antifungal drugs for clinical use make their combination an important therapeutics strategy to treat fungal infection. More interestingly, the potential benefits of combination therapy have several advantages, such as multiple mode of actions, broad-spectrum activity, reduced toxicity due to lower dosage, and decreased number of resistant fungal organisms. This chapter describes the Candida species infections, treatment, and their resistance development. In addition, it discusses combination therapy, a promising alternative strategy for treating fungal infections.