Efflux Pump Mediated Azole Resistance in Candida Albicans

Overview

Candida albicans is the major fungal pathogen causing infections in humans, ranging from superficial mucosal infection to systemic mycoses. In recent years, Candida infections have increased disproportionately as a result of the increased number of compromised host populations, such as patients with AIDS, diabetes and various cancers, and organ-transplant recipients. Severe oro-pharyngeal candidiasis afflicts many AIDS patients and is a significant infection in cancer patients being treated with chemotherapy and/or radiotherapy.

In cancer patients, the increased incidence of oro-pharyngeal candidiasis results both from the debilitating effects of the cancer itself and from the immuno-suppressive treatment for the cancer. Administration of broad-spectrum antibiotics for the management of bacterial infections in these patients may further predispose them to oro-pharyngeal candidiasis . Systemic fungal infections are often hard to diagnose, which contributes to their high attributable mortality. In addition, there are far fewer classes of antifungal agent than antibacterial drugs, limiting therapeutic options. The azole antifungals are commonly used to treat fungal infections, as they are conveniently administered and have few side effects . the number of drug-resistant Candida strains has also increased dramatically owing to the increased use of antifungal agents. The major mechanism responsible for high-level azole resistance in clinical Candida isolates is overexpression of plasma membrane efflux pumps . There are two main families of efflux proteins, the ATP-binding cassette pumps and the major facilitator superfamily transporters . Azole resistance calls for the use of alternative antifungal drugs like echinocandins, voriconazole, posaconazole, ravuconazole and Amphotericin B. But constraints like high costs or adverse effects associated with these agents often limit their usage. Some recent pioneering studies have reported the modulating effect of verapamil, oestradiol, progesterone and ibuprofen on resistance of Candida isolates. While fluconazole MIC decreased in most strains after exposure to these modulators, this effect was particularly remarkable for Ibuprofen. The molecular basis of this reversal of resistance has also been demonstrated recently. Thus, drugs capable of reversing fluconazole resistance might offer novel breakthroughs in the treatment of resistant Candida infections. As investigators have previously observed a high prevalence of fluconazole resistance among Candida isolates recovered in our centre. consequently ,implementing the concept of combination therapy using an efflux pump inhibitor seems an adequate strategy for overcoming resistance. in this study investigators were interested in exploring if the resistant phenotype could be reversed in a proportion of these isolates by the use of Ibuprofen .Expression levels of the target genes associated with antifungal resistance of C.albicans (CDR1, CDR2 and MDR1) were assessed by quantitative real-time The relative quantities of the target genes were normalized against ACT1 housekeeping gene expression and analysed using the comparative DDCt method, taking the amplification efficiency into consideration .

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