Fluconazole resistance

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Perea S, JL Lopez-Ribot, WR Kirkpatrick, RK McAtee, RA Santillan, M Martinez, D Calabrese, D Sanglard, TP Patterson (2001) Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antibicrob Agents Chemother 45 2676-2684. 

Twenty percent of HIV-infected patients develop fluconazole-resistant Candida albicans isolates after repeated exposure to fluconazole.33 To treat fluconazole-resistant oropharyngeal candidiasis, daily itraconazole for 2 to 4 weeks may be used. Oral itraconazole solution exhibits a mycological cure rate of 88% and a clinical cure rate of 97% in immunocompromised patients.34 Fluconazole-resistant esophageal candidiasis should be treated with intravenous amphotericin B or caspofungin. 

Prophylactic use of fluconazole has been demonstrated to reduce fungal disease in bone marrow transplant recipients and AIDS patients, but the emergence of fluconazole-resistant fungi has raised concerns about this indication. 

Voriconazole is similar to itraconazole in its spectrum of action, having excellent activity against Candida sp (including fluconazole-resistant species such as C krusei) and the dimorphic fungi. Voriconazole is less toxic than amphotericin and is the treatment of choice for invasive aspergillosis. 

L. Millon, A. Manteaux, G. Reboux, C. Drobacheff, M. Monod, T. Barale, and Y. Michel-Briand, Fluconazole-resistant recurrent oral candidiasis in human immunodeficiency virus-positive patients persistence of Candida albicans strains with the same genotype,. Clin. Microbiol., 32, 1115, 1994. 

G.D. Albertson, M. Niimi, R.D. Cannon, and H.F. Jenkinson, Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance, Antimicrob. Agents Chemother., 40, 2835, 1996. 

Koks C, Meenhorst P, Bult A, and Beijnen J. Itraconazole Solution Summary of Pharmacokinetic Features and Review of Activity in the Treatment of Fluconazole-resistant Oral Candidosis in HIV-infected Persons. Pharmacol Res 2002 46 195-201. 

D.J., Ward, D.J., Marsden, K., and Bennett, J.E. (1998) Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDHl, in Candida glabrata. Antimicrobial Agents and Chemotherapy, 42, 1695-1701. 

Fluconazole is less toxic and easier to administer than amphotericin B. However, fluconazole resistance among C. albicans has been well described among HIV-infected individuals and is increasing in immunocompetent adults." C. glabrata often has reduced susceptibility to fluconazole. Itraconazole exhibits a similar activity profile to fluconazole and is well known to be active against mucosal forms of candidiasis. However, formal clinical trials using intravenous... 

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