Azole resistance

Grim SA, Smith KM, RomaneUi F, Ofotoknn 1. Treatment of azole-resistant oropharyngeal candidiasis with topical amphotericin. Ann Pharmacother 2002 36(9) 1383-6. 

Klausmeyer P, McCloud TG, Tucker KD, Cardellina IIJH, Shoemaker RH (2005) Aspirochlorine Class Compounds from Aspergillus flavus Inhibit Azole-Resistant Candida albicans. J Nat Prod 68 1300... 

Pharmacotherapy of fungal disease has been revolutionized by the introduction of the relatively nontoxic oral azole drugs and the echinocandins. Combination therapy is being reconsidered, and new formulations of old agents are becoming available. Unfortunately, the appearance of azole-resistant organisms, as well as the rise in the number of patients at risk for mycotic infections, has created new challenges... 

Fluconazole 400 mg/day IV/po (restrict to patienis with a low risk for invasive aspergillosis or azole-resistant strains of Candida in patienis with no previous azole exposure or signs and symptoms suggesting aspergillosis)... 

Micafungin has activity against Candida, including azole-resistant C. albicans. It has some activity against molds such as Aspergillus but no activity against Fusarium. 

Continuous infusion of amphotericin has been assessed in an open study in six lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections who were treated for 40 (17-73) days by 24-hour continuous infusions of amphotericin 1 mg/kg (113). They received at least 1000 ml/day of 0.9% saline intravenously. Apart from ciclosporin, five patients received aminoglycosides for at least 2 weeks, and four received ganciclovir. Calculated creatinine clearance fell from 57 (43-73) ml/minute to a nadir of 35 (28-39) and recovered to 52 (33-60) after the end of therapy. One patient needed temporary hemofiltration for 7 days. Besides three episodes of mild hypokalemia there were no adverse effects attributable to amphotericin. Asymptomatic colonization with Candida persisted for 10 months in one case, but the other five patients were cured. 

Azole resistance in C. glabrata may also occur through a different mechanism. In... 

Tsai, H.F., Krol, A.A., Sarti, K.E.. and Bennett, J.E. (2006) Candida glabrata PDRl, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrobial Agents and Chemotherapy, 50. 1384—1392. 

Chabasse, D., and Bouchara, J.P. (2004) Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrobial Agents and Chemotherapy, 48, 1788-1796. 

Grim SA, Smith KM, Romanelli F, Ofotokun L Treatment of azole-resistant oropharygeal candidiasis with topical amphotericin B. Ann Phar-macother 2002 36 1383-1386. 

We thus had to investigate whether azole resistance can be explained by one of these mechanisms. Resistance to azoles can be produced quite easily in vitro, and we selected a triadimenol-resistant yeast strain by UV-irradiation on a nutrient solution containing triadimenol (8). The resistant isolate grew rapidly in... 

Both Aspergillus and Candida are very common nosocomial infections in the environment, although infections with C. Tropicalis, albicans and C. par ap silo sis which used to be very prevalent have now decreased and there is a corresponding increase in infections with azole-resistant species such as C. glabrata and krusei (Dignani et al., 2002). The incidence and severity of invasive fungal infections is closely related to the presence and severity of various other risk factors. These include ... 

A crystal structure of human P450 51 is not yet available but high resolution structure of the soluble Mycobacterium tuberculosis P450 51 is (ref [1495]). Two notable features are a bent I helix and an open conformation of the BC loop. The bacterial structure has been utilized in consideration of mammalian models, and the SRS predictions do not seem to apply well . Further, the mutation hotspots for known azole-resistant... 

Mariehal, P., L. Koymans, S. Willemsens, D. Bellens, P. Verhasselt, W. Luyten et al. (1999). Contribution of mutations in the cytochrome P450 14a-demethylase (Ergllp, CYP51p) to azole resistance in Candida albicans. Microbiology 145, 2701-2713. 

Watson, P.F., M.E. Rose, S.W. Ellis, H. England, and S.L. Kelly (1989). Defective sterol C5-6 desaturation and azole resistance A new hypothesis for the mode of action of azole antifungals. Biochem. Biophys. Res. Commun. 164, 1170-1175. 

Kakeya, H., Y. Miyazaki, H. Miyazaki, K. Nyswaner, B. Grimberg, and J.E. Bennett (2000). Genetic analysis of azole resistance in the Darlington strain of Candida albicans. Antimicrob. Agents Chemother. 44, 2985-2990. 

Sanglard, D., F. Ischer, L. Koymans, and J. Bille (1998). Amino-acid substitutions in the cytochrome P450 lanosterol 14a-demethylase (CYP51A1) from azole resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob. Agents Chemother. 42, 241-253. 

White, T.C. (1997). Increased mRNA levels of ERG 16, CDR and MDRl correlate with increases in azole resistance in Candida albicans isolates from an HIV-infected patient. Antimicrob. Agents Chemother. 41, 1482-1487. 

Azole resistance has caused clinical failure in patients with far-advanced HP/ infection and oropharyngeal or esophageal candidiasis. The primary mechanism of resistance in C. albicans is accumulation ( mutations in the gene encoding 14-OC-sterol demethylase cross-resistance to all azoles results. 

Echinocandins inhibit formation of j3(l,3)D-glucans in the cell wall < /Candida and caspofungin is approved for clinical use. Susceptible fungi include Candida and Aspergillus species. Resistance can be conferred in C. albicans by mutation in one of the genes that encodes /3f l,3)D-glucan synthase. Azole-resistant isolates of C. albicans remain susceptible to echinocandins. 

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