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PubMed1992

Azole antifungal agents.

The discovery of the antifungal activity of azole compounds represented an important therapeutic advance. Miconazole, ketoconazole, and fluconazole are currently commercially available, and itraconazole has undergone extensive clinical evaluation. Because of its limited activity and toxicity, miconazole has been replaced by newer agents. Ketoconazole has proven useful in therapy for superficial infections and invasive infections caused by the pathogenic fungi. Among its disadvantages are limited absorption in the absence of gastric acid and its potential for drug-drug interactions. Fluconazole is the only azole available as oral and intravenous preparations. Unlike other azoles, it is only minimally metabolized in the liver and largely excreted in the urine as active drug. It is more effective than ketoconazole against superficial candidal infections and is the drug of choice for maintenance therapy for cryptococcal meningitis in patients infected with human immunodeficiency virus. An advantage of itraconazole is its activity against aspergillosis. It is also active against many infections caused by pathogenic fungi. Other azole compounds are at varying stages of preclinical and clinical investigation.

Animals↗
PubMed1993

Resistance of yeasts to azole-derivative antifungals.

There are relatively few antifungal agents available for the treatment of systemic mycoses. The incidence of these infections, particularly among the immunocompromised, has increased significantly in recent years. Amphotericin B, flucytosine and the azole-derivatives--fluconazole, itraconazole and ketoconazole--are the only drugs of value in the treatment of systemic yeast infections currently available. To date resistance among individual yeast species or strains has only been a serious problem with flucytosine. However, resistance among Candida spp. to orally administered azole-derivatives has been observed. The frequency with which resistance has been described in clinical practice among yeasts differs considerably between the three azole antifungal agents. Fluconazole has been implicated in emergent resistance more frequently than ketoconazole, and ketoconazole more often than itraconazole. It must be a matter for concern that, by analogy with the known emergence of antibiotic-resistance among bacteria, that the widespread use of a drug inactive against a particular species may lead to an increased incidence of such infections. An international epidemiological survey is required to establish the extent and degree of resistance to the azole antifungals.

Antifungal Agents↗
PubMed1991

Synergistic action of nikkomycin X/Z with azole antifungals on Candida albicans.

Fluconazole, ketoconazole and tioconazole were shown to act synergistically in vitro with the antibiotic nikkomycin X/Z on the pathogenic fungus Candida albicans. The phenomenon was demonstrated using a checkerboard technique and growth inhibition experiments. The azole antifungal agents, even at concentrations not affecting growth, decreased the incorporation of the 14C-label from [14C]glucose into chitin of the candidal cell wall. After 3 h incubation with tioconazole, 1 microgram ml-1, the incorporation of the radiolabelled glucose into chitin of intact cells and regenerating spheroplasts of C. albicans was inhibited by 43% and 30%, respectively. Moreover, the relative chitin content was approximately 45% lower than that of control cells. The chitin content increased after prolonged incubation with azoles, thus confirming the known phenomenon of azole-induced uncoordinated chitin synthesis and deposition. On the other hand, azole derivatives had very little effect on the rate of nikkomycin transport into C. albicans cells. A sequential blockade mechanism of synergism is proposed.

Aminoglycosides↗
PubMedDate not supplied

Post-antibiotic effect and post-expositional polyene antagonism of azole antifungal agents in Candida albicans: dependence on substance lipophilia.

The lipophilic azoles itraconazole (ICZ), ketoconazole (KCZ) and miconazole (MCZ) have two things in common regarding their effect on Candida albicans. First, these azoles cause a growth inhibition that persists for at least 24 h after exposure (post-antibiotic effect), although this is only occasionally observed for ICZ. Secondly, these substances cause a decrease in the fungicidal activity of amphotericin B (AMB, 1 mg l-1) upon subsequent exposure to this drug. In contrast, fluconazole (FCZ) exhibits neither of these two effects. Further tests suggest that both of these phenomena observed may be related to the non-covalent binding of the three lipophilic azoles to lipophilic cytoplasmic components of yeast cells. With fluconazole, such bonds seem to be much weaker. The amount of relatively hydrophilic fluconazole that is bound non-specifically to the fungal cell is evidently too low to produce long-lasting post-exposure effects like those caused by lipophilic azoles.

Amphotericin B↗
PubMed2006

A new, broad-spectrum azole antifungal: posaconazole--mechanisms of action and resistance, spectrum of activity.

Posaconazole, a new triazole antifungal, exerts principally the same mechanism of action as the other azole derivatives, i.e. it inhibits the ergosterol production by binding and inhibiting the lanosterol-14alpha-demethylase which is present in almost all fungi except Pneumocystis and Pythium. Posaconazole has an exquisitely high affinity to this target. Since posaconazole has a chemical structure different from fluconazole and voriconazole, it can interact with an additional domain of the target so that it may inhibit even mutated strains resistant to fluconazole and voriconazole. In addition posaconazole is a bad substrate for efflux pumps in fungi, so it can stay active when other azoles are already inactive. Furthermore, the spectrum of posaconazole is rather large including also some zygomycetes resistant to other azoles. In conclusion, posaconazole is actually the most potent azole derivative used in medicine. A combination of posaconazole with other groups of antifungals may have a favourable effect. There are several methods to test the in vitro activities of posaconazole including the E-test, though interpretive breakpoints are still lacking.

Antifungal Agents↗
PubMed2005

Prevention of cryptococcosis in HIV-infected patients with limited access to highly active antiretroviral therapy: evidence for primary azole prophylaxis.

Despite advances in the treatment of HIV disease, the incidence and mortality of invasive cryptococcal disease remain significant. A matched, case-control study was performed to examine the impact of highly active antiretroviral therapy (HAART) and azole use on the incidence of invasive cryptococcal disease in HIV-infected patients. The study was performed at a metropolitan hospital with a large indigent population and an incidence of seven cases of cryptococcal disease per 1000 persons with AIDS. Bivariate analysis, matched on CD4 count, revealed that both HAART use [odds ratio (OR) 0.43; 95% confidence interval (CI) 0.23-0.99] and azole use (OR 0.14; 95% CI 0.06-0.34) had a protective effect. Conditional logistic regression stratified on CD4 lymphocyte count revealed a protective role for azole use (OR 0.15; 95% CI 0.06-0.40) but not for HAART use (OR 0.47; 95% CI 0.18-1.26). Of note, the prevalence of HAART use was low in both cases and controls, with only 12% of cases and 23% of controls on HAART. The results of this study support previous evidence that azole use prevents invasive cryptococcal disease. Although current guidelines for the prophylaxis of opportunistic infections do not suggest routine prophylaxis for cryptococcal infection, this issue should be reconsidered, especially in populations that have a low prevalence of HAART use.

AIDS-Related Opportunistic Infections↗
PubMed1997

Molecular mechanisms of azole resistance in fungi.

This paper reviews the current status of our understanding of azole antifungal resistance mechanisms at the molecular level and explores their implications. Extensive biochemical studies have highlighted a significant diversity in mechanisms conferring resistance to azoles, which include alterations in sterol biosynthesis, target site, uptake and efflux. In stark contrast, few examples document the molecular basis of azole resistance. Those that do refer almost exclusively to mechanisms in laboratory mutants, with the exception of the role of multi-drug resistance proteins in clinical isolates of Candida albicans. It is clear that the technologies required to examine and define azole resistance mechanisms at the molecular level exist, but research appears distinctly lacking in this most important area.

Antifungal Agents↗
PubMed1997

Neutrophil phagocytosis in AIDS patients with azole resistant candidiasis.

OBJECTIVE AND SUBJECTS: This study aimed to evaluate phagocytosis of C. albicans by neutrophils in 10 AIDS patients and 50 control subjects. Five of the AIDS patients were colonised with azole-resistant C. albicans isolates and five with azole-sensitive isolates. RESULTS AND CONCLUSIONS: Percentage phagocytosis was within normal limits for seven of the 10 AIDS patients and was reduced in the remaining three patients. Phagocytosis was unaffected by the carriage of azole resistant C. albicans, and the patients' own strains were phagocytosed as readily as a standard strain of C. albicans. This study suggests that azole resistance is not related to impaired phagocytosis in AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed1992

Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo.

Nikkomycins X and Z (NZ), competitive inhibitors of fungal chitin synthetase, were combined with azoles in a series of in vitro checkerboard assays to test for synergism against Candida spp. All combinations of nikkomycins and azoles tested resulted in marked synergistic activity against an isolate of Candida albicans, with fractional inhibitory concentration indices ranging from 0.016 to 0.28. No synergistic effect was demonstrable with isolates of C. tropicalis, C. parapsilosis, or C. krusei, though results for the latter two were suggestive of an additive effect. In survival models of mice infected intravenously with C. albicans, NZ administered singly in doses ranging from 5 to 50 mg/kg of body weight twice a day was able to delay the onset of mortality but showed no dose-response effect. The combination of NZ and the azole R 3783 administered orally in a ratio of 8:1 to 40:1 or greater (wt/wt) enhanced survival better than did the drugs given individually, but this effect was less evident for combinations involving fluconazole. In short-term organ load assays with outbred mice infected intravenously with C. albicans, high ratios of NZ to R 3783 reduced the CFU per gram in kidneys more significantly than did the drugs individually. Statistically significant reductions were not seen for short-term fungal burden assays using combinations of NZ and fluconazole in outbred mice or in inbred mice more susceptible to candidiasis. In a model of rat vaginal candidiasis, the combination of NZ and R 3783 administered either orally or vaginally was more effective than the drugs used singly. Thus, under certain conditions, combination therapy with nikkomycin and select azoles may offer promise for an increased therapeutic effect in candidiasis.

Aminoglycosides↗
PubMed1996

Correlation between rhodamine 123 accumulation and azole sensitivity in Candida species: possible role for drug efflux in drug resistance.

A wide variety of prokaryotic and eukaryotic cells exhibit a multidrug resistance (MDR) phenotype, indicating that resistance to potentially toxic compounds is mediated by their active efflux from the cell. We have sought to determine whether resistance to azoles in some strains of Candida species may be due in part to active drug efflux. Rhodamine 123 (Rh123) is a fluorescent compound that is transported by a wide variety of MDR cell types. We have shown that certain azole-resistant strains of Candida albicans, C. glabrata, and C. krusei accumulate less Rh123 than azole-susceptible ones. In C. albicans, Rh123 accumulation was growth phase and temperature dependent and was increased by proton uncouplers and by reserpine, an MDR modulator. This is consistent with an energy-dependent efflux mechanism for Rh123, mediated by an MDR transporter. In C. glabrata, but not in C. albicans, there was competition between Rh123 and fluconazole for efflux. Thus, in C. glabrata, Rh123 and fluconazole appear to be transported via a common MDR-like transporter, whereas in C. albicans, the Rh123 transporter does not appear to transport azoles.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Accumulation of 3-ketosteroids induced by itraconazole in azole-resistant clinical Candida albicans isolates.

The effects of itraconazole on ergosterol biosynthesis were investigated in a series of 16 matched clinical Candida albicans isolates which had been previously analyzed for mechanisms of resistance to azoles (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother., 39:2378-2386, 1995). Under control conditions, all isolates contained ergosterol as the predominant sterol, except two strains (C48 and C56). In isolates C48 and C56, both less susceptible to azoles than their parent, C43, substantial concentrations (20 to 30%) of 14alpha-methyl-ergosta-8,24(28)-diene-3beta,6alpha-dio l (3, 6-diol) were found. Itraconazole treatment of C43 resulted in a dose-dependent inhibition of ergosterol biosynthesis (50% inhibitory concentration, 2 nM) and accumulation of 3,6-diol (up to 60% of the total sterols) together with eburicol, lanosterol, obtusifoliol, 14alpha-methyl-ergosta-5,7,22,24(28)-tetraene-3betaol, and 14alpha-methyl-fecosterol. In strains C48 and C56, no further increase of 3,6-diol was observed after exposure to itraconazole. Ergosterol synthesis was less sensitive to itraconazole inhibition, as was expected for these azole-resistant isolates which overexpress ATP-binding cassette transporter genes CDR1 and CDR2. In addition to 3,6-diol, substantial amounts of obtusifolione were found after exposure to itraconazole. This toxic 3-ketosteroid was demonstrated previously to accumulate after itraconazole treatment in Cryptococcus neoformans and Histoplasma capsulatum but has not been reported in Candida isolates. Accumulation of obtusifolione correlated with nearly complete growth inhibition in these azole-resistant strains compared to that found in the susceptible parent strain, although the onset of growth inhibition only occurred at higher concentrations of itraconazole. ERG25 and ERG26 are the only genes assigned to the 4-demethylation process, of which the 3-ketoreductase is part. To verify whether mutations in these ERG25 genes contributed to obtusifolione accumulation, their nucleotide sequences were determined in all three related isolates. No mutations in ERG25 alleles of isolates C48 and C56 were found, suggesting that this gene is not involved in obtusifolione accumulation. The molecular basis for the accumulation of this sterol in these two strains remains to be established.

Antifungal Agents↗
PubMed1999

Genetic analysis of azole resistance by transposon mutagenesis in Saccharomyces cerevisiae.

The increasing resistance of Candida species to fluconazole is cause for concern. To determine the molecular mechanisms involved in resistance to fluconazole, I used a scheme of transposon mutagenesis in Saccharomyces cerevisiae, a genetically tractable yeast that is closely related to Candida albicans. This technique, which permits the generation and analysis of multiple random Tn3::LEU2::lacZ fusions, can be used as a disruption mutagen (N. B. Burns et al., Genes Dev. 8:1087-1105, 1994). By using the Tn3::LEU2::lacZ library as a disruption mutagen, I found recessive mutations in genes that were previously found to be involved in azole resistance, e.g., PDR5 and CPR1, and in genes previously found to be involved in azole sensitivity, e.g., ERG3. This approach also enabled me to identify recessive mutations in three genes not previously known to be involved in azole sensitivity. Two of the genes, ADA3 and SPT7, are general transcriptional regulators; the third, YMR034c, is a putative sterol transporter. Finally, by screening the Tn3::LEU2::lacZ library for lacZ fusions induced by a low concentration of fluconazole, I identified genes known to be induced by azoles as well as a variety of other genes not previously known to be induced by the drug. In conclusion, transposon mutagenesis is a promising screening tool for use in identifying novel drug targets and in uncovering the mechanisms involved in the response of S. cerevisiae to antifungal drugs.

Antifungal Agents↗
PubMed2002

In vitro low-level resistance to azoles in Candida albicans is associated with changes in membrane lipid fluidity and asymmetry.

The present study tracks the development of low-level azole resistance in in vitro fluconazole-adapted strains of Candida albicans, which were obtained by serially passaging a fluconazole-susceptible dose-dependent strain, YO1-16 (fluconazole MIC, 16 microg ml(-1)) in increasing concentrations of fluconazole, resulting in strains YO1-32 (fluconazole MIC, 32 microg ml(-1)) and YO1-64 (MIC, 64 microg ml(-1)). We show that acquired resistance to fluconazole in this series of isolates is not a random process but is a gradually evolved complex phenomenon that involves multiple changes, which included the overexpression of ABC transporter genes, e.g., CDR1 and CDR2, and the azole target enzyme, ERG11. The sequential rise in fluconazole MICs in these isolates was also accompanied by cross-resistance to other azoles and terbinafine. Interestingly, fluorescent polarization measurements performed by using the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene revealed that there was a gradual increase in membrane fluidity of adapted strains. The increase in fluidity was reflected by observed change in membrane order, which was considerably decreased (decrease in fluorescence polarization values, P value) in the adapted strain (P value of 0.1 in YO1-64, compared to 0.19 in the YO1-16 strain). The phospholipid composition of the adapted strain was not significantly altered; however, ergosterol content was reduced in YO1-64 from that in the YO1-16 strain. The asymmetrical distribution of phosphatidylethanolamine (PE) between two monolayers of plasma membrane was also changed, with PE becoming more exposed to the outer monolayer in the YO1-64 strain. The results of the present study suggest for the first time that changes in the status of membrane lipid phase and asymmetry could contribute to azole resistance in C. albicans.

Antifungal Agents↗
PubMed2004

Mechanisms of azole resistance in petite mutants of Candida glabrata.

We previously showed that resistant colonies of Candida glabrata inside the azole inhibition zones had respiratory deficiency due to mutations in mitochondrial DNA. Here, we analyzed the mechanisms of azole resistance in petite mutants of C. glabrata obtained by exposure to fluconazole or induced by ethidium bromide. The respiratory deficiency of these mutants was confirmed by oxygraphy and flow cytometric analysis with rhodamine 123, and its mitochondrial origin was demonstrated by transmission electron microscopy and restriction endonuclease analysis of the mitochondrial DNA. Flow cytometry with rhodamine 6G suggested an increased drug efflux in mutant cells, which was further supported by Northern blot analysis of the expression of the C. glabrata CDR1 (CgCDR1) and CgCDR2 genes, encoding efflux pumps. Conversely, the expression of CgERG11, which encodes the azole target, was not affected by petite mutations, and no differences were seen in the sequence of this gene between parent isolates and mutants. Moreover, sterol analysis showed similar overall amount of sterols in parent and mutant cells, but quantitative modifications were observed in the mutants, with almost undetectable biosynthesis intermediates. Further analysis performed after separation of free sterols from steryl esters revealed a defect in sterol esterification in mutant cells, with free ergosterol representing 92% of the overall sterol content. Thus, resistance or decreased susceptibility to azoles in petite mutants of C. glabrata is associated with increased expression of CgCDR1 and, to a lesser extent, of CgCDR2. In addition, the marked increase in free ergosterol content would explain their increased susceptibility to polyenes.

Antifungal Agents↗
PubMed2004

Disruption of the Candida albicans CYB5 gene results in increased azole sensitivity.

Sterol synthesis in fungi is an aerobic process requiring molecular oxygen and, for several cytochrome-mediated reactions, aerobically synthesized heme. Cytochrome b(5) is required for sterol C5-6 desaturation and the encoding gene, CYB5, is nonessential in Saccharomyces cerevisiae. Cyb5p and Ncp1p (cytochrome P-450 reductase) appear to have overlapping functions in this organism, with disruptions of each alone being viable. The cytochrome P-450 reductase phenotype has also been shown to demonstrate increased sensitivity to azole antifungals. Based on this phenotype, the CYB5 gene in the human pathogen Candida albicans was investigated to determine whether the cyb5 genotype was viable and would also demonstrate azole sensitivity. Sequential disruption of the CYB5 alleles by direct transformation resulted in viability, presumably conferred by the presence of a third copy of the CYB5 gene. Subsequent disruption procedures with a pMAL2-CYB5 rescue cassette and a CYB5-URA3 blaster cassette resulted in viable cyb5 strains with no third copy. The C. albicans CYB5 gene is concluded to be nonessential. Thus, the essentiality of this gene and whether we observed two or three alleles was dependent upon the gene disruption protocol. The C. albicans cyb5 strains produced a sterol profile containing low ergosterol levels and sterol intermediates similar to that reported for the S. cerevisiae cyb5. The C. albicans cyb5 shows increased sensitivity to azoles and terbinafine, an inhibitor of squalene epoxidase, and, unexpectedly, increased resistance to morpholines, which inhibit the ERG2 and ERG24 gene products. These results indicate that an inhibitor of Cyb5p would not be lethal but would make the cell significantly more sensitive to azole treatment.

Alleles↗
PubMed1999

Current and emerging azole antifungal agents.

Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

Animals↗
PubMed1998

Comparison of three methods for testing azole susceptibilities of Candida albicans strains isolated sequentially from oral cavities of AIDS patients.

Three susceptibility testing procedures were compared to determine fluconazole, itraconazole, and ketoconazole MICs against 47 Candida albicans strains isolated sequentially from the oral cavities of five AIDS patients undergoing azole therapy. They included the broth microdilution method (BM), performed according to the National Committee for Clinical Laboratory Standards' tentative standard, the agar dilution method (AD), and the Etest; the latter two tests were performed both in Casitone agar (AD-Cas and Etest-Cas) and in RPMI (AD-RPMI and Etest-RPMI). Twenty-four- and 48-h MICs obtained by AD and Etest were compared with 48-h MICs obtained by BM. The MICs of all the azoles determined by BM were usually lower than those obtained by the other methods, mainly due to different reading criteria. In order to assess the most appropriate way of evaluating the agreement of MICs obtained by different methods with those produced by the proposed reference method (BM), we used the mean differences calculated according to Bland and Altman's method. Comparison of fluconazole MICs obtained by BM and AD-Cas yielded a mean difference of 3, and the percentages of agreement within +/-2 dilutions were 98 and 100% at 24 and 48 h, respectively. For ketoconazole and itraconazole MICs, lower mean differences were noted, and agreement ranged from 96 to 100%. Agreement between the AD-RPMI and BM results was poor for all azoles, and an increase in MICs was always observed between the 1st- and 2nd-day readings. Similarly, Etest-Cas gave better agreement with BM than did Etest-RPMI for all the azoles. BM, AD-Cas, and Etest-Cas each demonstrated a progressive increase in fluconazole MICs against strains isolated sequentially from a given patient, in accordance with the decreased clinical response to fluconazole.

AIDS-Related Opportunistic Infections↗
PubMed2005

Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species.

The lipophilic yeast Malassezia is an exacerbating factor in atopic dermatitis (AD) and colonizes the skin surface of patients with AD. With the goal of reducing the number of Malassezia cells, we investigated the antifungal activities of a therapeutic agent for AD, tacrolimus, and the azole agents itraconazole and ketoconazole against Malassezia species in vitro. We examined 125 strains of the 11 currently accepted Malassezia species by using the agar dilution method. All strains of the 11 Malassezia species were very susceptible to both azole agents, with MICs ranging from 0.016 to 0.25 mug/ml. Tacrolimus had antifungal activities against half of the strains, with MICs ranging from 16 to 32 mug/ml. Two of the major cutaneous floras, Malassezia globosa and Malassezia restricta, have several genotypes in the intergenic spacer region of the rRNA gene; the azole agents had slightly higher MICs for specific genotype strains of both microorganisms. A combination of azole agents and tacrolimus had a synergistic effect against Malassezia isolates, based on a fractional inhibitory index of 0.245 to 0.378. Our results provide the basis for testing these agents in future clinical trials to reduce the number of Malassezia cells colonizing the skin surface in patients with AD.

Antifungal Agents↗