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PubMed1997

Azole antifungals: weak inhibitors of inducible nitric oxide synthase in mouse and human cells.

The effect of three azole antifungals on inducible nitric oxide (iNOS) activity in different mouse and human cells was evaluated. The iNOS activity was determined by L-citrulline and nitrite measurement. In the murine macrophage cell line RAW 264.7, in mouse peritoneal macrophages (MPM) and in human colorectal adenocarcinoma cells (DLD-1), iNOS activity could be induced with lipopolysaccharides and cytokines. Under similar conditions, no iNOS induction was found in human monocytes/macrophages. The concentration of itraconazole, ketoconazole or miconazole needed to inhibit iNOS activity by 50% in RAW 264.7 cells, MPM and DLD-1 cells was > or = 10 mumol l-1. This is at least 100 times more than the concentrations of these azole antifungals required to produce a 50% inhibition of yeast growth and ergosterol synthesis of, for example, Candida albicans after the same incubation period. These results show that azole antifungals are weak inhibitors of iNOS in intact cells.

Adenocarcinoma↗
PubMed1990

Azole susceptibility and hyphal formation in a cytochrome P-450-deficient mutant of Candida albicans.

A cytochrome P-450-deficient mutant of Candida albicans, strain D10, was employed to study the mode of action of imidazole antifungal agents. This mutant accumulates exclusively 14-alpha-methylsterols, resulting in a sterol profile which mimics that of azole-treated wild-type strains. Since the widely accepted primary effect of imidazoles is the inhibition of cytochrome P-450-mediated demethylation of the ergosterol precursor lanosterol, strain D10 and its wild-type revertant, strain D10R, were grown in the presence of concentrations of clotrimazole, miconazole, and ketoconazole known to inhibit demethylation. The growth of strain D10 was unaffected by these antifungal agents, while that of strain D10R was significantly reduced. At higher azole concentrations (which are known to exert a direct, disruptive action on the cell membrane), the growth of both strains was immediately and completely inhibited by clotrimazole and miconazole. Ketoconazole was membrane disruptive only for strain D10; this is the first report of a direct membrane effect for this drug. Because hyphal formation has been implicated in the pathogenesis of C. albicans and because it has been shown to be inhibited by azoles, the hypha-forming capability of strain D10 was examined. Strain D10 was shown to be seriously defective in hyphal formation, suggesting that this function may be dependent on the 14-alpha-demethylation of lanosterol. The results of this study suggest that inhibition of lanosterol demethylation per se is neither fungicidal nor fungistatic, although the growth rate is reduced. In addition, the substitution of 14-alpha-methylsterols for ergosterol results in defective hyphal formation and in a cell that is more susceptible to membrane-active agents such as ketoconazole.

Azoles↗
PubMed1992

Characterization of an azole-resistant Candida glabrata isolate.

A Candida (Torulopsis) glabrata strain (B57149) became resistant to fluconazole after a patient carrying the organism was treated with the drug at 400 mg once daily for 9 days. Growth of the pretreatment isolate (B57148) was inhibited by 50% with 0.67 microM ketoconazole, 1.0 microM itraconazole, and 43 microM fluconazole, whereas growth of B57149 was inhibited slightly by 10 microM ketoconazole but was unaffected by 10 microM itraconazole or 100 microM fluconazole. This indicates cross-resistance to all three azole antifungal agents. The cellular fluconazole content of B57149 was from 1.5- to 3-fold lower than that of B57148, suggesting a difference in drug uptake between the strains. However, this difference was smaller than the measured difference in susceptibility and, therefore, cannot fully explain the fluconazole resistance of B57149. Moreover, the intracellular contents of ketoconazole and itraconazole differed by less than twofold between the strains, so that uptake differences did not account for the azole cross-resistance of B57149. The microsomal cytochrome P-450 content of B57149 was about twice that of B57148, a difference quantitatively similar to the increased subcellular ergosterol synthesis from mevalonate or lanosterol. These results indicate that the level of P-450-dependent 14 alpha-demethylation of lanosterol is higher in B57149. Increased ergosterol synthesis was also seen in intact B57149 cells, and this coincided with a decreased susceptibility of B57149 toward all three azoles and amphotericin B. B57149 also had higher squalene epoxidase activity, and thus, more terbinafine was needed to inhibit the synthesis of 2,3-oxidosqualene from squalene. P-450 content and ergosterol synthesis both decreased when isolate B57149 was subcultured repeatedly on drug-free medium. This repeated subculture also fully restored the strain's itraconazole susceptibility, but only partly increased its susceptibility to fluconazole. The results suggest that both lower fluconazole uptake and increased P-450-dependent ergosterol synthesis are involved in the mechanism of fluconazole resistance but that only the increased ergosterol synthesis contributes to itraconazole cross-resistance.

Antifungal Agents↗
PubMed1999

Effects of azole antifungal drugs on the transition from yeast cells to hyphae in susceptible and resistant isolates of the pathogenic yeast Candida albicans.

Oral infections caused by the yeast Candida albicans are some of the most frequent and earliest opportunistic infections in human immunodeficiency virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug resistance, creating a major problem in the treatment of yeast infections in AIDS patients and other immunocompromised individuals. Several molecular mechanisms that contribute to drug resistance have been identified. In C. albicans, the ability to morphologically switch from yeast cells (blastospores) to filamentous forms (hyphae) is an important virulence factor which contributes to the dissemination of Candida in host tissues and which promotes infection and invasion. A positive correlation between the level of antifungal drug resistance and the ability to form hyphae in the presence of azole drugs has been identified. Under hypha-inducing conditions in the presence of an azole drug, resistant clinical isolates form hyphae, while susceptible yeast isolates do not. This correlation is observed in a random sample from a population of susceptible and resistant isolates and is independent of the mechanisms of resistance. 35S-methionine incorporation suggests that growth inhibition is not sufficient to explain the inhibition of hyphal formation, but it may contribute to this inhibition.

Antifungal Agents↗
PubMed2000

Efficacy of FK463, a (1,3)-beta-D-glucan synthase inhibitor, in disseminated azole-resistant candida albicans infection in mice.

The efficacy of FK463, a new (1,3)-beta-D-glucan synthase inhibitor, against azole-resistant Candida albicans strains has been studied. The MIC of FK463 was lower than those of azoles and amphotericin B against CDR1-expressing C26 and CaMDR-expressing C40 strains. All mice treated with FK463 (1 mg/kg) survived disseminated murine candidiasis. The fungal burden in the kidney after 6 days was markedly reduced after therapy with FK463 and amphotericin B sodium deoxycholate, and plasma (1,3)-beta-D-glucan concentration was found to be lower in FK463-treated mice. In our study, FK463 was found to be a potent antifungal agent against disseminated infection with azole-resistant C. albicans.

Animals↗
PubMed2001

Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans.

The development of azole resistance in Candida albicans is most problematic in patients with AIDS who receive long courses of drug for therapy or prevention of oral candidiasis. Recently, the rapid development of resistance was noted in other immunosuppressed patients who developed disseminated candidiasis despite fluconazole prophylaxis. One of these series of C. albicans isolates became resistant, with an associated increase in mRNA specific for a CDR ATP-binding cassette transporter efflux pump (K. A. Marr, C. N. Lyons, T. R. Rustad, R. A. Bowden, and T. C. White, Antimicrob. Agents Chemother. 42:2584-2589, 1998). Here we study this series of C. albicans isolates further and examine the mechanism of azole resistance in a second series of C. albicans isolates that caused disseminated infection in a recipient of bone marrow transplantation. The susceptible isolates in both series become resistant to fluconazole after serial growth in the presence of drug, while the resistant isolates in both series become susceptible after serial transfer in the absence of drug. Population analysis of the inducible, transiently resistant isolates reveals a heterogeneous population of fluconazole-susceptible and -resistant cells. We conclude that the rapid development of azole resistance occurs by a mechanism that involves selection of a resistant clone from a heterogeneous population of cells.

Antifungal Agents↗
PubMed2004

Constitutive activation of the PDR16 promoter in a Candida albicans azole-resistant clinical isolate overexpressing CDR1 and CDR2.

Candida albicans azole-resistant clinical isolates overexpressing the CDR1 and CDR2 genes (multidrug transporters) also overexpress the PDR16 gene (phosphatidylinositol transfer protein). We show here that the PDR16 promoter displays higher transcriptional activity following integration in an azole-resistant isolate than in the matched azole-susceptible one. Thus, the upregulation of PDR16 in the resistant strain results from a mutation acting in trans.

ATP-Binding Cassette Transporters↗
PubMed2004

Comparison of gene expression profiles of Candida albicans azole-resistant clinical isolates and laboratory strains exposed to drugs inducing multidrug transporters.

Azole resistance in Candida albicans can be due to upregulation of multidrug transporters belonging to ABC (ATP-binding cassette) transporters (CDR1 and CDR2) or major facilitators (CaMDR1). Upregulation of these genes can also be achieved by exposure to fluphenazine, resulting in specific upregulation of CDR1 and CDR2 and by exposure to benomyl, resulting in specific CaMDR1 upregulation. In this study, these two different states of gene upregulation were used to determine coregulated genes that often share similar functions or similar regulatory regions. The transcript profiles of a laboratory strain exposed to these drugs were therefore determined and compared with those of two matched pairs of azole-susceptible and -resistant strains expressing CDR1 and CDR2 (CDR strains) or CaMDR1 (MDR isolates). The results obtained revealed that, among 42 commonly regulated genes (8.6% of all regulated genes) between fluphenazine-exposed cells and CDR isolates, the most upregulated were CDR1 and CDR2 as expected, but also IFU5, RTA3 (which encodes putative membrane proteins), HSP12 (which encodes heat shock protein), and IPF4065 (which is potentially involved in stress response). Interestingly, all but HSP12 and IPF4065 contain a putative cis-acting drug responsive element in their promoters. Among the 57 genes (11.5% of all regulated genes) commonly regulated between benomyl-exposed cells and MDR isolates, the most upregulated were CaMDR1 as expected but also genes with oxido-reductive functions such as IFD genes, IPF5987, GRP2 (all belonging to the aldo-keto reductase family), IPF7817 [NAD(P)H oxido-reductase], and IPF17186. Taken together, these results show that in vitro drug-induced gene expression only partially mimics expression profiles observed in azole-resistant clinical strains. Upregulated genes in both drug-exposed conditions and clinical strains are drug resistance genes but also genes that could be activated under cell damage conditions.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Surface-active fungicidal D-peptide inhibitors of the plasma membrane proton pump that block azole resistance.

A 1.8-million-member D-octapeptide combinatorial library was constructed in which each member comprised a diversity-containing N-terminal pentapeptide and a C-terminal amidated triarginine motif. The C-terminal motif concentrated the library members at the fungal cell surface. A primary screen for inhibitors of Saccharomyces cerevisiae and Candida albicans growth, together with an in vitro secondary screen with the S. cerevisiae plasma membrane ATPase (Pma1p) as a target, identified the antifungal D-octapeptide BM0 (D-NH(2)-RFWWFRRR-CONH(2)). Optimization of BM0 led to the construction of BM2 (D-NH(2)-RRRFWWFRRR-CONH(2)), which had broad-spectrum fungicidal activity against S. cerevisiae, Candida species, and Cryptococcus neoformans; bound strongly to the surfaces of fungal cells; inhibited the physiological activity of Pma1p; and appeared to target Pma1p, with 50% inhibitory concentrations in the range of 0.5 to 2.5 microM. At sub-MICs (<5 microM), BM2 chemosensitized to fluconazole (FLC) S. cerevisiae strains functionally hyperexpressing fungal lanosterol 14alpha-demethylase and resistance-conferring transporters of azole drugs. BM2 chemosensitized to FLC some FLC-resistant clinical isolates of C. albicans and C. dubliniensis and chemosensitized to itraconazole clinical isolates of C. krusei that are intrinsically resistant to FLC. The growth-inhibitory concentrations of BM2 did not cause fungal cell permeabilization, significant hemolysis of red blood cells, or the death of cultured HEp-2 epithelial cells. BM2 represents a novel class of broad-spectrum, surface-active, Pma1p-targeting fungicides which increases the potencies of azole drugs and circumvents azole resistance.

Amino Acid Sequence↗
PubMed1998

Stable phenotypic resistance of Candida species to amphotericin B conferred by preexposure to subinhibitory levels of azoles.

The fungicidal activity of amphotericin B (AmB) was quantitated for several Candida species. Candida albicans and C. tropicalis were consistently susceptible to AmB, with less than 1% survivors after 6 h of exposure to AmB. C. parapsilosis and variants of C. lusitaniae and C. guilliermondii were the most resistant, demonstrating 50 to 90% survivors in this time period and as high as 1% survival after a 24-h exposure time. All Candida species were killed (<1% survivors) after 24 h of exposure to AmB. In contrast, overnight exposure to either fluconazole or itraconazole resulted in pronounced increases in resistance to subsequent exposures to AmB. Most dramatically, C. albicans was able to grow in AmB cultures after azole preexposure. Several other Candida species did not grow in AmB but showed little or no reduction in viability after up to 24 h in AmB. Depending on the growth conditions, Candida cells preexposed to azoles may retain AmB resistance for days after the azoles have been removed. If this in vitro antagonism applies to the clinical setting, treatment of patients with certain antifungal combinations may not be beneficial. The ability of some Candida isolates to survive transient exposures to AmB was not reflected in the in vitro susceptibility changes as measured by standard MIC assays. This finding should be considered in studies attempting to correlate patient outcome with in vitro susceptibilities of clinical fungal isolates. Patients who fail to respond to AmB may be infected with isolates that are classified as susceptible by standard in vitro assays but that may be resistant to transient antifungal exposures which may be more relevant in the clinical setting.

Amphotericin B↗
PubMedDate not supplied

Efficacy of amphotericin B and azoles alone and in combination against disseminated trichosporonosis in neutropenic mice.

The activities of amphotericin B, miconazole, fluconazole, and itraconazole against Trichosporon beigelii were assessed in a mouse model of disseminated infection. Cyclophosphamide plus prednisolone-immunosuppressed ICR mice, intravenously challenged with a lethal inoculum of (6 x 10(6) CFU/ mouse), were assigned to receive 7 days of therapy with amphotericin B (0.5 or 2 mg/kg/day), miconazole (10 or 40 mg/kg/day), fluconazole (10 or 40 mg/kg/day), or itraconazole (10 and 40 mg/kg/day). The efficacy of a combination of amphotericin B (1 mg/kg/day) with that fluconazole (10 mg/kg/ day) or itraconazole (20 mg/kg/day) with that of each agent alone was also compared. Both amphotericin B and azoles improved survival and reduced the fungal counts in kidneys of infected mice in a dose-dependent pattern. In general, fluconazole was superior to amphotericin B and the other azoles, whereas the latter two drugs were as effective as amphotericin B. The activity of amphotericin B combined with fluconazole appeared to be superior to that of each agent alone, especially in reducing the organ fungal burden. The other combination (amphotericin B plus itraconazole) had a weaker effect, but no antagonism was observed. In conclusion, azoles may be an alternative to amphotericin B for the treatment of T. beigelii infection. Furthermore, their combination with amphotericin B may improve the poor outcome seen in profoundly neutropenic patients with disseminated trichosporonosis.

Amphotericin B↗
PubMed2002

Treatment of azole-resistant oropharyngeal candidiasis with topical amphotericin B.

OBJECTIVE: To report a case of successful treatment of azole-refractory oropharyngeal candidiasis with topical amphotericin B. CASE SUMMARY: A 30-year-old white woman presented with recurrent oral thrush. The patient had been exposed to azole antifungals for >20 years, and in vitro susceptibility tests revealed class resistance. The patient started taking amphotericin B 100 mg oral suspension swish-and-spit 4 times daily. After 4 weeks of topical amphotericin B treatment, the patient reported significant symptomatic improvement. The oral candidiasis worsened following a course of oral antibiotics, but improved once the antibiotic was discontinued and after receiving amphotericin B swish-and-swallow for 4 additional weeks. DISCUSSION: Current Infectious Diseases Society of America guidelines include topical amphotericin B as a potentially effective option for the treatment of oropharyngeal candidiasis. There is limited evidence to support this recommendation. Besides lack of data, an appropriate dosing regimen and consistent means of product formulation need to be determined. CONCLUSIONS: This report demonstrates the potential role for topical amphotericin B in the treatment of azole-refractory oral candidiasis. Double-blind, randomized, controlled trials are needed to define dosing, efficacy, administration, and long-term safety of oral amphotericin B.

Administration, Topical↗
PubMed2004

Clinical significance of breakthrough fungemia caused by azole-resistant Candida tropicalis in patients with hematologic malignancies.

A 5-year retrospective analysis of fungemia in patients with hematologic malignancies revealed that four patients, who received fluconazole and itraconazole during neutropenia, developed breakthrough candidemia due to azole-resistant Candida tropicalis isolates. This observation suggests that causative organisms of candidemia in neutropenic patients receiving azoles should be suspected of being azole-resistant.

Adult↗
PubMed1987

[Anti-Candida activity of azoles].

The in vitro activity of the broad-spectrum antifungals miconazole, ketoconazole and itraconazole was evaluated by the decimal dilution method in liquid media, for respectively 2511, 1536 and 1859 strains of yeasts belonging to 31 species. Sabouraud broth was used for miconazole and brain heart infusion broth for ketoconazole and itraconazole. These three azoles proved to be potent anti-yeast compounds. Activity by oral treatment of miconazole, ketoconazole and itraconazole was compared in gastro-intestinal candidosis of the guinea-pig, in vaginal candidosis of the rat and in systemic candidosis of the guinea-pig. Ketoconazole and itraconazole are more efficacious than miconazole in gastro-intestinal candidosis. Miconazole showed marginal activity in the other two experimental models: the spectrum of activity of miconazole was a lead for research which resulted in the synthesis and selection of ketoconazole and itraconazole. Ketoconazole was highly active in these experimental models. Itraconazole cured the animals at distinctly lower doses. No side-effects due to these azoles were observed during these experiments. A proposal is made to classify the broad-spectrum azoles in three classes: compounds for topical use (e.g. miconazole), compounds with oral activity without activity in aspergillosis (e.g. ketoconazole), compounds with oral activity including activity in aspergillosis (e.g. itraconazole).

Animals↗
PubMed2004

Azoles for allergic bronchopulmonary aspergillosis associated with asthma.

BACKGROUND: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay of treatment for allergic bronchopulmonary aspergillosis remains oral corticosteroids, though this does not completely prevent exacerbations and may not prevent the decline in lung function. OBJECTIVES: The purpose of this review was to determine the efficacy of azoles in the treatment of allergic bronchopulmonary aspergillosis. SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register using the terms: (allergic bronchopulmonary aspergillosis OR aspergillosis OR allergic pulmonary aspergillosis OR allergic fungal and disease OR allergic mycotic and disease) AND (azole OR triazole OR itraconazole OR ketoconazole). Date of last search January 2003. SELECTION CRITERIA: All controlled trials that assessed the effect of azole antifungal agents compared to placebo or other standard therapy for allergic bronchopulmonary aspergillosis were reviewed. Patients with cystic fibrosis were not included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twelve trials were identified, but only three were prospective, randomised and controlled. A total of 94 participants were included. One demonstrated a reduction in immunological markers of disease activity and symptom scores using ketoconazole 400 mg daily for 12 months. There was no significant improvement in lung function. The other two examined the use of itraconazole for 16 weeks. In one there was a reduction in sputum eosinophils by 35% compared to 19% with placebo (p < 0.01). In the same trial, the number of exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p < 0.03). Meta-analysis of data from both trials showed that itraconazole treated patients were more likely to have decline in serum IgE over 25% or more (Peto OR 3.30; 95% confidence intervals 1.30 to 8.15). REVIEWERS' CONCLUSIONS: Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks. Adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.

Antifungal Agents↗
PubMed2006

In search of ionic liquids incorporating azolate anions.

Twenty-eight novel salts with tetramethyl-, tetraethyl-, and tetrabutylammonium and 1-butyl-3-methylimidazolium cations paired with 3,5-dinitro-1,2,4-triazolate, 4-nitro-1,2,3-triazolate, 2,4-dinitroimidazolate, 4,5-dinitroimidazolate, 4,5-dicyanoimidazolate, 4-nitroimidazolate, and tetrazolate anions have been prepared and characterized by using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and single-crystal X-ray crystallography. The effects of cation and anion type and structure on the physicochemical properties of the resulting salts, including several ionic liquids, have been examined and discussed. Ionic liquids (defined as having m.p.<100 degrees C) were obtained with all combinations of the 1-butyl-3-methylimidazolium cation ([C(4)mim](+)) and the heterocyclic azolate anions studied, and with several combinations of tetraethyl or tetrabutylammonium cations and the azolate anions. The [C(4)mim](+) azolates were liquid at room temperature exhibiting large liquid ranges and forming glasses on cooling with glass-transition temperatures in the range of -53 to -82 degrees C (except for the 3,5-dinitro-1,2,4-triazolate salt with m.p. 33 degrees C). Six crystal structures of the corresponding tetraalkylammonium salts were determined and the effects of changes to the cations and anions on the packing of the structure have been investigated.

Journal Article↗
PubMed1997

Selection of Candida glabrata strains with reduced susceptibility to azoles in four liver transplant patients with invasive candidiasis.

The cases of four liver transplant recipients who developed invasive candidiasis (2 cholangitis, 1 perihepatic abscess, 1 candidemia) due to azole-resistant, Candida glabrata are reported. Three patients were receiving azolic compounds (2 itraconazole, 1 fluconazole) when the infection was diagnosed. All four patients received fluconazole as intestinal decontamination during the first three weeks post transplantation. The infections occurred two months after transplantation in all patients, and in one patient Candida infection was the direct cause of death. Infection of the biliary tree was the origin of candidiasis in three patients; the fourth patient developed neutropenic-related candidemia. Fluconazole MICs exceeded 16 micrograms/ml in all cases; itraconazole MICs were 16, 2, 1, and 2 micrograms/ml, respectively. The potential role of Candida species other than albicans in these patients after administration of azole agents is discussed.

Antifungal Agents↗
PubMed1989

The activity of ketoconazole and other azoles against Trypanosoma cruzi: biochemistry and chemotherapeutic action in vitro.

Trypanosoma cruzi epimastigotes in culture medium, and amastigotes and trypomastigotes in cultured human diploid lung cells were exposed to the antimycotic agent ketoconazole and their growth and/or sterol biosynthesis observed. Propagation of epimastigotes and amastigotes was impaired by concentrations of ketoconazole achievable in human serum, and amastigotes were more sensitive than were epimastigotes. Epimastigotes and trypomastigotes (non-dividing stage) displayed changes in their membrane sterol content such that the amounts of normal, end-product sterols (ergosterol, ergosta-5,7-dien-3 beta-ol, 24-ethylcholesta-5,7,22-trien-3 beta-ol, 24-ethylcholesta-5,7-dien-3 beta-ol) were notably decreased and the amounts of 14 alpha-methyl sterol precursors of these sterols (24-methylenedihydrolanosterol, obtusifoliol, lanosterol) were increased. Other azole drugs, itraconazole and fluconazole, when tested on epimastigotes, evoked the same qualitative pattern of changes in free sterols. Itraconazole was nearly as potent as ketoconazole, but fluconazole was significantly less potent. The nature of the sterols found in T. cruzi and the actions of azole drugs on their biosynthesis were similar in many respects to those observed in fungi and in Leishmania species. By analogy, it would seem that the primary mechanism of action of azole drugs on T. cruzi life-cycle stages is the impairment of the cytochrome P-450 sterol 14 alpha-demethylase. The consequent loss of normal sterols and accumulation of 14 alpha-methyl sterols may be responsible for the coincident retardation or cessation of growth.

Animals↗