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PubMedDate not supplied

Fluconazole and other azoles: translation of in vitro activity to in vivo and clinical efficacy.

Fluconazole is polar, soluble in water, and metabolically stable and exhibits low protein binding. In contrast, other systemic azoles are lipophilic, metabolically vulnerable compounds with high protein binding and negligible solubility in water. The physical and pharmacokinetic properties of these drugs plus their inherent antifungal potency determine their efficacy. Although fluconazole is less active than ketoconazole in vitro, its distribution throughout the body and the high levels of free drug reached in the blood contribute to and are of value in predicting its efficacy. Even for ketoconazole the levels of free drug in blood may be indicative of efficacy. For very lipophilic agents (itraconazole), blood levels of drug are very low, and organ levels may correlate better with efficacy, although tissue binding will be high and total drug levels in an organ may be misleading indicators of efficacy. The excellent efficacy of fluconazole in vivo despite its low activity in vitro has caused confusion. Consequently, a disk test is being developed to assess whether fungal isolates are sensitive to therapeutically achievable levels of drug.

Animals↗
PubMed1991

Antifungal therapy and the new azole compounds.

At present there are weaknesses in the range and scope of antifungal chemotherapy. The development of a new group of azole drugs, the triazoles, has introduced antifungal agents with broad-spectrum activity which can be given by the oral route. Fluconazole is very well absorbed and has good penetration. While its principal activity is against yeasts and there are clinical data to support its use in candida and cryptococcus infections, little work has been completed on its clinical use in aspergillosis. Itraconazole is less well absorbed, but highly bound in tissue. Its spectrum of activity is somewhat broader than that of fluconazole and it is clinically active against superficial mycoses and some of the infections caused by pathogenic fungi such as Histoplasma capsulatum. There is some early evidence of efficacy in aspergillosis but more studies are required in neutropenic patients. Both drugs show promise but comparative assessments are sorely needed.

Animals↗
PubMed2003

Identification of genes differentially expressed in association with reduced azole susceptibility in Saccharomyces cerevisiae.

OBJECTIVE: An isolate of S. cerevisiae with reduced susceptibility to fluconazole and itraconazole was developed in the laboratory and used to identify genes that are differentially expressed in association with this phenotype. METHODS: S. cerevisiae strain ATCC 9763 was passaged in increasing concentrations of itraconazole. Itraconazole and fluconazole MICs for the initial isolate (9763S) were 2 and 16 mg/L and for the final isolate (9763I) were 16 and > or =64 mg/L, respectively. Duplicate sets of total RNA from 9763S and 9763I were isolated and hybridized to Affymetrix S98 yeast arrays. To validate results, six differentially expressed genes were further examined by RT-PCR. RESULTS: Of the nearly 6400 open reading frames represented on the array, a total of 116 genes (1.8%) were found to be differentially expressed. Cell wall maintenance genes TIR4 and CCW12, sterol metabolism gene UPC2, small molecule transport genes AUS1 and YHK8, and stress response gene CUP1-1 were expressed at a level at least 2.5-fold higher than the expression level found in 9763S. Eleven energy generation genes, ionic homeostasis genes FRE1, FRE2 and FRE4, and sterol metabolism genes ERG8 and ERG13 were expressed at least 2.5-fold lower than the expression level found in 9763S. CONCLUSIONS: Several genes found to be differentially expressed in this study have been shown previously to be differentially expressed in the fungal response to azole treatment. In addition, the potential role of AUS1 and/or YHK8 as mediators of drug efflux is intriguing and warrants further study.

Amino Acids↗
PubMed2003

Efficacy of caspofungin combined with amphotericin B against azole-resistant Candida albicans.

The activity of caspofungin (CFG) combined with amphotericin B (AMB) against azole-resistant Candida albicans was evaluated in vitro (chequerboard) and in vivo (murine). CFG+AMB resulted in positive interactive effects in vitro (fractional inhibitory concentration index 0.75). Compared with untreated controls, CFG+AMB prolonged mouse survival (P = 0.006) and compared with AMB alone, CFG+AMB prolonged mouse survival (P = 0.36); however, the latter difference was not significant. CFG+AMB treatment significantly reduced kidney cfu compared with untreated controls and CFG-treated groups (P < or = 0.05 for both comparisons). In addition, this combination reduced brain cfu significantly compared with untreated controls and AMB-treated mice (P = 0.005 and 0.05, respectively).

Amphotericin B↗
PubMed2004

Oral Candida isolates in patients undergoing radiotherapy for head and neck cancer: prevalence, azole susceptibility profiles and response to antifungal treatment.

Oral pseudomembranous candidiasis and mucositis were assessed in 39 patients receiving a total dose of 39-70 Gy radiotherapy for head and neck cancer. Mucositis was scored using the Radiation Therapy Oncology Group criteria, and oral candidiasis was diagnosed on the basis of clinical evaluation and quantitative laboratory findings. Radiation-induced mucositis was observed in 9/39 patients. Only 3/39 patients discontinued radiotherapy due to acute severe mucosal effects. Candidiasis (colony-forming units 35 to > or = 60/lesion) associated with mucositis was diagnosed in 30/39 patients: the most frequent aetiology of the infection was Candida albicans (n = 23), followed by Candida glabrata (n = 3), Candida krusei (n = 2), Candida tropicalis (n = 1) and Candida kefyr (n = 1). Patients with confirmed oral pseudomembranous candidiasis were treated with either fluconazole 200 mg/day or itraconazole 200 mg/day for 2 weeks. Clinical improvement and concomitant negative Candida cultures (mycologic cure) were the criteria determining a response to antifungal treatment. Etest revealed very low voriconazole MICs (0.004-0.125 microg/ml) for all isolates, and fluconazole resistance for eight C. albicans strains (MIC > 64 microg/ml) and for the C. krusei isolates (MIC > 32 microg/ml). The same strains showed itraconazole susceptibility dose dependence (MIC 0.5 microg/ml). Despite the itraconazole susceptible dose dependent MIC readings, all patients with oral pseudomembranous candidiasis caused by these strains responded to antifungal treatment with 200 mg/day itraconazole. Oral mycologic surveillance of patients undergoing radiotherapy for head and neck malignancies and susceptibility testing of isolates may be indicated in cases with mucositis-associated confirmed oral pseudomembranous candidiasis to ensure prompt administration of targeted antifungal treatment. On the basis of the low MIC values found, clinical evaluation of voriconazole is indicated for management of oral pseudomembranous candidiasis refractory to other azoles.

Adult↗
PubMedDate not supplied

In vitro susceptibility of Malassezia furfur against azole compounds.

The minimum inhibitory concentrations (MICs) for 30 isolates of Malassezia furfur of four azole compounds-bifonazole, climbazole, clotrimazole and ketoconazole were determined as these substances are used in the topical therapy of M. furfur-associated skin conditions. M. furfur is a lipophilic fungus with complex growth requirements; the MICs were measured in a microdilution test system in modified Leeming-Notman medium by a colorimetric read-out with alamarBlue. The MICs of bifonazole ranged between < 0.06 and 1 microgram ml-1 with an empirical median of 0.06 microgram ml-1 for climbazole the MICs were < 0.06 to 0.5 microgram ml-1 (median < 0.06 microgram ml-1), for clotrimazole < 0.06 to 8 micrograms ml-1 (median 1 microgram ml-1), and for ketoconazole < 0.06 to 0.12 microgram ml-1 (median < 0.06 microgram ml-1). Climbazole and ketoconazole showed similar in vitro activity against M. furfur, with bifonazole having slightly lower, and clotrimazole the lowest in vitro activity. These findings may be explained by the extremely low water solubility of the last two compounds; the results have yet to be correlated with the in vivo efficacy of these substances.

Antifungal Agents↗
PubMed2004

History of the development of azole derivatives.

Until the 1940s, relatively few agents were available for the treatment of systemic fungal infections. The development of the polyene antifungals represented a major advance in medical mycology. Although amphotericin B quickly became the mainstay of therapy for serious infections, its use was associated with infusion-related side-effects and dose-limiting nephrotoxicity. The continued search for new and less toxic antifungals led to the discovery of the azoles several decades later. Ketoconazole, the first available compound for the oral treatment of systemic fungal infections, was released in the early 1980s. For almost a decade, ketoconazole was regarded as the drug of choice in nonlife-threatening endemic mycoses. The introduction of the first-generation triazoles represented a second major advance in the treatment of fungal infections. Both fluconazole and itraconazole displayed a broader spectrum of antifungal activity than the imidazoles and had a markedly improved safety profile compared with amphotericin B and ketoconazole. Despite widespread use, however, these agents became subject to a number of clinically important limitations related to their suboptimal spectrum of activity, the development of resistance, the induction of hazardous drug-drug interactions, their less than optimal pharmacokinetic profile (itraconazole capsules), and toxicity. In order to overcome these limitations, several analogues have been developed. These so-called 'second-generation' triazoles, including voriconazole, posaconazole and ravuconazole, have greater potency and possess increased activity against resistant and emerging pathogens, in particular against Aspergillus spp. If the toxicity profile of these agents is comparable to or better than that of the first-generation triazoles and drug interactions remain manageable, then these compounds represent a true expansion of our antifungal arsenal.

Antifungal Agents↗
PubMed1995

Defective sterol delta 5(6) desaturase as a cause of azole resistance in Ustilago maydis.

Resistance to azole antifungals in Ustilago maydis was associated with a leaky defect in sterol delta 5(6)desaturase. This defect resulted in reduced accumulation of 14 alpha-methylergosta-24(28)-diene-3 beta,6 alpha-diol and an increase in the proportion of 14 alpha-methylfecosterol in treated cells when compared to the parent strain. The results demonstrate the importance of this mechanism in pathogenic fungi.

Antifungal Agents↗
PubMed2000

Bactericidal and inhibitory effects of azole antifungal compounds on Mycobacterium smegmatis.

Azole antifungals are central to therapy and act by inhibiting a cytochrome P450, sterol 14-demethylase and blocking normal sterol synthesis. Our recent identification of a mycobacterial sterol biosynthetic pathway led us to probe the efficacy of a range of these compounds against Mycobacterium smegmatis. Several showed equivalent or greater inhibitory effects to those against Candida albicans, and bactericidal activity was demonstrated for four compounds, clotrimazole, econazole, miconazole and tebuconazole. The major drug used clinically, fluconazole, was ineffective. The results are discussed in the light of the world-wide spread of tuberculosis, including drug-resistant forms and the requirement for new drugs.

Antifungal Agents↗
PubMed1990

Effects of lovastatin (mevinolin) on sterol levels and on activity of azoles in Saccharomyces cerevisiae.

The hypocholesterolemic drug lovastatin (mevinolin) was found to be very effective in lowering the sterol levels of the wild-type yeast Saccharomyces cerevisiae. Lovastatin dramatically decreased the steryl ester content from 2.62 to 0.8 micrograms/mg (dry weight), whereas the free sterol content decreased only from 2.79 to 2.24 micrograms/mg (dry weight) when lovastatin was present in the medium at 10 micrograms/ml. At higher concentrations (100 micrograms/ml), lovastatin nearly abolished the accumulation of steryl esters and decreased the free sterol concentration to less than 1.3 micrograms/mg (dry weight). As a result of the lowered sterol levels, proportional amounts of exogenous sterol were taken up from the medium during aerobic, respiratory conditions. Nearly all of the exogenous sterol taken up was partitioned into the free sterol fraction. The inhibition of sterol esterification in the presence of lovastatin was dependent on heme synthesis. The result of these combined effects caused the MICs of three azole antifungal drugs (ketoconazole, clotrimazole, and miconazole) to be lowered from 6- to 32-fold when lovastatin was present in the medium at 10 micrograms/ml.

Azoles↗
PubMed1992

Effect of cyclodextrin on the pharmacology of antifungal oral azoles.

Concentrations of oral azoles in serum were compared in a single-dose pharmacologic study in mice. When hydroxypropyl-beta-cyclodextrin was used as a carrier and compared with a standard carrier, polyethylene glycol, drug concentrations determined by bioassay showed that the peak concentration and area under the concentration-time curve were greatly enhanced for itraconazole and saperconazole; moderately enhanced for ketoconazole; but negligibly affected for fluconazole, miconazole, and SCH 42427.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1995

Activities of amphotericin B and antifungal azoles alone and in combination against Pseudallescheria boydii.

In order to develop new approaches to treatment of infections due to Pseudallescheria boydii, the in vitro antifungal activity of amphotericin B alone and in combination with miconazole, itraconazole, and fluconazole was studied. Combinations of amphotericin B and antifungal azoles were synergistic, additive, or indifferent in their interaction against P. boydii. Antagonism was not observed.

Amphotericin B↗
PubMed1995

Cross-resistance to polyene and azole drugs in Cryptococcus neoformans.

Fluconazole was observed to inhibit sterol 14 alpha-demethylase in the human pathogen Cryptococcus neoformans, and accumulation of a ketosteroid product was associated with growth arrest. A novel mechanism(s) of azole and amphotericin B cross-resistance was identified, unrelated to changes in sterol biosynthesis, as previously identified in Saccharomyces cerevisiae. Reduced cellular content of drug could account for the resistance phenotype, indicating the possible involvement of a mechanism similar to multidrug resistance observed in higher eukaryotes.

Amphotericin B↗
PubMed1996

Efficacy of UK-109496, a new azole antifungal agent, in an experimental model of invasive aspergillosis.

The efficacy of UK-109496, a new azole antifungal agent, was evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Oral therapy with UK-109496 at a dosage of 10 or 15 mg/kg of body weight every 8 h was begun 24 h after a lethal or sublethal challenge, and results were compared with those for amphotericin B therapy and untreated controls. UK-109496 eliminated mortality and also reduced the tissue burden of Aspergillus fumigatus 10- to 100-fold in liver and kidney tissues and to a lesser degree in lung tissue, and at the higher dose, no viable organisms were recovered from brain tissue from these animals. Both dosages of UK-109496 decreased or eliminated circulating antigen. The half-life of UK-109496 in rabbits was 2.5 to 3 h, and no accumulation of drug was seen even after 15 doses in either uninfected or infected animals. Thus, UK-109496 shows activity in this rabbit model of invasive aspergillosis. Additional studies are needed to determine the potential of the drug for use in the treatment of this infection.

Animals↗
PubMed1997

In vitro activity of a new pneumocandin antifungal, L-743,872, against azole-susceptible and -resistant Candida species.

The in vitro activity of a new pneumocandin, L-743,872, was evaluated with 108 strains of Candida and compared with the activities of various antifungals. L-743,872 demonstrated the best activity against azole-susceptible and -resistant strains of C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. kefyr and less activity against C. krusei, C. lusitaniae, and C. guilliermondii.

Anti-Bacterial Agents↗
PubMed1998

Thirteen-year evolution of azole resistance in yeast isolates and prevalence of resistant strains carried by cancer patients at a large medical center.

Drug resistance is emerging in many important microbial pathogens, including Candida albicans. We performed fungal susceptibility tests with archived isolates obtained from 1984 through 1993 and fresh clinical isolates obtained from 1994 through 1997 by testing their susceptibilities to fluconazole, ketoconazole, and miconazole and compared the results to the rate of fluconazole use. All isolates recovered prior to 1993 were susceptible to fluconazole. Within 3 years of widespread azole use, we detected resistance to all agents in this class. In order to assess the current prevalence of resistant isolates in our hematologic malignancy and transplant patients, we obtained rectal swabs from hospitalized, non-AIDS, immunocompromised patients between June 1995 and January 1996. The swabs were inoculated onto sheep's blood agar plates containing 10 microg of vancomycin and 20 microg of gentamicin/ml of agar. One hundred one yeasts were recovered from 97 patients and were tested for their susceptibilities to amphotericin B, fluconazole, flucytosine, ketoconazole, and miconazole. The susceptibility pattern was then compared to those for all clinical isolates obtained throughout the medical center. The antifungal drug histories for each patient were also assessed. The yeasts from this surveillance study were at least as susceptible as the overall hospital strains. There did not appear to be a direct linkage between prior receipt of antifungal agent therapy and carriage of a new, drug-resistant isolate. Increased resistance to newer antifungal agents has occurred at our medical center, but it is not focal to any high-risk patient population that we studied. Monitoring of susceptibility to antifungal agents appears to be necessary for optimizing clinical therapeutic decision making.

Antifungal Agents↗
PubMed1999

Multilocus genotypes and DNA fingerprints Do not predict variation in azole resistance among clinical isolates of Candida albicans.

If variation in azole resistance is due to inherent differences in strains of Candida albicans, as a predominantly clonal organism, then correlation between multilocus genotypes and drug resistance would be expected. A sample of 81 clinical isolates from patients infected with human immunodeficiency virus in Toronto, Canada, plus 3 reference isolates were genotyped at 16 loci, distributed on all linkage groups, by means of oligonucleotide hybridizations specific for each of the alleles at each locus. These multilocus genotypes were significantly correlated with DNA fingerprints obtained with the species-specific probe 27A, indicating widespread linkage disequilibrium in the genome. There were 64 multilocus diploid genotypes and 77 DNA fingerprint types delineated in this sample. Neither the multilocus genotyping nor DNA fingerprinting alone identified all of the 81 types identified by the combination of these two methods. Multilocus genotypes were not predictive of fluconazole resistance, suggesting that resistance is gained or lost too quickly to be predicted by linkage with neutral markers.

Antifungal Agents↗