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PubMed1998

Update on drug interactions with azole antifungal agents.

OBJECTIVE: To review and update the incidence, mechanism, and clinical relevance of drug interactions with itraconazole, ketoconazole, and fluconazole. DATA SOURCES: Literature was identified by MEDLINE search (from January 1990 to May 1997) using the name of each antifungal and the term "interaction" as MeSH headings. Abstracts were identified by literature citation and by review of Interscience Conference on Antimicrobial Agents and Chemotherapy from 1995 to 1996. STUDY SELECTION: Randomized, controlled, double-blind studies were emphasized; however, uncontrolled studies and case reports were also included. In vitro data were selected from literature review and citations. DATA EXTRACTION: Data were evaluated with respect to study design, clinical relevance, magnitude of interaction, and recommendations provided. DATA SYNTHESIS: The incidence of fungal infections and consequent azole antifungal usage continues to increase. By virtue of their antifungal mechanism (i.e., inhibition of cytochrome P450 fungal enzyme systems), azoles have been investigated and implicated in several drug interactions. The magnitude of interactions can vary from trivial to potentially fatal, and also vary with specific azole and interactant. CONCLUSIONS: The azole antifungal agents represent a commonly used class of agents with a broad range of potential interactions. Recent data have increased our understanding of drug--drug interactions with azoles. Pharmacists are in a unique position to identify these interactions and to intervene to decrease their morbidity and improve patient care.

Animals↗
PubMed2026

Detection of TR34/L98H pan-azole-resistant Aspergillus fumigatus in poultry farm environments.

INTRODUCTION: Poultry farms have been recognized as environments prone to fungal contamination. However, the occurrence of azole-resistant Aspergillus fumigatus and its cytotoxic potential remain insufficiently characterized. This study aimed to characterize the occurrence, cytotoxic potential, and azole-resistance profile ofAspergillus section Fumigati in poultry farms. METHODS: A total of 420 samples, including air (n = 47), electrostatic dust cloths (n = 87), bedding (n = 87), feed (n = 95), swabs (n = 87), workers' masks (n = 2), and broiler breast (n = 15), were obtained. Fungal characterization was performed through culture-based methods (27 °C and 37 °C), followed by azole resistance screening according to EUCAST guidelines. Resistant isolates were subjected to whole-genome sequencing and a targeted analysis of cyp51A mutations. The cytotoxicity potential of fungal isolates and environmental samples was evaluated using selected cell lines representing respiratory organs (human alveolar [A549]) and detoxification organs (swinekidney [SK]/hepatocellular carcinoma [HepG2]). RESULTS: Seven putative Aspergillus fumigatus isolates exhibited pan-azole resistance (MICs: ≥ 2 mg/L ITR/VOR; ≥ 1mg/L for POS). Four isolates carried the TR34/L98H mutation and were recovered from bedding (n = 3) and air (n = 1), suggesting the presence of resistant A. fumigatus in poultry farm matrices. Although 12% of isolates induced toxicity on both cell lines (17/145), no significant association was observed between isolate cytotoxicity and environmental sample toxicity, suggesting that additional biological and chemical components may contribute to the overall toxicological profile of farm environments. DISCUSION: The study highlights the occurrence of azole-resistant A. fumigatus in poultry farms and support integrated surveillance approaches addressing antifungal resistance and environmental exposure risks in poultry production.

Aspergillus fumigatus↗
PubMed2000

[Azole resistance in Candida albicans].

The molecular mechanisms of azole resistance in Candida albicans include alterations in the target enzyme (lanosterol 14-demethylase) and overexpression of efflux transporters that decrease the intracellular concentration of the drug. Although the rate of azole resistance in systemic isolates of C. albicans remains very low, resistance to fluconazole appears as an important issue in the management of oropharyngeal candidiasis (OPC) in patients with AIDS. In order to establish the prevalence of resistance to azole antifungal agents in this setting, we investigated the molecular mechanisms of resistance to azoles in highly resistant C. albicans isolates (fluconazole MIC 64 mg/l) from HIV-infected patients with OPC. Antifungal susceptibility testing of serial C. albicans isolates was performed by NCCLS methodology. Strain identity was investigated by DNA-typing techniques. Overexpression of genes encoding lanosterol 14-demethylase (erg11) and efflux transporters (mdr1 and cdr) implicated in the development of resistance was monitored in matched sets of susceptible and resistant isolates. In addition, erg11 genes were PCR-amplified and their nucleotide sequences determined in order to detect point mutations. A combination of different mechanisms of resistance contributed to the development of resistance to fluconazole. The multifactorial character of the azole resistance in C. albicans makes necessary the development of approaches to overcome the problem. Accordingly, new triazoles have been developed; new classes of antifungals are being investigated; and combinations with inhibitors of efflux transporters are being studied.

Antifungal Agents↗
PubMed1998

Enhanced anti-Candida activity of neutrophils and azole antifungal agents in the presence of lactoferrin-related compounds.

We investigated the effects of lactoferrin (Lf)-related compounds on growth inhibition of Candida albicans by neutrophils or antifungal agents in vitro. Human neutrophils partially inhibited the growth of C.albicans. The growth inhibition caused by human neutrophils was augmented by the addition of human Lf at concentrations which did not show any inhibitory effect in the absence of neutrophils. Similar observations were obtained also with the following combinations: human neutrophils + bovine Lf, murine neutrophils + bovine Lf, and murine neutrophils + iron saturated bovine Lf, but not in the case of murine neutrophils + human transferrin. The minimum inhibitory concentration (MIC) of azole antifungal agents, clotrimazole, ketoconazole, fluconazole, and itraconazole was reduced by 1/4 to 1/16 in the presence of a sub-MIC level of each of bovine Lf, bovine Lf pepsin hydrolysate, and the antimicrobial peptide "lactoferricin B" (Lfcin B). Other types of antifungal agents, amphotericin B, nystatin, and flucytosine did not show such combined effects with these Lf-related compounds. The anti-Candida activity of bovine Lf or Lfcin B in combination with clotrimazole was shown to be synergistic by checkerboard analysis. Clinically isolated azole-resistant C. albicans strains were more susceptible to bovine Lf or Lfcin B than azole-susceptible strains. Trailing growth of an azole-resistant strain in the presence of fluconazole was reduced by the addition of sub-MIC levels of bovine Lf or Lfcin B. These results suggest that Lf-related compounds even at relatively low concentrations may function as an antifungal effector in combination with neutrophils thereby modulating azole antifungal efficacies in vivo.

Animals↗
PubMed2000

Synergistic effect of ofloxacin and fluconazole against azole-resistant Candida albicans.

We investigated the combination effects of ofloxacin and fluconazole against azole-resistant Candida albicans strains in vitro and in vivo. Ofloxacin alone showed no efficacy against the azole-resistant C. albicans strain, C26. The in-vitro combination effects were evaluated by the checkerboard method, calculated as the fractional inhibitory concentration (FIC) index, but there was no synergistic effect of the combination. The activity of the drug efflux pump in the azole-resistant C. albicans strains was measured by intracellular rhodamine 6G concentration. When the cells were incubated with ofloxacin or grepafloxacin, the intracellular rhodamine 6G concentration was significantly increased in the azole-resistant C. albicans strain. In-vivo combination effects were evaluated in murine disseminated candidiasis. The survival of the mice was not prolonged, but counts of the yeast cells in the kidney and spleen were reduced following treatment with the combination of ofloxacin (20 mg/kg) and fluconazole (20 mg/kg). The combination of ofloxacin and fluconazole may represent an effective strategy to treat infections caused by azole-resistant C. albicans.

Anti-Infective Agents↗
PubMed1995

Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients.

Azole antifungal compounds are important in the treatment of Cryptococcosis, a major cause of mortality in AIDS patients. The target of the azole drugs is P450 mediated sterol 14 alpha-demethylase. We have investigated the P450 system of Cryptococcus neoformans with respect to azole tolerance observed in clinical isolates which were obtained following the failure of fluconazole therapy. The clinical failure was correlated with in vitro tolerance of azole antifungal when compared to wild-type strains. The microsomal P450 system was typical of yeast and fungi and fluconazole tolerance was not associated with defective sterol biosynthesis. The strains had slightly elevated P450 content and slightly reduced azole levels in the cells, but a clear cause for resistance was the increased level of drug needed to inhibit the sterol 14 alpha-demethylase in vitro.

AIDS-Related Opportunistic Infections↗
PubMed2001

Oropharyngeal candidiasis in patients with human immunodeficiency virus: correlation of clinical outcome with in vitro resistance, serum azole levels, and immunosuppression.

Azole-resistant thrush has emerged as a problem in people who are infected with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), especially those who have low CD4 cell counts who have had a previous relapse of oral candidiasis, and in those who require long-term suppressive antifungal therapy. Because of the development of a standardized methodology for antifungal susceptibility testing and interpretive criteria for resistance testing, studies of the clinical predictive value of in vitro results are possible. In this study, 61% of organisms isolated from patients who were receiving azole therapy and who had clinically resistant thrush had minimal inhibitory concentration values that would classify the isolate as "resistant" or "susceptible dose dependent." In contrast, 86% of isolates from patients with thrush that was clinically responsive to an azole were classified in vitro as "susceptible" or "susceptible dose dependent." No resistant isolates were detected in samples obtained from asymptomatic control patients who were not exposed to azole drugs. Serum levels of azole and CD4 cell counts were also important parameters with regard to prediction of response. We conclude that in vivo and in vitro correlations compare favorably to studies of susceptibility testing in bacteria.

AIDS-Related Opportunistic Infections↗
PubMed1984

A simple and convenient synthesis of 3'-5'- or 2'-5'-linked oligoribonucleotide by polymerization of unprotected ribonucleoside using phosphorus tris-azole.

Oligoribonucleotides have been synthesized directly from unprotected ribonucleosides by a chemical polymerization approach using phosphorus tris-azoles. The procedure involves two steps: (i) the reaction of unprotected ribonucleoside with phosphorus tris-azole and (ii) the in situ oxidation of the resulting phosphite with iodine and water. Several phosphorus tris-azoles were investigated for generating oligoribonucleotide chains. Phosphorus tris-azoles of which azoles are imidazole, 2-methylimidazole, and 2-ethyl-4-methylimidazole were found to be most effective. Uridine, adenosine, and cytidine oligonucleotides were obtained rapidly in high yields without any protection. The inter-ribonucleotidic linkage of the oligomers consists of 3'-5'- and 2'-5'-linkages. The linkage isomers were easily separated by a reverse phase column chromatography. The present approach provides a convenient and potentially useful method for preparing 3'-5'- or 2'-5'-linked oligoribonucleotides.

Animals↗
PubMed1997

Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis.

OBJECTIVES: To determine the proportion of fluconazole-resistant Candida albicans isolates that have clinically significant cross-resistance to itraconazole or ketoconazole, that is sufficient to result in failure of these agents at their standard doses (200 and 400 mg daily for 7 days, respectively). METHODS: Seven hundred C. albicans isolates from HIV-positive patients with oral candidosis underwent susceptibility testing using a relative growth method, for which cut-off values corresponding to clinical drug failure have been established. RESULTS: A total of 431 isolates were fully azole-susceptible and three main resistance patterns were detected: isolates resistant to fluconazole alone (n = 100); isolates resistant to fluconazole and ketoconazole but susceptible to itraconazole (n = 94); and isolates resistant to all three drugs (n = 50). No isolates were consistently resistant to ketoconazole without being fluconazole-resistant, and no itraconazole resistance was detected without ketoconazole resistance. Resistance to fluconazole alone was more common in specimens obtained soon after first clinical fluconazole failure, whereas specimens from patients with a longer history of fluconazole-unresponsive candidosis were more likely to be infected with cross-resistant isolates. Median days of prior azole exposure and cumulative fluconazole dose were significantly less for those with isolates resistant to fluconazole alone than for those with ketoconazole cross-resistant isolates, who had received less azole therapy and smaller cumulative fluconazole doses than those with isolates cross-resistant to all three drugs (although not statistically significant). After the diagnosis of fluconazole-unresponsive candidosis, increasing cumulative doses of itraconazole solution were associated with increasing likelihood of cross-resistance. CONCLUSIONS: Clinically significant cross-resistance to other azoles may occur in fluconazole-resistant isolates of C. albicans, although initially most isolates are not cross-resistant and the detection of cross-resistant isolates is associated with a history of greater prior azole exposure. Patients who have been treated for fluconazole-resistant candidosis for longer and with greater cumulative doses of itraconazole solution tend to become infected with increasingly cross-resistant isolates of C. albicans.

AIDS-Related Opportunistic Infections↗
PubMed1995

[Post-antibiotic effect and post-exposure polyene antagonism of azole antimycotics in Candida albicans: dependency on lipophilia].

With the lipophilic azoles itraconazole (ICZ), ketoconazole (KCZ), and miconazole (MCZ) two effects, occurring in parallel, on Candida albicans were observed: Firstly, these azoles caused a growth inhibition which persisted for at least 24 hours (post-antibiotic effect, found regularly with KCZ and MCZ, with ICZ only occasionally). Furthermore, the fungicidal activity of amphotericin B (AMB, 1 mg/1) after exposure to the azoles was reduced. In contrast, to this, fluconazole (FCZ) produced neither of these effects. Additional experiments indicate that both actions of the three lipophilic azoles may be related to their noncovalent binding to lipophilic cytoplasmatic components of the yeast cells. In the case of fluconazol such bonds seem to be much weaker. Presumably, the amount of the relatively hydrophilic fluconazole, which will be bound to the cell, is too low as to produce long lasting post-exposure effects like those caused by the lipophilic azoles.

Amphotericin B↗
PubMed2006

Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants.

Candida glabrata, a yeast with intrinsically low susceptibility to azoles, frequently develops increased azole resistance during prolonged treatment. Transposon mutagenesis revealed that disruption of CgPDR1 resulted in an 8- to 16-fold increase in fluconazole susceptibility of C. glabrata. CgPDR1 is a homolog of Saccharomyces cerevisiae PDR1, which encodes a transcriptional regulator of multidrug transporters. Northern blot analyses indicated that CgPDR1 regulated both constitutive and drug-induced expression of CgCDR1, a multidrug transporter gene. In agreement with the Northern analysis, the Cgpdr1 mutant had increased rhodamine accumulation, in contrast to the decreased accumulation in the CgPDR1-overexpressing strain. Northern analyses also indicated the importance of CgPDR1 in fluconazole resistance arising during therapy. Two clinically resistant isolates had higher expression of CgPDR1 and CgCDR1 compared to their paired susceptible isolates. Integrative transformation of CgPDR1 from the two resistant isolates converted the Cgpdr1 mutant into azole-resistant strains with upregulated CgPDR1 expression. Two different amino acid substitutions, W297S in one isolate and F575L in the other, accounted for the upregulated CgPDR1 expression and the resistance. Finally, CgPDR1 was shown to be required for the azole resistance due to mitochondrial deficiency. Thus, CgPDR1 encodes a transcriptional regulator of a pleiotropic drug resistance network and contributes to the azole resistance of clinical isolates and petite mutants.

ATP-Binding Cassette Transporters↗
PubMed2006

Clinical significance of azole antifungal drug cross-resistance in Candida glabrata.

Candida glabrata, which can become resistant to fluconazole, is a common cause of bloodstream infection. This study was performed to determine the significance of cross-resistance to new azole drugs among C. glabrata isolates recovered as a cause of infection in azole-treated hematopoietic stem cell transplant (HSCT) recipients. Seven cases of invasive candidiasis caused by C. glabrata occurred in HSCT recipients who were receiving azole therapy between January 2000 and December 2004 in our institution. Case characteristics were ascertained. Sequential colonizing and invasive isolates were examined to determine susceptibilities to fluconazole, itraconazole, and voriconazole, and molecular relatedness by restriction fragment length polymorphism (RFLP) analysis. Twenty-three C. glabrata isolates were recovered from 4 patients who developed candidemia while receiving fluconazole and three patients who developed candidemia while receiving voriconazole. The mode MICs of fluconazole, itraconazole, and voriconazole for these isolates were > or =64 microg/ml (range, 4 to > or =64 microg/ml), 2 microg/ml (range, 0.25 to > or =16 microg/ml), and 1 microg/ml (range, 0.03 to > or =16 microg/ml), respectively. Kendall tau b correlation coefficients demonstrated significant associations between the MICs of voriconazole with fluconazole (P = 0.005) and itraconazole (P = 0.008). Colonizing and invasive isolates exhibiting variable susceptibilities had similar RFLP patterns. These observations suggest that C. glabrata exhibits considerable clinically significant cross-resistance between older azole drugs (fluconazole and itraconazole) and voriconazole. Caution is advised when considering voriconazole therapy for C. glabrata candidemia that occurs in patients with extensive prior azole drug exposure.

Adult↗
PubMed1995

Altered P450 activity associated with direct selection for fungal azole resistance.

Azole antifungals inhibit CYP51A1-mediated sterol 14 alpha-demethylation and the mechanism(s) of resistance to such compounds in Ustilago maydis were examined. The inhibition of growth was correlated with the accumulation of the substrate, 24-methylene-24,25-dihydrolanosterol (eburicol), and depletion of ergosterol. Mutants overcoming the effect of azole antifungal treatment exhibited a unique phenotype with leaky CYP51A1 activity which was resistant to inhibition. The results demonstrate that alterations at the level of inhibitor binding to the target site can produce azole resistance. Similar changes may account for fungal azole resistance phenomena in agriculture, and also in medicine where resistance has become a problem in immunocompromised patients suffering from AIDS.

Azoles↗
PubMed1994

Adenosine deaminase inhibitors: synthesis and structure-activity relationships of 2-hydroxy-3-nonyl derivatives of azoles.

A series of erythro-1-(2-hydroxy-3-nonyl)azole derivatives have been synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity, in order to introduce simplifications in the ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1a). The synthesis of most of the reported compounds was achieved by reaction of 2-bromo-3-nonanone with the suitable azole followed by reduction of the carbonyl group to give a diastereoisomeric mixture of N-substituted (2-hydroxy-3-nonyl)azoles. Separation of diastereoisomers was achieved by HPLC or by preparative TLC plates. The results of the enzymatic test indicate that the nitrogen in the 3-position, and secondly, the nitrogen in the 5-position are very important for the interaction of the azole ring with the inhibitory site on the enzyme. In fact, the pyrazole and the 2-substituted 1,2,3-triazole derivatives (10 and 15, respectively) are nearly inactive, whereas the erythro-1-(2- hydroxy-3-nonyl)-1,2,4-triazole (18e) was the most potent ADA inhibitor in the series with Ki = 0.3 microM.

Adenosine Deaminase Inhibitors↗
PubMed2002

Synthetic applications of azolium ylides to a traceless solid-phase synthesis of 2-substituted azoles.

A new approach for the preparation of 2-substituted azole libraries using a polystyrene-carbamyl chloride resin in a traceless fashion is described. Azole substrates II are assembled in a one-pot condensation reaction of azoles and aldehydes with a resin-bound carbamyl chloride. Treatment of the azolyl-carbamate II with boron trifluoride etherate under thermal or microwave-assisted solvolysis conditions afforded 2-substituted azoles. [reaction: see text]

Azoles↗
PubMed1990

Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14 alpha-sterol demethylase purified from Candida albicans.

The interaction of azole antifungal antibiotics with purified Candida albicans cytochrome P-450-dependent 14 alpha-sterol demethylase (P-450DM) was measured spectrophotometrically and by inhibition of enzyme activity. Ketoconazole and ICI 153066 (a triazole derivative) formed low-spin complexes with the ferric cytochrome and induced type II difference spectra. These spectra are indicative of an interaction between the azole moiety and the sixth co-ordination position of P-450DM haem. Both azoles inhibited the binding of CO to the sodium dithionite-reduced ferrous cytochrome, and inhibited reconstituted P-450DM activity by binding to the cytochrome with a one-to-one stoichiometry. Similarly, total inhibition of enzyme activity occurred when equimolar amounts of clotrimazole, miconazole or fluconazole were added to reconstituted P-450DM. These results correlated with the inhibition of P-450DM in broken cell preparations, confirming that all five azoles are potent inhibitors of ergosterol biosynthesis in C. albicans.

Antifungal Agents↗
PubMed2005

The ergosterol biosynthesis pathway, transporter genes, and azole resistance in Aspergillus fumigatus.

The continuous use of triazoles can result in the development of drug resistance. Azole-resistant clinical isolates, spontaneous and induced mutants of Aspergillus fumigatus have been documented. The azoles block the ergosterol biosynthesis pathway by inhibiting the enzyme 14-alpha-demethylase, product of the CYP51. Fungal azole resistance involves both amino acid changes in the target site that alter drug-target interactions and those that decrease net azole accumulation. The reduced intracellular accumulation has also been correlated with overexpression of multidrug resistance (MDR) efflux transporter genes of the ATP-binding cassette (ABC) and the major facilitator superfamily (MFS) classes. About 20 genes are involved in the A. fumigatus ergosterol biosynthesis pathway. There are several duplicated genes in this pathway. Interestingly, erg3 and erg11 showed two copies in A. fumigatus. In general, Aspergillus spp. have proportionally more MFS transporter encoding genes than Saccharomyces cerevisiae, S. pombe, and Neurospora crassa. The drug H+ (12 and 14 spanners) sub-families are also proportionally greater than in the other species. Although the numbers of ABC transporter encoding genes are comparable, again the Aspergillus spp. have more ABC transporters related to multidrug permease than the other fungal species.

ATP-Binding Cassette Transporters↗
PubMed2002

Detection of human P-glycoprotein-like molecule in azole-resistant Candida albicans from HIV+ patients.

Azole resistance in Candida albicans may be due to several mechanisms. It has been demonstrated that C. albicans possesses sequences with a high degree of homology with the human MDR-1 gene coding for P-glycoprotein (P-gp), belonging to the ATP-binding cassette transporter (ABC) superfamily and responsible for the multidrug resistance (MDR) in tumor cells. On this basis, the expression and intracellular localization of human P-gp-like molecule in C. albicans strains showing different sensitivity to fluconazole were investigated by flow cytometry and immunoelectron microscopy. Post-embedding immunolabeling revealed that monoclonal antibody (mAb) MM4.17, which recognizes an external epitope of human P-gp, reacted with both fluconazole-sensitive (3153 and CO 23-1) and fluconazole-resistant (AIDS 68 and CO 23-2, isolated from AIDS patient and in vitro drug-selected, respectively) strains of C. albicans. However, the resistant strains displayed a number of MM4.17-reactive epitopes much higher than the drug-sensitive ones. The C. krusei ATCC 6458 strain, whose resistance is not mediated by the presence of ABC transporters, was not reactive at all with mAb MM4.17. The specificity of the immunolabeling was confirmed by a competitive inhibition assay performed by using phage clone particles capable of mimicking the MM4.17-reactive epitope. The flow cytometric analysis confirmed a higher level of intracytoplasmic P-gp expression in azole-resistant strains of C. albicans. Both cyclosporin A and verapamil, which are well-known MDR inhibitors, strongly reduced the MICs for fluconazole and itraconazole of the tested azole-resistant AIDS 68 strain, while they did not influence the MICs of either the sensitive 3153 strain of C. albicans or the ATCC 6458 strain of C. krusei. Overall, our data suggest the existence of a P-gp-like drug efflux pump in C. albicans that may participate in the mechanisms of azole-resistance of this fungus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗