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

Cartledge, J; Midgley, J.; Gazzard, Brian

doi:10.1097/00002030-199715000-00008

Cited by 59 publications

(35 citation statements)

References 15 publications

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“…When we compared the results for MICs of fluconazole and voriconazole for each strain there was a correlation between the two as reported earlier for azole drugs including voriconazole (5,29,34,40). The five 2-log steps by which MICs of voriconazole were lower brought the less fluconazole-susceptible species C. glabrata and C. krusei into the range of voriconazole susceptibility.…”

Section: Discussionsupporting

confidence: 54%

Fluconazole and Voriconazole Multidisk Testing of Candida Species for Disk Test Calibration and MIC Estimation

Kronvall

Karlsson

2001

J Clin Microbiol

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Fluconazole and voriconazole MICs were determined for 114 clinical Candida isolates, including isolates of Candida albicans, Candida glabrata, Candida krusei, Candida lusitaniae, Candida parapsilosis, and Candida tropicalis. All strains were susceptible to voriconazole, and most strains were also susceptible to fluconazole, with the exception of C. glabrata and C. krusei, the latter being fully fluconazole resistant. Single-strain regression analysis (SRA) was applied to 54 strains, including American Type Culture Collection reference strains. The regression lines obtained were markedly different for the different Candida species. Using an MIC limit of susceptibility to fluconazole of <8 g/ml, according to NCCLS standards, the zone breakpoint for susceptibility for the 25-g fluconazole disk was calculated to be >18 mm for C. albicans and >22 mm for C. glabrata and C. krusei. SRA results for voriconazole were used to estimate an optimal disk content according to rational criteria. A 5-g disk content of voriconazole gave measurable zones for a tentative resistance limit of 4 g/ml, whereas a 2.5-g disk gave zones at the same MIC level for only three of the species. A novel SRA modification, multidisk testing, was also applied to the two major species, C. albicans and C. glabrata, and the MIC estimates were compared with the true MICs for the isolates. There was a significant correlation between the two measurements. Our results show that disk diffusion methods might be useful for azole testing of Candida isolates. The method can be calibrated using SRA. Multidisk testing gives direct estimations of the MICs for the isolates.Infections with Candida species are common complications in immunocompromised patients and require adequate treatment, often with newer azole drugs. Particularly in AIDS patients with oropharyngeal and/or esophageal candidiasis there have been reports of increased azole resistance among Candida isolates (6,14,24,29,(32)(33)(34)44). This emergence of resistance to drugs has led to a growing demand for susceptibility testing of clinical yeast isolates (14,32,41,43). Comparisons between the standardized NCCLS broth macrodilution method (27) and microdilution methods (12,22,33,38), Etests (7,8,12,25,33,38), and disk diffusion methods (2,3,26,35,36,41) suggest a possibility of using the less expensive disk method in clinical microbiology laboratories. We have extended the analysis of azole disk diffusion tests by using singlestrain regression analysis (SRA) for studying azole regression lines among Candida species and for calibration of the disk test. Such a calibration method is required since no interpretive zone breakpoints are yet available. The SRA-derived multidisk test (M-test) was also used for MIC estimations of susceptibility to fluconazole and voriconazole, the two azole drugs included. Voriconazole is a new azole with more avid binding to the sterol 14␣-demethylase, thereby more effectively inhibiting ergosterol synthesis (22, 34). MATERIALS AND METHODSCandida isolates, species identifica...

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Section: Discussionsupporting

confidence: 54%

Fluconazole and Voriconazole Multidisk Testing of Candida Species for Disk Test Calibration and MIC Estimation

Kronvall

Karlsson

2001

J Clin Microbiol

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“…Moreover, the existing agents had disadvantages, such as the significant nephrotoxicity of amphotericin B 3 and the emergence of resistance to the azoles. 4 To overcome these defects, lipid formulations of polyenes were developed to reduce toxicity, and new triazoles (for example, voriconazole, ravuconazole and posaconazole) were developed to improve the antifungal spectra or susceptibility to azoleresistant isolates. 5 Despite a number of therapeutic advancements, there was a need to develop a new class of antifungal agents with novel mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Micafungin: a sulfated echinocandin

Hashimoto

2009

J Antibiot

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Micafungin is the second approved antifungal agent in the echinocandin series and is now used worldwide in chemotherapy for life-threatening fungal infections. It is water-soluble and is semi-synthesized from the acylated cyclic hexapeptide FR901379, a natural product from the fungus Coleophoma empetri F-11899, through enzymatic deacylation of FR901379, followed by chemical reacylation with the optimized N-acyl side chain. The water solubility of micafungin is ascribed to a sulfate moiety in the molecule. This feature differentiates micafungin from other echinocandin members. Micafungin is a potent inhibitor of 1,3-b-glucan synthase, an enzyme necessary for cell-wall synthesis of several fungal pathogens. The Journal of Antibiotics (2009) and Cryptococcus neoformans are a threat to human health. Incidences of these systemic fungal infections have increased significantly over the past few years. The major reasons for this dramatic increase are the extensive use of broad-spectrum antibiotics and the growing number of immunocompromised patients with acquired immunodeficiency syndrome (AIDS), cancer and transplants. 1,2 In the mid 1900s, few compounds, such as polyenes (for example, nystatin and amphotericin B) and flucytosine, were available for antifungal chemotherapy. Although the development of azole drugs started in the early 1970s, only a limited number of antifungal agents were available for treatment of life-threatening fungal infections. Moreover, the existing agents had disadvantages, such as the significant nephrotoxicity of amphotericin B 3 and the emergence of resistance to the azoles. 4 To overcome these defects, lipid formulations of polyenes were developed to reduce toxicity, and new triazoles (for example, voriconazole, ravuconazole and posaconazole) were developed to improve the antifungal spectra or susceptibility to azoleresistant isolates. 5 Despite a number of therapeutic advancements, there was a need to develop a new class of antifungal agents with novel mechanisms of action.

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“…A combination of factors such as the fungistatic nature of the inhibition of Candida albicans observed for azole compounds, impaired host immune responses in infected patients, long treatment periods and use of low antifungal doses, creates favourable breeding conditions for mutation and selection of less susceptible isolates (Cartledge et al, 1997). Over the last 5 years multiple biochemical studies have been published to elucidate the underlying causes of 0002-3382 # 1999 SGM azole resistance in pathogenic fungi.…”

Section: Introductionmentioning

confidence: 99%

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

et al. 1999

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The cytochrome P450 14α-demethylase, encoded by the ERG11 (CYP51) gene, is the primary target for the azole class of antifungals. Changes in the azole affinity of this enzyme caused by amino acid substitutions have been reported as a resistance mechanism. Nine Candida albicans strains were used in this study. The ERG11 base sequence of seven isolates, of which only two were azole-sensitive, were determined. The ERG11 base sequences of the other two strains have been published previously. In these seven isolates, 12 different amino acid substitutions were identified, of which six have not been described previously (A149V, D153E, E165Y, S279F, V452A and G465S). In addition, 16 silent mutations were found. Two different biochemical assays, subcellular sterol biosynthesis and CO binding to reduced microsomal fractions, were used to evaluate the sensitivity of the cytochromes for fluconazole and itraconazole. Enzyme preparations from four isolates showed reduced itraconazole susceptibility, whereas more pronounced resistance to fluconazole was observed in five isolates. A three-dimensional model of C. albicans Cyp51p was used to position all 29 reported substitutions, 98 in total identified in 53 sequences. These 29 substitutions were not randomly distributed over the sequence but clustered in three regions from amino acids 105 to 165, from 266 to 287 and from 405 to 488, suggesting the existence of hotspot regions. Of the mutations found in the two N-terminal regions only Y132H was demonstrated to be of importance for azole resistance. In the Cterminal region three mutations are associated with resistance, suggesting that the non-characterized substitutions found in this region should be prioritized for further analysis.

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

Cited by 59 publications

References 15 publications

Fluconazole and Voriconazole Multidisk Testing of Candida Species for Disk Test Calibration and MIC Estimation

Fluconazole and Voriconazole Multidisk Testing of Candida Species for Disk Test Calibration and MIC Estimation

Micafungin: a sulfated echinocandin

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

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