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Emergence of fungal strains showing resistance to triazole drugs can make treatment of fungal disease problematic. Triazole resistance can arise due to single mutations in the drug target lanosterol 14α-demethylase (Erg11p/CYP51). We have determined how commonly occurring single site mutations in pathogenic fungi affect triazole binding using Saccharomyces cerevisiae Erg11p (ScErg11p) as a target surrogate. The mutations Y140F/H were introduced into full-length hexahistidine-tagged ScErg11p. Phenotypes and high-resolution X-ray crystal structures were determined for the mutant enzymes complexed with short-tailed (fluconazole and voriconazole) or long-tailed (itraconazole and posaconazole) triazoles and wild type enzyme complexed with voriconazole. The mutations disrupted a water-mediated hydrogen bond network involved in binding of short-tailed triazoles, which contain a tertiary hydroxyl not present in long-tailed triazoles. This appears to be the mechanism by which resistance to these short chain azoles occurs. Understanding how these mutations affect drug affinity will aid the design of azoles that overcome resistance.
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Incidence of cryptococcosis of the central nervous system has risen sharply since AIDS became pandemic; from early 1998, the Instituto de Neurología y Neurocirugía in Havana has beaten its own record in the number of cases attended.
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Although C albicans continues to be the dominant Candida species in oral Candida carriage of HIV-infected patients in Nigeria, the nonalbicans Candida species are increasing. Furthermore, the finding of resistant isolates in our study emphasizes the need for antifungal susceptibility testing whenever antifungal treatment is desired especially in HIV-infected subjects.
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A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound's half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.
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S. prolificans was isolated in 15 patients. Eight were affected with cystic fibrosis and the isolation of S. prolificans in their airways did not worsen their clinical status. Among the remaining 7 cases there were five leukemic patients with neutropenia and two immunocompetent hosts with cutaneous infection and endocarditis. Four of five neutropenic patients died of sudden sepsis and S. prolificans was isolated from blood cultures made a few days before their death, and the fifth neutropenic case suffered a bilateral pneumonia with improving course probably due to recovery from neutropenia. As to the immunocompetent group the clinical course was good in the cutaneous infection case, but the endocarditis case died four days after the antifungical therapy was started. All the isolates tested were found to be resistant to amphotericin, 5 flucytosine, fluconazole, itraconazole, voriconazole, miconazole and terbinafine.
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A global collection of Cladophialophora carrionii strains (n = 81) was tested against nine antifungal drugs. MIC90s of all strains were as follows in increasing order: itraconazole and posaconazole, 0.063 μg/ml; terbinafine, 0.125 μg/ml; isavuconazole and voriconazole, 0.25 μg/ml; caspofungin, 2 μg/ml; micafungin, 4 μg/ml; amphotericin B, 8 μg/ml; and fluconazole, 64 μg/ml.
Although Cryptococcus neoformans is recognized for its ability to cause meningoencephalitis and pneumonia among immunocompromised persons, subclinical pulmonary infection is also common among immunocompetent persons. The significance of this infection is unknown. Using a rat model, we explored the potential for pulmonary cryptococcosis to modify allergic responses and airway reactivity. Our findings indicate that localized pulmonary cryptococcal infection (but not disseminated infection) can exacerbate allergic responses to respiratory challenge with ovalbumin, as measured by total immunoglobulin E levels, ovalbumin-specific immunoglobulin E titers, and eosinophil content of bronchoalveolar lavage fluid. Infection-associated enhancement of allergic responses was not dependent on cryptococcal encapsulation and was partially ameliorated by the administration of fluconazole. Increases in both the number of goblet cells and airway responsiveness, which are also features of reactive airway disease, were also present with pulmonary infection. An examination of lung cytokine levels in the context of active pulmonary infection revealed increased expression of interleukin (IL)-10, tumor necrosis factor- alpha , and IL-13, but not IL-12 or interferon- gamma . In contrast, systemic infection was associated with higher levels of interferon- gamma but lower levels of IL-13. Our studies highlight the potential for localized pulmonary C. neoformans infection to potentiate allergic responses and airway reactivity and suggest a potential role for subclinical pulmonary cryptococcosis in the pathogenesis of asthma.
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Babies had mean birth weight 1590 + 533 g, mean gestation 32.3 + 3.1 wks and fungal sepsis was diagnosed at a mean age of 14.3 + 7.9 days. Candida albicans (43.5%), C. tropicalis (21.7%), C. guillermondii (13%), C. parapsillosis (13%) and C. krusei (8.7%) were the species isolated. Fluconazole was effective in 82.3% cases with no side effects. Four resistant cases were C. parapsillosis (n = 2), C. albicans (n = 1) and C. guillermondii (n = 1) and there were three deaths, all in resistant cases though one death was unrelated to candidemia.
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Peak concentrations occurred within 2 hours after enteral dosing and 15 minutes after IV dosing. The relative bioavailability was 77%. Weight, AUC, Ke, and T1/2 did not differ between enteral and IV dosing.
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Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.
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Results can be summarized as follows: 1) the number of blastospores adhering to the HIV-positive donor' cells is higher than that of blastospores adhering to the healthy donors' cells (rate is 2.7:1); 2) blastospores from strains producing rough or very coarse fringes show adhesive properties higher than those of strains with different morphology; 3) in the group of HIV-positive patients the adhesivity inhibition of blastospores from strains producing rough or very coarse fringes was higher (38.3%) than that of strains with different morphology (33.8%); 4) overall, adhesivity inhibition due to exposure to fluconazole is higher for epithelial cells from healthy donors.