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The results presented in this report demonstrated that the synergistic effect of CsA and FLC on inhibited C. albicans biofilm formation and enhanced susceptibility to FLC was in part through a mechanism involved in suppressing the expression of biofilm related and drug-resistant genes, and reducing cellular surface hydrophobicity, as well as evoking intracellular calcium concentration.
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Prompt valve replacement is advocated in patients in whom candidal prosthetic valve endocarditis develops. Unfortunately, some patients with this condition are considered nonsurgical candidates, and they are unable to tolerate long-term administration of amphotericin B with or without flucytosine. Herein we describe a patient with Candida parapsilosis-induced prosthetic valve endocarditis in whom oral administration of fluconazole during an 11-month period successfully suppressed the fungal infection. Three previously published cases indicate that long-term noncurative suppressive therapy for C. parapsilosis-induced prosthetic valve endocarditis may allow prolonged symptom-free survival for such patients.
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An outbreak of nosocomial fungemia due to the unusual yeast, Pichia anomala occurred in the pediatric wards of our hospital over a period of 23 months (April 1996 to February 1998). A total of 379 neonates and children (4.2% admissions) were infected. The probable index case was admitted to the pediatric emergency ward, with subsequent transmission to the premature nursery, pediatric intensive care units, and other children wards. Carriage on the hands of health care personnel was likely to be responsible for dissemination of the fungus. The outbreak could only be controlled after a health education campaign to improve hand-washing practices was instituted and after nystatin-fluconazole prophylaxis to all premature neonates and high-risk infants was introduced. In a case-control study, we identified a lower gestational age, a very low birth weight (<1,500 g), and a longer duration of hospital stay as significant risk factors associated with P. anomala fungemia in premature neonates. We conducted a culture prevalence survey of 50 consecutive premature neonates and found that 28% were colonized with P. anomala at a skin or mucosal site on the date of delivery and that 20% of these neonates subsequently developed P. anomala fungemia. We performed multilocus enzyme electrophoresis on 40 P. anomala outbreak isolates (including patient and health care workers' hand isolates), and the results suggested that these isolates were identical. Our study highlights the importance of P. anomala as an emerging nosocomial fungal pathogen.
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This research evaluated the fungistatic and fungicidal activities of red propolis alcoholic extract (RPAE) against different Candida species isolated from chronic periodontitis cases, and compared with chlorhexidine (CHX). Nineteen samples of Candida species (C. albicans [n = 12], C. tropicalis [n = 5] and C. glabrata [n = 2]) isolated from chronic periodontitis cases were analyzed. The fungistatic and fungicidal activity of both RPAE and CHX were evaluated using fluconazole and C. parapsilosis (ATCC 6258) as a control. Fungistatic activity was analyzed based on the Clinical and Laboratory Standards Institute (CLSI) reference procedure to determine the minimum inhibitory concentrations. Fungicidal activity was established according to the absence of fungal growth on Sabouraud Dextrose Agar medium. The fungistatic and fungicidal activities of RPAE were observed, respectively, at 32-64 μg/mL and 64-512 μg/mL for C. albicans, 64 μg/mL and 64-256 μg/mL for C. glabrata, and 32-64 μg/mL and 64 µg/mL for C. tropicalis. CHX fungistatic activity was observed at concentrations of 0.003-1.92 µg/mL for C. albicans, 1.92 µg/mL for C. glabrata, and 0.03-1.92 µg/mL for C. tropicalis. Fluconazole fungistatic activity ranged between 1-64 μg/mL, and fungicidal activity occurred at 8-64 μg/mL, for the three Candida species analyzed. All the Candida species were susceptible to RPAE antifungal activity, but five samples of C. albicans, one of C. tropicalis and one of C. glabrata were resistant to fluconazole antifungal activity. CHX showed fungistatic activity against all the Candida species analyzed. The antifungal potential of these substances suggests that they can be applied as an alternative treatment for diseases affected by these species.
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An observational study of 2 subsequent epochs of inborn infants with birth weight of <1500 g or gestational age of <32 weeks, 1 before (control) and 1 after (fluconazole) initiation of routine targeted fluconazole prophylaxis in March 2003, was performed. Targeted fluconazole (3 mg/kg) prophylaxis was administered to infants for whom a decision was made to administer broad-spectrum antibiotics for >3 days.
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Oral fluconazole seems to be a safe and effective treatment for Candida albicans septicaemia even in premature infants.
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C. tropicalis was found in 53% of the patients and C. albicans in 36%. Urine cultures yielded more than 20.000 yeast colonies/ml in 76% of cases. Neurological, cardiac and other chronic diseases, cancer, and trauma were frequent underlying illnesses. Diabetes mellitus was present in 25% of patients. The major predisposing factors associated with candiduria were previous antibiotic therapy (93%) indwelling urinary catheter (83%), surgery in the last 60 days (48%), renal failure (32%), concomitant bacterial infections (28%), use of corticosteroids (20%), and use of other immunosuppressive drugs (10%). Therapy for candiduria, fluconazole or amphotericin B with one exception, was given only to 43/100 patients. The overall mortality in the 60 days after the candiduria episode was 40%.
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Series of new ring-substituted styrylquinolines and two oxorhenium complexes were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against fungal and bacterial strains. Some compounds were active against bacteria at micromolar level and against fungi at submicromolar level. Compounds 5,7-dichloro-2-[2-(2-ethoxyphenyl)vinyl]quinolin-8-ol expressed excellent antifungal activity comparable with or higher than the standard fluconazole as well as antibacterial activity against Staphylococcus strains comparable with or higher than the standards bacitracin, penicillin and ciprofloxacin. The structure-activity relationships are discussed.
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Pulmonary cryptococcosis with lymph node involvement is relatively rare in immunocompetent patients. We report a case of pulmonary cryptococcosis with massive mediastinal lymphadenopathy in an immunocompetent young patient. In this report, a 17-year-old boy presented with high-grade fever and persistent cough. Chest X-ray and computed tomography showed massive mediastinal lymphadenopathy. Endobronchial ultrasound-guided transbronchial needle aspiration revealed histological evidence of cryptococcal lymphadenitis. He was treated with liposomal amphotericin B plus flucytosine followed by fluconazole and recovered.
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Three systemic agents commonly are used for the treatment of onychomycosis. Until the introduction of ciclopirox in 1999, these were the only FDA-approved therapeutic options for managing these infections. With the recent approval of two new topical antifungal agents-efinaconazole in the azole class, and tavaborole, a unique boron-containing medication- clinicians and patients have an improved roster of medications for managing onychomycosis. Semin Cutan Med Surg 34(supp3):S46-S50 © 2015 published by Frontline Medical Communications.
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We have isolated a Candida albicans gene that confers resistance to the azole derivative fluconazole (FCZ) when overexpressed in Saccharomyces cerevisiae. This gene encodes a protein highly homologous to S. cerevisiae yAP-1, a bZip transcription factor known to mediate cellular resistance to toxicants such as cycloheximide (CYH), 4-nitroquinoline N-oxide (4-NQO), cadmium, and hydrogen peroxide. The gene was named CAP1, for C. albicans AP-1. Cap1 and yAP-1 are functional homologues, since CAP1 expression in a yap1 mutant strain partially restores the ability of the cells to grow on toxic concentrations of cadmium or hydrogen peroxide. We have found that the expression of YBR008c, an open reading frame identified in the yeast genome sequencing project and predicted to code for a multidrug transporter of the major facilitator superfamily, is dramatically induced in S. cerevisiae cells overexpressing CAP1. Overexpression of either CAP1 or YAP1 in a wild-type strain results in resistance to FCZ, CYH, and 4-NQO, whereas such resistance is completely abrogated (FCZ and CYH) or strongly reduced (4-NQO) in a ybr008c deletion mutant, demonstrating that YBR008c is involved in YAP1- and CAP1-mediated multidrug resistance. YBR008c has been renamed FLR1, for fluconazole resistance 1. The expression of an FLR1-lacZ reporter construct is strongly induced by the overexpression of either CAP1 or YAP1, indicating that the FLR1 gene is transcriptionally regulated by the Cap1 and yAP-1 proteins. Taken collectively, our results demonstrate that FLR1 represents a new YAP1-controlled multidrug resistance molecular determinant in S. cerevisiae. A similar detoxification pathway is also likely to operate in C. albicans.
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Three strains of FCZ-susceptible and 10 FCZ-resistent C. albicans were isolated from the urethra, vagina, oropharynx, respiratory tract, prostate secretion and blood samples. ERG11 gene was amplified by PCR using C.albicans genomic DNA extracts as the templates and the DNA sequences of the PCR products were determined and compared using BLAST and Clustal-W softwares.
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The search for the mechanism of action of improgan (a nonopioid analgesic) led to the recent discovery of CC12, a compound that blocks improgan antinociception. Because CC12 is a cytochrome P450 inhibitor, and brain P450 mechanisms were recently shown to be required in opioid analgesic signaling, pharmacological and transgenic studies were performed in rodents to test the hypothesis that improgan antinociception requires brain P450 epoxygenase activity. Intracerebroventricular (i.c.v.) administration of the P450 inhibitors miconazole and fluconazole, and the arachidonic acid (AA) epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) potently inhibited improgan antinociception in rats at doses that were inactive alone. MW06-25, a new P450 inhibitor that combines chemical features of CC12 and miconazole, also potently blocked improgan antinociception. Although miconazole and CC12 were weakly active at opioid and histamine H(3) receptors, MW06-25 showed no activity at these sites, yet retained potent P450-inhibiting properties. The P450 hypothesis was also tested in Cpr(low) mice, a viable knock-in model with dramatically reduced brain P450 activity. Improgan (145 nmol, i.c.v.) antinociception was reduced by 37% to 59% in Cpr(low) mice, as compared with control mice. Moreover, CC12 pretreatment (200 nmol, i.c.v.) abolished improgan action (70% to 91%) in control mice, but had no significant effect in Cpr(low) mice. Thus, improgan's activation of bulbospinal nonopioid analgesic circuits requires brain P450 epoxygenase activity. A model is proposed in which (1) improgan activates an unknown receptor to trigger downstream P450 activity, and (2) brainstem epoxygenase activity is a point of convergence for opioid and nonopioid analgesic signaling.
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Pulmonary fungal infections in non-neutropenic ICU-patients are not frequent, however, their incidence is increasing with high morbidity and mortality, leading to prolonged stay in ICU wards and to excessive costs dependent on difficult delayed diagnosis. Candida as well as Aspergillus spp. are most important pathogens, but also species of less frequent genera must be taken into account, such as Fusarium, Scedosporium, Cryptococcus and others. Newly evaluated antimycotic agents, such as voriconazole and caspofungin, apart from fluconazole, are not only new options, but must be regarded as agents of choice in non-neutropenic patients.
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Cryptococcus neoformans causes disseminated infection in 7-8% of HIV positive patients admitted to Hospital F. J. Muñiz in Buenos Aires. Meningoencephalitis is the most frequent clinical manifestation and is one of the main causes of death in those patients with AIDS. The standard treatment for this mycosis consists of amphotericin B followed by fluconazole until two successive cultures of CFS are negative. Although resistance to these drugs is infrequent, minimal inhibitory concentrations (MIC) of some antifungals can be high. Since it is important to know the susceptibility levels of this fungus to the antifungal drugs usually employed in our institution, we analyzed the susceptibility test results of C. neoformans with two diffusion methods (Etest and NeoSensitabs tablets) employing Mueller-Hinton agar with 2% glucose and 0.5 microg/ml methylene blue. These results were compared with MICs obtained through the use of the broth microdilution reference method (CLSI). Results showed good agreement with the reference method, with no very major errors and only two major errors for fluconazole using NeoSensitabs tablets. For all the above mentioned, we confirm the usefulness of Mueller-Hinton agar to evaluate C. neoformans susceptibility to amphotericin B and fluconazole with these two agar diffusion methods.
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Twelve 1-(1H-1, 2, 4-triazole-1-yl) -2-( 2, 4-difluorophenyl)-3-substituted amino-2-propanol compounds and thirteen 2-substituted phenyl-5-(1H-1, 2, 4-triazole-1-methyl ) 5-( 2, 4-difluorophenyl)-N-substituted oxazolidine compounds were synthesized and confirmed by 1HNMR and MS. In vitro inhibitory tests showed that most of them have more or less inhibitory effects on C. albicans and some inhibit S. cerevisiae also. Especially the effects of A10, A12 and A13 on C. albicans were more potent than (or equal to) that of fluconazole or itraconazole.
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Use of a central venous catheter (CVC) in neonates is associated with an increase in nosocomial infection. Numerous strategies exist to prevent catheter-related bloodstream infection (CRBSI); however, CRBSI continues to be a major problem. Antibiotic locking catheters is a new and promising treatment that potentially prevents this severe condition.
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Ketoconazole is an imidazole oral antifungal agent with a broad spectrum of activity. Ketoconazole has been reported to cause liver damage, but the mechanism is unknown. However, ketoconazole and a related rug, miconazole, have been shown to have inhibitory effects on oxidative phosphorylation in fungi. Fluconazole, another orally administered antifungal azole, has also been reported to cause liver damage despite its supposedly low toxicity profile. The primary objective of this study was to evaluate the metabolic integrity of adult rat liver mitochondria after exposure to ketoconazole, miconazole, fluconazole, and the deacetylated metabolite of ketoconazole by measuring ADP-dependent oxygen uptake polarographically and succinate dehydrogenase activity spectrophotometrically. Ketoconazole, N-deacetyl ketoconazole, and miconazole inhibited glutamate-malate oxidation in a dose-dependent manner such that the 50% inhibitory concentration (I50) was 32,300, and 110 microM, respectively. In addition, the effect of ketoconazole, miconazole, and fluconazole on phosphorylation coupled to the oxidation of pyruvate/malate, ornithine/malate, arginine/malate, and succinate was evaluated. The results demonstrated that ketoconazole and miconazole produced a dose-dependent inhibition of NADH oxidase in which ketoconazole was the most potent inhibitor. Fluconazole had minimal inhibitory effects on NADH oxidase and succinate dehydrogenase, whereas higher concentrations of ketoconazole were required to inhibit the activity of succinate dehydrogenase. N-deacetylated ketoconazole inhibited succinate dehydrogenase with an I50 of 350 microM. In addition, the reduction of ferricyanide by succinate catalyzed by succinate dehydrogenase demonstrated that ketoconazole caused a dose-dependent inhibition of succinate activity (I50 of 74 microM). In summary, ketoconazole appears to be the more potent mitochondrial inhibitor of the azoles studied; complex I of the respiratory chain is the apparent target of the drug's action.
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A case of Cryptococcus neoformans osteomyelitis involving both the femur and rib is reported. A 50-year-old male presented with a 1-month history of a persistently painful right hip. Radiography revealed an osteolytic area in the subcapital region of the right femoral neck and trochanteric region, and magnetic resonance imaging (MRI) revealed an intramedullary lesion in the peritrochanteric region. A Tc99m whole body bone scan showed significantly increased uptake in the posterior aspect of the right 7th rib as well as the right femoral region. Hemiarthroplasty with a bipolar prosthesis was performed. Because a permeative osteolytic lesion was identified intraoperatively, surgical resection was also performed. A culture from intraoperative specimens yielded C. neoformans. The rib infection was not treated surgically. Intravenous fluconazole was administered postoperatively. The patient became seronegative for cryptococcal antigen with no further illness over the next five years.
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We searched MEDLINE (1966-2001) for studies in which oral treatments, griseofulvin, ketoconazole, terbinafine (continuous and pulse), itraconazole (continuous and pulse), and fluconazole, were used to treat dermatophyte onychomycosis.
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Candida species are frequently encountered as part of the human commensal flora. Colonization mostly precedes candidemia and is an independent risk factor for the development of candidemia. Genotyping methods showed the similarity between colonizing and infecting strains, thus making endogenous origin likely, though exogenous sources like total parenteral nutrition also have been described. Health care workers (HCWs) play an important role in the transmission of yeasts. Candida species are frequently isolated from the hands of HCWs and can be transmitted from hands to patients. Granulocytopenia and damage of the mucosal lining resulting from intensive chemotherapy due to cancer, the increasing use of broad spectrum antibiotics, and the use of intravenous catheters are other important risk factors for the development of candidemia. Candidemia is associated with a high mortality and prolonged hospitalization. Therefore, and because of the high frequency of dissemination, all candidemias should be treated. Amphotericin B was considered the standard drug for the systemic treatment of candidemia. Fluconazole has been shown to be an effective and safe alternative in non-neutropenic patients. 5-Fluorocytosine has been used in combination with amphotericin B in the treatment of deep-seated infections. Liposomal formulations of amphotericin B and other new antifungal drugs currently are under investigation. C. albicans is the most frequently isolated Candida species, although the proportion of infections caused by non-C. albicans species is increasing. Also, there are reports of development of resistance to amphotericin B. C. lusitaniae is known for primary resistance and the development of resistance to amphotericin B. Development of resistance to fluconazole is mainly seen in AIDS patients with recurrent oropharyngeal candidiasis who receive longer courses of therapy.
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The purpose of this study was to analyze the chest CT findings of immunocompetent patients with primary pulmonary cryptococcosis and to evaluate the utility of CT-guided percutaneous biopsy in the diagnosis.
Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole + L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial Po2 ~37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole + L-NMMA reduced (P < 0.05) forearm vascular conductance (FVC) by ~10% and ~18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 ± 0.37 and 0.95 ± 0.35 units in control and experimental forearms, respectively (P < 0.05). During hypoxia and fluconazole + L-NMMA (trial 2), FVC increased by 2.32 ± 0.51 and 0.72 ± 0.22 units in control and experimental forearms, respectively (P < 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n = 8) FVC increased by 1.51 ± 0.46 and 0.45 ± 0.32 units in control and experimental forearms, respectively (P < 0.05). These effects were not due to altered skin blood flow. We conclude that endothelium-derived hyperpolarizing factor contributes to basal vascular tone and to hypoxia-induced skeletal muscle vasodilation and could be particularly relevant when other vasodilator systems are impaired.
In the modeled simulation, posaconazole therapy was associated with a lower probability of IFI development (0.05 versus 0.09), increased discounted life-years (7.87 life-years versus 7.66 life-years), and higher discounted costs per patient ($8,860 versus $5,710 in 2006 U.S. dollars) relative to fluconazole therapy. The estimated incremental cost-effectiveness of posaconazole versus fluconazole for IFI prophylaxis was $85,300 per IFI avoided and $15,300 per life-year saved. A sensitivity analysis indicated a 90% probability that the use of posaconazole for this purpose would be cost-effective at a threshold of $50,000 per life-year saved.
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An automatic drug concentration simulator (DCS) has been developed and its applicability has been demonstrated by in vitro simulation of the human plasma concentration-time curve of fluconazole (FLCZ) against hyphal growth of Candida albicans and Aspergillus fumigatus. The response of hyphal growth to FLCZ was continually monitored and analyzed using an automatic hyphal growth analyzing system (Bio-Cell Tracer). The simulated concentration of FLCZ by DCS was confirmed by HPLC. The DCS assay was reproducible with a mean coefficient of variation (C.V., n=3) of 5.38 %. When the growth of C. albicans hyphae was tested, there was a lag of onset of FLCZ effect between the time when FLCZ concentration became maximal (C MAX, 7.95 microg/ml ) and the point at which hyphal growth ceased. In contrast, FLCZ was found inactive against A. fumigatus. The newly devised technique could provide clinicians with important information in determining optimal dosing regimens for antifungal drugs.