Diflucan
Ocular penetration and pharmacokinetics of topical fluconazole.

Yee RW, Cheng CJ, Meenakshi S, Ludden TM, Wallace JE, Rinaldi MG.

Department of Ophthalmology and Visual Science, University of Texas Health Science Center, San Antonio, USA.

The high bioavailability and low toxicity of fluconazole, a stable, water-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent. The penetration of fluconazole (0.2%) into the corneas and aqueous humors of New Zealand white rabbits was assayed by gas liquid chromatography (GLC). Peak corneal levels occurred essentially immediately at 5 min in the corneas [debrided, 8.2 +/- 1.2 micrograms/g; nondebrided, 1.6 +/- 0.6 microgram/g; (mean +/- SEM)] and at 15 min after application in the aqueous [debrided, 9.4 +/- 2.3 micrograms/ml; nondebrided, 1.6 +/- 0.6 microgram/ml; (mean +/- SEM)]. Estimating from semilogarithmic plots of the data, the halflife (t1/2) in the debrided eyes was 15 min; in the nondebrided eyes, t1/2 was 30 min. A loading dose of a 20-microliter drop per min for 5 min yielded levels of 59.9 +/- 11.3 micrograms/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 micrograms/ ml (mean +/- SEM) in the corresponding aqueous humor. A regimen consisting of this loading dose followed by one 20 microliters drop/h for 6 h showed 45.9 +/- 3.5 micrograms/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 micrograms/ml (mean +/- SEM) in the corresponding aqueous. The same regimen yielded values of 3.1 +/- 0.2 micrograms/g in the nondebrided corneas and 1.3 +/- 0.2 micrograms/ml (mean +/- SEM) in the aqueous. Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from < 1.25 to 20 micrograms/ml, for hyaline molds from 2.5 to > 20 micrograms/ml, and dematiaceous molds from < 1.25 to > 20 micrograms/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8985636&dopt=Abstract fluconazole Diflucan



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In vitro susceptibility of clinical yeast isolates to fluconazole and terconazole.

Cooper CR Jr, McGinnis MR.

Medical Mycology Research Center, University of Texas Medical Branch, Galveston 77555-0609, USA.

OBJECTIVE: Fifty clinical yeast isolates, representing equally Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, and Torulopsis glabrata, were tested in vitro for their susceptibility to terconazole and fluconazole. STUDY DESIGN: The minimal inhibitory concentrations of terconazole and fluconazole were determined by use of a proposed standardized broth macrodilution assay. Also, the response of selected yeast isolates to 25 micrograms of either drug was measured by agarose disk diffusion experiments. RESULTS: For all species the minimum inhibitory concentrations for terconazole were significantly lower than those for fluconazole (p < 0.05). In fact, for each individual isolate the minimum inhibitory concentration of terconazole was consistently lower than that of fluconazole. Differences in the geometric mean of terconazole and fluconazole minimum inhibitory concentrations were largest among C. krusei and T. glabrata, followed by C. parapsilosis, C. tropicalis, and C. albicans, in order of decreasing difference. Disk diffusion experiments suggested that terconazole is a more effective fungistatic agent than fluconazole is. CONCLUSION: Terconazole may be more effective than fluconazole against yeast species other than C. albicans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8987951&dopt=Abstract fluconazole Diflucan



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Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole.

Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, Fusco D.

Birth Defects Unit, Institute of Pediatrics, Catholic University, Rome, Italy.

OBJECTIVE: Our purpose was to study prospectively the pregnancy outcome after first-trimester exposure to fluconazole, an effective antifungal agent teratogenic in animals. STUDY DESIGN: We conducted a prospective cohort study of women who contacted three Italian teratogen information services. We compared the pregnancy outcomes of 226 women exposed to fluconazole with that of 452 women exposed to nonteratogenic agents, with use of logistic regression to control for potential confounders. RESULTS: Among the 226 pregnancies exposed to fluconazole there were 22 miscarriages, 1 stillbirth, and 7 infants with congenital anomalies. The prevalence of these outcomes and of neonatal growth parameters and the rate of neonatal complications were similar to those in the reference group. Women in the fluconazole group had a fivefold increased occurrence of induced abortions. CONCLUSIONS: First-trimester exposure to fluconazole does not appear to increase the prevalence of miscarriages, congenital anomalies, and low birth weight.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8987954&dopt=Abstract fluconazole Diflucan



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Infection due to fluconazole-resistant Candida in patients with AIDS: prevalence and microbiology.

Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD, Gallant JE.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

A cross-sectional study was conducted to assess the prevalence and microbiology of oral infection due to fluconazole-resistant Candida in patients with AIDS. Oral swab specimens for fungal cultures were obtained from 100 consecutive outpatients with CD4 lymphocyte counts of < 200/mm3. At least one fungal organism demonstrating in vitro resistance to fluconazole (minimum inhibitory concentration, > or = 8 micrograms/mL) was isolated from 26 (41%) of 64 patients for whom cultures were positive. When fluconazole-resistant C. albicans was isolated, in vitro resistance correlated with clinical thrush. None of 10 patients from whom only non-albicans species of Candida were isolated had active thrush. The patients from whom fluconazole-resistant Candida albicans was isolated had lower CD4 cell counts (median, 9/mm3), a greater number of treated episodes of thrush (median, 4.5), and a greater median duration of prior fluconazole treatment (231 days) than did patients from whom fluconazole-susceptible C. albicans was isolated (median CD4 cell count, 58/mm3 [P = .004]; median number of treated episodes of thrush, 2.0 [P = .001]; and median duration of prior fluconazole treatment, 10 days [P = .01]; respectively). In a multivariate analysis, the number of episodes and duration of fluconazole therapy were independent predictors of resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8994752&dopt=Abstract fluconazole Diflucan



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Fluconazole as prophylaxis against fungal infection in patients with advanced HIV infection.

Manfredi R, Mastroianni A, Coronado OV, Chiodo F.

Department of Clinical and Experimental Medicine, University of Bologna, Italy.

BACKGROUND: There is limited information regarding the usefulness of primary antifungal prophylaxis in patients with advanced human immunodeficiency virus (HIV) disease. OBJECTIVE: To evaluate the efficacy and safety of oral fluconazole treatment for the prevention of systemic fungal diseases related to the acquired immunodeficiency syndrome. METHODS: We evaluated the clinical records of more than 1300 HIV-infected patients followed up for 6 years to identify subjects with a CD4+ lymphocyte count less than 0.20 x 10(9)/L (200/microL) and no prior systemic fungal disease. We compared 128 patients who received oral fluconazole (100 mg/d every third week) with 121 subjects who received no antifungal treatment. MAIN OUTCOME MEASURES: The occurrence of visceral mycoses or death was considered an end point. The frequency of esophageal candidiasis and extrapulmonary cryptococcosis and their related clinical and laboratory features, as well as overall patient survival, were assessed and compared between the 2 study groups. RESULTS: Subjects not treated with fluconazole experienced a significantly higher incidence of systemic mycoses than patients who received fluconazole: 28.4 vs 8.8 cases per 100 patient-years (P < .001). Fluconazole treatment was more effective in preventing esophageal candidiasis than cryptococcosis and was more effective in subjects with a CD4+ cell count less than 0.10 x 10(9)/L. Moreover, fungal complications occurred later and were associated with a significantly lower CD4+ cell count among treated vs untreated patients, while the duration of antiretroviral therapy did not play a significant role. Although mortality rates were similar in the 2 study groups, the fatal outcome of disease was less frequently caused by a fungal disease in subjects who underwent fluconazole prophylaxis. Fluconazole had a favorable tolerability profile. CONCLUSIONS: In our experience, primary fluconazole prophylaxis proved safe and effective in the prevention of systemic candidiasis and cryptococcosis in patients with advanced HIV disease but it did not improve overall survival. Prospective controlled trials are advisable to confirm efficacy, to find the drug of choice and its best dosage and schedule of administration, to identify patient subgroups showing the most favorable cost-benefit ratios, and to evaluate the effects on overall life expectancy and the risk of emergence and spread of antifungal drug resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8996042&dopt=Abstract fluconazole Diflucan



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Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation.

Kelly SL, Lamb DC, Kelly DE, Manning NJ, Loeffler J, Hebart H, Schumacher U, Einsele H.

Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, Sheffield University, UK. S.Kelly Sheffield.ac.uk

Fluconazole resistance occurs in > 10% of cases of candidosis during the late stages of AIDS. We show here in two clinical isolates that resistance was caused by defective sterol delta5,6-desaturation. This altered the type of sterol accumulating under fluconazole treatment from 14alpha-methylergosta-8,24(28)-dien-3beta,6alpha -diol to 14alpha-methylfecosterol which is capable of supporting growth. A consequence of this mechanism of azole resistance is that an absence of ergosterol causes cross-resistance to the other major antifungal agent available, amphotericin B. The results also show that growth arrest after fluconazole treatment of C. albicans in clinical conditions is caused by 14alpha-methylergosta-8,24(28)-dien-3beta,6alpha -diol accumulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9000517&dopt=Abstract fluconazole Diflucan



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A new pharmaceutical concept for the treatment of oropharyngeal and oesophageal candidosis with fluconazole.

Wildfeuer A, Laufen H, Yeates RA, Zimmermann T.

Research and Development, Pfizer/Mack, Illertissen, Germany.

Administration of fluconazole in capsule form has proved effective in the prophylaxis and treatment of mucosal candidosis, particularly in immunosuppressed patients. An additional topical effect in oropharyngeal and oesophageal candidosis might be expected with a fluconazole suspension. This hypothesis was therefore tested in a crossover study in 12 healthy volunteers in whom the concentrations of the antimycotic were measured in saliva and plasma after oral administration of 100 mg fluconazole as either a capsule or a suspension. The time courses of the fluconazole concentrations were very similar with the two formulations in plasma, but significantly different in saliva. Thus, the mean Cmax for fluconazole in saliva of 551 micrograms ml-1 was reached 5 min after ingestion of the suspension, compared with a value of 3 micrograms ml-1 some 4 h after taking the capsule. The mean concentration of the antimycotic in saliva over the observation period (0-96 h) was more than 80% higher with the suspension than with the capsule.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9009658&dopt=Abstract fluconazole Diflucan



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In vitro activity of fluconazole on Candida albicans.

Abecia LC, Arevalo JM, Lopez MJ.

Department of Preventive Medicine and Public Health, Faculty of Medicine, University of the Basque Country, Vitoria, Spain.

Fluconazole is a triazole antifungal compound suitable for the treatment of fungal infections, including those caused by Candida albicans. Fluconazole, as all azole antifungals, is a potent inhibitor of ergosterol biosynthesis. The aims of this study are to evaluate the susceptibility of C. albicans strains isolated from clinical specimens against fluconazole, and to assess the decrease in ergosterol produced on these strains when they are incubated in vitro with this antifungal compound. Sixty six yeast strains were isolated and identified from vaginal specimens of 710 women of a tocogynecology surgery (9.3%), C. albicans being the most frequent species (n = 52, ca. 79%). An agar dilution technique was used to determine the minimal inhibitory concentration (MIC) of fluconazole for the C. albicans strains. The MICs rank was between 1 and 20 micrograms/ml (mean = 6.6 micrograms/ml). Ergosterol content from ten C. albicans strains (MIC for fluconazole = 5 micrograms/ml) was assessed using the method proposed by Breivik and Owades, with three concentrations of fluconazole (2.5, 5 and 20 micrograms/ml) and four contact times (1, 6, 12 and 24 h), in comparison to no treated strains (control). The mean content of ergosterol was lower in the treated strains than in the control ones, and became statistically significant after 12 h of incubation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9018696&dopt=Abstract fluconazole Diflucan