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Fluconazole in cats: pharmacokinetics following intravenous and oral administration and penetration into cerebrospinal fluid, aqueous humour and pulmonary epithelial lining fluid.

Vaden SL, Heit MC, Hawkins EC, Manaugh C, Riviere JE.

Department of Companion Animal and Special Species Medicine, College of Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.

The pharmacokinetics of fluconazole following intravenous (i.v.) and oral (p.o.) administration and the penetration of fluconazole into cerebrospinal fluid, aqueous humour and epithelial lining fluid (ELF) of the lungs were evaluated in adult male cats. Pharmacokinetic parameters were calculated from serum concentration-time data obtained following i.v. and p.o. administration of 50 mg per cat using a cross-over study design. Fluconazole concentrations were measured using a high-performance liquid chromatography assay. Mean total body clearance of fluconazole was 37.7 mL/h.kg, mean volume of distribution at steady state was 1.14 L/kg, mean residence time was 31.0 h and mean half-life of elimination was 25 h as derived by non-compartmental analysis of data. Absorption was complete. Mean ratios of fluid:serum fluconazole concentrations following administration of 50 mg fluconazole per day for 8 days were as follows: cerebrospinal fluid, 0.88; aqueous humour 0.79; ELF, 1.20. Fluconazole concentrations in cerebrospinal fluid, aqueous humour and ELF exceeded reported minimum inhibitory concentrations of fluconazole for pathogenic fungi. Results of this study suggest fluconazole can effectively be administered to cats at 50 mg per cat per day.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9185083&dopt=Abstract fluconazole Diflucan



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Variations in fluconazole susceptibility and DNA subtyping of multiple Candida albicans colonies from patients with AIDS and oral candidiasis suffering one or more episodes of infection.

Redding SW, Pfaller MA, Messer SA, Smith JA, Prows J, Bradley LL, Fothergill AW, Rinaldi MG.

Department of General Dentistry, University of Texas Health Science Center, San Antonio 78284, USA.

Five Candida albicans colonies from each infection in AIDS patients receiving fluconazole therapy for oropharyngeal candidiasis over a 2-year period were evaluated by antifungal susceptibility testing and DNA subtyping, and the results were correlated with clinical response to determine the occurrence of clinically significant selection of more-resistant C. albicans over multiple infections. A total of 534 C. albicans isolates were obtained from 38 patients who exhibited 84 episodes of infection. Antifungal susceptibility testing revealed that the MICs for 93% of the isolates were < or = 8.0 microg/ml and the MICs for 7% of the isolates were > or = 64 microg/ml. DNA subtyping revealed 70 different subtypes, with 78% of patients with one infection exhibiting one DNA subtype and 80% of patients with more than one infection exhibiting multiple DNA subtypes. Also, patients who had multiple infections had lower CD4 counts than those with single infections. Differences between the single-infection group and the multiple-infection group regarding the number of DNA subtypes and CD4 counts were both statistically significant. Of the 74 evaluable infections all were successfully treated with regular-dose (100-mg/day) fluconazole, except for three patients who ultimately responded to higher-dose fluconazole. Only one patient may have shown clinically significant selection of a more-resistant C. albicans strain over multiple courses of treatment. Interestingly, MICs reached only 8.0 microg/ml, even though doses of 400 mg of fluconazole were necessary for clinical cure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9196188&dopt=Abstract fluconazole Diflucan



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Efficacy of D0870 treatment of experimental Candida vaginitis.

Fidel PL Jr, Cutright JL, Sobel JD.

Department of Microbiology, Immunology, and Parasitology, Louisiana State University Medical Center, New Orleans 70112-1393, USA. pfidel lsumc.edu

In this study, oral administration of the triazole D0870 was compared to oral administration of fluconazole in the treatment of experimental vaginal candidiasis. With an estrogen-dependent murine model of Candida albicans vaginal infection, the effects of D0870 on several isolates, including fluconazole-susceptible and -resistant isolates, were tested. D0870, at doses of 0.5 and 2.5 mg/kg of body weight given once over the course of a 10-day infection, was effective in eradicating vaginitis caused by fluconazole-susceptible laboratory and clinical isolates, respectively. In contrast, a stricter treatment regimen (every 24 to 48 h) with 10 and 25 mg of fluconazole per kg was required to achieve similar reductions in vaginal fungal titers induced by the same isolates. Whereas fluconazole was consistently ineffective in infections induced by fluconazole-resistant isolates, as predicted by in vitro susceptibility tests, D0870 was effective, although a daily regimen of 25 mg/kg was required. Additional studies showed that despite the in vitro activity of D0870 against two clinical Candida glabrata isolates, neither D0870 nor fluconazole was effective at daily doses as high as 100 and 125 mg/kg, respectively. Taken together, although D0870 failed to show efficacy against experimental C. glabrata vaginitis, D0870 was superior to fluconazole in the treatment of experimental C. albicans vaginitis caused by isolates that were either susceptible or resistant to fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9210665&dopt=Abstract fluconazole Diflucan



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Activity of the triazole SCH 56592 against disseminated murine coccidioidomycosis.

Lutz JE, Clemons KV, Aristizabal BH, Stevens DA.

Department of Medicine, Santa Clara Valley Medical Center, and California Institute for Medical Research, San Jose 95128, USA.

SCH 56592 (SCH) is a new triazole antifungal with a broad spectrum of activity. In vitro susceptibility testing against five strains of Coccidioides immitis revealed MICs from 0.39 to 3.13 microg/ml and minimal fungicidal concentrations from 1.56 to 3.13 microg/ml. A murine model of systemic coccidioidomycosis was established in female CD-1 mice. Groups received either no treatment or oral therapy with fluconazole at 10 or 100 mg/kg of body weight; itraconazole at 10 or 100 mg/kg; SCH at 0.5, 2, 10, or 25 mg/kg; or its methylcellulose diluent alone. Therapy began 2 days postinfection and continued once daily for 19 days. Surviving mice were euthanized 49 days postinfection, and infectious burdens were determined by culture. All drugs were superior to no-treatment or diluent-treatment controls (P < 0.001) in prolonging survival but were not significantly different from one another. Itraconazole at 100 mg/kg was superior to fluconazole in reduction of CFU in the spleen, liver, and lung (P < 0.01 to 0.001). SCH at 0.5 mg/kg was superior to either fluconazole or itraconazole at 10 mg/kg in reduction of CFU in all three organs (P < 0.05 to 0.001). SCH at 2 mg/kg was not significantly different from itraconazole at 100 mg/kg in all three organs. SCH at 10 and 25 mg/kg was superior to either dose of fluconazole or itraconazole in all three organs (P < 0.05 to 0.001). In terms of reduction of CFU, SCH was > or = 200-fold as potent as fluconazole and > or = 50-fold as potent as itraconazole. There was a clear dose-responsive relationship for SCH in each of the organs. It is noteworthy that SCH effected cures (no detectable C. immitis in any organ) in 1 of 9, 6 of 10, or 9 of 9 surviving mice in animals given 2, 10, or 25 mg/kg, respectively. Neither fluconazole nor itraconazole cured any survivor. SCH has potent, fungicidal activity in vivo against C. immitis. It should be considered for clinical trials in patients with coccidioidomycosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9210684&dopt=Abstract fluconazole Diflucan



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Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis.

Ding JC, Bauer M, Diamond DM, Leal MA, Johnson D, Williams BK, Thomas AM, Najvar L, Graybill JR, Larsen RA.

Department of Medicine (Infectious Diseases), University of Southern California, Los Angeles 90033, USA.

We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe meningitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9210691&dopt=Abstract fluconazole Diflucan



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Single-dose systemic oral fluconazole for the treatment of vaginal candidiasis.

Kaplan B, Rabinerson D, Gibor Y.

Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tiqva, Israel.

OBJECTIVES: To evaluate the acceptance of fluconazole given in a single oral dose, for the safe, effective treatment of vaginal candidiasis. METHODS: A total of 428 patients who had a first or recurrent episode of vaginal candidiasis diagnosed clinically or by culture, were offered treatment with fluconazole by 40 primary care gynecologists who were unfamiliar with fluconazole treatment of vaginal candidiasis. The efficacy of this treatment was evaluated by both physicians and patients. RESULTS: Most of the physicians (72%) and most of the patients (69%) found the drug effective in relieving or at least alleviating the signs and symptoms of the disease. The majority of patients (83.5%) rated it better than other drugs they had received for vaginitis in the past. No recurrences were noted at the 6-week follow-up. CONCLUSIONS: Fluconazole has been found effective by physicians and patients. Both physician willingness to use it and patient compliance are satisfactory.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9215491&dopt=Abstract fluconazole Diflucan



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In-vitro activity of D0870, a new triazole antifungal drug, in comparison with fluconazole and itraconazole against Aspergillus fumigatus and Candida krusei.

Venkateswarlu K, Denning DW, Kelly SL.

Krebs's Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, The University of Sheffield, UK.

The activity of the new triazole antifungal D0870 was compared with those of itraconazole and fluconazole against Candida krusei and Aspergillus fumigatus, two fungi showing inherent tolerance of fluconazole. The activity of D0870 resembled that of itraconazole against whole cells of C. krusei, but it was less effective against A. fumigatus. However, the effect on sterol biosynthesis, in terms of the sterol type accumulating and IC50 for in-vitro biosynthesis, appeared similar in both species. The superior antifungal effect of D0870 over fluconazole appeared related to better inhibition of ergosterol biosynthesis in A. fumigatus, but in C. krusei this did not account for the entire difference which may result mainly from reduced efflux of drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9222042&dopt=Abstract fluconazole Diflucan



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Molecular analysis of cyp51 from fluconazole-resistant Candida albicans strains.

Loffler J, Kelly SL, Hebart H, Schumacher U, Lass-Florl C, Einsele H.

Medizinische Klinik, Abt. II, Universitat Tubingen, Germany.

The target enzyme for fluconazole is sterol 14 alpha-demethylase, a cytochrome P450 encoded by cyp51. One mechanism of fluconazole resistance likely to occur in Candida albicans is through an altered target site. To test this hypothesis DNA sequencing of the cyp51 coding sequence from 19 fluconazole-resistant and 19 fluconazole-sensitive C. albicans was undertaken. A number of point mutations were identified in the resistant isolates which were not present in the sensitive ones: F105L (five), E266D (five), K287R (one), G448G (one), G450E (one), G464S (three) and V488I (one). These alterations are discussed in the light of a molecular model of the enzyme regarding potential roles in resistance. It was also demonstrated that sequence-specific primers can be employed to identify polymorphisms which may be associated with resistance; diagnostic tests for resistant strains will prove of value in combating this serious clinical problem.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9228762&dopt=Abstract fluconazole Diflucan