Diflucan
Comparison of the efficacy of amphotericin B and fluconazole in the treatment of cryptococcosis in human immunodeficiency virus-negative patients: retrospective analysis of 83 cases. French Cryptococcosis Study Group.

Dromer F, Mathoulin S, Dupont B, Brugiere O, Letenneur L.

Unite de Mycologie, Institut Pasteur, Paris, France.

We retrospectively analyzed clinical outcome of meningeal and extrameningeal cryptococcosis in HIV-negative patients treated with amphotericin B (43 patients) or fluconazole (40 patients). Amphotericin B and fluconazole were prescribed equally to patients with neoplastic diseases and no risk factor, but organ transplant recipients and patients with other diseases were mostly given fluconazole and amphotericin B, respectively. Patients with more severe infections (i.e., meningitis, neurological disorders, or higher levels of antigen in cerebrospinal fluid) were more frequently treated with amphotericin B. A cure rate of > 70% was achieved regardless of the initial treatment and the severity of the infection. A Cox regression analysis showed that age of > 60 years, neoplastic disease, abnormal mental status, disseminated infection at the time of diagnosis, and therapeutic failure were independent predictors of death. Although fluconazole appears to be as effective as amphotericin B, only a prospective multicenter study will determine the best treatment regimen for patients with cryptococcal meningitis who do not have AIDS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8722844&dopt=Abstract fluconazole Diflucan



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Variation in fluconazole efficacy for Candida albicans strains sequentially isolated from oral cavities of patients with AIDS in an experimental murine candidiasis model.

Barchiesi F, Najvar LK, Luther MF, Scalise G, Rinaldi MG, Graybill JR.

Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7750, USA.

Four strains of Candida albicans, isolated from two patients with AIDS who had undergone prolonged fluconazole therapy for oral candidiasis, were studied in a model of disseminated murine candidiasis. Pre- and posttreatment isolates from each patient were genetically related, and the fluconazole MICs for the strains had increased significantly, from 0.25 to 32 micrograms/ml for the strains isolated from patient 1 and from 1.0 to 16 micrograms/ml for the strains isolated from patient 2. Mice were infected intravenously and were treated orally with fluconazole. For survival studies, mice were treated from day 1 to day 10 postinfection and were observed through day 30. The fluconazole dosages were as follows: 0.25, 0.5, 1.0, and 5.0 mg/kg of body weight twice a day. For tissue burden studies, two groups of mice (each group received fluconazole at 0.25 or 5.0 mg/kg) were treated from day 1 to day 7 and were sacrificed 1 day later for quantitative tissue cultures of the spleen and both kidneys. For pretreatment isolates from both patients, all fluconazole dosing regimens were effective at prolonging survival compared with the survival of the control groups. For posttreatment isolates, only fluconazole at 5.0 mg/kg was effective at prolonging survival. Both fluconazole dosing regimens used in the tissue burden studies significantly reduced the counts of the pretreatment isolate from patient 1 in the spleen and kidney, while fluconazole at 5.0 mg/kg was effective at reducing the counts of the posttreatment isolate. For both isolates from patient 2, only fluconazole at 5.0 mg/kg was effective at reducing the counts in the spleen and kidney. The study indicates that C. albicans mutation to resistance to fluconazole may play a critical role in fluconazole-refractory oral candidiasis in AIDS patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8723495&dopt=Abstract fluconazole Diflucan



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Pharmacokinetics of fluconazole in people with HIV infection: a population analysis.

McLachlan AJ, Tett SE.

St Vincent's Hospital Darlinghurst, Australia.

1. The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration-time data (between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation (13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection. 2. A one-compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P-PHARM computer programs. 3. The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h-1 and 47.61, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model-dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P-PHARM were in close agreement. 4. Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4 + T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates. 5. Fluconazole clearance (estimated using NONMEM) in subjects with a CD4 + T-lymphocyte count less than and greater than 200 cells mm3 was 0.73 l h-1 (95% CI; 0.64-0.82 l h-1) and 0.99 l h-1 (95% CI; 0.86-1.12 l h-1), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL (l h-1) = 0.25 (33%) + 0.0057 (32%) x CLcr (in ml min-1) + 0.00068 (10%) x CD4 cell count (in cells mm-3) where intersubject variability (expressed as %CV) is shown in brackets. 6. Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8730974&dopt=Abstract fluconazole Diflucan



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Molecular karyotyping of multiple yeast species isolated from nine patients with AIDS during prolonged fluconazole therapy.

Espinel-Ingroff A, Quart A, Steele-Moore L, Metcheva I, Buck GA, Bruzzese VL, Reich D.

Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0049, USA.

Variations in molecular karyotype and fluconazole susceptibility of serial yeast isolates from the oral cavities of nine patients with AIDS receiving fluconazole for single or multiple episodes of oropharyngeal candidiasis were monitored. Multiple yeast species were isolated from the initial oral specimens in six patients. Molecular karyotyping identified at least eight different DNA subtypes of C. albicans, at least eight of T. glabrata and only one DNA subtype each of C. krusei, C. tropicalis and C. parapsilosis. Among isolates of T. glabrata, fluconazole MICs in each patient were consistently within one or two dilutions, regardless of strain variations. Similarly, among five patients monitored during one course of therapy, the MICs of fluconazole of C. albicans isolates of either the same or different DNA subtypes remained within two dilutions. However, increases in MICs of fluconazole of C. albicans were observed in four patients who received two or more courses of fluconazole, three of whom had the same DNA subtype and one of whom changed from one DNA subtype to another.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8732356&dopt=Abstract fluconazole Diflucan



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[Fluconazole in treatment of urinary candidiasis. Experience with 24 patients]

[Article in Spanish]

Thompson L, Pino M, Castrillon MA, Schenone D, del Canto E.

Departamento de Microbiologia, Universidad de Chile, Santiago.

Since fluconazole achieves high urine concentrations, we assessed its usefulness in the treatment of urinary candidiasis. We studied 24 patients (8 male) aged 23 to 97 years old, that presented pyuria with a negative urine culture for bacteria and fungal colony counts in urine of 10(4) CFU/ml or more. Isolated strains were Candida albicans in 20 cases, Candida kefyr in one case, Candida glabrata in one case and Candida spp in two cases. All patients were treated with fluconazole in doses of 50 to 100 mg/day for 2 to 4 weeks. The fungus was eradicated in 21 patients (88%), the infection persisted in two (8.5%) and one had a relapse (4.2%). Two patients had transient elevations of transaminases, one had abdominal pain and one, a purpuric syndrome without thrombocytopenia in whom the drug was discontinued. It is concluded that fluconazole is efficacious and safe in the treatment of urinary candidiasis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8733268&dopt=Abstract fluconazole Diflucan



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Serum level determination of fluconazole by high-performance liquid chromatography and bioassay.

Hulsewede JW, Dermoumi H.

Institute of Medical Microbiology, University of Essen, Germany.

An HPLC method using a reverse phase system, an isocratic mobile phase and 1-phenyl-1,2 ethanediol as internal standard and a well diffusion bioassay using a strain of Candida pseudotropicalis were compared for the measurement of fluconazole in serum. Both methods permit determination of fluconazole in the range from 1 mg/L to 30 mg/L. The correlation between both methods was found to be r = 0.89. Both methods are useful for monitoring the serum level of fluconazole in clinical routine work.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8737947&dopt=Abstract fluconazole Diflucan



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Fluconazole versus oral polyenes in the prophylaxis of immunocompromised patients: a cost-minimization analysis.

Wakerly L, Craig AM, Malek M, Hoffmeyer U, Lloyd A, Valette F, Phillips R, Zabihollah M.

National Economic Research Associates, London, UK.

This study compares 100 mg daily fluconazole with oral polyenes four times daily in the prophylaxis of fungal infections in immunocompromised patients, to determine a cost-minimization strategy. Data was gathered through a literature survey and clinical interviews conducted in nine different UK hospitals. This was used to construct a decision tree, modelling the drug choices available to a clinician at various stages of a patient's treatment, and assigning probabilities to the different corresponding outcomes. UK cost data were fed into this model to determine the expected cost per patient of the different prophylaxis strategies. Two different patient groups were considered: chemotherapy-only patients, and bone-marrow-transplant (BMT) patients who have higher risks of fungal infection. Probabilities derived from the literature suggest that a cost-minimization strategy to manage both chemotherapy patients and BMT patients is to administer oral fluconazole, both as prophylaxis and as first line treatment, against superficial fungal infection. Probabilities gathered from clinical interviews yield similar results, suggesting that the cost-minimization strategy with chemotherapy-only patients is to administer oral polyenes as prophylaxis, and oral fluconazole in case of superficial fungal infection, while for BMT patients it is a combination of fluconazole and oral polyenes as prophylaxis, with oral fluconazole for the treatment of superficial fungal infections. Using the probabilities from the literature, the lowest cost strategies produce an expected cost of pounds 567.20 for chemotherapy-only patients, and an expected cost of pounds 804.87 for BMT patients for a course of treatment lasting from seven to 28 days. The clinical interview probabilities produce expected costs of pounds 826.48 and pounds 1529.43, respectively. Sensitivity analysis was then conducted, and it was found that in the majority of cases, using the literature probabilities, the cost-minimizing strategy remained prophylaxis with oral fluconazole. The sensitivity analysis for chemotherapy-only patients using the interview probabilities tended to favour oral polyenes as the cost-minimization strategy, whereas for BMT patients the sensitivity analysis favoured a combination of fluconazole and oral polyenes in the majority of cases. The key economic advantage of prophylaxis with fluconazole or a combination of fluconazole with oral polyenes in the prophylaxis of fungal infection in immunocompromised patients, results from the reduction of the expected cost of subsequent fungal infection among those who are most at risk.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8738200&dopt=Abstract fluconazole Diflucan



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Fluconazole treatment of candidal infections caused by non-albicans Candida species.

van 't Wout JW.

Department of Infectious Diseases, University Hospital Leiden, The Netherlands.

Fluconazole is an effective alternative to amphotericin B for the treatment of serious infections caused by Candida albicans. Through a literature survey of candidal infections caused by non-albicans Candida spp., 43 cases treated with fluconazole were found. The most common causative organisms were Candida parapsilosis (14 patients), Candida glabrata (12 patients), and Candida tropicalis (11 patients). The dose of fluconazole varied from 50 to 400 mg daily. The median duration of treatment was 21 days. Overall efficacy was 77%. The efficacy against the various species was 93% for Candida parapsilosis, 50% for Candida glabrata, and 82% for Candida tropicalis. In conclusion, fluconazole is effective against the most common non-albicans Candida spp., although higher doses may be required for infections caused by Candida glabrata. Infections caused by Candida krusei should not be treated with fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8740860&dopt=Abstract fluconazole Diflucan