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Correlation between E-test, disk diffusion, and microdilution methods for antifungal susceptibility testing of fluconazole and voriconazole.

Matar MJ, Ostrosky-Zeichner L, Paetznick VL, Rodriguez JR, Chen E, Rex JH.

Laboratory of Mycology Research, Division of Infectious Diseases, University of Texas-Houston Medical School, Houston, Texas 77030.

The activities of fluconazole and voriconazole against isolates of Candida spp. (n = 400) were tested by the E-test, disk diffusion, and the National Committee for Clinical Laboratory Standards (NCCLS) M27-A2 broth microdilution-based reference methods. More than 96% of isolates found to be susceptible to fluconazole by the reference method were identified as susceptible by the agar-based methods. Lesser degrees of correlation with the reference method were seen for isolates identified as resistant by the agar-based methods. Interpretive categories are not available for voriconazole, but results qualitatively similar to those for fluconazole were seen. The agar-based E-test and disk diffusion methods are reliable alternatives to the NCCLS M27-A2 reference microdilution method for isolates that test susceptible to fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12709335&dopt=Abstract fluconazole Diflucan



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[Diminution of antifungal activity of fluconazole associated with ibuprofen and piroxicam in experimental histoplasmosis of hamsters (Mesocricetus auratus)]

[Article in Spanish]

Finquelievich JL, Iovannitti C, Landaburu F, Raffin G, SanJuan N, Elias-Costa MR, Negroni R.

Centro de Micologia, Departamento de Microbiologia, Parasitologia e Inmunologia, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina. ctromic janssen.com.ar

The aim of this study was to determine if tha association of non-steroid antiinflammatory drugs (piroxicam and ibuprofen) with fluconazole, affects the antifungal activity of the azole compound, in an experimental model histoplasmosis in hamsters (Mesocricetus auratus). Sixty hamsters were intracardially inoculated with 4x10(6) yeasts of Histoplasma capsulatum var. capsulatum. Treatments began one week after the challenge and continued for three weeks. The hamsters were divided in six groups of ten animals each and received the following treatment: 1- fluconazole 8 mg/kg/day; 2- ibuprofen 20 mg/kg/day; 3- piroxicam 20 mg/kg/day; 4- fluconazole+ibuprofen; 5- fluconazole+piroxicam and 6- only received the solvent of these drugs. One week after ending the treatment, all the animals were sacrified and the evaluation of the treatments was based on the results of blood cultures, on the determination of colony forming units per gram of spleen, and the histopathologic studies of the same organ. The animals treated with fluconazole plus ibuprofen or piroxicam showed more colony colony forming units per gram (3.9x10(7) and 3.3x10(7)) when compared with the animals treated with fluconazole alone (0.9x10(7)). The histopathologic results of the hamsters that received fluconazole showed well-organized granulomas with few yeast-like elements inside the macrophages. In contrast, those which received fluconazole associated with antiinflammatory drugs presented lax granulomas containing numerous yeast-like elements. These findings let us to conclude that non-steroids antiinflammatory drugs diminish the antifungal efficacy of fluconazole in this animal model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12716230&dopt=Abstract fluconazole Diflucan



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Persistence of oropharyngeal Candida albicans strains with reduced susceptibilities to fluconazole among human immunodeficiency virus-seropositive children and adults in a long-term care facility.

Makarova NU, Pokrowsky VV, Kravchenko AV, Serebrovskaya LV, James MJ, McNeil MM, Lasker BA, Warnock DW, Reiss E.

Laboratory of Bacteriology and Mycology, Department of Laboratory Medicine, Russia AIDS Centre, Central Institute of Epidemiology, Moscow, Russia.

Nineteen oropharyngeal Candida albicans isolates from six children and seven adults living with AIDS at the Russia AIDS Centre, Moscow, from 1990 to 1998 were selected for molecular typing. Two fluconazole-resistant C. albicans genotypes were identified from a child who contracted human immunodeficiency virus infection during the Elista Hospital outbreak in the Kalmyk Republic in 1989. Highly related strains were observed 4 years later in the oral lesions and colonization of two patients and a health care worker. There may be a tendency for persons who are living with AIDS in a long-term care facility and who receive fluconazole therapy for oropharyngeal candidiasis to harbor and spread fluconazole-resistant C. albicans strains.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12734213&dopt=Abstract fluconazole Diflucan



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Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location.

Pfaller MA, Messer SA, Boyken L, Tendolkar S, Hollis RJ, Diekema DJ.

Department of Pathology, Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. michael-pfaller uiowa.edu

We examined the susceptibilities to fluconazole of 559 bloodstream infection isolates of Candida glabrata and grouped the isolates by patient age and geographic location within the United States. Susceptibility of C. glabrata to fluconazole was lowest in the Pacific (44%) and East South Central (47%) regions and was highest in the West South Central region (82%) (regions are as designated by the U.S. Bureau of the Census). Isolates from pediatric patients were virtually all susceptible to fluconazole, whereas the highest frequency of resistance was observed in isolates from patients 16 to 64 years of age.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12734273&dopt=Abstract fluconazole Diflucan



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Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence.

Sanglard D, Ischer F, Marchetti O, Entenza J, Bille J.

Institute of Microbiology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 44, CH-1011 Lausanne, Switzerland. Dominique.Sanglard chuv.hospvd.ch

The azole antifungal fluconazole possesses only fungistatic activity in Candida albicans and, therefore, this human pathogen is tolerant to this agent. However, tolerance to fluconazole can be inhibited when C. albicans is exposed to fluconazole combined with the immunosuppressive drug cyclosporin A, which is known to inhibit calcineurin activity in yeast. A mutant lacking both alleles of a gene encoding the calcineurin A subunit (CNA) lost viability in the presence of fluconazole, thus making calcineurin essential for fluconazole tolerance. Consistent with this observation, tolerance to fluconazole was modulated by calcium ions or by the expression of a calcineurin A derivative autoactivated by the removal of its C-terminal inhibitory domain. Interestingly, CNA was also essential for tolerance to other antifungal agents (voriconazole, itraconazole, terbinafine, amorolfine) and to several other metabolic inhibitors (caffeine, brefeldin A, mycophenolic acid, fluphenazine) or cell wall-perturbing agents (SDS, calcofluor white, Congo red), thus indicating that the calcineurin pathway plays an important role in the survival of C. albicans in the presence of external growth inhibitors. Several genes, including PMC1, a vacuolar calcium P-type ATPase, were regulated in a calcineurin- and fluconazole-dependent manner. However, PMC1 did not play a direct role in the survival of C. albicans when exposed to fluconazole. In addition to these different properties, calcineurin was found to affect colony morphology in several media known to modulate the C. albicans dimorphic switch. In particular, calcineurin was found to be essential for C. albicans viability in serum-containing media. Finally, calcineurin was found to be necessary for the virulence of C. albicans in a mice model of infection, thus making calcineurin an important element for adequate adaptation to the conditions of the host environment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12753189&dopt=Abstract fluconazole Diflucan



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Combined topical fluconazole and corticosteroid treatment for experimental Candida albicans keratomycosis.

Schreiber W, Olbrisch A, Vorwerk CK, Konig W, Behrens-Baumann W.

Department of Ophthalmology, Faculty of Medicine, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.

PURPOSE: To determine the most efficient time point and concentration of topical corticosteroids in Candida albicans keratitis treated with fluconazole. METHODS: Corneas of 105 rabbits were infected with viable yeast cells of C. albicans (2.5 x 10(5)). After a 48-hour incubation period, seven groups of animals were treated for 21 days with fluconazole, with group I acting as a control, and groups II to VII receiving adjunct therapy with the corticosteroid prednisolone (5 or 10 times daily; 3, 9, or 15 days after infection). The degree of corneal infiltration, ulceration, corneal clouding, hypopyon, conjunctivitis, neovascularization, and corneal perforation was monitored over a 24-day period, as well as recultivation and resistance to fluconazole of the C. albicans pathogen. RESULTS: The control group showed the highest level of corneal clouding and neovascularization. In comparison, by day 24, the majority of groups also treated with prednisolone displayed significantly less corneal clouding and neovascularization. An immediate decrease in corneal clouding was observed in groups treated with additional low- or high-dose prednisolone from day 9 after inoculation. After additional prednisolone treatment from day 9 or 15 after inoculation, no significant difference was detected in the recultivation rate of C. albicans compared with the control. Early administration of prednisolone (day 3, low and high dose) resulted in the recultivation of significantly more C. albicans. CONCLUSIONS: Fluconazole plus adjunct high-dose prednisolone treatment was most effective when administered 9 days after infection. The delayed application of corticosteroids after treatment with antimycotic drugs in cases of fungal keratitis is therefore not contraindicated and may be beneficial in patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12766067&dopt=Abstract fluconazole Diflucan



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Stable susceptibility of Candida blood isolates to fluconazole despite increasing use during the past 10 years.

Chen YC, Chang SC, Luh KT, Hsieh WC.

Department of Internal Medicine, National Taiwan University Hospital No. 7, and College of Medicine, National Taiwan University, Taipei, Taiwan. sc4030 ha.mc.ntu.edu.tw

The prevalence of drug-resistant bacterial pathogens is very high in Taiwan. Accordingly, there was great concern that the introduction of fluconazole would result in rapid emergence of drug-resistant yeasts. Thus, we recommended in 1991 that fluconazole be used for treatment only. To explore the impact of this policy fluconazole susceptibility of Candida species blood culture isolates and outcome of patients with nosocomial candidaemia were monitored prospectively at National Taiwan University Hospital during 1994-2000. The MICs of fluconazole were determined by the disc diffusion method. There were 1095 episodes of nosocomial candidaemia during 1994-2000. Candida albicans was the most common species (50.4%), followed by Candida tropicalis (20.5%), Candida parapsilosis (14.2%) and Candida glabrata (12.0%). There were 0-2 isolates of Candida krusei per year. The incidence of nosocomial candidaemia and the proportion of C. glabrata peaked in 1996 and decreased thereafter. Fluconazole susceptibility was determined for 552 Candida blood isolates. Only 0.7% of blood isolates were resistant to fluconazole. Fluconazole susceptibility was 94.0% in 1994-1995 and 97.9% in 1999-2000 (P = 0.06). Attributable mortality for patients with nosocomial candidaemia was 43.2% in 1994-1995 and was 25% in 2000 (P = 0.005). Despite an increase in the incidence of nosocomial fungal infection and increased consumption of fluconazole from 1994 to 2000, there was no significant change in the susceptibility to fluconazole for bloodstream isolates of Candida species. These findings appear to be attributed to several factors. These include low prevalence of C. krusei and C. glabrata, changing patterns of use of antifungal drugs and broad-spectrum antibiotics, and efforts to improve the rational use of antifungal agents at our hospital.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12775680&dopt=Abstract fluconazole Diflucan



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High-dose fluconazole therapy in Intensive Care Unit.

[Article in English, Italian]

De Bellis P, Bonfiglio M, Gerbi G, Bacigalupo P, Buscaglia G, Guido P, Massobrio B.

Anesthesia and Intensive Care Unit, Ospedali Galliera, Genoa, Italy. debellispasquale fastwebnet.it

AIM: Fungal infections have become one of the emerging complications in intensive care patients and the morbidity and mortality linked to these infections underlines the importance of managing these pathologies. METHODS: The clinical and laboratory difficulties of diagnosing candidiasis prompted us to identify patients at risk and to intervene as soon as possible, where there was the "suspicion" of active infection, using adequate, so-called "empiric" treatment. The major risk factors include the use of invasive devices (central venous catheters), the administration of multiple antibiotic treatment and parenteral nutrition. In our Intensive Care ward (multi-purpose), we examined 1933 patients who had undergoing 1211 urine cultures (following consolidated clinical criteria). "Empiric treatment" was used in 378 high-risk patients with unstable clinical symptoms and positive urinary fungal colonisations using high-dose fluconazole (800 mg/die) according to the guidelines set down by BSAC. The mean duration of treatment was 12+2 days and urine cultures became negative in all patients after 1 or 2 weeks of treatment. RESULTS: We observed that fluconazole was generally well tolerated: only 10% of patients presented augmented hepatic transaminase. This phenomenon was always transient. Renal function remained unchanged (creatinine clearance). A severe infection with hematogenous dissemination was reported in 6 cases: "empiric treatment" was used in 5 cases with 800 mg/die of fluconazole and 1 case received amphotericin B 1 mg/kg/die (because no clinical improvement was observed after 48-72 hours of fluconazole treatment). Three of these 6 cases died, 2 of which were not directly linked to fungal infection, and 3 patient were discharged from the ward. CONCLUSIONS: We found that fluconazole offers a treatment option that is less toxic, less expensive and equally effective for these infections, provided that it is used at an adequate dose and that high-risk patients are identified for "empiric treatment". No significant increases in resistance were noted, as is demonstrated by the fact that only 1 case of candidemia required conversion to amphotericin B.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12792583&dopt=Abstract fluconazole Diflucan