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In vivo activity of micafungin in a persistently neutropenic murine model of disseminated infection caused by Candida tropicalis.

Warn PA, Sharp A, Morrissey G, Denning DW.

School of Medicine, University of Manchester, UK. pwarn fs1.ho.man.ac.uk

Micafungin is a new echinocandin with broad-spectrum in vitro and in vivo antifungal activity against both Aspergillus and Candida species. We compared the activity of micafungin with that of amphotericin B and fluconazole in a persistently immunocompromised murine model of disseminated candidiasis against a strain of Candida tropicalis that was resistant to amphotericin B and fluconazole in vitro. Mice were rendered persistently neutropenic with multiple doses of cyclophosphamide and infected intravenously with C. tropicalis. Mice were treated with either intraperitoneal amphotericin B (0.5-5 mg/kg per dose), oral fluconazole (50 mg/kg twice a day), intravenous micafungin (1-10 mg/kg per dose) or solvent control for 7 days. Mice were killed at 11 days post-infection and kidneys, lungs, brain and liver removed for quantitative culture. Overall mortality in the model was low, with rates varying between 10% and 25% in treatment groups. Micafungin at doses between 2 and 10 mg/kg were the only regimes able to reduce cfu below the level of detection of tissues infected with C. tropicalis. Micafungin was well tolerated by the mice and was much more effective than amphotericin B or fluconazole against an amphotericin B- and fluconazole-resistant C. tropicalis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12461036&dopt=Abstract fluconazole Diflucan



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Comparison of microdilution and disc diffusion methods in assessing the in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil against vaginal Candida isolates.

Ergin A, Arikan S.

University of Hacettepe, School of Health Services, Department of Microbiology and Clinical Microbiology, Ankara, Turkey.

The in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil was evaluated against 99 vaginal Candida strains by the broth microdilution and disc diffusion methods. The microdilution method was performed in accordance with NCCLS-M27A guidelines. An investigational method was used for the disc diffusion test. Fluconazole and tea tree oil minimum inhibitory concentrations (MICs) obtained at 48 h tended to increase 1- to 2-fold or remain the same compared to 24 h readings for most of the isolates tested. C. krusei and C. norvegensis had significantly higher MICs and smaller inhibition zones for fluconazole compared to other species. Tea tree oil MICs were found to be similar, in general, for all Candida spp. tested. The geometric mean MIC of tea tree oil for all isolates was 2.2% (range, 0.25-4%) at 24 h and 3.0% (range, 1-8%) at 48 h. Tea tree oil mean inhibition zone diameter was 24 mm (range, 14-42 mm) at 24 h and 15.8 mm (range, 10-35 mm) at 48 h. In vitro activity of tea tree oil against fluconazole-resistant Candida strains was of particular interest. The isolates had similar tea tree oil MICs and inhibition zone diameters regardless of their fluconazole susceptibility profile. Tea tree oil MIC ranges (inhibition zone diameter ranges) were 2-4% (12-21 mm) and 2% (35 mm) at 48 h for C. krusei and C. norvegensis, respectively. These results suggest that tea tree oil MICs of the fluconazole-resistant isolates are comparable to those of fluconazole-susceptible isolates. This in vitro finding is promising for potential use of topical tea tree oil formulations in the treatment of candidiasis due to fluconazole-resistant strains.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12462426&dopt=Abstract fluconazole Diflucan



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Fluconazole downregulates metallothionein expression and increases copper cytotoxicity in Microsporum canis.

Uthman A, Rezaie S, Dockal M, Ban J, Soltz-Szots J, Tschachler E.

Ludwig Boltzmann Institute for venero-dermatological infection, University of Vienna Medical School, Wahringer Gurtel 18-20, A-1090, Vienna, Austria.

Azole antifungals are widely used to treat infections with dermatophyte fungi. Whereas it is well established that this class of drugs interferes with fungal ergosterol synthesis, little is known about its potential other biological effects. Here we report the isolation and structural organization of Microsporum canis metallothionein gene and demonstrate that fluconazole is able to downregulate the baseline as well as copper-induced expression of this gene. Since this effect occurred within 30 min after exposure of the fungus to fluconazole, it is unlikely that it is due to impaired ergosterol synthesis. Our additional demonstration that fluconazole enhances copper toxicity for M. canis suggests that inhibition of metallothionein expression by fluconazole is biologically relevant and may represent an important additional mode of the antifungal action of this drug. Therefore our data indicate that antifungal effects of azole derivatives might not only be due to interference with cell wall synthesis but may also affect other biological circuits within the fungal cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12470632&dopt=Abstract fluconazole Diflucan



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Fluconazole susceptibility of vaginal isolates obtained from women with complicated Candida vaginitis: clinical implications.

Sobel JD, Zervos M, Reed BD, Hooton T, Soper D, Nyirjesy P, Heine MW, Willems J, Panzer H.

Department of Internal Medicine, Wayne State University, Detroit, Michigan, USA. jsobel intmed.wayne.edu

Despite considerable evidence of azole resistance in oral candidiasis due to Candida species, little is known about the azole susceptibilities of the genital tract isolates responsible for vaginitis. The fluconazole susceptibilities of vaginal isolates obtained during a multicenter study of 556 women with complicated Candida vaginitis were determined by evaluating two fluconazole treatment regimens. Of 393 baseline isolates of Candida albicans, 377 (96%) were highly susceptible to fluconazole (MICs, <8 microg/ml) and 14 (3.6%) were resistant (MICs, >or=64 microg/ml). Following fluconazole therapy, one case of in vitro resistance developed during 6 weeks of monitoring. In accordance with the NCCLS definition, in vitro fluconazole resistance correlated poorly with the clinical response, although a trend of a higher mycological failure rate was found (41 versus 19.6% on day 14). By using an alternative breakpoint of 1 micro g/ml, based upon the concentrations of fluconazole achievable in vaginal tissue, no significant differences in the clinical and mycological responses were observed when isolates (n = 250) for which MICs were <or=1 microg/ml were compared with isolates (n = 30) for which MICs were >1 microg/ml, although a trend toward an improved clinical outcome was noted on day 14 (odds ratio, >2.7; 95% confidence interval, 0.91, 8.30). Although clinical failure was uncommon, symptomatic recurrence or mycological relapse almost invariably occurred with highly sensitive strains (MICs, <1.0 microg/ml). In vitro fluconazole resistance developed in 2 of 18 initially susceptible C. glabrata isolates following fluconazole exposure. Susceptibility testing for women with complicated Candida vaginitis appears to be unjustified.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12499165&dopt=Abstract fluconazole Diflucan



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Caspofungin modulates in vitro adherence of Candida albicans to plastic coated with extracellular matrix proteins.

Soustre J, Rodier MH, Imbert-Bouyer S, Daniault G, Imbert C.

Laboratoire de Parasitologie et Mycologie Medicales, Centre Hospitalier Universitaire La Miletrie, BP 577, 86021 Poitiers Cedex, France.

OBJECTIVES: Some manifestations of candidiasis are associated with the formation of biofilms on inert or biological surfaces and the intrinsic resistance of Candida albicans biofilms to the most commonly used antifungal agents has been demonstrated. In this study, we report on the influence of the growth of C. albicans in medium containing a sub-inhibitory concentration (MIC/2) of caspofungin, on subsequent fungal adherence to plastic coated with extracellular matrix (ECM) proteins. METHODS: Eleven strains of C. albicans were studied: six strains were susceptible to fluconazole in vitro and five strains were resistant to this antifungal agent. RESULTS: Caspofungin induced a decrease in the adherence of all the tested strains that were susceptible to fluconazole but induced a decrease in the adherence of only 60% of the fluconazole-resistant strains. CONCLUSIONS: This study demonstrated the anti-adherent activity of caspofungin but indicated a reduced effect in the case of in vitro fluconazole resistance. These results indicated a possible relationship between the efficiency of caspofungin to inhibit the first step of the development of C. albicans biofilm and the resistance of C. albicans to fluconazole in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14749343&dopt=Abstract fluconazole Diflucan



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Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species.

Lupetti A, Paulusma-Annema A, Welling MM, Dogterom-Ballering H, Brouwer CP, Senesi S, Van Dissel JT, Nibbering PH.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

In light of the need for new antifungal regimens, we report that at noncandidacidal concentrations, the lactoferrin-derived peptide hLF(1-11), which is highly active against fluconazole-resistant Candida albicans, acts synergistically with fluconazole against this yeast and a fluconazole-sensitive C. albicans strain as well as C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. When these yeasts were exposed to hLF(1-11) for 5 min and then incubated with fluconazole, they were killed effectively, while no candidacidal activity was observed when they were incubated first with fluconazole and then exposed to the peptide, indicating that the candidacidal activity is initiated by the peptide while fluconazole is only required during the effector phase. Investigations of the effect of azide, which inhibits mitochondrial respiration, on the activity of combinations of hLF(1-11) and fluconazole against fluconazole-resistant C. albicans revealed that it inhibits this activity, even when added during the effector phase only. As expected, azide inhibited the accumulation of rhodamine 123 in mitochondria and the production and release of ATP by C. albicans that occurred upon exposure to the combination of hLF(1-11) and fluconazole. Accordingly, oxidized ATP (oATP), an antagonist of ATP receptors, completely blocked the candidacidal activity of the hLF(1-11)-fluconazole combination, whereas oATP did not block the activity when its presence was restricted to the effector phase. The candidacidal activity of combinations of hLF(1-11) and fluconazole, which is initiated by the peptide through the involvement of energized mitochondria, renders fluconazole-resistant C. albicans sensitive to this azole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12499200&dopt=Abstract fluconazole Diflucan



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Fluconazole in the treatment of pediatric tinea capitis caused by Microsporum canis.

Valari M, Iordanidou A, Raftopoulou A, Pangalis A.

Department of Dermatology, A. Sophia Children's Hospital, Goudi 11527, Athens, Greece.

Fluconazole has been shown to be effective in the treatment of fungal scalp infections in children; however, there is limited experience of its use in Microsporum scalp infections. We studied 11 children with tinea capitis caused by Microsporum canis who received oral fluconazole at a dose of 5-7.5 mg/kg/day for 6 weeks. Mycological cure was observed in two of the 11 patients at week 4 from the start of therapy, in four patients at week 8 and in three patients at week 16. One of the remaining patients had positive mycology at week 8, but was unavailable for further evaluation. Fluconazole was effective in treating pediatric tinea capitis caused by Microsporum canis and was well tolerated. Clinical and mycological response was achieved in some patients weeks after the cessation of the administration of fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12512234&dopt=Abstract fluconazole Diflucan



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Characterization of heteroresistance to fluconazole among clinical isolates of Cryptococcus neoformans.

Yamazumi T, Pfaller MA, Messer SA, Houston AK, Boyken L, Hollis RJ, Furuta I, Jones RN.

Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, 52242, USA.

Strains of Cryptococcus neoformans expressing heteroresistance to fluconazole have been described previously. The present study was conducted to investigate the prevalence of heteroresistance among clinical isolates of C. neoformans and to characterize the heteroresistant phenotypes. A total of 107 clinical isolates of C. neoformans for which the MICs of fluconazole ranged from 0.25 to 32 microg/ml were selected. The isolates were chosen to represent a broad geographic distribution. Of the 107 C. neoformans isolates tested, 4 grew on medium containing fluconazole at concentrations that were four to eight times higher than the MICs for each strain. A fifth isolate, for which the fluconazole MIC was 32 microg/ml, grew on agar with 64 microg of fluconazole per ml. These five isolates (4.7% of the total number) were confirmed to exhibit heteroresistant compositions by population analysis. The degree and frequency of resistance varied among the isolates. Stepwise selection by exposure to fluconazole resulted in subclones of all five strains for which the fluconazole MIC was >64 microg/ml. Subclones of three strains demonstrated a homogeneous population of resistant cells on medium containing 64 microg of fluconazole/ml. The resistance was sensitive to incubation temperature, that is, heteroresistance was demonstrable only at 30 degrees C by agar-based tests, and was reversible through serial transfers on fluconazole-free medium over a period of 8 days. These results suggest that the fluconazole-heteroresistant phenotype of C. neoformans exists in a significant proportion of clinical isolates and that fluconazole resistance can be developed by selection from heteroresistant clones and induction by exposure to fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12517859&dopt=Abstract fluconazole Diflucan