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Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis.

Cartledge JD, Midgley J, Gazzard BG.

Department of HIV/GU Medicine, St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.

OBJECTIVES: To determine the proportion of fluconazole-resistant Candida albicans isolates that have clinically significant cross-resistance to itraconazole or ketoconazole, that is sufficient to result in failure of these agents at their standard doses (200 and 400 mg daily for 7 days, respectively). METHODS: Seven hundred C. albicans isolates from HIV-positive patients with oral candidosis underwent susceptibility testing using a relative growth method, for which cut-off values corresponding to clinical drug failure have been established. RESULTS: A total of 431 isolates were fully azole-susceptible and three main resistance patterns were detected: isolates resistant to fluconazole alone (n = 100); isolates resistant to fluconazole and ketoconazole but susceptible to itraconazole (n = 94); and isolates resistant to all three drugs (n = 50). No isolates were consistently resistant to ketoconazole without being fluconazole-resistant, and no itraconazole resistance was detected without ketoconazole resistance. Resistance to fluconazole alone was more common in specimens obtained soon after first clinical fluconazole failure, whereas specimens from patients with a longer history of fluconazole-unresponsive candidosis were more likely to be infected with cross-resistant isolates. Median days of prior azole exposure and cumulative fluconazole dose were significantly less for those with isolates resistant to fluconazole alone than for those with ketoconazole cross-resistant isolates, who had received less azole therapy and smaller cumulative fluconazole doses than those with isolates cross-resistant to all three drugs (although not statistically significant). After the diagnosis of fluconazole-unresponsive candidosis, increasing cumulative doses of itraconazole solution were associated with increasing likelihood of cross-resistance. CONCLUSIONS: Clinically significant cross-resistance to other azoles may occur in fluconazole-resistant isolates of C. albicans, although initially most isolates are not cross-resistant and the detection of cross-resistant isolates is associated with a history of greater prior azole exposure. Patients who have been treated for fluconazole-resistant candidosis for longer and with greater cumulative doses of itraconazole solution tend to become infected with increasingly cross-resistant isolates of C. albicans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9412702&dopt=Abstract fluconazole Diflucan



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[Effect of keratin on the efficacy of fluconazole]

[Article in German]

Klimke K, Schafer-Korting M.

Abteilung fur Pharmakologie und Toxikologie, Freie Universitat Berlin, BR Deutschland.

In this study we have investigated the influence of keratin on the efficacy and pharmacokinetics of fluconazole and additional azole antifungal agents. It is well known that the penetration and distribution of oral antifungals is strongly influenced by plasma protein binding. Especially, itraconazole and ketoconazole show a high binding affinity to plasma proteins, whereas fluconazole binds only with 12%. All of these antifungals, however, are accumulated in the stratum corneum of the skin. These observations have stimulated interest, if structure proteins of the skin like keratin interact with antifungals may explain of the accumulation process. Therefore we have measured the binding kinetics between keratin and the azoles. Keratin from sheep wool was degreased, purified and incubated with azole antifungals. After defined incubation periods the azoles were extracted and assayed by thin layer chromatography following UV-detection. There was a specific binding between keratin and all of the used substances. Interestingly, the binding affinity of fluconazole to keratin was much higher than to plasma proteins. Thus our observations indicate that the accumulation in the stratum corneum is a consequence of the interaction between keratin and azole derivatives.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9417512&dopt=Abstract fluconazole Diflucan



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[Evaluation of a breakpoint test for determination of fluconazole susceptibility of yeasts]

[Article in German]

Fegeler W.

Institut fur Medizinische Mikrobiologie, Westfalische Wilhelms-Universitat Munster, BR Deutschland.

Using the breakpoint test at 1 g/ml and 4 g/ml fluconazole, a minimal inhibitory concentration (MIC) of < or = 4 g/ml fluconazole was determined against 78.5% of the 1254 clinical yeast isolates. When compared with the micro broth dilution test, none of a subset of 128/1254 strains had a higher MIC in the dilution test than in the breakpoint test, however, in 43.0% of the 128 strains the MIC was lower in the micro broth dilution test when compared to the MIC of the breakpoint test. In a subset of 94 strains with an MIC of > 4 g/ml fluconazole determined in the breakpoint test, the elevated MIC could be confirmed only in 45.7% of the strains when using the micro broth dilution test. The percentage of breakpoint test confirmation as well as the number of strains with decreased susceptibility towards fluconazole (> 4 g/ml) were species dependent, thus, the number of decreased-susceptible Candida albicans strains was smaller than that of C. glabrata or other Candida species such as C. krusei, C. inconspicua and some C. tropicalis strains. The breakpoint test allows to identify susceptible strains with a high accuracy. Strains with an MIC > 4 g/ml fluconazole should be tested in the micro dilution test to confirm decreased susceptibility and thus to indicate the need for higher dosage of fluconazole or a change of the antifungal therapy. The breakpoint test proved to be a rapid and reliable screening test.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9417513&dopt=Abstract fluconazole Diflucan



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[Fluconazole-resistant Candida species from HIV infected patients with recurrent Candida stomatitis: cross resistance to itraconazole and ketoconazole]

[Article in German]

Metzger S, Hofmann H.

Klinik und Poliklinik fur Dermatologie und Allergologie am Biederstein, Technische Universitat Munchen, BR Deutschland.

In vitro susceptibility to fluconazole of Candida species isolated from 83 HIV-infected patients treated with fluconazole because of recurrent Candida stomatitis was monitored over a period of two years. A microdilution assay with high-resolution antifungal assay (HR) medium and RPMI 1640-medium were compared. In vitro less susceptible and fluconazole resistant C. species were observed in 23 patient at the end of the study. The Candida isolates recovered from oral rinsing fluids at the beginning and the end of study were tested for crossresistance to itraconazole and ketoconazole. Susceptibility to ketoconazole and to itraconazole was reduced using RPMI 1640-medium. Susceptibility of the isolates to fluconazole was not influenced by the assay medium. In 21 patients in vitro fluconazole resistant or less susceptible C. albicans were observed. 9 of 21 isolates showed crossresistance to itroconazole and ketoconazole, in 10 isolates only crossresistance to itraconazole was observed. During fluconazole treatment double infections due to combination of C. albicans and C. glabrata or C. krusei increased from 20% to 78% C. krusei was resistant to the three azoles. C. glabrata was less susceptible (4-8 mg/l) or resistant (> 8 mg/l) to fluconazole and resistant to itraconazole and ketoconazole High dosed intravenous fluconazole treatment with 400 to 600 mg daily failed in 11 patients with fluconazole resistant C. albicans and in 3 (3/10) patients with les susceptible C. albicans isolates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9417515&dopt=Abstract fluconazole Diflucan



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The treatment of systemic candidiasis in neonates with oral fluconazole.

Driessen M, Ellis JB, Muwazi F, De Villiers FP.

Department of Paediatrics and Child Health, Ga-Rankuwa Hospital, South Africa.

Fungal septicaemia has become a frequent problem in neonatal intensive care units. The usual treatment for this condition, amphotericin B alone or in combination with 5-fluorocytosine, is sometimes unsatisfactory, especially in neonates. We report our experience of fluconazole in neonates. Neonates who developed Candida septicaemia in the neonatal unit of Ga-Rankuwa Hospital (MEDUNSA) over a 1-year period were treated with oral fluconazole. The diagnosis was based on fungal cultures obtained from sites which are normally sterile. Blood cultures and renal, haematological and liver functions were monitored regularly. Therapy was continued for at least 1 week after the first negative culture was obtained. Twenty-one neonates were treated; the clinical and microbiological cure rate was 90.5%. No serious renal, haematological or hepatic complications were detected; mild hepatotoxicity was evidenced by elevated enzymes in a third of the children. Relapse occurred in one baby who received inadequate doses of fluconazole. Two babies died of causes unrelated to a systemic fungal infection. We conclude that fluconazole may be a safe and effective alternative for the management of systemic candidiasis in neonates. A comparative trial is necessary.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9425383&dopt=Abstract fluconazole Diflucan



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Efficacy of amphotericin B and azoles alone and in combination against disseminated trichosporonosis in neutropenic mice.

Kamberi P, Atsuro H, Takayoshi T, Masaru N.

Second Department of Internal Medicine, Oita Medical University, Japan.

The activities of amphotericin B, miconazole, fluconazole, and itraconazole against Trichosporon beigelii were assessed in a mouse model of disseminated infection. Cyclophosphamide plus prednisolone-immunosuppressed ICR mice, intravenously challenged with a lethal inoculum of (6 x 10(6) CFU/ mouse), were assigned to receive 7 days of therapy with amphotericin B (0.5 or 2 mg/kg/day), miconazole (10 or 40 mg/kg/day), fluconazole (10 or 40 mg/kg/day), or itraconazole (10 and 40 mg/kg/day). The efficacy of a combination of amphotericin B (1 mg/kg/day) with that fluconazole (10 mg/kg/ day) or itraconazole (20 mg/kg/day) with that of each agent alone was also compared. Both amphotericin B and azoles improved survival and reduced the fungal counts in kidneys of infected mice in a dose-dependent pattern. In general, fluconazole was superior to amphotericin B and the other azoles, whereas the latter two drugs were as effective as amphotericin B. The activity of amphotericin B combined with fluconazole appeared to be superior to that of each agent alone, especially in reducing the organ fungal burden. The other combination (amphotericin B plus itraconazole) had a weaker effect, but no antagonism was observed. In conclusion, azoles may be an alternative to amphotericin B for the treatment of T. beigelii infection. Furthermore, their combination with amphotericin B may improve the poor outcome seen in profoundly neutropenic patients with disseminated trichosporonosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9444410&dopt=Abstract fluconazole Diflucan



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Optimizing the correlation between results of testing in vitro and therapeutic outcome in vivo for fluconazole by testing critical isolates in a murine model of invasive candidiasis.

Rex JH, Nelson PW, Paetznick VL, Lozano-Chiu M, Espinel-Ingroff A, Anaissie EJ.

Department of Internal Medicine, Center for the Study of Emerging and Reemerging Pathogens, University of Texas Medical School, Houston 77030, USA. jrex heart.med.uth.tmc.edu

The trailing growth phenomenon seen when determining the susceptibilities of Candida isolates to the azole antifungal agents makes consistent endpoint determination difficult, and the M27-A method of the National Committee for Clinical Laboratory Standards addresses this problem by requiring an 80% reduction in growth after 48 h of incubation. For some isolates, however, minor variations of this endpoint criterion can produce up to 128-fold variations in the resulting MIC. To investigate the significance of this effect, isolates of Candida that exhibited various forms of trailing growth when tested against fluconazole were identified. The isolates were examined in a murine model of invasive candidiasis and were ranked by their relative response to fluconazole by using both improvement in survival and reduction in fungal burden in the kidney. The resulting rank order of in vivo response did not match the MICs obtained by using the M27-A criterion, and these MICs significantly overestimated the resistance of three of the six isolates tested. However, if the MIC was determined after 24 h of incubation and the endpoint required a less restrictive 50% reduction in growth, MICs which better matched the in vivo response pattern could be obtained. Minor variations in the M27-A endpoint criterion are thus required to optimize the in vitro-in vivo correlation for isolates that demonstrate significant trailing growth when tested against fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9449272&dopt=Abstract fluconazole Diflucan



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Fluconazole resistant oral candidiasis in HIV-infected patients.

Tumbarello M, Tacconelli E, Caldarola G, Morace G, Cauda R, Ortona L.

Department of Infectious Diseases, Catholic University, Rome, Italy.

OBJECTIVE: To evaluate the risk factors associated with the emergence of fluconazole resistant Candida spp. in HIV-infected patients with oral candidiasis. METHODS: Candida spp. were isolated from oral swabs and tested in vitro for resistance to fluconazole. The factors potentially correlated with vazole-resistent Candida spp. infections were investigated. RESULTS: Fifty-one out of 118 patients (43%) with oral candidiasis had fluconazole resistant Candida spp. The following factors were significantly associated with the development of fluconazole resistance: (1) more than five episodes of oral candidiasis in the previous year (P < 0.001); (2) fluconazole therapy in the previous 6 months (P < 0.001); (3) C3 category of HIV infection (P < 0.001); and (4) low number of TCD4+ cells (< 50 mm3, P = 0.002). According to multivariate analysis, previous therapy with fluconazole was the only risk factor that independently influenced the development of Candida spp. resistance (P = 0.003). CONCLUSIONS: The prophylaxis and therapy of mild fungal infections in HIV-infected patients, which may lead to azole resistance, should be carefully considered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9456668&dopt=Abstract fluconazole Diflucan