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In-vitro antifungal activity of liposomal nystatin in comparison with nystatin, amphotericin B cholesteryl sulphate, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B desoxycholate, fluconazole and itraconazole.

Carrillo-Munoz AJ, Quindos G, Tur C, Ruesga MT, Miranda Y, del Valle O, Cossum PA, Wallace TL.

Department of Microbiology, Asesoria Cientifica y de Investigacion Aplicada, Barcelona, Spain. ajcm.acia bcn.servicom.es

The in-vitro susceptibilities of 120 clinical isolates of yeasts to liposomal nystatin were compared with those to amphotericin B lipid complex (ABLC), liposomal amphotericin B (LAB), amphotericin B cholesteryl sulphate (ABCD), amphotericin B desoxycholate, nystatin, fluconazole and itraconazole. Yeast isolates examined included strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida krusei, Candida guilliermondii, Candida tropicalis, Candida kefyr, Candida viswanathii, Candida famata, Candida rugosa, Rhodotorula rubra, Trichosporon spp., Cryptococcus laurentii and Cryptococcus neoformans. The mean MICs for all strains examined were: liposomal nystatin 0.96 mg/L; nystatin 0.54 mg/L; ABLC 0.65 mg/L; LAB 1.07 mg/L; ABCD 0.75 mg/L; amphotericin B 0.43 mg/L; fluconazole 5.53 mg/L; and itraconazole 0.33 mg/L. No significant differences were seen between the activity of liposomal nystatin and the polyene drugs or itraconazole, but liposomal nystatin was more active than fluconazole. MICs were lower than the reported blood concentrations following therapeutic doses of this drug, indicating the potential for a therapeutic use of liposomal nystatin in humans. These results indicate good activity in vitro against medically important yeasts, which compares favourably with the activities of other currently available antifungal drugs. Liposomal nystatin may have a role in the treatment of disseminated and systemic mycoses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10511410&dopt=Abstract fluconazole Diflucan



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Antifungal activities of D0870 against fluconazole-resistant Candida albicans.

Kojima M, Yamada H, Nakamura S, Kikuchi M, Nakanishii T, Takahashi Y, Mochizuki H, Mikami Y.

Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara Gotemba, Shizuoka 412-8524, Japan.

We compared the in vitro and in vivo antifungal activities of D0870, a new triazole antifungal agent, with those of other antifungal agents against 8 clinical isolates of fluconazole-resistant Candida albicans. Microdilution testing was performed according to National Committee for Clinical Laboratory Standards (NCCLS) document M27-T. Minimal inhibitory concentration of D0870 (<0.004-1.0 micro g/ml) was lower than those of fluconazole (2->64 microEg/ml) and itraconazole (0.031-8.0 microEg/ml). In systemic infection models with C. albicans in normal and immunosuppressed mice, D0870 at 0. 3-30 mg/kg/day for 5 days after infection prolonged survival of the animals and showed the highest efficacy among the triazole antifungal agents. At pH 7 and 37C in Sabouraud dextrose broth (SDB), D0870 inhibited the growth of C. albicans and acted cytocidally against one of the middle-resistant strains. In an in vivo study against this strain, D0870 at 10 mg/kg/day for 5 days after infection significantly reduced kidney colony counts (2850+406-997+537 CFU/kidney, P<0.05) on day 7 after infection in comparison with those of the control mice at 24 h after infection. Plasma concentration of D0870 after a single oral administration at 10 mg/kg maintained a sufficient level for interpretation of in vivo antifungal activities. These results suggest that D0870 has strong antifungal activities against clinical isolates of fluconazole-resistant C. albicans in vitro and in vivo, and that these strong activities are at least partially concerned with the fungicidal action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10536307&dopt=Abstract fluconazole Diflucan



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Synergistic fungistatic effects of lactoferrin in combination with antifungal drugs against clinical Candida isolates.

Kuipers ME, de Vries HG, Eikelboom MC, Meijer DK, Swart PJ.

Section of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Studies, University Centre for Pharmacy, 9713 AV Groningen, The Netherlands. kuipers.nl yamanouchi-eu.com

Because of the rising incidence of failures in the treatment of oropharyngeal candidosis in the case of severely immunosuppressed patients (mostly human immunodeficiency virus [HIV]-infected patients), there is need for the development of new, more effective agents and/or compounds that support the activity of the common antifungal agents. Since lactoferrin is one of the nonspecific host defense factors present in saliva that exhibit antifungal activity, we studied the antifungal effects of human, bovine, and iron-depleted lactoferrin in combination with fluconazole, amphotericin B, and 5-fluorocytosine in vitro against clinical isolates of Candida species. Distinct antifungal activities of lactoferrin were observed against clinical isolates of Candida. The MICs generally were determined to be in the range of 0.5 to 100 mg. ml(-1). Interestingly, in the combination experiments we observed pronounced cooperative activity against the growth of Candida by using lactoferrin and the three antifungals tested. Only in a limited concentration range was minor antagonism detected. The use of lactoferrin and fluconazole appeared to be the most successful combination. Significant reductions in the minimal effective concentrations of fluconazole were found when it was combined with a relatively low lactoferrin concentration (1 mg/ml). Such combinations still resulted in complete growth inhibition, while synergy of up to 50% against several Candida species was observed. It is concluded that the combined use of lactoferrin and antifungals against severe infections with Candida is an attractive therapeutic option. Since fluconazole-resistant Candida species have frequently been reported, especially in HIV-infected patients, the addition of lactoferrin to the existing fluconazole therapy could postpone the occurrence of species resistance against fluconazole. Clinical studies to further elucidate the potential utility of this combination therapy have been initiated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10543740&dopt=Abstract fluconazole Diflucan



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Molecular aspects of fluconazole resistance development in Candida albicans.

Franz R, Ruhnke M, Morschhauser J.

Zentrum fur Infektionsforschung, Universitat Wurzburg, Germany.

Serial Candida albicans isolates from recurrent episodes of oropharyngeal candidosis (OPC) in four AIDS patients which became fluconazole-resistant during therapy were analysed by molecular methods. The CARE-2 fingerprint patterns of the isolates demonstrated that in all four patients fluconazole resistance developed in a previously more susceptible strain. In two cases resistance correlated with enhanced expression of genes encoding multiple drug resistance proteins that mediate active drug efflux. Enhanced mRNA levels of the CDR1/CDR2 genes encoding ABC transporters were observed in fluconazole-resistant isolates from one patient compared with the corresponding susceptible isolates. The fluconazole-resistant isolates from another patient exhibited high mRNA levels of the MDR1 gene encoding a membrane transport protein of the major facilitator superfamily that was not detectably expressed in any of the fluconazole-susceptible isolates. These results demonstrate that in AIDS patients with recurrent OPC the development of fluconazole resistance is usually caused by molecular changes in a previously susceptible C. albicans strain from the same patient.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10546486&dopt=Abstract fluconazole Diflucan



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[In vitro activity of caspofungin against fluconazole-resistant Candida isolates from patients with HIV infection]

[Article in Spanish]

Ortiz de la Tabla-Ducasse V, Masia-Canuto M, Martin-Gonzalez C, Gutierrez-Rodero F.

Seccion de Microbiologia, Hospital Universitario de San Juan, San Juan, Alicante, Spain. ortiz_vic gva.es

INTRODUCTION: Antifungal therapy for mucosal candidiasis caused by fluconazole-resistant Candida species is problematic. The aim of this study was to investigate the in vitro activity of caspofungin against Candida strains with reduced susceptibility to fluconazole isolated from HIV-infected patients. METHODS: The in vitro activity of caspofungin was assessed in 28 fluconazole-resistant Candida isolates obtained from the oral cavity of a cohort of 174 consecutive HIV-infected patients. Minimum inhibitory concentrations (MICs) were determined by a standardized broth microdilution method, as recommended by the NCCLS. RESULTS: Overall, caspofungin MICs ranged from < or = 0.06 microg/ml to 1 microg/ml. MICs at which 50% (MIC50) and 90% (MIC90) of isolates were inhibited were 0.25 microg/ml and 0.5 microg/ml, respectively. MICs ranged from < or = 0.06 microg/ml to 0.5 microg/ml for Candida albicans (n = 11), and < 0.06 microg/ml to 1 microg/ml or Candida glabrata (n = 11). MICs for the two strains of Candida krusei were 0.125 microg/ml and 1 microg/ml. The range of MICs for Candida tropicalis and Candida inconspicua strains was 0.25 microg/ml to 0.5 microg/ml. CONCLUSION: Caspofungin was very active in vitro against a variety of fluconazole-resistant Candida strains recovered from a clinical cohort of HIV-infected patients. The MIC50 values and MIC ranges were slightly higher for Candida glabrata than for Candida albicans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15228899&dopt=Abstract fluconazole Diflucan



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Y132H substitution in Candida albicans sterol 14alpha-demethylase confers fluconazole resistance by preventing binding to haem.

Kelly SL, Lamb DC, Kelly DE.

Institute of Biological Sciences, University of Wales Aberystwyth, Aberystwyth, UK. Steven.Kelly aber.ac.uk

Fungal cytochrome P450 sterol 14alpha-demethylase (CYP51) is required for ergosterol biosynthesis and is the target for azole antifungal compounds. The amino acid substitution Y132H in CYP51 from clinical isolates of Candida albicans can cause fluconazole resistance by a novel change in the protein. Fluconazole binding to the mutant protein did not involve normal interaction with haem as shown by inducing a Type I spectral change. This contrasted to the wild-type protein where fluconazole inhibition was reflected in coordination to haem as a sixth ligand and where the typical Type II spectrum was obtained. The Y132H substitution occurred without drastic perturbation of the haem environment or activity allowing resistant mutants to produce ergosterol and retain fitness, an efficient strategy for resistance in nature.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10556708&dopt=Abstract fluconazole Diflucan



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Detection of fluconazole-resistant Candida strains by a disc diffusion screening test.

Sandven P.

Department of Bacteriology, National Institute of Public Health, 0462 Oslo, Norway. per.sandven folkehelsa.no

A commercial disc diffusion test has been evaluated as a screening method for the detection of Candida species with decreased susceptibility to fluconazole. A total of 1,407 Candida strains of different species were tested, and the results were compared with the MIC results. The recently published National Committee for Clinical Laboratory Standards breakpoint criteria have been used. Isolates were classified as susceptible if the MIC for the isolates was </=8 microg/ml, susceptible-dose dependent (S-DD) if the MIC was 16 to 32 microg/ml, and resistant if the MIC was >/=64 microg/ml. All 77 resistant strains and 121 of 122 S-DD strains had fluconazole zone diameters of </=21 mm, and most of the strains (91%) had zone diameters of </=15 mm. It was not possible to distinguish between resistant and S-DD strains by the disc test. Among a total of 1,208 strains found to be susceptible by the microdilution method, 49 (4. 1%) yielded fluconazole zone sizes of </=21 mm and would have been misclassified as resistant or S-DD strains on the basis of the disc test. For the majority (86%) of these 49 strains the fluconazole MIC was 8 microg/ml. The fluconazole disc test is recommended as a simple and reliable screening test for the detection of Candida strains with decreased susceptibility to fluconazole. Fluconazole MICs should be determined for strains found to be resistant by the disc test. The reason for confirmatory testing is twofold: to determine if isolates are resistant or S-DD, since the disc test does not make this distinction, and to identify fluconazole-susceptible strains that are found to be falsely resistant by the fluconazole disc test.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10565896&dopt=Abstract fluconazole Diflucan



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Candida albicans switch phenotypes display differential levels of fitness.

Vargas K, Srikantha R, Holke A, Sifri T, Morris R, Joly S.

The University of Iowa, College of Dentistry, Iowa City, IA 52242, USA. kaaren-g-vargas uiowa.edu

BACKGROUND: Candidiasis is a significant cause of morbidity and mortality in immunosuppressed individuals. Currently, there are limited treatment options for this opportunistic infection and there have been many reports in the literature of increased resistance to treatment. There is evidence to suggest that phenotypic switching of Candida albicans may play a role in this resistance. It was therefore, the purpose of this study to assess the variability among C. albicans switch phenotypes isolated from a single strain. MATERIAL/METHODS: Four switch phenotypes from a single strain of Candida albicans isolated from an HIV+ individual were evaluated for growth rates, post-antifungal effects in the presence of fluconazole, fluconazole uptake and morphological changes after fluconazole exposure. RESULTS: We found that, overall, smooth white and very wrinkled grew significantly faster then either ring or heavily myceliated and were most drastically affected by 4X and 6X MIC concentrations of fluconazole over a 24 hour period. When all four phenotypes were exposed to 64. CONCLUSIONS: These results suggest that switch phenotypes from Candida albicans serve different roles in providing adaptability and survivability under differing conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15232493&dopt=Abstract fluconazole Diflucan