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Antifungal activity of ibuprofen alone and in combination with fluconazole against Candida species.

Pina-Vaz C, Sansonetty F, Rodrigues AG, Martinez-De-Oliveira J, Fonseca AF, Mardh PA.

Department of Microbiology, Porto School of Medicine, University of Porto, Portugal. micfam ip.pt

Ibuprofen, a non-steroidal anti-inflammatory drug, exhibited antimicrobial activity against Candida albicans and non-albicans strains. At 10 mg/ml, ibuprofen showed a rapid cidal activity against exponential growth phase C. albicans, accompanied by rapid and extensive leakage of intracellular K+, permeation to propidium iodide, lysis of spheroplasts and severe membrane ultrastructural alterations. These results indicate that the killing of Candida cells is due to direct damage to the cytoplasmic membrane. At 5 mg/ml, ibuprofen inhibited growth; however, it did not kill the yeasts and did not directly affect the cytoplasmic membrane. Evaluation of yeast metabolic vitality with the fluorescent probe FUN-1 showed that growth inhibition induced by the fungistatic drug concentration was due to metabolic alterations. The combination of ibuprofen with fluconazole resulted in synergic activity with eight of the 12 Candida strains studied, including four of the five fluconazole-resistant strains. The MICs of fluconazole for the fluconazole-resistant strains decreased 2-128-fold when the drug was associated with ibuprofen. When in combination with fluconazole, MICs for ibuprofen decreased by up to 64-fold for all the 12 strains studied. These results point to the practicability of using ibuprofen, alone or in combination with azoles, in the treatment of candidosis, particularly when applied topically, taking advantage of the drug's antifungal and anti-inflammatory properties.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10966233&dopt=Abstract fluconazole Diflucan



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Lanoconazole, a new imidazole antimycotic compound, protects MAIDS mice against encephalitis caused by Cryptococcus neoformans.

Furukawa K, Sasaki H, Pollard RB, Suzuki F.

The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.

The protective effect of a new antifungal compound, lanoconazole, against Cryptococcus neoformans infection in C57BL/6 mice exposed to LP-BM5 murine leukaemia virus (MuLV) (MAIDS mice) was investigated. Mice were infected intratracheally with C. neoformans, strain 613D, 40 days after infection with LP-BM5 MuLV. They were treated orally with various doses of lanoconazole or with fluconazole 10 mg/kg (a positive control) once daily beginning 1 day after the fungal infection and continuing until the end of the experimental period. The number of C. neoformans cells in the lungs and brains of infected mice was determined. Lanoconazole and fluconazole had a similar inhibitory effect on the growth of C. neoformans in the brains and lungs of normal mice. Whereas lanoconazole inhibited the growth of C. neoformans in the brains and lungs of MAIDS mice, the pathogen grew in the brains of MAIDS mice treated with fluconazole. Lanoconazole reduced the number of C. neoformans in the brains of normal mice treated with a type 2 cytokine mixture, whereas fluconazole did not. A predominance of type 2 T-cell responses was demonstrated in MAIDS mice. Splenic T cells from MAIDS mice, but not those from normal mice, released interleukins 4 and 10 into the culture medium when they were stimulated with an anti-CD3 monoclonal antibody. These results suggest that lanoconazole may have the potential to inhibit the growth of C. neoformans in AIDS patients with a predominance of type 2 T-cell responses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10980172&dopt=Abstract fluconazole Diflucan



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Efficacy of fluconazole and liposome entrapped fluconazole for C. albicans induced experimental mycotic endophthalmitis in rabbit eyes.

Gupta SK, Dhingra N, Velpandian T, Jaiswal J.

Department of Pharmacology, All India Institute of Medical Sciences, New Delhi. skgup hotmail.com

PURPOSE: To study the efficacy of intravitreally injected plain and liposome encapsulated fluconazole in the doses of 100 and 200 microg in Candidal endophthalmitis in rabbit eyes. METHOD: Endophthalmitis was induced by injecting Candida albicans (1000 CFU/0.1 ml). Seventy two hours after inoculation, plain and liposome encapsulated fluconazole (REVs) were injected. At day 16 sterility was studied using vitreous culture. RESULTS: In the 100 & 200 microg plain fluconazole group, vitreous sterility was seen in 62.5% and 75%, respectively. In the liposome entrapped fluconazole a culture sterility of 25% and 50% for 100 microg and 200 microg, respectively, was seen. CONCLUSION: Plain fluconazole in the dose of 100 and 200 microg was equally effective against Candidal endophthalmitis in rabbits, but a failure of 25-37.5% of the eyes to respond, discourages one from using fluconazole as a sole therapy. Liposome entrapped fluconazole was found to be inferior to plain fluconazole in this model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10990049&dopt=Abstract fluconazole Diflucan



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In vivo activity of amphotericin B lipid complex in immunocompromised mice against fluconazole-resistant or fluconazole-susceptible Candida tropicalis.

Warn PA, Morrissey J, Moore CB, Denning DW.

Department of Medicine, Section of Infectious Diseases, Hope Hospital, University of Manchester, United Kingdom.

We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10991841&dopt=Abstract fluconazole Diflucan



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Pharmacoeconomic analysis of ciclopirox nail lacquer solution 8% and the new oral antifungal agents used to treat dermatophyte toe onychomycosis in the United States.

Gupta AK.

Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Sciences Center (Sunnybrook site), and the University of Toronto.

BACKGROUND: Recently a novel topical nail lacquer, ciclopirox solution 8%, has been approved for the treatment of onychomycosis. OBJECTIVE: This was undertaken to determine the most cost-effective treatment for the treatment of dermatophyte onychomycosis of the toes in the United States in 2000. METHODS: The nature of the problem was defined. The drug comparators were ciclopirox nail lacquer, terbinafine, itraconazole (pulse), itraconazole (continuous), fluconazole, and griseofulvin. A decision analytic model that reflected the manner in which pedal tinea unguium is managed was produced. Studies that have evaluated the efficacy of the nail lacquer and the oral antifungal agents for this indication were identified. Appropriate studies were used in a meta-analysis to determine the mycologic and clinical response rates when the drug comparators are used for the treatment for toe dermatophyte onychomycosis. For each drug comparator a cost of regimen analysis was carried out. This is the sum of the drug acquisition cost, the cost of medical management, and the cost of managing adverse effects. Next, the expected cost of management was calculated, disease free days were determined, and a sensitivity analysis was conducted. RESULTS: For each comparator the meta-analytic average mycologic cure (MC) rate and clinical response (CR) rates were: ciclopirox nail lacquer (MC: 52.6 +/- 4.2%, CR: 52.4 +/- 9.0%), griseofulvin (MC: 41.1 +/- 20.4%, CR: 33.7 +/- 14.1%), itraconazole (continuous) (MC: 66.3 +/- 4.2%, CR: 70.3 +/- 4.2%), itraconazole (pulse) (MC: 70.8 +/- 5.7%, CR: 73.6 +/- 4.6%), terbinafine (MC: 77.2 +/- 4.0%, CR: 75.3 +/- 2.9%), and fluconazole (MC: 65.6 +/- 7.1%, CR: 66.5 +/- 11.7%). The cost of regimen for the drug comparators was: ciclopirox nail lacquer $325.2, griseofulvin $1413.1, itraconazole (continuous) $1410.2, itraconazole (pulse) $811.7, terbinafine $890.1, and fluconazole $966.8. The cost/mycologic cure rate and expected cost/expected symptom free day were, ciclopirox nail lacquer ($618.2, 1.69), griseofulvin ($3438.2, 5.3), itraconazole (continuous) ($2126.9, 3.52), itraconazole (pulse) ($1146.4, 2.01), terbinafine ($1153.0, 2.14), and fluconazole ($1473.7, 2.10). The relative cost-effectiveness was ciclopirox nail lacquer 1.00, itraconazole (pulse) 1.19, fluconazole 1.24, terbinafine 1.27, itraconazole (continuous) 2.08, and griseofulvin 3.13. Sensitivity analysis indicated that ciclopirox nail lacquer was a cost effective alternative compared with the oral regimens of terbinafine, itraconazole (continuous), and griseofulvin when clinical response rate was used as the primary efficacy parameter. CONCLUSION: Ciclopirox nail lacquer solution 8% is a recent addition to the armamentarium of therapies available to the physician and patient for the treatment of onychomycosis. The nail lacquer is a cost effective agent compared with the oral antifungal therapies, terbinafine, itraconazole, fluconazole, and griseofulvin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11002199&dopt=Abstract fluconazole Diflucan



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Determinants for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients.

Masia Canuto M, Gutierrez Rodero F, Ortiz de la Tabla Ducasse V, Hernandez Aguado I, Martin Gonzalez C, Sanchez Sevillano A, Martin Hidalgo A.

Servicio de Medicina Interna, Unidad de Enfermedades Infecciosas, Hospital General Universitario de Elche, Alicante, Spain. fgutierrezr medynet.com

A point prevalence study to document oral yeast carriage was undertaken. Risk factors for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients were investigated with a case-control design. Cases included all patients with fluconazole-resistant strains (MIC> or =64 microg/ml), and controls were those with susceptible (MIC< or =8 microg/ml) or susceptible-dependent-upon-dose (MIC 16-32 microg/ml) strains. One hundred sixty-eight Candida strains were isolated from 153 (88%) patients, 28 (16%) of whom had oropharyngeal candidiasis. Overall, 19 (12%) of the patients harbored at least one resistant organism (MIC > or = 64 microg/ml). Among patients with resistant strains, tuberculosis (P<0.001), esophageal candidiasis (P = 0.001), clinical thrush (P<0.001), and a CD4 + cell count < 200/mm3 (P = 0.03) were more frequent. These patients had also been treated more commonly with antituberculous drugs (adjusted odds ratio [OR] 6.13; 95% confidence interval [CI] 2.11-17.80), ciprofloxacin (OR 6.0; 95% CI 1.23-29.26), fluconazole (OR 4.59; 95% CI 1.55-13.52), and steroids (OR 4.13; 95% CI 1.11-15.39). Multivariate analysis showed that the determinants for fluconazole resistance were therapy with antituberculous drugs (OR 3.61; 95% CI 1.08-12.07; P=0.03) and one of the following: previous tuberculosis (OR 3.53; 95% CI 1.08-14.57; P=0.03) or fluconazole exposure (OR 3.41; 95% CI 1.10-10.54). Findings from this study indicate that treatment with antituberculous drugs, previous tuberculosis, and fluconazole exposure are the strongest determinants for development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11014621&dopt=Abstract fluconazole Diflucan



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Fluconazole plus cyclosporine: a fungicidal combination effective against experimental endocarditis due to Candida albicans.

Marchetti O, Entenza JM, Sanglard D, Bille J, Glauser MP, Moreillon P.

Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.

Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicans experimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and >10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal growth in both the vegetations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this dissociation. In the vegetations, only the fungicidal fluconazole-Cy combination significantly decreased fungal densities compared to all groups, including amphotericin B (P < 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P < 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11036003&dopt=Abstract fluconazole Diflucan



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Changes of virulence factors accompanying the phenomenon of induced fluconazole resistance in Candida albicans.

Fekete-Forgacs K, Gyure L, Lenkey B.

Department of Microbiology and Biotechnology, Kossuth Lajos University, Debrecen, Hungary.

We investigated a fluconazole-sensitive (MICflu = 5 micrograms ml-1) clinical isolate and a fluconazole-resistant (MICflu > 80 micrograms ml-1) laboratory mutant Candida albicans strain developed from the sensitive one. We studied putative virulence factors including germination, adherence ability to either buccal epithelial cells or acrylate surface, the secreted aspartic proteinase, and the extracellular phospholipase activity of the two strains as well as their growth. The fluconazole-resistant strain proved to be superior to the original strain in all the virulence traits tested. The higher virulence of the fluconazole-resistant strain was also supported by a mouse model. These results suggest that the development of fluconazole resistance can be accompanied by serious morphological and physiological changes: several putative virulence traits, moreover the in vivo virulence can increase simultaneously.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11036397&dopt=Abstract fluconazole Diflucan