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Elimination of fluconazole interference in gas chromatography/mass spectrometric confirmation of benzoylecgonine, the major metabolite of cocaine using pentafluoropropionyl derivative.

Dasgupta A, Mahle C, McLemore J.

University of New Mexico Health Sciences Center, Albuquerque, USA.

Cocaine is a widely abused drug and causes death from overdose. Benzoylecgonine, the major metabolite of cocaine in urine is usually confirmed after derivatization by gas chromatography/mass spectrometry to demonstrate cocaine abuse. Recently, Wu et al. demonstrated that fluconazole coelutes with benzoylecgonine after conversion to trimethylsilyl analogs and causes false-negative result in the confirmation test. However, fluconazole did not interfere with the screening assay using a enzyme multiplied immunoassay technique. We demonstrated that by converting benzoylecgonine to the corresponding pentafluoropropionyl derivative, the interference of fluconazole can be completely eliminated. The pentafluoropropionyl derivative of benzoylecgonine eluted at 14.7 min while the derivatized fluconazole eluted at 15.6 min. The mass spectral fragmentation pattern of derivatized benzoylecgonine was distinctively different from the mass spectral features of derivatized fluconazole in both electron ionization and chemical ionization mode of operation of mass spectrometers. The quantitation of benzoylecgonine in positive urine specimens has not affected when the specimens were supplemented with 50 micrograms/mL of fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8656195&dopt=Abstract fluconazole Diflucan



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Comparison of D0870 and fluconazole in the treatment of murine cryptococcal meningitis.

Correa AL, Velez G, Albert M, Luther M, Rinaldi MG, Graybill JR.

Department of Medicine University of Texas Health Science Center, San Antonio, USA.

Cryptococcal meningitis is a common infection in patients with AIDS. Using a murine cryptococcosis model, we compared treatment with a new triazole, D0870, and fluconazole. Groups of ICR (Institute for Cancer Research) mice were infected intracerebrally with eight different isolates of Cryptococcus neoformans variety neoformans with different in vitro susceptibilities to fluconazole. For survival studies mice were challenged with two to four times LD(50) or six to nine times LD(50). Treatment was given for 10 days. Mice were observed through to day 30. To assess the effect of treatment on fungal tissue burden, mice received a three to five times LD(50) inoculum and treatment for 10 days. They were sacrificed on day 12 and serial dilutions of brain homogenates were cultured. Fluconazole prolonged survival primarily in isolates which were susceptible in vitro. D0870 prolonged survival in all isolates except one, which was also resistant in vitro to D0870 and fluconazole. Both drugs reduced colony counts of all isolates. D0870 warrants further development for use in cryptococcosis, and appears effective for isolates relatively resistant to fluconazole. There is a relative correlation of in vivo and in vitro susceptibility to D0870 as well as fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8683404&dopt=Abstract fluconazole Diflucan



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Evaluation of fluconazole resistance mechanisms in candida albicans clinical isolates from HIV-infected patients in Brazil.

Goldman GH, da Silva Ferreira ME, dos Reis Marques E, Savoldi M, Perlin D, Park S, Godoy Martinez PC, Goldman MH, Colombo AL.

Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Sao Paulo, Brazil. ggoldman usp.br

In this study, we describe resistance mechanisms in fluconazole-resistant isolates of C. albicans isolated from AIDS patients from nine Brazilian hospitals. These mechanisms include the presence of point mutations in the ERG11 gene and overexpression of ERG11, and several genes encoding efflux pumps, as measured by quantitative real-time reverse transcriptase polymerase chain reaction. Several fluconazole-resistant strains had multiple mechanisms of resistance. Four mutations previously described, Y132F, K143R, E266D, and V437I, were identified among the strains, whereas some isolates contained more than one mutation. Fourteen novel mutations were identified. Interestingly, all Brazilian fluconazole-resistant isolates showed homozygosity at mating-type loci (MTL) associated with fluconazole resistance. This is the first comprehensive assessment at molecular level of mechanisms of fluconazole resistance in C. albicans isolates from South America.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15380275&dopt=Abstract fluconazole Diflucan



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Candida glabrata: in vitro susceptibility of 84 isolates to eight antifungal agents.

Arias A, Arevalo MP, Andreu A, Rodriguez C, Sierra A.

Catedra de Medicina Preventiva y Salud Publica, Facultad de Medicina, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.

The in vitro susceptibility of 84 isolates of Candida glabrata from patients treated at the University Hospital of the Canary islands to eight antifungal agents (amphotericin B, itraconazole, fluconazole, miconazole, clotrimazole, tioconazole and econazole) has been studied using the broth dilution micro-method. Among the eight antifungal agents tested, the smaller geometric mean corresponded to tioconazole, econazole, clotrimazole and miconazole. In contrast with fluconazole, a greater geometric mean has been achieved. All the C. glabrata isolates tested were sensitive to concentrations of 3.125 micrograms/ml of clotrimazole and miconazole, 6.25 micrograms/ml of amphotericin and ketoconazole. Concentrations of 12.5 micrograms/ml were needed to obtain 100% inhibition of isolates for econazole and tioconazole and concentrations of 25 and 50 micrograms/ml, respectively for itraconazole and fluconazole. Among our C. glabrata isolates, 2.4% were found to be resistant to amphotericin B. For fluconazole and itraconazole, 19.1% and 7.9% of isolates, respectively, were resistant. With reference to imidazoles, we obtained 2.4% and 3.6% resistance for tioconazole and econazole, respectively. No isolates were found to be resistant to ketoconazole, miconazole and clotrimazole. The results have shown a high activity of amphotericin B and itraconazole, observing a similar response with the five imidazole antifungals tested. The highest rate of resistance was found when fluconazole was used.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8697885&dopt=Abstract fluconazole Diflucan



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[Clinical studies of fluconazole in patients with deep-seated fungal infection in intravenous hyperalimentation (IVH)]

[Article in Japanese]

Takeda S, Tatara I, Kono K, Arakawa K.

Second Department of Internal Medicine, Fukuoka University School of Medicine, Japan.

Clinical efficacy of fluconazole on fungal infections was evaluated. Fluconazole was administrated orally or intravenously to 16 cases with fungal infections (chronic renal failure 4, congestive heart failure 2, cerebral infarction 2, etc). All cases were suspected of mycosis. The details of those administrated were 16 cases of pneumonia 3 cases, fungemia 9 cases (suspected 7 cases) and urinary tract infection 3 cases. Clinical efficacy rate was 71.4%. Side-effects were observed in only 1 case, and this consisted of transient increase of leukocytes and thrombocytes. Fluconazole is considered to be a potent, safe antifungal agent for the treatment of suspected fungal infection during intravenous hyperalimentation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8699090&dopt=Abstract fluconazole Diflucan



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Relative growth measurement of Candida species in a single concentration of fluconazole predicts the clinical response to fluconazole in HIV infected patients with oral candidosis.

Cartledge JD, Midgley J, Gazzard BG.

Department of HIV/Genito-urinary Medicine, Chelsea & Westminster Health Care Trust, London, UK.

The growth of 113 Candida spp. isolated prospectively from 104 HIV-positive patients treated for thrush was determined using a single concentration of 3 mg/L (10(-5) M) fluconazole relative to growth in drug free medium. Using a receiver operator characteristic curve, a relative growth in fluconazole of > or = 88% best discriminated between isolates from 56 patients who responded to treatment with fluconazole and 48 who failed to respond to 7 days, treatment with at least 100 mg/d drug with a sensitivity of 98% and a specificity of 96%. When the isolates from the eight patients with mixed infections due to both resistant and susceptible yeasts were excluded, the sensitivity and specificity both reached 100%. Relative growth of Candida spp. in a single concentration of fluconazole can therefore be used to accurately predict the clinical response to standard fluconazole treatment of thrush in patients infected with HIV.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8707737&dopt=Abstract fluconazole Diflucan



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Intermittent fluconazole dosing in patients with onychomycosis: results of a pilot study.

Assaf RR, Elewski BE.

Center for Medical Mycology, University Hospital of Cleveland, Case Wastern Reserve University School of Medicine, OH, USA.

BACKGROUND: Therapeutic limitations of griseofulvin in treating onychomycosis have led to a search for alternative antimycotic agents. An optimal dosing regimen for fluconazole has yet to be defined. OBJECTIVE: Our purpose was to evaluate the intermittent use of fluconazole (either once-weekly or alternate-day dosing) without concurrent nail avulsion in patients with moderate to severe onychomycosis. METHODS: Eleven patients with mycologically confirmed onychomycosis of the toenails or fingernails (43 infected nails) were treated with intermittent fluconazole until clinical cure was obtained. Eight patients received fluconazole 300 mg once weekly, one patient received 200 mg once weekly, and two patients received 100 or 200 mg of fluconazole every other day. Eight patients also used an adjunctive topical antimycotic preparation. RESULTS: All six patients with toenails involved (32 infected nails) were clinically cured after a mean treatment duration of 6 months, and all five patients with fingernails involved (11 infected nails) were cured after 3.7 months. There were no significant clinical or laboratory adverse events. CONCLUSION: Intermittent fluconazole, taken once weekly or on alternate days, is a well-tolerated and efficacious method to treat onychomycosis.

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Testing susceptibility of Candida species to fluconazole and itraconazole using the microdilution assay.

Seibold M, Werner E.

Mycology Unit, Robert Koch Institute, Berlin, Germany.

A microdilution system was established for testing the susceptibility of Candida species to fluconazole and itraconazole. The assay used a sodium phosphate-buffered (0.1 mol l-1) Casitone/glucose medium (pH 7.2) supplemented with potassium, iron, magnesium, trace elements and vitamins. Tests were read photometrically after 24 h, and the minimum inhibitory concentration (MIC) was defined as the IC90. In nearly all strains sharp end points were observed. The MICs against Candida species without any known pre-exposure to azoles were found to range from 0.2 to 1.56 micrograms ml-1 for fluconazole and from 2.3 to 12 ng ml-1 for intraconazole. For strains from candidosis patients refractory to treatment with fluconazole the MICs of fluconazole ranged from 6.25 to 100 micrograms ml-1, while those for itraconazole varied between 12 and > 450 ng ml-1. The strains did not respond congruent to both azoles. A similar disparity of the MICs was observed with Candida tropicalis and Candida krusei. The unusually low MICs of itraconazole were attained because (1) the dilution series was prepared from a preformed (concentrated) dilution series in 75% dimethylsulphoxide and not directly by serial dilution in the broth and (2) the incubation was performed in microtitre plates made of quartz glass rather than in the generally used polystyrene microtitre plates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8720193&dopt=Abstract fluconazole Diflucan