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PubMed1998

Accumulation of fluconazole in scalp hair.

The accumulation in scalp hair of the antimycotic triazole, fluconazole, was studied during and after administration. Fluconazole 50 mg was administered to 12 healthy subjects as a single capsule each day for 28 days. The concentration of fluconazole 5 hours after administration was measured in different 1-cm sections of scalp hair at intervals during treatment and for 6 months after the end of treatment. In each section of scalp hair the concentration of fluconazole increased during treatment and was consistently higher than values found in plasma. For example, the mean concentration in the first hair section on day 28, 19.8 micrograms/g, corresponded to a mean penetration ratio relative to plasma of 9.42. During administration, the maximal concentration of fluconazole was found in the first hair section. After cessation of administration, the measured concentrations of fluconazole decreased and greater concentrations were found in the distal hair sections, presumably as a result of hair growth. Fluconazole was detectable, however, in the hair of 9 of the 12 subjects even 6 months after treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1 micrograms/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a second study, fluconazole was administered as a single oral 150-mg capsule per week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole concentration in whole scalp hair 5 hours after the last dose was 3.2 micrograms/g.

Adult↗

PubMed1995

Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia.

All-trans-retinoic acid induces acute promyelocytic leukemia cell differentiation in vitro, and it produces greater than 90% complete remissions in patients with acute promyelocytic leukemia. Despite the high response rate, the majority of patients relapse with continued trans-retinoic acid therapy, and disease progression has been observed to be accompanied by an increase in the metabolism of trans-retinoic acid in the patients. In this study, the pharmacokinetic disposition of trans-retinoic acid was determined by HPLC in patients with acute promyelocytic leukemia before and after concurrent therapy with the triazole antimycotic agent fluconazole. Treatment with trans-retinoic acid for 1 week reduced the area under the plasma trans-retinoic acid concentration vs time curve in one patient by 67%, from 277 to 91 ng/mL/hr. Trans-retinoic acid pharmacokinetics were repeated after the second dose of fluconazole, administered 1 hour prior to the retinoid, and the AUC was found to be 401 ng/mL/hr, a greater than 4-fold increase from the pre-fluconazole level. A similar, though more modest, effect of fluconazole was seen in a second acute promyelocytic leukemia patient. The effect of fluconazole on trans-retinoic acid metabolism was examined in vitro using isolated human hepatic microsomes. Fluconazole inhibited the NADPH-dependent cytochrome P450-mediated catabolism of trans-retinoic acid in a concentration-dependent manner. Although fluconazole was approximately one-half as potent an inhibitor when compared with ketoconazole, a related antifungal drug, 60-90% inhibition was observed at the concentrations of fluconazole measured in the acute promyelocytic leukemia patients. Neither fluconazole nor ketoconazole inhibited lipid hydroperoxide-mediated metabolism of trans-retinoic acid. Since fluconazole is a well-tolerated agent frequently administered to leukemia patients, its use in combination with trans-retinoic acid merits further consideration.

Adult↗

PubMed2004

Carboxylic acid and phosphate ester derivatives of fluconazole: synthesis and antifungal activities.

Two classes of fluconazole derivatives, (a) carboxylic acid esters and (b) fatty alcohol and carbohydrate phosphate esters, were synthesized and evaluated in vitro against Cryptococcus neoformans, Candida albicans, and Aspergillus niger. All carboxylic acid ester derivatives of fluconazole (1a-l), such as O-2-bromooctanoylfluconazole (1g, MIC=111 microg/mL) and O-11-bromoundecanoylfluconazole (1j, MIC=198 microg/mL), exhibited higher antifungal activity than fluconazole (MIC > or = 4444 microg/mL) against C. albicans ATCC 14053 in SDB medium. Several fatty alcohol phosphate triester derivatives of fluconazole, such as 2a, 2b, 2f, 2g, and 2h, exhibited enhanced antifungal activities against C. albicans and/or A. niger compared to fluconazole in SDB medium. For example, 2-cyanoethyl-omega-undecylenyl fluconazole phosphate (2b) with MIC value of 122 microg/mL had at least 36 times greater antifungal activity than fluconazole against C. albicans in SDB medium. Methyl-undecanyl fluconazole phosphate (2f) with a MIC value of 190 microg/mL was at least 3-fold more potent than fluconazole against A. niger ATCC 16404. All compounds had higher estimated lipophilicity and dermal permeability than those for fluconazole. These results demonstrate the potential of these antifungal agents for further development as sustained-release topical antifungal chemotherapeutic agents.

Antifungal Agents↗

PubMed2006

Pattern of Candida species isolated from patients with diabetes mellitus and vulvovaginal candidiasis and their response to single dose oral fluconazole therapy.

OBJECTIVE: Patients with diabetes mellitus are at increased risk of vulvovaginal candidiasis (VVC). Besides Candida albicans, they often have infection due to non-C. albicans Candida species such as C. glabrata. Oral single dose fluconazole (150 mg) is commonly used to treat VVC in non-diabetic individuals with response rate varying from 70 to 90%. However, there is paucity of related information in diabetic women with VVC. Present study has been conducted to systematically assess the effect of fluconazole therapy among diabetic patients with clinically symptomatic VVC. METHODS: Study subjects included 85 consecutive patients with diabetes mellitus (type 2=70 and type 1=15) and 62 non-diabetic women who had clinical signs and symptoms of VVC and in whom evidence of candidiasis was documented by presence of yeast on direct microscopy followed by culture. Single dose fluconazole (150 mg) was given orally to all the subjects in a supervised manner. Subjects were reassessed on 14th day after fluconazole therapy and a repeat high vaginal swab was taken for direct microscopy and fungal culture. Total glycosylated haemoglobin (HbA1) was measured to assess glycaemic control. RESULTS: There were no significant differences in the frequency of pruritus (55.9 vs. 56.7%), vaginal discharge (63.8 vs. 69.0%), dyspareunia (25.0 vs. 20.0%), and percentage yeast positivity (67.5 vs. 54.7%) between diabetic and control groups before the start of fluconazole therapy. Following fluconazole therapy, vaginal discharge on examination and yeast positivity on direct microscopy continued to remain positive in higher percentage of subjects in the diabetic group as compared to non-diabetic subjects (52.5 vs. 36.4%; P =0.22 and 50.7 and 29.0%, respectively, P =0.07, respectively). Overall 67.1% of patients with diabetes and 47.3% of controls continued to show persistence of Candida growth on high vaginal swab culture following fluconazole treatment (P=0.042). Candida glabtara was the most common species isolated in patients with diabetes mellitus and its frequency was significantly higher in them when compared to control group (54.1 vs. 22.6%, P<0.001). C. albicans was the most common species isolated in controls. Species-specific response to fluconazole showed that 81.3% of patients in the diabetic group and 78.6% of the non-diabetic controls continued to show fungal growth when C. glabrata was the organism grown (P=0.99). However, in case of C. albicans, 45.4% of the patients in the diabetic group and only 21.5% of the controls had persistent Candida growth following fluconazole therapy (P=0.22). CONCLUSION: Overall only one third of patients with diabetes mellitus and VVC respond to single dose 150 mg of fluconozole therapy. Limited response in the clinical symptoms and culture negativity following single dose fluconazole therapy in diabetic subjects with VVC is explained by the high prevalence of C. glabrata in them. The present study involved only 85 patients and majority of them had type-2 diabetes mellitus. There is need to perform similar study in large number of diabetics subjects including patients with type-1 diabetes mellitus and assess various alternative treatment protocol which are also effective in C. glabrata infection.

Administration, Oral↗

PubMed1999

Pharmacokinetics of fluconazole in skin and nails.

Two studies on the pharmacokinetics of fluconazole in skin and nails are reported here. In 1 study, 12 healthy volunteers received fluconazole 50 mg once daily for 12 days and 11 healthy volunteers received fluconazole 150 mg once weekly for 2 weeks. Fluconazole assays were performed on samples of serum, stratum corneum, dermis-epidermis, and eccrine sweat. In a second study, 36 patients with toenail onychomycosis received either fluconazole 150 mg once weekly or griseofulvin 1000 mg once daily for 12 months. Fluconazole assays were performed on nail clippings and serum samples from the patients receiving fluconazole. Tissue concentrations of fluconazole regularly exceeded plasma concentrations in these studies. In the skin study, the highest concentrations were achieved in stratum corneum, with accumulation occurring up to the end of dosing. Subjects who received 50 mg once daily had higher levels of fluconazole in stratum corneum, sweat, and epidermis-dermis than those subjects who received 150 mg once weekly. In the toenail study, fluconazole concentrations increased for the first 6 months, reaching levels much higher than serum concentrations (P < .001), with no significant difference between healthy and diseased nails.

Administration, Oral↗

PubMed2002

Prognostic factors for the clinical effectiveness of fluconazole in the treatment of oral candidiasis in HIV-1-infected individuals.

OBJECTIVE: To identify prognostic factors for the clinical effectiveness of fluconazole in HIV-1-infected patients with oropharyngeal candidiasis. DESIGN AND SETTING: The study was designed as a prospective, open label, non-comparative, dose escalating, single centre trial. PATIENTS AND METHODS: Thirty-four HIV-1-infected patients with oropharyngeal Candida infection were treated with 50 or 100mg fluconazoleday(-1), depending on the clinical manifestation (erythematous or pseudomembranous). The dose was doubled weekly until clinical cure. The predictive value of potential prognostic factors for the duration of treatment and cumulative fluconazole dose until cure was studied: exposure to fluconazole, previous use of fluconazole, the use of antiretroviral drugs, the CD4(+) cell count, erythematous or pseudomembranous appearance, the minimum inhibitory concentration (MIC) for fluconazole of the isolated Candida strain, and xerostomia. RESULTS: Twenty-eight patients (with 30 episodes of oropharyngeal candidiasis) were evaluated. Twenty-five episodes were cured within 1-week of treatment, the remaining five episodes were cured within 2 weeks. No predictive value for any of the studied factors on the duration of fluconazole treatment or the cumulative fluconazole dose until cure was demonstrated. CONCLUSION: Because of the high susceptibility to fluconazole and the positive clinical outcome, the variation in outcome measurements was too modest to establish a significant relationship between any of the investigated potentially prognostic factors and the cumulative fluconazole dose and the duration of treatment to reach cure. On the other hand it can be concluded, that fluconazole is very effective in patients with advanced HIV infection and low CD4(+) cell counts, even if they are not using antiretroviral agents.

AIDS-Related Opportunistic Infections↗

PubMed1996

Fluconazole distribution to the brain: a crossover study in freely-moving rats using in vivo microdialysis.

PURPOSE: The purpose of this study was to determine if the microdialysis sampling technique is feasible to study the central nervous system distributional kinetics of a novel triazole antifungal agent, fluconazole, in an awake, freely-moving rat model, and to determine fluconazole distribution to the extracellular fluid (ECF) of the brain. METHODS: The relative recovery of the microdialysis probes (CMA-12) was determined in vitro and in vivo by retrodialysis using UK-54,373, a fluorinated analog of fluconazole. Sprague-Dawley rats received 10 mg/kg and 20 mg/kg fluconazole IV bolus doses in a crossover design, and brain extracellular fluid fluconazole concentrations were monitored using microdialysis and on-line HPLC analysis. The plasma fluconazole concentration vs. time data were determined using sequential blood sampling and HPLC analysis. RESULTS: There was no statistical difference between relative probe recoveries for both fluconazole and UK-54,373, either in vitro or in vivo, and probe recoveries did not change during the course of the in vivo crossover experiment. Fluconazole rapidly distributes into in the brain ECF and the average brain distribution coefficient (brain/plasma AUC ratio) was 0.60 +/- 0.18 and was independent of dose. Plasma pharmacokinetic parameters were linear in the dose range studied. CONCLUSIONS: Fluconazole rapidly reaches a distributional equilibrium between brain extracellular fluid and plasma, and the distribution to the brain is substantial and not dependent on dose over a two-fold range. Furthermore, the results indicate that microdialysis utilizing UK-54,373 as the in vivo retrodialysis probe calibrator is a feasible method to study the transport of fluconazole into the central nervous system.

Animals↗

PubMed2000

Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group.

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but Fluconazole was significantly better tolerated.

Adult↗

PubMed2005

An evaluation of butoconazole nitrate 2% site release vaginal cream (Gynazole-1) compared to fluconazole 150 mg tablets (Diflucan) in the time to relief of symptoms in patients with vulvovaginal candidiasis.

BACKGROUND: It is estimated that as many as 13 million cases of vulvovaginal infection occur in the United States annually, the majority of which are the result of Candida albicans infection. The symptoms of vulvovaginal infections are often painful and distressing to the patient. The objective of this study was to compare the time to symptomatic relief of vulvovaginal candidiasis (VVC) with butoconazole nitrate 2% Site Release vaginal cream (Gynazole-1) and oral fluconazole 150 mg tablets (Diflucan). METHODS: This randomized, open-label, parallel study evaluated 181 female patients with moderate to severe symptoms of VVC. Patients were randomized to single-dose therapy with either butoconazole nitrate 2% Site Release vaginal cream or fluconazole. The primary outcome measure was the time to onset of first relief of symptoms. Secondary measures included the time to overall relief of symptoms and the reinfection rate over the first 30 days following treatment. The overall safety of both products was investigated through the collection of adverse event reports. RESULTS: The median time to first relief of symptoms occurred at 17.5 h for butoconazole patients as compared to 22.9 h for fluconazole patients (p < 0.001). The time at which 75% of patients experienced first relief of symptoms was 24.5 h versus 46.3 h for butoconazole and fluconazole, respectively (p < 0.001). By 12- and 24-h post-treatment, 44.4% and 72.8% of patients in the butoconazole treatment group reported first relief of symptoms versus 29.1% and 55.7% of patients in the fluconazole group (p = 0.044 and p = 0.024 respectively). In patients experiencing first relief of symptoms within 48 h of dosing, the median time to first relief of symptoms in the butoconazole treatment group was significantly shorter at 12.9 h compared to 20.7 h for the fluconazole treatment group (p = 0.048). There were no significant differences between the two groups with respect to time to total relief of symptoms or reoccurrence of infection within 30 days of treatment. Butoconazole therapy was shown to have fewer reported adverse events, including drug-related adverse events, than fluconazole therapy. Vulvovaginal pruritus and vulvovaginal burning were the most common drug-related adverse events attributed to butoconazole. Headache, diarrhea, nausea, upset stomach and skin sensitivity were the most common drug-related adverse events attributable to fluconazole. CONCLUSIONS: Single-dose butoconazole nitrate 2% Site Release vaginal cream provides statistically significant improvement in time to first relief of symptoms in the treatment of VVC compared to fluconazole. There is no difference between these two treatments with respect to total relief of symptoms or reinfection rate. Although there was no significant difference in the incidence of adverse events judged by the investigator to be treatment-related, butoconazole treatment did result in fewer patients experiencing adverse events than fluconazole.

Administration, Topical↗

PubMed1995

Synergy of fluconazole with human monocytes or monocyte-derived macrophages for killing of Candida species.

Possible synergy between fluconazole and monocyte-derived macrophages (MDM) for significant killing of Candida species and between fluconazole and monocytes for increased candidacidal activity were studied. Human serum in test medium (RPMI 1640 with 10% fresh autologous human serum) was highly fungistatic for Candida species. Fluconazole in test medium, even at high concentrations, was not fungicidal. Monocytes alone were fungicidal for all Candida species and synergized with fluconazole for increased killing of a fluconazole-sensitive and a fluconazole-resistant Candida albicans isolate. MDM obtained by culturing for 3 or 5 days were not significantly fungicidal for C. albicans but could synergize with fungistatic fluconazole for significant killing. MDM alone killed Candida krusei and Candida glabrata but did not synergize with fluconazole for significantly increased killing. These results, which demonstrate synergy of fluconazole and mononuclear phagocytes for killing, help explain the in vivo efficacy of fluconazole against candidiasis.

Antifungal Agents↗

PubMed2001

Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients.

OBJECTIVE: Whereas the antifungal azole ketoconazole interferes with steroidogenesis and can cause adrenal insufficiency, fluconazole in standard doses is thought to not interfere with cortisol production. The objective was to evaluate the effect of high-dose fluconazole therapy on adrenal function in critically ill patients in an intensive care setting. DESIGN: Descriptive case reports. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Two patients, a 77-yr-old man (case 1) with esophageal cancer and a 66-yr-old woman (case 2) with multiple organ failure developed reversible adrenal insufficiency temporally related to the institution and withdrawal of high-dose fluconazole. INTERVENTIONS: Short cosyntropin (adrenocorticotropic hormone; ACTH) stimulation tests. MEASUREMENTS AND MAIN RESULTS: Two days after high-dose fluconazole in case 1, the serum ACTH level was 121 pg/mL (normal range is 9-52 pg/mL), and the peak cortisol after ACTH stimulation was 15.5 microg/dL (normal response is >or=18 microg/dL). Eleven days after discontinuation of fluconazole, the peak cortisol level after ACTH stimulation was 43.4 microg/dL. Twenty-four hours after high-dose fluconazole in case 2, an ACTH stimulation test had a low peak serum cortisol of 16.8 microg/dL. Fluconazole was withdrawn, and 5 days later, the peak stimulated cortisol was 20.6 microg/dL. CONCLUSIONS: Although fluconazole is the therapy of choice for patients in the intensive care setting with Candida infections, two patients with multiple organ failure who received high-dose fluconazole appeared to develop adrenal insufficiency. Although preliminary and anecdotal, these data suggest a need to further investigate the possibility that high-dose fluconazole might cause adrenal insufficiency in already compromised critically ill patients.

Adrenal Insufficiency↗

PubMed1991

Interaction between cyclosporine and fluconazole in renal allograft recipients.

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.

Adolescent↗

PubMed2006

Comparison of itraconazole and fluconazole treatments in a murine model of coccidioidal meningitis.

Coccidioidal meningitis (CM) is a devastating disease that requires long-term therapy and for which there is little hope of a cure. A model was used to compare the efficacies of itraconazole and fluconazole. CD-1 mice were infected intrathecally with 30 to 36 viable arthroconidia of Coccidioides. Oral therapy with cyclodextrin (control) or itraconazole or fluconazole at 10, 25, or 50 mg/kg of body weight twice daily (BID) was given for 12 days, from day 3 of infection. Treatment with both antifungals at all doses prolonged survival compared with that of the control treatment (P < 0.01 to 0.0001). At 50 mg/kg, itraconazole and fluconazole were equivalent, whereas itraconazole at 10 or 25 mg/kg prolonged survival compared to that achieved with fluconazole at these dosages (P < 0.05 and 0.01, respectively). Early histologic analysis (10 days of treatment) with 50 mg/kg BID itraconazole or fluconazole showed suppression of CM in all five animals per group; in quantitative cultures, three of three animals from each group had no detectable infection in the brain, spinal cord, or a site of secondary infection, the lungs. In contrast, four of seven controls showed mild to severe meningitis, with arteritis detected in three animals. In a short-term organ clearance study, 5 days of treatment with 10 or 50 mg/kg BID itraconazole or fluconazole reduced the tissue burdens in the brain and spinal cord compared to the tissue burdens in the controls (P < 0.02 to 0.0003). Fluconazole at 10 mg/kg did not reduce the fungal burden in secondary sites, the lungs and kidneys, whereas this itraconazole dose was more effective in clearing the fungi from both organs (P < 0.05 and P < 0.001, respectively). At 50 mg/kg, itraconazole and fluconazole were equivalent in clearing the fungi from the brain and kidney, but itraconazole was superior to fluconazole in clearing the fungi from the spinal cord and lungs (P < 0.05). Thus, both itraconazole and fluconazole were effective at controlling CM, but neither eliminated Coccidioides from tissues. Overall, itraconazole was more efficacious on an mg/kg basis; at high doses they were similarly effective.

Animals↗

PubMed1991

Comparison of fluconazole and amphotericin B for prevention and treatment of experimental Candida endocarditis.

Fluconazole and amphotericin B were compared in the prophylaxis and treatment of Candida albicans aortic endocarditis in a rabbit model. In the prophylaxis study, catheterized rabbits received, prior to intravenous (i.v.) challenge with C. albicans (2 x 10(7) blastospores), either no therapy, single-dose i.v. amphotericin B (1 mg/kg of body weight), single-dose fluconazole (50 mg/kg or 100 mg/kg i.v. or intraperitoneally [i.p.]), or fluconazole (50 mg/kg or 100 mg/kg i.v. or i.p.) with a second dose 24 h after inoculation. A single dose of amphotericin B was significantly more effective than either the one- or two-dose regimens of fluconazole at both 50 mg/kg (P less than 0.001 and P less than 0.03, respectively) and 100 mg/kg (P less than 0.01 and P less than 0.001, respectively) in the prevention of C. albicans endocarditis. In parallel treatment studies of established C. albicans endocarditis, i.v. amphotericin B (1 mg/kg) or i.p. fluconazole (50 mg/kg) was begun 24 or 60 h postinfection and continued daily for 9 or 12 days. At these dose regimens, amphotericin B was consistently more effective than fluconazole in reducing fungal vegetation densities, regardless of the timing of initiation of therapy. We also examined the efficacy of fluconazole at a daily dose of 100 mg/kg i.p. administered for 21 days in the treatment of established C. albicans endocarditis. When therapy was continued for 2 weeks or longer, fluconazole was more effective than no drug and approximately twice as effective as 12 days of amphotericin B in reducing intravegetation fungal densities. Our results suggest that amphotericin B is superior to fluconazole in both the prophylaxis and treatment of C. albicans endocarditis in the rabbit model. These findings may relate to the predominantly fungistatic activity of fluconazole against C. albicans in vitro.

Amphotericin B↗

PubMed1997

Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro.

Cryptococcus neoformans infections in patients with AIDS are often incurable, despite aggressive antifungal therapy. Combination regimens with additive or synergistic drugs could provide additional options for treating cryptococcal meningitis. We evaluated the efficacy of combination therapies using L-743,872, a pneumocandin antifungal drug, and amphotericin B or fluconazole against 18 strains of C. neoformans, including 11 C. neoformans var. neoformans, 3 C. neoformans var. gattii, and 4 fluconazole-resistant isolates. The combination of subinhibitory concentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C. neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Clinical and Laboratory Standards method), quantitative CFU, and tetrazolium salt reduction assays. Similarly, the addition of subinhibitory concentrations of L-743,872 to fluconazole enhanced fluconazole activity, but the effect was less dramatic than for the pneumocandin-amphotericin B combination. A marked synergism was observed in all combinations of amphotericin B and L-743, 872 (fractional inhibitory concentration index [FIC] of < or = 0.5). Fluconazole-resistant strains showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates. Combinations of pneumocandin with fluconazole revealed different activities for the various strains, including synergism (FIC < 1.0), additivity (FIC = 1.0), and autonomy (FIC between 1.0 and 2.0). Combination studies with fluconazole and L-743,872 showed additive and autonomous activities against fluconazole-resistant isolates. No antagonistic interactions (FIC < 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole. The results of this study suggest that L-743,872 can enhance the efficacy of fluconazole or amphotericin B in vitro and indicate a potential role for L-743,872 in combination therapy against C. neoformans.

Amphotericin B↗

PubMed1997

Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro.

Candida dubliniensis is a recently described species of Candida associated with oral candidiasis in human immunodeficiency virus (HIV)-infected individuals. Nineteen oral isolates of C. dubliniensis recovered from 10 HIV-positive and 4 HIV-negative individuals and one vaginal isolate from an additional HIV-negative subject were assessed for fluconazole susceptibility by broth microdilution (BMD), hyphal elongation assessment, and Etest. The susceptibilities of these 20 isolates to itraconazole and amphotericin B and of 10 isolates to ketoconazole were also determined by BMD only. Sixteen of the C. dubliniensis isolates were susceptible to fluconazole (MIC range, 0.125 to 1.0 microgram ml-1), and four (recovered from two AIDS patients) were fluconazole resistant (MIC range, 8 to 32 micrograms ml-1). Fluconazole susceptibility data obtained by hyphal elongation assessment correlated well with results obtained by BMD, but the corresponding Etest MIC results were one to four times higher. All of the isolates tested were found to be sensitive to itraconazole, ketoconazole, and amphotericin B. Sequential exposure of two fluconazole-sensitive (MIC, 0.5 microgram ml-1) C. dubliniensis isolates to increasing concentrations of fluconazole in agar medium resulted in the recovery of derivatives which expressed a stable fluconazole-resistant phenotype (BMD-determined MIC range, 16 to 64 micrograms ml-1), even after a minimum of 10 consecutive subcultures on drug-free medium and following prolonged storage at -70 degrees C. The clonal relationship between the parental isolates and their respective fluconazole-resistant derivatives was confirmed by genomic DNA fingerprinting and karyotype analysis. The results of this study demonstrate that C. dubliniensis is inherently susceptible to commonly used antifungal drugs, that fluconazole resistance does occur in clinical isolates, and that stable fluconazole resistance can be readily induced in vitro following exposure to the drug.

Antifungal Agents↗

PubMed2000

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

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.

Animals↗

PubMed2000

Correlation of fluconazole MICs with clinical outcome in cryptococcal infection.

We have correlated the in vitro results of testing the susceptibility of Cryptococcus neoformans to fluconazole with the clinical outcome after fluconazole maintenance therapy in patients with AIDS-associated cryptococcal disease. A total of 28 isolates of C. neoformans from 25 patients (24 AIDS patients) were tested. The MICs were determined by the broth microdilution technique by following the modified guidelines described in National Committee for Clinical Standards (NCCLS) document M27-A, e.g., use of yeast nitrogen base medium and a final inoculum of 10(4) CFU/ml. The fluconazole MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90), obtained spectrophotometrically after 48 h of incubation, were 4 and 16 microg/ml, respectively. Of the 25 patients studied, 4 died of active cryptococcal disease and 2 died of other causes. Therapeutic failure was observed in five patients who were infected with isolates for which fluconazole MICs were > or =16 microg/ml. Four of these patients had previously had oropharyngeal candidiasis (OPC); three had previously had episodes of cryptococcal infection, and all five treatment failure patients had high cryptococcal antigen titers in either serum or cerebrospinal fluid (titers, >1:4,000). Although 14 of the 18 patients who responded to fluconazole therapy had previously had OPC infections, they each had only a single episode of cryptococcal infection. It appears that the clinical outcome after fluconazole maintenance therapy may be better when the infecting C. neoformans strain is inhibited by lower concentrations of fluconazole for eradication (MICs, <16 microg/ml) than when the patients are infected with strains that require higher fluconazole concentrations (MICs, > or =16 microg/ml). These findings also suggest that the MICs determined by the modified NCCLS microdilution method can be potential predictors of the clinical response to fluconazole therapy and may aid in the identification of patients who will not respond to fluconazole therapy.

AIDS-Related Opportunistic Infections↗