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PubMed1995

Different components in human serum inhibit multiplication of Cryptococcus neoformans and enhance fluconazole activity.

The inhibitory effect of human serum on the multiplication of Cryptococcus neoformans and the interaction with fluconazole were studied. Compared with cryptococcal multiplication in RPMI 1640 medium alone, 5% human serum in medium inhibited multiplication by 76% +/- 6% (n = 8). The inhibitory effect of human serum was donor independent, [corrected] heat stable (56 degrees C, 30 min), and not due to albumin or globulin. Bovine and murine sera were not inhibitory at that concentration. A fungistatic concentration of fluconazole (5.0 micrograms/ml) in medium plus 5% human serum resulted in 40% +/- 5% (n = 8) killing (reduction of inoculum CFU) in a 24-h assay. Bovine or murine sera did not have the enhancing effect, and this human serum activity was heat stable and donor independent. At 2.5 micrograms of fluconazole per ml, fungistasis by fluconazole plus human serum was significantly greater than with either alone. Higher serum concentrations [corrected] potentiated fluconazole more. At higher fluconazole concentrations (e.g., 20 micrograms/ml) fluconazole alone could kill, but serum potentiated this. A fluconazole-resistant isolate (MIC, 100 micrograms/ml) was not killed by fluconazole (5.0 micrograms/ml) in 5% human serum, but human serum potentiated the partial fluconazole inhibition. When human serum was dialyzed (molecular weight cutoff, 6,000 to 8,000) against phosphate-buffered saline, it lost the ability to synergize with fluconazole for killing Cryptococcus organisms but not the capacity to inhibit multiplication. Filtration of serum suggested the filtrate with a molecular weight of < 10,000 could interact synergistically with fluconazole for killing but could not inhibit cryptococcal multiplication. These findings indicate that human serum has two components, one (macromolecular) with a unique ability to inhibit C. neoformans and a low-molecular-weight component that enhances fluconazole anticryptococcal activity.

Animals↗

PubMed1998

Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients.

To evaluate a potential pharmacokinetic interaction of coadministration of fluconazole, and indinavir, a human immunodeficiency virus (HIV) protease inhibitor, 13 patients were enrolled in a multiple-dose, three-period, placebo-controlled, crossover study. Patients were randomly assigned to receive indinavir at 1,000 mg every 8 h for 7 1/3 days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The pharmacokinetics of both drugs were measured on day 8 of each treatment period. The peak concentration in plasma (Cmax) and the time to reach Cmax were obtained by inspection, and the area under curve (AUC) was calculated for indinavir and fluconazole for each treatment period in which the respective drugs were administered. There was a marginally (P = 0.08) statistically significant decrease in the AUC from 0 to 8 h (AUC(0-8)) for indinavir when it was administered with fluconazole. However, the magnitudes of the decreases in Cmax and the concentration at 8 h postdosing (C8) were not as great as the decrease in AUC(0-8). Although the 90% confidence interval for the geometric mean ratio was within the hypothesized limits, the clinical significance is not clear. Indinavir coadministration with fluconazole had no statistically (P > 0.5) or clinically significant effect on the Cmax and C8 of indinavir. Fluconazole coadministration with indinavir had no statistically or clinically significant effect on the pharmacokinetics of fluconazole. One patient was discontinued because of mild to moderate abdominal pain and diarrhea while on indinavir and fluconazole in combination. No serious adverse experience according to the results of laboratory tests was noted. Total bilirubin levels in serum were mildly increased in most patients treated with indinavir. This was not clinically significant and was not affected by the coadministration of fluconazole. Although the values of the pharmacokinetic parameters for indinavir decrease in the presence of fluconazole, indinavir and fluconazole can be administered concomitantly to HIV-infected patients without adjustment of the dose of either drug, and both drugs are generally well tolerated.

Adolescent↗

PubMed2001

Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant.

BACKGROUND: Candidal infections are an important cause of morbidity and mortality in the very low birth weight (VLBW) infant. Current intervention focuses on treatment once candidal septicemia is either suspected or diagnosed. Studies have suggested that colonization with candidal species is an important risk factor for subsequent infection. OBJECTIVE: To determine whether prophylactic fluconazole for the first 28 days of life results in a decreased incidence of candidal colonization in the VLBW infant. RESEARCH DESIGN: Prospective, randomized, controlled, intention-to-treat design comparing prophylaxis with fluconazole versus placebo for the first 28 days of life. SETTING: A tertiary level intensive care nursery in a major teaching hospital in Charleston, South Carolina. PATIENTS: One hundred three infants with a birth weight of <1500 g, either inborn or outborn, who were admitted to the intensive care nursery between January 1998 and February 1999. METHODS: Infants were enrolled within 72 hours of life with rectal cultures performed on the day of randomization (DOR), as well as day of life (DOL) 7, 14, and 28. Those infants with a birth weight of <1250 g had additional cultures on DOL 35, 49, and 56. Cultures were plated on selective media for isolation of candidal organisms. Infants were randomized to receive either fluconazole (6 mg/kg) or placebo on the DOR. Subsequent doses were given every 72 hours until DOL 7 and then every 24 hours until DOL 28. Medication was given either intravenously or by feeding tube once the infant had been gavage feeding for a 48-hour period without feeding intolerance. Aspartate aminotransferase and alanine aminotransferase levels were obtained on DOR and DOL 7, 14, and 28 to assess for fluconazole toxicity. The minimal inhibitory concentration to fluconazole was determined for all positive cultures to assess the development of resistance. RESULTS: The infants who received fluconazole (n = 53) and placebo (n = 50) had no statistical difference in the major risk factors known to increase the chances of candidal septicemia in the VLBW infant. Rectal colonization by candidal species was detected in 8 of the 53 fluconazole-treated patients (15.1%) and in 23 of the 50 infants treated with placebo (46%). Fluconazole significantly reduced rectal colonization from DOL 14 through DOL 56 in all infants with a birth weight of <1250 g, and from DOL 14 through DOL 56 in all infants with a birth weight of 1250 to 1500 g. Alanine aminotransferase levels were higher in the fluconazole versus the placebo-treated group on DOL 14 (18.1 IU/L vs 15 IU/L), but no clinically significant abnormalities were observed. Candida albicans was the most common species isolated. There was no increase in species of Candida noted for their intrinsic resistance to fluconazole, and there was no statistically significant difference in the minimal inhibitory concentrations to fluconazole for all C albicans isolates in either group at any period. CONCLUSION: Prophylactic administration of fluconazole to the VLBW infant for the first 28 days of life is safe and results in a decreased risk of rectal colonization by candidal species. Larger studies to determine the effect of prophylaxis on candidal septicemia and development of resistance in such a selective high-risk group are warranted before initiation of routine prophylaxis.fluconazole, very low birth weight infant, prophylaxis, candidal sepsis, sensitivities to fluconazole.

Antifungal Agents↗

PubMed1993

Fluconazole prophylaxis of fungal infections in patients with acute leukemia. Results of a randomized placebo-controlled, double-blind, multicenter trial.

OBJECTIVE: To evaluate the efficacy and safety of fluconazole for prevention of fungal infections. DESIGN: A randomized, placebo-controlled, double-blind, multicenter trial. PATIENTS: Adults (257) undergoing chemotherapy for acute leukemia. INTERVENTION: Patients were randomly assigned to receive either fluconazole (400 mg orally once daily or 200 mg intravenously every 12 hours) or placebo. The study drug was started at initiation of chemotherapy and continued until recovery of neutrophil count, development of proven or suspected invasive fungal infection, or the occurrence of a drug-related toxicity. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, empiric antifungal therapy with amphotericin B, drug-related side effects, and mortality. MAIN RESULTS: Fluconazole decreased fungal colonization (83 of 122 [68%] placebo patients compared with 34 of 119 [29%] fluconazole patients colonized at end of prophylaxis, P < 0.001) and proven fungal infections (27 of 132 [21%] placebo patients compared with 11 of 123 [9%] fluconazole patients infected, P = 0.02). Superficial fungal infections occurred in 20 of 132 (15%) placebo patients but in only 7 of 123 (6%) fluconazole patients (P = 0.01), whereas invasive fungal infections developed in 10 of 132 (8%) placebo patients and in 5 of 123 (4%) fluconazole patients (P = 0.3). Fluconazole was especially effective in eliminating colonization and infection by Candida species other than Candida krusei (66 of 122 [64%] placebo patients colonized at end of prophylaxis compared with 11 of 119 [9%] fluconazole patients, P < 0.001; 22 of 132 [17%] placebo patients infected compared with 7 of 123 [6%] fluconazole patients, P = 0.005). Aspergillus infections were infrequent in both fluconazole (3 cases) and placebo groups (3 cases). The use of amphotericin B, the incidence of drug-related side effects, and overall mortality were similar in both study groups. CONCLUSION: Prophylactic fluconazole prevents colonization and superficial infections by Candida species other than Candida krusei in patients undergoing chemotherapy for acute leukemia and is well tolerated. Fluconazole could not be clearly shown to be effective for preventing invasive fungal infections, reducing the use of amphotericin B, or decreasing the number of deaths.

Acute Disease↗

PubMed2001

Decrease in Candida albicans strains with reduced susceptibility to fluconazole following changes in prescribing policies.

This study was undertaken to identify prescribing policies likely to favour or limit fluconazole resistance within a clinical department. Fluconazole exposure within the infectious diseases and clinical haematology units was investigated, and data were compared with in vitro susceptibility of Candida albicans isolates obtained in these units. Fluconazole utilization was determined by the number of fluconazole treatment-days per 100 hospitalization days (penetration index). In the infectious diseases unit, separate evaluations for low-dose fluconazole (50 mg) prescribed as intermittent or prolonged treatment, and for higher-dosing schedules (fluconazole 200 mg) were made. Susceptibility of C. albicans isolates was surveyed in a broth microdilution assay by measuring the inhibitory concentration 50% (IC50). The penetration index (PI) for fluconazole 50mg declined from 1992 to 1977 in infectious diseases (P= 0.0048). In the meantime, total usage of fluconazole increased, due to increased prescribing of fluconazole 200 mg (P = 0.0724). The IC50 of C. albicans isolates tested in infectious diseases decreased between 1994 and 1996 from 7.33 mg/ml to 1.64 mg/ml (P = 0.0075). In clinical haematology, declines in C. albicans IC50 and fluconazole PI were not significant (P = 0.35 and P = 0.07, respectively). These data suggest that prolonged or repeated exposure to low-dose fluconazole, rather than total cumulative use, was associated with fluconazole resistance in the infectious diseases unit. Moreover, restoration of a normal ecology was observed when low-dose prolonged or intermittent prescriptions were reduced.

Analysis of Variance↗

PubMed1995

Emergence of azole drug resistance in Candida species from HIV-infected patients receiving prolonged fluconazole therapy for oral candidosis.

We examined the effect of different fluconazole treatment regimens on the emergence of azole drug resistance among Candida species recovered from the mouths of 54 HIV-infected individuals. Patients were assigned to one of three treatment groups depending on their history of oral candidosis and fluconazole use. Mouthwashes obtained at regular intervals were cultured and isolates identified using standard methods. Antifungal broth micro-dilution tests were performed to determine IC30s of fluconazole and ketoconazole. Sixty-four Candida albicans isolates from 20 patients with no evidence of oral candidosis who had not received fluconazole all had IC30s of < or = 4 mg/L. Thirty-four (83%) of 41 C. albicans isolates from ten patients receiving intermittent, short-term fluconazole treatment for oral candidosis had IC30s of < or = 4 mg/L, but only two isolates (5%) had IC30s > or = 64 mg/L. In contrast, 26 (40%) of 65 C. albicans isolates from 15 patients given long-term fluconazole (50-200 mg/day or 150 mg/week) were classified as resistant having IC30s of fluconazole of > or = 64 mg/L. Ten of these 26 fluconazole-resistant isolates were susceptible to ketoconazole with IC30s of < or = 4 mg/L suggesting azole drug cross-resistance is not inevitable. Tests on multiple colonies from individual isolation plates showed that it was not unusual to obtain differing IC30 values, indicating that a sweep inoculum is essential if resistance is to be detected. Nine (60%) of the 15 patients given long-term fluconazole harboured isolates of C. albicans that were resistant to fluconazole at some time during the study period. All had low CD4 counts and were approaching the final stage of their illness. Three patients on long-term treatment had resistant organisms at the outset of the study; in the remainder, resistant strains emerged during the study period. In six of the nine cases, emergence of resistance in vitro correlated with persistent clinical signs of oral infection. Thirty-six isolates of Candida species other than C. albicans were also recovered from patients receiving long-term fluconazole and 29 (81%) of these had IC30s of > or = 64 mg/L. Our experience with C. albicans in patients with HIV infection, suggests that the long-term azole drug use may be an important factor in the development of fluconazole resistance as such resistance was rare and transient in patients on intermittent short-term treatment.

Antifungal Agents↗

PubMed1996

Variation in fluconazole efficacy for Candida albicans strains sequentially isolated from oral cavities of patients with AIDS in an experimental murine candidiasis model.

Four strains of Candida albicans, isolated from two patients with AIDS who had undergone prolonged fluconazole therapy for oral candidiasis, were studied in a model of disseminated murine candidiasis. Pre- and posttreatment isolates from each patient were genetically related, and the fluconazole MICs for the strains had increased significantly, from 0.25 to 32 micrograms/ml for the strains isolated from patient 1 and from 1.0 to 16 micrograms/ml for the strains isolated from patient 2. Mice were infected intravenously and were treated orally with fluconazole. For survival studies, mice were treated from day 1 to day 10 postinfection and were observed through day 30. The fluconazole dosages were as follows: 0.25, 0.5, 1.0, and 5.0 mg/kg of body weight twice a day. For tissue burden studies, two groups of mice (each group received fluconazole at 0.25 or 5.0 mg/kg) were treated from day 1 to day 7 and were sacrificed 1 day later for quantitative tissue cultures of the spleen and both kidneys. For pretreatment isolates from both patients, all fluconazole dosing regimens were effective at prolonging survival compared with the survival of the control groups. For posttreatment isolates, only fluconazole at 5.0 mg/kg was effective at prolonging survival. Both fluconazole dosing regimens used in the tissue burden studies significantly reduced the counts of the pretreatment isolate from patient 1 in the spleen and kidney, while fluconazole at 5.0 mg/kg was effective at reducing the counts of the posttreatment isolate. For both isolates from patient 2, only fluconazole at 5.0 mg/kg was effective at reducing the counts in the spleen and kidney. The study indicates that C. albicans mutation to resistance to fluconazole may play a critical role in fluconazole-refractory oral candidiasis in AIDS patients.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species.

In light of the need for new antifungal regimens, we report that at noncandidacidal concentrations, the lactoferrin-derived peptide hLF(1-11), which is highly active against fluconazole-resistant Candida albicans, acts synergistically with fluconazole against this yeast and a fluconazole-sensitive C. albicans strain as well as C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. When these yeasts were exposed to hLF(1-11) for 5 min and then incubated with fluconazole, they were killed effectively, while no candidacidal activity was observed when they were incubated first with fluconazole and then exposed to the peptide, indicating that the candidacidal activity is initiated by the peptide while fluconazole is only required during the effector phase. Investigations of the effect of azide, which inhibits mitochondrial respiration, on the activity of combinations of hLF(1-11) and fluconazole against fluconazole-resistant C. albicans revealed that it inhibits this activity, even when added during the effector phase only. As expected, azide inhibited the accumulation of rhodamine 123 in mitochondria and the production and release of ATP by C. albicans that occurred upon exposure to the combination of hLF(1-11) and fluconazole. Accordingly, oxidized ATP (oATP), an antagonist of ATP receptors, completely blocked the candidacidal activity of the hLF(1-11)-fluconazole combination, whereas oATP did not block the activity when its presence was restricted to the effector phase. The candidacidal activity of combinations of hLF(1-11) and fluconazole, which is initiated by the peptide through the involvement of energized mitochondria, renders fluconazole-resistant C. albicans sensitive to this azole.

Candida↗

PubMed2003

Efficacy of CS-758, a novel triazole, against experimental fluconazole-resistant oropharyngeal candidiasis in mice.

The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study. CS-758 exhibited potent in vitro activity (MICs, 0.004 to 0.06 micro g/ml) against the strains used in this murine model including fluconazole-susceptible dose-dependent and fluconazole-resistant strains (fluconazole MICs, 16 to 64 micro g/ml). CS-758 exhibited excellent efficacy against the infections induced by all the strains including a fluconazole-resistant strain, and the reductions in viable cell counts were significant at 10 and 50 mg/kg of body weight/dose. Fluconazole was not effective even at 50 mg/kg/dose against infections induced by a fluconazole-resistant strain (fluconazole MIC, 64 micro g/ml). These results suggest that CS-758 is a promising compound for the treatment of oropharyngeal candidiasis including fluconazole-refractory infections.

Animals↗

PubMed1995

Rifampin-fluconazole interaction in critically ill patients.

OBJECTIVE: To report the influence of rifampin coadministration on the pharmacokinetics of fluconazole in 2 critically ill patients. CASE SUMMARIES: The pharmacokinetics of fluconazole are reported in 5 patients in the intensive care unit (ICU), 2 of whom received rifampin and 3 who received only fluconazole. Patient 1 was a 52 year-old man with bilateral pneumonia who received rifampin for 9 days in addition to other antibiotics when fluconazole was added for suspected fungal superinfection. Patient 2, a 39-year-old man with steroid-dependent asthma was admitted to the ICU with a right middle lobe pneumonia and ventilatory insufficiency. Because of rapid clinical deterioration, intravenous rifampin 600 mg q12h and fluconazole 100 mg q24h were added to conventional antibacterial therapy. Patients 3-5 received intravenous fluconazole therapy, but were never administered rifampin prior to their antifungal therapy. DISCUSSION: Fluconazole has gained wide use as an antifungal agent because of its efficacy, limited toxicity, and the paucity of reported drug interactions. In some clinical situations, however, the drug must be coadministered with rifampin. Limited data in healthy volunteers suggest that the coadministration of rifampin and fluconazole results in a 23% reduction in the fluconazole area under the concentration-time curve (AUC). In this report, we found a statistically significant lowering of the AUC (52%) and a 93% higher total body clearance of fluconazole in patients treated with rifampin. CONCLUSIONS: Although limited data are available describing the magnitude of the interaction between fluconazole and rifampin in patients, our data suggest a more significant interaction than previously reported. If the concurrent administration of the 2 drugs in unavoidable, the patient's clinical response to treatment should be monitored closely, as the unexpectedly large reduction in fluconazole serum concentrations may lead to poor treatment outcomes.

Adult↗

PubMed1990

Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.

Fluconazole is a bis-triazole antifungal drug with novel pharmacokinetic properties (metabolic stability, relatively high water solubility) which contribute to its therapeutic activity. Clinical experience is limited to a relatively small number of mycoses and, as might be expected at this early stage of development, optimal dosage and duration of treatment for some serious mycoses is not yet established. Further study to evaluate higher dosages and to establish the efficacy of fluconazole relative to more established antifungal agents is required. In patients with oropharyngeal or oesophageal candidiasis, fluconazole produces rapid relief and eradicates the yeast in 50 to 90% of patients. Relapse of oral infection is common in chronically immunocompromised patients regardless of the antifungal used, and adequate primary therapy plus long term prophylaxis appears necessary in patients with AIDS. A single oral dose of fluconazole was comparable to standard topical azole therapy in women with acute vaginal candidiasis. Preliminary reports of success against deep-seated candidiasis are encouraging; moreover, experience in noncomparative clinical trials suggests that fluconazole 200 to 400mg once daily resolves infection in the majority of seriously ill patients. Clinical improvement has been reported in a few cases of pulmonary Aspergillus infection but the overall efficacy of conventional dosages of fluconazole in this mycosis has not been as impressive. Early experience in coccidioidosis, predominantly meningitis, suggests a beneficial clinical effect with oral fluconazole in this difficult to treat mycosis but relapse remains a problem. Fluconazole is a promising treatment of cryptococcal meningitis. The rate of clinical resolution and eradication of Cryptococcus neoformans from cerebrospinal fluid has been similar between fluconazole and amphotericin B treatment groups in comparative trials. Comparative trials of maintenance therapy indicate a similar low rate of relapse among patients given oral fluconazole once daily and intravenous amphotericin B once weekly. However, these results are preliminary and further study is required. Fluconazole has been well tolerated to date but wider clinical experience is needed, especially with regard to the rate occurrence of hepatotoxicity and exfoliative skin reactions. The promising clinical response of patients with various forms of candidiasis or cryptococcosis--together with convenient administration regimens--recommends fluconazole as a useful addition to currently available systemic antifungal therapies, in particular for the treatment of mycoses in patients with AIDS.

Animals↗

PubMed1999

The uptake of fluconazole in finger and toe nails.

OBJECTIVE: The uptake of the antimycotic agent fluconazole in finger and toe nail following various treatment schedules was investigated in order to characterize the pharmacokinetic basis for the systemic treatment of onychomycosis with fluconazole. SUBJECTS: Between 8 and 12 healthy, male and female Caucasian subjects were included in four separate studies. Mean age of the subjects in the single studies ranged between 34 years (study 4, group 2; n = 4 male and 4 female) and 38 years (study 4, group 1; n = 4 male and 4 female). METHODS: Fluconazole was administered orally over 4 weeks in all studies. The treatment schedules were 150 mg once weekly (study 1), 300 mg once weekly (study 2), 50 mg once daily (study 3) and 150 or 300 mg once weekly in a parallel group study (study 4). At fixed times samples of blood, nail cuttings and nail dust were taken, up to two months after end of treatment. Fluconazole was analyzed in blood plasma and in the nail samples using a highly specific and sensitive gas chromatographic procedure. RESULTS: High concentrations of fluconazole were found in distal nail clippings with all three treatments. Mean maximum concentrations which occurred in the third or fourth week of treatment amounted to 2.1 microg/g (150 mg/w), 5.4 microg/g (300 mg/w) and 6.5 microg/g (50 mg/d) in finger nails and to 9.6 microg/g (150 mg/w), 12.3 microg/g (300 mg/w) and 12.2 microg/g (50 mg/d) in toe nails. The nail concentrations were 1-2 times (finger) and 2-3 times (toe) higher than the corresponding fluconazole plasma levels and were within the MIC range for dermatophytes and yeasts occurring commonly in onychomycosis. The residence times of fluconazole in the nail plate after the end of treatment was long, with approximate half-lives of 33 days in finger nail and 30 days in toe nail. In pharmacokinetic terms there was no evidence of advantages of the daily dosage (50 mg) over the once-weekly (300 mg) dosage. Fluconazole was found to penetrate into both finger and toe nails at a very fast rate. On the first two days of the 150 mg/w and 300 mg/w treatments, i.e. after the first dosage, fluconazole concentrations in the distal nail plates amounted to 50-80% of the later observed peak levels. The initial concentrations in the upper dorsal plate were particularly high, with mean peak concentrations of 11.9 microg/g (150 mg) and 33.7 microg/g (300 mg) in finger nails and 5.7 microg/g (150 mg) and 24.4 microg/g (300 mg) in toe nails. CONCLUSIONS: Fluconazole is rapidly and highly distributed into finger and foot nail, reaching there higher concentrations than in the plasma. The rapid initial uptake of fluconazole in nail, which is unlike the uptake of other antifungal agents, suggests the existence of special routes of access to the nail for fluconazole, possibly based on high diffusion rates.

Adolescent↗

PubMed1991

Fluconazole: a new antifungal agent.

The chemistry, activity, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and administration of fluconazole are reviewed. Fluconazole is a triazole antifungal agent labeled for use in the treatment of oropharyngeal and esophageal candidiasis and cryptococcal meningitis. Like the imidazoles, fluconazole inhibits the C-14 demethylation of lanosterol, but it has little or no effect on mammalian cytochrome P-450 enzymes. Fluconazole's activity in vitro does not reflect its effectiveness in vivo. Pharmacokinetic characteristics include water solubility and excellent bioavailability, low protein binding, extensive tissue distribution, and penetration into the cerebrospinal fluid. Fluconazole is eliminated primarily by the kidneys; dosage adjustments are necessary in patients with renal insufficiency. Studies have shown fluconazole to be effective in patients with cryptococcal meningitis and candidiasis, but the superiority of fluconazole over such agents as amphotericin B, ketoconazole, clotrimazole, and itraconazole remains to be proved. Fluconazole has shown varying degrees of success in the treatment of other systemic mycoses. The adverse effects of fluconazole are relatively infrequent and are primarily gastrointestinal. Tolbutamide, warfarin, rifampin, cyclosporine, and phenytoin interact with fluconazole. The drug is available in both oral and intravenous formulations. Fluconazole is a broad-spectrum antifungal drug that appears to be similar in efficacy to other antifungals in the treatment of some systemic mycoses. More studies must be completed before fluconazole can be recommended as a first-line antifungal therapy.

Animals↗

PubMed1989

[In vitro activity of fluconazole, a novel bistriazole antifungal agent].

Fluconazole is a novel triazole antifungal agent with excellent activities against a broad range of medically important fungi. The in vitro antifungal activities of fluconazole especially against Candida albicans were examined and the results summarized as follows: 1. Fluconazole was proved to exhibit the highest antifungal activity in synthetic amino-acid medium, fungal (SAAMF), well buffered in a physiologically neutral range. 2. In a exposed time-killing test performed using SAAMF (pH 7.4), the growth inhibition by fluconazole was enhanced in proportion to an increase of fluconazole concentration and 99% inhibition was observed at a concentration of 1 microgram/ml though further increases of concentration up to 80 micrograms/ml failed to demonstrate complete inhibition. 3. Activities of fluconazole against medically important various yeasts were determined by a broth dilution method in SAAMF using the viable counts technique. Among 9 species tested, C. albicans and Candida kefyr were the most sensitive to fluconazole with a IC99 range from 0.20 microgram/ml to 0.39 microgram/ml. On the contrary, Candida glabrata, Cryptococcus neoformans and Trichosporon cutaneum were the least sensitive with a IC99 range from 3.13 micrograms/ml to 12.5 micrograms/ml. 4. Growth inhibition activities of fluconazole against 4 species of Aspergillus were measured on the basis of mycelial protein content. IC50 and IC90 of fluconazole against Aspergillus fumigatus were distributed in the range of 23.9-43.5 micrograms/ml and 50- greater than 100 micrograms/ml, respectively. 5. The anti-Candida activity of fluconazole was little affected by serum concentrations. Fluconazole at a concentration of 0.20 microgram/ml inhibited significantly the mycelial-phase growth and germ tube elongation of C. albicans in a medium supplemented with serum. 6. The germ tube formation and elongation of C. albicans cells engulfed by murine peritoneal exudative cells were significantly affected in a medium containing 1 microgram fluconazole per ml.

Animals↗

PubMed1996

Asymptomatic oral yeast carriage in HIV-infected patients: frequency and fluconazole susceptibility profile.

OBJECTIVES: Fluconazole-resistant oropharyngeal candidiasis (OPC) is a rapidly growing problem in HIV-infected patients. To better understand the pathogenesis of fluconazole resistance in this setting, asymptomatic candidal carriage was determined by means of oral swabs regularly performed in all patients without clinical signs of OPC seen at our HIV outpatient clinic. Controls were 204 asymptomatic healthcare workers without previous exposure to fluconazole. METHODS: Swabs were plated on three solid media and put in a Sabouraud broth. Phenotypically different colonies were identified to the species level. Susceptibility to fluconazole was determined using a disk diffusion test with 50 microg fluconazole disks on yeast nitrogen agar, with a cut-off value of 25 mm. RESULTS: Swabs were performed in 538 consecutive HIV-positive patients, of whom 216 (40%) had had prior episode(s) of OPC and/or were previously exposed to fluconazole. Yeasts were grown in 418/538 HIV-positive patients (78%), compared to 57/204 controls (28%) (p < 0.05). In HIV-positive patients, yeasts were grown in 189/216 (88%) of those with past fluconazole exposure, and in 229/322 (71%) without exposure (p < 0.05). A total of 589 isolates were grown in the 538 HIV-positive patients (451 C. albicans, 88 C. glabrata, 22 C. tropicalis, 11 C. krusei, and 17 isolates from 12 other species). Resistance to fluconazole was present in 121/589 (21%) Candida species isolates in HIV-positive patients and in 2/59 (3%) in controls. Among C. albicans isolates, there were 18 fluconazole-resistant strains in HIV-positive patients (4%) and none in controls.CONCLUSIONS: Using sensitive culture methods, oral yeast colonization was detected significantly more frequently in HIV-infected patients (78%) than in a control group of HIV-negative persons (28%). In addition, yeast colonization was quantitatively more important in patients with lower CD4+ lymphocyte counts and for those who had been exposed to fluconazole for episode(s) of OPC. Fluconazole-resistant C. albicans isolates were observed only in HIV-positive patients, and all patients (17/18) for whom this information could be ascertained had had prior exposure to fluconazole.

Journal Article↗

PubMed2001

Serum levels of fluconazole in patients after cytotoxic chemotherapy for hematological malignancy.

We performed a prospective evaluation of pharmacokinetics of fluconazole administered for prophylactic purposes to 19 patients after cytotoxic chemotherapy for hematological malignancies. On days 7 and 15, we obtained 5 ml of blood from each patient. If fluconazole was administered orally, blood samples were drawn 2, 8, and 24 hr after ingestion of the drug. If it was administered intravenously, blood samples were drawn 1, 8, and 24 hr post-injection. Serum fluconazole levels were analyzed by HPLC with ultraviolet light detection. In patients receiving 200 or 400 mg of fluconazole per day, maximal serum levels were 7.9 and 15.6 mg/l and minimum levels were 5.0 and 10.3 mg/l, respectively. There was no significant difference in serum fluconazole levels comparing the levels after oral and intravenous administration, and pharmacokinetic parameters of fluconazole were comparable at each time point within one dose level. However, considerable variation in serum fluconazole levels was noted in this study, as the maximal serum levels ranged from 4.0 to 13.3 mg/l and from 8.7 to 26.9 mg/l in patients receiving 200 and 400 mg of fluconazole orally, respectively. These variations may be associated with prophylactic failures for patients with insufficient fluconazole concentrations. Multiple regression analysis showed significant correlation between serum fluconazole levels and some variables including dose of fluconazole, age, serum aspartate aminotransferase levels and blood urea nitrogen levels. These variations may be associated with disturbance of body water balance, such as massive hemorrhage and dehydration.

Adult↗

PubMed2001

Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients.

OBJECTIVES: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150 mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. METHODS: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37 months in 132 HIV + patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. RESULTS: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorp tion from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79 l/h, the volume of distribution 571 and the absorption constant (ka) 0.93 h(-1). Inter-occasion variability in clearance (45%) was large relative to intersubject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. CONCLUSION: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary prevention.

AIDS-Related Opportunistic Infections↗

PubMed2000

A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer.

PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.

Amphotericin B↗