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PubMed1998

Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail.

BACKGROUND: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. OBJECTIVE: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. METHODS: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. RESULTS: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. CONCLUSION: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

Adult↗

PubMed2002

Hepatobiliary excretion of fluconazole and its interaction with cyclosporin A in rat blood and bile using microdialysis.

In order to investigate the hepatobiliary excretion of Fluconazole, we develop a rapid and sensitive method using high-performance liquid chromatography coupled with microdialysis for the simultaneous determination of unbound fluconazole in rat blood and bile. Microdialysis probes were inserted into both the jugular vein toward the right atrium and bile duct of male Sprague-Dawley rats for biological fluid sampling after administration of fluconazole at 10 mg/kg through the femoral vein. Fluconazole and dialysates were separated using a Zorbax phenyl column maintained at ambient temperature. The detection limit of fluconazole was 50 ng/ml. Biological fluid sampling thereby allowed the simultaneous determination of fluconazole levels in blood and bile. The disposition of fluconazole in the blood and bile fluid suggests that there was rapid exchange and equilibration between the blood and hepatobiliary system. In addition, to investigate the mechanism of P-glycoprotein related hepatobiliary excretion of fluconazole, we examined the drug-drug interaction of fluconazole and cyclosporin A in the aspect of pharmacokinetics. These results indicate that the plasma level of fluconazole was no different than that in bile, and that fluconazole undergoes hepatobiliary excretion, maybe unrelated to the P-glycoprotein transported system.

Animals↗

PubMed2006

Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?

Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.

Antifungal Agents↗

PubMed2001

Effective fluconazole therapy for liver transplant recipients during continuous hemodiafiltration.

Fungal infections are still one of the main causes of death and complications after solid organ and bone marrow transplants. The authors evaluated the effect of continuous hemodiafiltration (CHDF) on the pharmacokinetics of fluconazole in liver transplant recipients. Six liver transplant patients (primary biliary cirrhosis, n = 2; fulminant hepatitis, n = 2; viral hepatitis, n = 2) were enrolled in this study. In one patient not receiving CHDF, the fluconazole levels increased with increasing dosages. In contrast, in patients undergoing CHDF, the dosage of fluconazole was increased from 100 mg/d to 200 mg/d, but fluconazole did not reach the targeted levels. It appears that the targeted trough level cannot be achieved by administration of fluconazole at a dosage of 100 to 200 mg/d during CHDF. A higher dosage (600-1000 mg/d) of fluconazole may be required to achieve the therapeutic drug level in patients undergoing CHDF. In patients undergoing CHDF, fluconazole was given at a dosage of 800 mg/d and reached the targeted levels. In addition, after CHDF, the dosage of fluconazole was decreased to 100 mg/d, and fluconazole reached the near-targeted trough level. These results demonstrate that CHDF removes fluconazole from the blood at an efficiently high rate, resulting in its ineffective blood level. To guarantee safe and effective fluconazole therapy, the trough levels should be monitored routinely during CHDF.

Adult↗

PubMed2002

Randomized controlled trial of oral itraconazole solution versus intravenous/oral fluconazole for prevention of fungal infections in liver transplant recipients.

BACKGROUND: Liver transplant recipients at high risk for serious fungal infections frequently receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole, safety with amphotericin B, and the cost of lipid formulations of amphotericin, alternative prophylactic regimens are needed. In this randomized, controlled trial, we compared the efficacy and safety of oral itraconazole solution with intravenous/oral fluconazole for prevention of fungal infections. METHODS: Adult liver transplant recipients were randomized to receive either oral itraconazole solution (200 mg every 12 hr) or intravenous/oral fluconazole (400 mg every 24 hr). Each study drug was started immediately before transplant surgery and continued for 10 weeks after transplantation. Patients were evaluated for fungal colonization, proven invasive or superficial fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization decreased from baseline to week 8 after transplantation in both the itraconazole patients (67% to 25%, P<0.001) and the fluconazole patients (77% to 30%, P<0.001). Proven fungal infection developed in 9 (9%) of 97 itraconazole patients and in 4 (4%) of 91 fluconazole patients (P =0.25). The number of proven invasive fungal infections (seven with itraconazole [7%], three with fluconazole [3%]) and proven superficial fungal infections (two with itraconazole [2%], one with fluconazole [1%]) were also similar in both groups of patients. Organisms causing infection were (four patients), (three patients), and species (two patients) in the itraconazole group and (two patients), (one patient), and species (one patient) in the fluconazole group. Mortality from fungal infection was very low and occurred in only 1 (0.5%) of 188 patients. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea) with itraconazole, both itraconazole and fluconazole were well tolerated and not associated with any hepatotoxicity. Mean trough plasma concentrations of itraconazole were greater than 250 ng/mL throughout the study and were not affected by H -receptor antagonists or antacids. CONCLUSION: Oral itraconazole solution has adequate bioavailability in liver transplant recipients for effective antifungal prophylaxis. Similar to fluconazole, prophylactic oral itraconazole decreases fungal colonization and is associated with a low incidence of serious or fatal fungal infections. Except for gastrointestinal side effects, oral itraconazole solution is well tolerated and has no significant hepatotoxicity.

Administration, Oral↗

PubMed2003

Fluconazole improves survival in septic shock: a randomized double-blind prospective study.

OBJECTIVE: To demonstrate whether fluconazole reduces multiple organ failure and mortality in early septic shock (<24 hrs). DESIGN: A prospective randomized double-blind study. SETTING: A medical and surgical adult intensive care unit in a tertiary referral center. PATIENTS: Values were obtained from 71 general adult intensive care unit patients. INTERVENTIONS: During a 2.5-yr period, December 1998-June 2001, 71 patients with septic shock attributed to either nosocomial pneumonia (n = 37) or intra-abdominal sepsis (n = 34) were admitted to our intensive care unit and met the criteria of early septic shock and were entered into this study. All patients were randomized by our clinical pharmacist to receive daily either 200 mg of fluconazole in isotonic saline (fluconazole group = 32) or isotonic saline alone (placebo group = 39) intravenously during the course of their septic shock. MEASUREMENTS AND MAIN RESULTS: All patients were closely monitored with pulmonary artery catheters and parameters to calculate daily organ dysfunction and Acute Physiology and Chronic Health Evaluation II scores. There was a highly significant increase in 30-day survival in the fluconazole-treated patients compared with the placebo patients (78% vs. 46%). However, fluconazole was found to be more effective in patients with septic shock attributed to intra-abdominal sepsis than to nosocomial pneumonia. Increased survival in the intra-abdominal sepsis clinical category was mirrored by a significantly lower number of organ failures in the treated group compared with the placebo group whereas the number of organ failures in the fluconazole group attributed to nosocomial pneumonia were not significantly increased compared with the control group. The septic shock state was considered in all cases to be attributed to bacterial and not to disseminated yeast infection with the exception of one patient in the control group who was admitted with candidemia. The mechanisms by which fluconazole exerts its protective effect against septic shock in patients is far from clear. However, fluconazole has been shown to enhance bactericidal activity of neutrophils and also to inhibit transmigration and adhesion of neutrophils in capillaries of distant organs. CONCLUSIONS: The development of organ failure and mortality in septic shock was significantly reduced by fluconazole given intravenously. The mechanism of action of fluconazole in reducing multiple organ dysfunction in this group of patients may be attributed to the ability of fluconazole to increase recruitment, improve bactericidal activity of neutrophils, and to contain microorganisms locally.

Adult↗

PubMed1997

Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients.

Fluconazole, an inhibitor of certain human cytochrome P-450 isozymes, is used for the prevention and treatment of a broad range of fungal infections that predominantly affect immunocompromised individuals. This study evaluated the influence of fluconazole on the steady-state pharmacokinetics of delavirdine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, in 13 HIV-1-infected patients with CD4 counts ranging from 186 to 480/mm3. Both the control group (n = 5) and the fluconazole group (n = 8) received 300 mg of delavirdine mesylate every 8 h for 30 days; subjects in the fluconazole group took a 400-mg, once-daily dose of fluconazole on study days 16 to 30. Harvested plasma from serial blood samples collected on days 15, 16, and 30 were assayed for concentrations of delavirdine and its N-desalkyl metabolite by a reversed-phase high-pressure liquid chromatography (HPLC) method. Blood samples obtained on days 16 and 30 were also assayed for fluconazole by HPLC. Delavirdine mesylate alone and in combination with fluconazole was well tolerated. There were no significant differences (P > 0.16) in delavirdine pharmacokinetic parameters between treatment groups on day 15 or day 30. After coadministration of fluconazole and delavirdine mesylate for 2 weeks (day 30), no significant differences (P > 0.058) were observed in any delavirdine pharmacokinetic parameters relative to those after receiving delavirdine mesylate alone (day 15) after in the fluconazole group. Fluconazole pharmacokinetic parameters were similar to those previously reported for healthy volunteers and HIV-positive patients. On the basis of these findings, fluconazole and delavirdine mesylate may be taken concurrently without adjustment of the dose of either drug.

Adult↗

PubMed2002

Replacement of Candida albicans with C. dubliniensis in human immunodeficiency virus-infected patients with oropharyngeal candidiasis treated with fluconazole.

Candida dubliniensis is an opportunistic yeast that has been increasingly implicated in oropharyngeal candidiasis (OPC) in human immunodeficiency virus (HIV)-infected patients but may be underreported due to its similarity with Candida albicans. Although most C. dubliniensis isolates are susceptible to fluconazole, the inducibility of azole resistance in vitro has been reported. Thus, the use of fluconazole prophylaxis in the treatment of these patients may have contributed to the increasing rates of isolation of C. dubliniensis. In this study, yeast strains were collected from the oral cavities of HIV-infected patients enrolled in a longitudinal study of OPC. Patients received fluconazole for the suppression or treatment of OPC, and isolates collected at both study entry and end of study were chosen for analysis. Samples were plated on CHROMagar Candida medium for initial isolation and further identified by Southern blot analysis with the species-specific probes Ca3 (for C. albicans) and Cd25 (for C. dubliniensis). Fluconazole MICs were determined by using NCCLS methods. At study entry, susceptible C. albicans isolates were recovered from oral samples in 42 patients who were followed longitudinally (1 to 36 months). C. albicans strains from 12 of these patients developed fluconazole resistance (fluconazole MIC, >/=64 micro g/ml). C. dubliniensis was not detected at end of study in any of these patients. Of the remaining 30 patients, eight (27%) demonstrated a replacement of C. albicans by C. dubliniensis when a comparison of isolates obtained at baseline and those from the last culture was done. For the 22 of these 30 patients in whom no switch in species was detected, the fluconazole MICs for initial and end-of-study C. albicans isolates ranged from 0.125 to 2.0 micro g/ml. For the eight patients in whom a switch to C. dubliniensis was detected, the fluconazole MICs for C. dubliniensis isolates at end of study ranged from 0.25 to 64 micro g/ml: the fluconazole MICs for isolates from six patients were 0.25 to 2.0 micro g/ml and those for the other two were 32 and 64 micro g/ml, respectively. In conclusion, a considerable number of patients initially infected with C. albicans strains that failed to develop fluconazole resistance demonstrated a switch to C. dubliniensis. C. dubliniensis in this setting may be underestimated due to lack of identification and may occur due to the impact of fluconazole on the ecology of oral yeast species.

AIDS-Related Opportunistic Infections↗

PubMed2003

Characterization of heteroresistance to fluconazole among clinical isolates of Cryptococcus neoformans.

Strains of Cryptococcus neoformans expressing heteroresistance to fluconazole have been described previously. The present study was conducted to investigate the prevalence of heteroresistance among clinical isolates of C. neoformans and to characterize the heteroresistant phenotypes. A total of 107 clinical isolates of C. neoformans for which the MICs of fluconazole ranged from 0.25 to 32 microg/ml were selected. The isolates were chosen to represent a broad geographic distribution. Of the 107 C. neoformans isolates tested, 4 grew on medium containing fluconazole at concentrations that were four to eight times higher than the MICs for each strain. A fifth isolate, for which the fluconazole MIC was 32 microg/ml, grew on agar with 64 microg of fluconazole per ml. These five isolates (4.7% of the total number) were confirmed to exhibit heteroresistant compositions by population analysis. The degree and frequency of resistance varied among the isolates. Stepwise selection by exposure to fluconazole resulted in subclones of all five strains for which the fluconazole MIC was >64 microg/ml. Subclones of three strains demonstrated a homogeneous population of resistant cells on medium containing 64 microg of fluconazole/ml. The resistance was sensitive to incubation temperature, that is, heteroresistance was demonstrable only at 30 degrees C by agar-based tests, and was reversible through serial transfers on fluconazole-free medium over a period of 8 days. These results suggest that the fluconazole-heteroresistant phenotype of C. neoformans exists in a significant proportion of clinical isolates and that fluconazole resistance can be developed by selection from heteroresistant clones and induction by exposure to fluconazole.

Antifungal Agents↗

PubMed1997

Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses.

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg gives a mean long term clinical cure rate of 84 +/- 5% and is considered a valuable alternative to other topical antifungal drugs for vaginal candidiasis. A clinical cure rate of 90.4% for oropharyngeal candidiasis was obtained with 100mg daily for a minimum of 14 days; however, as for the other azoles the rate of relapse was large (40%) in immunocompromised patients. A daily dose of 100mg for at last 3 weeks gave satisfying outcomes for oesophageal candidiasis. Most patients (71 to 86%) with signs and symptoms of urinary tract candidiasis show beneficial clinical results when given oral fluconazole 50mg for several weeks. Fluconazole 50 to 150 mg given for weeks or months results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmitis, pneumonia, hepatosplenic mycosis and endocarditis. Fluconazole is effective for treating the fungal peritonitis which can complicate continuous ambulatory peritoneal dialysis (CAPD). A regimen of 50 mg intraperitoneally or 100 mg orally was used in these patients with impaired renal function. The dosage schedules used to treat disseminated fungal infections due to systemic mycoses with different or multiple foci of infections vary widely, with doses of 50 to 400 mg given orally or intravenously for between 1 week and several months. The most recent clinical reports have investigated the use of prophylaxis with fluconazole 100 to 400 mg daily, in immunocompromised patients. Fluconazole is found in body fluids such as vaginal secretions, breast milk, saliva, sputum and cerebrospinal fluid at concentrations comparable with those determined in blood after single or multiple doses. There is an excellent linear plasma concentration-dose relationship, but the mycological and clinical responses do not appear to be well correlated with the dose. A total maximum daily dose of 1600 mg is recommended to avoid neurological toxicity. Data from pharmacokinetic studies conducted in patients, mainly those with AIDS, and using a 1-compartment model give very constant parameters similar to those obtained in healthy individuals. Bioavailability, measured in HIV-positive patients and those with AIDS, exceeded 93% for tablets, suspension and suppositories. The time to reach peak plasma concentrations (tmax) was 2.4 to 3.7 hours. The peak plasma drug concentration (Cmax) obtained after a 100 mg oral dose was 2 mg/L. Areas under the concentration-time curve (AUC) obtained in different studies all correlate well with the dose (r = 0.926). The AUC determined after 200 and 25 mg suppositories were similarly well correlated. Hypochlorhydria does not affect the absorption of fluconazole, neither does food intake, race (Japanese or Caucasian) or gastrointestinal resection. Binding to plasma protein is low (11.14%) and is increased to 23% in cancer patients. Fluconazole is rapidly distributed to the tissue, where it accumulates. Tissues fall into 1 of 4 groups of increasing drug concentration: blood, bone and brain have the lowest concentrations, and spleen has the highest. The volume of distribution (Vd) remains stable at 46.3 +/- 7.9L and is considered to be an 'invariant' parameter across species. Fluconazole is poorly metabolised and is mainly eliminated unchanged in the urine. The percentage of the dose recovered in the urine in 48 hours is close to 60%. Concentrations in the urine are high and the half-life (t1/2) is long (37.2 +/- 5.5h) in patients, mainly those with AIDS, which is not significantly different from the t1/2 (31.4 +/- 4.7 hours) in healthy individuals. (ABSTRACT TRUN

Age Factors↗

PubMed2004

Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS.

OBJECTIVE: To study the effect of rifampicin on the pharmacokinetics of fluconazole and on clinical outcomes of fluconazole treatment in patients with AIDS-related cryptococcal meningitis. PATIENTS: Forty Thai patients with AIDS and cryptococcal meningitis, of whom 20 had been receiving oral rifampicin for at least 2 weeks to treat tuberculosis. METHODS: Patients were treated for cryptococcal meningitis with amphotericin 0.7 mg/kg/day for 14 days followed by fluconazole 400 mg/day, which was reduced to 200 mg/day once culture of cerebrospinal fluid (CSF) became negative. Patients with tuberculosis received oral rifampicin 600 mg/day at night. Blood samples were collected from the first 12 patients in each group and pharmacokinetic parameters for fluconazole were calculated. CSF samples were collected by lumbar puncture and monitored for eradication of Cryptococcus neoformans. RESULTS: Concomitant administration of rifampicin with fluconazole resulted in significant changes in the pharmacokinetic parameters of fluconazole, including a 39% increase in elimination rate constant, 28% shorter elimination half-life, 22% decrease in area under the concentration-time curve, 17% decrease in maximum concentration and 30% increase in clearance (p < 0.05). Different fluconazole regimens did not affect the extent of change in the elimination rate constant. Although serum concentrations of fluconazole during the time that patients received rifampicin concomitantly with fluconazole 200 mg/day were generally lower than the minimum inhibitory concentration for C. neoformans, there were no significant differences in clinical outcomes between the two groups to date (p = 0.792). CONCLUSIONS: Coadministration of rifampicin with fluconazole caused significant changes in the pharmacokinetic parameters of fluconazole. Long-term monitoring for recurrence rates of cryptococcal meningitis is required to assess the clinical significance of this interaction.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Alopecia associated with fluconazole therapy.

OBJECTIVE: To describe the association between fluconazole and reversible alopecia. DESIGN: A retrospective survey of 1) patients enrolled in NIAID Mycoses Study Group (MSG) protocols involving the long-term use of fluconazole for treatment of endemic mycoses and 2) patients treated with fluconazole outside of a protocol setting but by the MSG investigators who were MSG members. SETTING: 26 MSG sites in the United States. PATIENTS: 33 patients with various deep and superficial mycoses who developed alopecia while receiving fluconazole. RESULTS: 11 of 26 investigators reported a total of 33 patients with substantial alopecia related to fluconazole therapy. Underlying mycoses included blastomycosis, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and mucosal candidiasis. In separate MSG studies, 17 of 136 (12.5%) and 8 of 40 (20%) patients had substantial reversible alopecia associated with fluconazole therapy. Eight patients who were not in the protocol had similar adverse effects. Twenty-nine of 33 patients (88%) received at least 400 mg of fluconazole daily for a mean of 7.1 months. Alopecia developed a median of 3 months after initiation of fluconazole therapy and involved the scalp in all patients. Other sites were involved in about one third of patients. Three patients required wigs because of extensive hair loss. Alopecia resolved within 6 months of discontinuation of fluconazole therapy or reduction of the daily dose by at least 50%. CONCLUSIONS: Alopecia appears to be a common adverse event associated with higher-dose (400 mg/d) fluconazole given for 2 months or longer. This effect may be severe but is reversed by discontinuing fluconazole therapy or substantially reducing the daily dose.

Adult↗

PubMed2003

Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial.

BACKGROUND: Allogeneic hematopoietic stem-cell transplant recipients often receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole and toxicity with amphotericin B, alternative prophylactic regimens have become necessary. OBJECTIVE: To compare the efficacy and safety of intravenous and oral itraconazole with the efficacy and safety of intravenous and oral fluconazole for long-term prophylaxis of fungal infections. DESIGN: Open-label, multicenter, randomized trial. SETTING: Five transplantation centers in the United States. PATIENTS: 140 patients undergoing allogeneic hematopoietic stem-cell transplantation. INTERVENTION: Itraconazole (200 mg intravenously every 12 hours for 2 days followed by 200 mg intravenously every 24 hours or a 200-mg oral solution every 12 hours) or fluconazole (400 mg intravenously or orally every 24 hours) from day 1 until day 100 after transplantation. MEASUREMENTS: Proven invasive or superficial fungal infection, drug-related side effects, mortality from fungal infection, and overall mortality. RESULTS: Proven invasive fungal infections occurred in 6 of 71 itraconazole recipients (9%) and in 17 of 67 fluconazole recipients (25%) during the first 180 days after transplantation (difference, -16 percentage points [95% CI, -29.2 to -4.7 percentage points]; P = 0.01). Superficial fungal infections occurred in 3 of 71 itraconazole recipients (4%) and in 2 of 67 fluconazole recipients (3%). In a multivariable analysis using factors known to affect the risk for invasive fungal infection after hematopoietic stem-cell transplantation, prophylaxis with itraconazole was still associated with fewer invasive fungal infections (odds ratio, 0.300 [CI, 0.111 to 0.814]; P = 0.02) caused by either yeasts or molds. More fungal pathogens were found to be resistant to fluconazole than to itraconazole. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea, or abdominal pain) in patients given itraconazole (24% vs. 9%; difference, 15 percentage points [CI, 2.9 to 27.0 percentage points]; P = 0.02), both itraconazole and fluconazole were well tolerated. The overall mortality rate was similar in each group (32 of 71 patients in the itraconazole group [45%] vs. 28 of 67 patients in the fluconazole group [42%]; difference, 3 percentage points [CI, -13.2 to 19.8 percentage points]; P > 0.2), but fewer deaths were related to fungal infection in patients given itraconazole (6 of 71 [9%]) than in patients given fluconazole (12 of 67 [18%]) (difference, 9 percentage points [CI, -20.6 to 1.8 percentage points]; P = 0.13). CONCLUSION: Itraconazole is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic hematopoietic stem-cell transplantation. Except for gastrointestinal side effects, itraconazole is well tolerated.

Administration, Oral↗

PubMed2000

Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials.

BACKGROUND: Fluconazole is used widely for fungal prophylaxis. Although studies with bone marrow transplantation (BMT) recipients clearly showed the usefulness of oral fluconazole, results of the studies in neutropenic patients other than BMT recipients have been inconsistent. Therefore, the authors performed a meta-analysis to evaluate the efficacy of fluconazole prophylaxis during chemotherapy-induced neutropenia. METHODS: The authors identified reports that were not restricted to those in English and not restricted to published trials through MEDLINE, CANCERLIT, or the data base of the Pfizer company. The authors included prospective, randomized studies comparing oral fluconazole with placebo, no treatment, or oral polyenes as prophylaxis for fungal infections in neutropenic patients. Two independent authors extracted data from 16 trials with 3734 patients enrolled. The outcome measures were the development of fungal-related death, systemic and superficial fungal infections, the use of empiric intravenous amphotericin-B, and infections or colonization with fluconazole-resistant fungi. The summarized odds ratios (ORs) were calculated using the Mantel-Haenszel method and the DerSimonian-Laird method. RESULTS: Prophylactic fluconazole was not effective in reducing fungal-related death or in reducing proven, systemic fungal infections in non-BMT patients (OR, 0.91; 95% confidence interval [CI], 0.30-2.82 and OR, 0.85; 95% CI, 0.47-1.55, respectively). However, fluconazole was very effective in reducing superficial fungal infections (OR, 0.44; 95% CI, 0.24-0.80), even when it was given in lower doses (50-200 mg per day). There was no increase in proven, systemic infection of fluconazole-resistant fungi, although colonization of those fungi increased. When the results were combined in studies in which the incidence of systemic fungal infections was > 15%, fluconazole was effective in reducing such infections (OR, 0.23; 95% CI, 0.15-0.36). CONCLUSIONS: The current analyses failed to find an effect of fluconazole on both fatal fungal infection and systemic fungal infection in non-BMT patients. Further studies on severely neutropenic patients are warranted because prophylactic fluconazole seemed to be effective when the incidence of systemic fungal infection was expected to be > 15%.

Administration, Oral↗

PubMed2006

Pharmacokinetic study of the combination of tacrolimus and fluconazole in renal transplant patients.

BACKGROUND: It was hypothesized that fluconazole in combination with tacrolimus can be used safely with an imitated area under curve (AUC) compared to tacrolimus. At every time point, this combination was presumed to correlate well with pre-intervention AUC, thus the dosage could be significantly reduced. MATERIAL AND METHOD: There were two groups of patients. Group I (n = 15) included patients who received tacrolimus at 0.1-0.3 mg/kg/day within one week after transplantation. These patients were studied for tacrolimus whole blood concentrations. The tacrolimus dosage was then reduced by 40% and given in combination with fluconazole at 100-200 mg/day for one week, tacrolimus whole blood concentrations were studied again. Group II (n = 8) included patients who had been transplanted for more than 3 months and had received a stable dosage of tacrolimus in combination with fluconazole for at least one month. RESULTS: In group I, before fluconazole combination, trough levels correlated well with AUC0-12. After fluconazole combination, trough levels still correlated well with AUC0-12. The after/before fluconazole-combination ratio of AUC0-12 and maximum tacrolimus concentration (Cmax) was 1.08 (90%CI; 0.98-1.19) and 1.17 (90%CI; 1.00-1.36), respectively. Correspondingly, the oral bioavailability, which was the after/ before fluconazole combination ratio of AUC0-12/dose and absorption rate (Cmax/dose/body weight), was significantly increased [2.08 (90%CI; 1.80-2.40) and 2.24 (90%CI; 1.99-2.51), respectively]. Tacrolimus clearance after the fluconazole combination was significantly reduced, compared with before the combination (14.74 vs 38.79 L/h, p = 0.001). Mean tacrolimus dosage in this group could be reduced from 10.7 mg/day before fluconazole combination to 5.7 mg/day after it and to 3.7 mg/day at 3 months after transplantation (p = 0.001). In group II, trough levels correlated well with AUC0-12 and the mean tacrolimus dosage in this group was only 2.9 mg/day. CONCLUSION: This present study showed a good correlation between tacrolimus trough levels and AUC, which occurred in monotherapy or in patients who received fluconazole. The tacrolimus trough levels could be trusted in monitoring patients who received a tacrolimus-based immunosuppressive regimen. The combination to fluconazole was ascertained and it was safe to reduce the dose of tacrolimus.

Adult↗

PubMed1994

Antifungal prophylaxis with low-dose fluconazole during bone marrow transplantation. The Bone Marrow Transplantation Team.

The present study investigated the prophylactic efficacy of fluconazole at 100-200 mg/day against invasive fungal infections during bone marrow transplantation (BMT). During July 1990 to December 1991, all BMT recipients received antifungal prophylaxis with fluconazole at either 200 mg/day or 100 mg/day. Historical controls were those that received no antifungal prophylaxis (January 1989 to June 1990). Fungemia occurred in 4 of 112 fluconazole recipients and 8 of 79 controls (p < 0.05) prior to engraftment. Torulopsis (Candida) glabrata (three patients), Cryptococcus terreus and Candida tropicalis (mixed in one patient) caused fungemia in four patients in the fluconazole group; Candida albicans caused six of eight fungemic episodes in the controls. All three Torulopsis glabrata isolates were fluconazole-resistant. Colonization due to C. albicans was markedly diminished in the fluconazole group (19 of 112 patients versus 53 of 79 controls). T. glabrata, on the other hand, was a more common colonizing organism in the fluconazole group (36 of 112 vs 10 of 79). The frequency of isolating C. albicans and/or T. glabrata was significantly different between fluconazole and control groups (p < 0.0001). Empiric use of amphotericin B therapy was markedly reduced in the fluconazole group (4.5% vs 34%; p < 0.0001). Fluconazole at 200 mg/day or 100 mg/day appeared equally effective. Fluconazole at a daily dose of 100 mg or 200 mg as antifungal prophylaxis during BMT: (1) significantly reduced the frequency of systemic fungal infections, (2) markedly reduced colonization and infection due to C. albicans, and (3) markedly reduced the need for empiric amphotericin B therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1996

The cardiopulmonary, eicosanoid, and tissue microanatomic effects of fluconazole during graded bacteremia.

Imidazole compounds have been shown to be beneficial in systemic sepsis and inflammation. The purpose of this study was to delineate the effects of fluconazole on systemic hemodynamics and on microanatomy of the heart, lung, liver, and kidney parenchyma of swine during graded bacteremia. Eighteen adult swine were studied in three groups: 1), anesthesia control; 2), septic control (Aeromonas hydrophila, 10(9)/mL, infused i.v. for 4 h); 3) fluconazole (fluconazole, 30 mg/kg i.v., followed by A. hydrophila infusion). After 4 h of graded bacteremia, autopsy was performed. Compared with the septic control group, cardiac index, oxygen delivery, and oxygen consumption were reduced significantly after fluconazole pretreatment, and mixed venous hemoglobin oxygen saturation (SVO2) and oxygen extraction were increased. Plasma thromboxane A2 and leukotriene levels were not affected by fluconazole. Computerized digital image analysis of the liver, heart, and kidney specimens revealed no statistically significant differences between the septic control group and fluconazole-pretreated animals. In the lung specimens, preinfusion of fluconazole decreased alveolar wall thickness in septic swine (anesthesia control group: 8.15 x 10(-3) +/- 1.3 x 10(-3)mm versus septic control group: 9.9 x 10(-3) +/- 1.3 x 10(-4) versus fluconazole group: 6.8 x 10(-3) +/- 1.6 x 10(-3); p < or = .05). Fluconazole pretreatment before graded bacteremia has no beneficial effect on cardiopulmonary performance or septic tissue edema of the heart, kidney, or liver. Tissue oxygen metabolism might be down-regulated by fluconazole. However, preinfusion of fluconazole appears to normalize the sepsis-induced increase in pulmonary alveolar wall thickness. The net significance of these changes on clinical outcome is not clear from these data.

Anesthesia↗

PubMed1997

Pharmacokinetic interaction of fluconazole and zidovudine in HIV-positive patients.

To investigate the interaction of fluconazole and zidovudine in HIV-positive non-smoking male patients with AIDS categorized as CDC group IV we studied two groups, each consisting of 10 male, non-smoking, HIV-positive patients with CDC group IV disease, with the patients in the first group additionally suffering from candida esophagitis. In the first group, the pharmacokinetics of 500 mg oral zidovudine were determined both before and after 7 days of treatment with fluconazole 400 mg/d. In the second group, the pharmacokinetics of 200 mg oral fluconazole were determined before and after 14 days of treatment with zidovudine 4 x 250 mg/d. In order to determine the microsomal enzyme activity, the 6-beta-hydroxycortisol/17-hydroxycorticosteroid ratio and antipyrine pharmacokinetic parameters were determined. 6-beta-hydroxycortisol was quantitated by RIA. The 17-hydroxycorticosteroids were determined by a colorimetric method. Zidovudine (ZDV) and zidovudine glucuronide (GZDV), and the fluconazole and antipyrine plasma and urine concentrations were measured by HPLC. Administration of fluconazole resulted in a significant increase in the half-life of zidovudine and antipyrine (0.97 +/- 0.17 h prior to vs. 1.11 +/- 0. 14 h after fluconazole administration and 11.9 +/- 1.9 h prior to vs. 13.7 +/- 3.0 h after fluconazole, respectively) while the 6-beta-hydroxycortisol excretion decreased significantly (472.3 +/- 80.6 microg/24 h before and 340.6 +/- 82.1 microg/24 h after administration of fluconazole). No changes were found in the GZDV plasma kinetics and the ZDV and GZDV urinary excretion. Treatment with ZDV did not have any impact on the half-life of fluconazole. Administration of zidovudine did, however, result in a significant reduction in antipyrine half-life (11.7 +/- 2.0 h before vs. 9.9 +/- 2.3h after ZDV) and a significant increase in 6-beta-hydroxycortisol excretion (438,7 +/- 138.2 microg/24 h before and 684.6 +/- 157.3 microg/24 h after ZDV). Since the antipyrine clearance is altered after administration of ZDV, it is assumed that zidovudine induces cytochrome P450 enzymes. This effect, however, does not alter the pharmacokinetics of fluconazole. High doses of fluconazole can inhibit the plasma elimination of both antipyrine and zidovudine, but the extent of this inhibitory effect is so small that no clinically relevant accumulation is to be expected.

17-Hydroxycorticosteroids↗