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PubMed1999

Quantitation of ergosterol content: novel method for determination of fluconazole susceptibility of Candida albicans.

MIC end points for the most commonly prescribed azole antifungal drug, fluconazole, can be difficult to determine because its fungistatic nature can lead to excessive "trailing" of growth during susceptibility testing by National Committee for Clinical Laboratory Standards broth macrodilution and microdilution methods. To overcome this ambiguity, and because fluconazole acts by inhibiting ergosterol biosynthesis, we developed a novel method to differentiate fluconazole-susceptible from fluconazole-resistant isolates by quantitating ergosterol production in cells grown in 0, 1, 4, 16, or 64 microg of fluconazole per ml. Ergosterol was isolated from whole yeast cells by saponification, followed by extraction of nonsaponifiable lipids with heptane. Ergosterol was identified by its unique spectrophotometric absorbance profile between 240 and 300 nm. We used this sterol quantitation method (SQM) to test 38 isolates with broth microdilution end points of </=8 microg/ml (susceptible), 16 to 32 microg/ml (susceptible dose-dependent [SDD]), or >/=64 microg/ml (resistant) and 10 isolates with trailing end points by the broth microdilution method. No significant differences in mean ergosterol content were observed between any of the isolates grown in the absence of fluconazole. However, 18 susceptible isolates showed a mean reduction in ergosterol content of 72% after exposure to 1 microg of fluconazole/ml, an 84% reduction after exposure to 4 microg/ml, and 95 and 100% reductions after exposure to 16 and 64 microg of fluconazole/ml, respectively. Ten SDD isolates showed mean ergosterol reductions of 38, 57, 73, and 99% after exposure to 1, 4, 16, and 64 microg of fluconazole/ml, respectively. In contrast, 10 resistant isolates showed mean reductions in ergosterol content of only 25, 38, 53, and 84% after exposure to the same concentrations of fluconazole. The MIC of fluconazole, by using the SQM, was defined as the lowest concentration of the drug which resulted in 80% or greater inhibition of overall mean ergosterol biosynthesis compared to that in the drug-free control. Of 38 isolates which gave clear end points by the broth microdilution method, the SQM MIC was within 2 dilutions of the broth microdilution MIC for 33 (87%). The SQM also discriminated between resistant and highly resistant isolates and was particularly useful for discerning the fluconazole susceptibilities of 10 additional isolates which gave equivocal end points by the broth microdilution method due to trailing growth. In contrast to the broth microdilution method, the SQM determined trailing isolates to be susceptible rather than resistant, indicating that the SQM may predict clinical outcome more accurately. The SQM may provide a means to enhance current methods of fluconazole susceptibility testing and may provide a better correlation of in vitro with in vivo results, particularly for isolates with trailing end points.

Antifungal Agents↗

PubMedDate not supplied

Parenteral and oral fluconazole for acute cryptococcal meningitis in AIDS: experience with thirteen patients.

OBJECTIVE: Cryptococcus neoformans infections of the central nervous system affect up to ten percent of AIDS patients. Standard therapy with amphotericin B with or without 5-flucytosine has a high rate of failure, relapse, and toxicity. Fluconazole is a new triazole antifungal agent available in both oral and intravenous forms that has shown efficacy in the primary and maintenance treatment of cryptococcal meningitis in AIDS patients. In this open, noncomparative trial, we evaluated the safety and efficacy of intravenous fluconazole followed by oral fluconazole in the treatment of acute cryptococcal meningitis in AIDS patients. METHODS: Thirteen AIDS patients with acute cryptococcal meningitis, or relapse after successful primary therapy, received 400 mg of intravenous fluconazole daily for 12-16 days followed by oral fluconazole 400 mg/d for the duration of primary therapy. If cerebrospinal fluid (CSF) cultures converted to negative within 32 weeks of treatment, the fluconazole dose was decreased to 200 mg/d as maintenance therapy. RESULTS: Fluconazole therapy was successful in six patients (46 percent) and unsuccessful in seven (54 percent). Of the seven patients considered unsuccessful, one demonstrated clinical improvement but remained CSF-culture positive, five were clinical failure and were switched to amphotericin B therapy, and one died after two weeks secondary to cryptococcal meningitis. No patient experienced any adverse reactions necessitating discontinuation of therapy. CONCLUSIONS: In this small group of patients, moderate doses of parenteral and oral fluconazole for acute cryptococcal meningitis in AIDS patients demonstrated failure rates similar to those reported in other studies with fluconazole and with amphotericin B. As there was no difference in initial Karnofsky scores or the severity of disease in treatment successes versus failures, it is difficult to determine who might respond to fluconazole as initial therapy or who should be treated initially with another agent. Further studies and clinical experience are needed.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Use of antifungal therapy in hospitalized patients. II. Results after the marketing of fluconazole.

OBJECTIVE: To evaluate the prescribing patterns of antifungal agents in the hospital setting after the introduction of fluconazole, a new broad-spectrum bis-triazole antifungal agent. Also compared are the prescribing patterns of antifungal agents prior to (phase I) and following (phase II) fluconazole marketing. DESIGN: A prospective cohort of hospitalized patients prescribed topical or systemic antifungal agents. Data were collected from December 1990 to April 1991. SETTING: Fifty-seven hospitals ranging in size from 100 to more than 500 beds. Sixty-three percent are affiliated with medical schools. PATIENTS: Participating pharmacists consecutively identified 15 patients receiving systemic antifungal therapy and 5 patients receiving topical antifungal therapy. INTERVENTIONS: Observational data on patient antifungal therapy, risk factors for fungal infections, comorbidities, concurrent medications, and culture data were collected. MEASURES: Differences in prescribing patterns before and after the marketing of fluconazole were assessed using t-tests and chi-square tests. RESULTS: Of 818 patients studied, 615 (75.2 percent) received systemic antifungal therapy. Five hundred forty-six patients received a single antifungal agent; 348 (63.7 percent) received fluconazole, 105 (19.2 percent) received ketoconazole, 92 (16.8 percent) received amphotericin B, and 1 (0.2 percent) received flucytosine. Sixty-nine patients received two or more systemic agents either concurrently or consecutively. The use of parenteral amphotericin B, alone or in combination with flucytosine and/or an azole, declined from 56.8 percent in the phase I study to 24.2 percent in the current study. The use of parenteral therapy also declined from 56.8 to 40.2 percent. Ketoconazole was used in more than 90 percent of the oral and esophageal infections in the phase I study, but its use declined to only 33 percent in this study. Fluconazole was used most frequently across all sites of presumed or documented infections, with the exception of fungemia. Of the presumed or proven systemic or blood infections, amphotericin B was used alone or in combination in 48.4 percent of the patients and fluconazole was used exclusively in 39.0 percent of the patients. Fluconazole was used more often than amphotericin B (22 vs. 3 patients, respectively) for prophylaxis of systemic infections. The overall use of antifungal prophylaxis also increased from the phase I (9.5 percent) to phase II (13.7 percent). CONCLUSIONS: The introduction of fluconazole had a major impact on the prescribing patterns of antifungal therapy. Although amphotericin B remained the preferred agent for treatment of suspected or proven systemic, central nervous system, or blood infections, use of fluconazole for these indications approached nearly 40 percent. Further studies are needed to address the role of fluconazole in the prophylaxis and treatment of systemic mycoses.

Administration, Oral↗

PubMed2004

Impact of fluconazole administration on outcomes in critically ill patients.

BACKGROUND: Serious infections caused by Candida spp. are an increasingly important cause of morbidity and mortality in critically ill patients. It is unclear which patients will benefit from therapy and at what point to institute treatment. OBJECTIVE: To evaluate the impact of administration of fluconazole therapy in critically ill trauma patients on mortality, length of hospital stay, incidence of deep-seated fungal infection, and positive fungal cultures from any site. METHODS: We conducted a retrospective, matched case-control study of 116 critically ill surgical trauma patients who did or did not receive fluconazole. Patients were followed until hospital discharge or death. A consecutive sample of 58 patients who received fluconazole was selected. A parallel group of patients was evaluated, from which 58 were matched with fluconazole-treated patients based on age (+/- 5 y), gender, and APACHE II score (+/- 3). RESULTS: The groups of patients were well matched, with the exception of central venous catheter placement and broad-spectrum antibiotic use. We found no difference between groups in hospital mortality (21% vs 26%; p = 0.661) or incidence of deep-seated fungal infection (0% vs 2%; p = NS). However, patients receiving fluconazole had a significantly longer stay in both the intensive care unit (ICU) (18 +/- 13 vs 7 +/- 11 days; p < 0.001) and hospital (25 +/- 15 vs 9 +/- 11 days; p < 0.001). Fluconazole patients were significantly more likely to have Candida cultured from sites associated with colonization (43% vs 2%; p < 0.001), possibly explaining why they received fluconazole. CONCLUSIONS: We were unable to detect a benefit from use of fluconazole in our surgical trauma patient population. Isolation of Candida from the mouth or throat alone, in the absence of correlating clinical signs of infection, should not lead to initiation of fluconazole therapy. Fluconazole use should be reserved for carefully selected patients in the trauma ICU setting.

Adult↗

PubMedDate not supplied

Preparations of liposomal fluconazole and their in vitro antifungal activity.

Fluconazole was successfully incorporated into multilamellar (MLV) and large unilamellar liposomes (LUV). Both MLV and LUV were stable up to 72 h in saline but were less stable in the high-resolution medium. The MLV-entrapped fluconazole was found to be four-fold more active than LUV-entrapped fluconazole against Candida pseudotropicalis and over six-fold more active against C. albicans. The MLV-fluconazole was one-fold less active than free fluconazole in terms of its endpoints (MIC value). However, when compared with free fluconazole, MLV-fluconazole was one-fold more active against two strains of C. albicans and equally active against C. kefyr and C. parapsilosis. In an incubation time-dependent assay against C. tropicalis, MLV-Fluconazole was one-fold more active after 16 h incubation and two-fold less active than fluconazole after 24 or 36 h post-incubation. Our results demonstrate the usefulness of liposomal formulation of the water-soluble azole, fluconazole, in the limited in vitro assay method used.

Antifungal Agents↗

PubMed1991

Pharmacokinetics of 18F-labeled fluconazole in rabbits with candidal infections studied with positron emission tomography.

[4-18F]Fluconazole was used to measure the pharmacokinetics of fluconazole in normal and infected animals. The biodistribution of fluconazole was determined after administration of the 18F-tracer with/without a pharmacological dose of unlabeled drug by radioactivity measurements on excised tissues. In normal rabbits and rabbits with candidal infection of the thigh, tissue concentrations of drug were determined by serial positron emission tomographic imaging. In rats, coinjection of tracer quantities of [4-18F]fluconazole with a pharmacological dose of unlabeled drug resulted in a relatively uniform distribution of radioactivity in most organs, whereas, when the 18F-tracer was injected alone, spleen, muscle and heart accumulation was decreased and liver accumulation was increased. In rabbits, this effect was less pronounced. Early accumulation of [4-18F]fluconazole was greater in infected muscle. The areas under the 2-hr uptake curves were 4.30 and 6.05 micrograms.hr.ml-1 for normal and infected tissue. A mathematical model was used to summarize the kinetics of fluconazole in normal and infected muscle. The model hypothesizes that fluconazole is compartmentalized in blood and tissue, with rate constants describing the transition between compartments. Direct measurement of the partition coefficient of fluconazole in muscle and predictions of the kinetic model were in close agreement, suggesting that fluconazole enters muscle via a passive transport mechanism. Transport rates of fluconazole, into (Kin) and out of tissue (kout), were increased in infected compared with normal muscle, possibly due to increased capillary permeability (Kin: 0.064 +/- 0.001 vs. 0.0270 +/- 0.0002, kout: 0.063 +/- 0.002 vs. 0.035 +/- 0.001).

Animals↗

PubMed1997

Emerging evidence of selection of fluconazole-tolerant fungi in surgical intensive care units.

OBJECTIVE: To determine whether increased use of fluconazole has coincided with a shift in the relative proportion of fluconazole-tolerant species isolated from critically ill surgical patients in 2 university hospitals. DESIGN: Microbiological data and fluconazole administration frequencies were reviewed among patients treated in the surgical intensive care units (SICUs) from January 1, 1990, through December 31, 1995. SETTING: The SICUs of the University of Virginia Medical Center, Charlottesville, and the Hospital of the University of Pennsylvania, Philadelphia. MAIN OUTCOME MEASURES: The number and species types of all fungal isolates and the number of patients treated with fluconazole for each of the 6 years were determined. RESULTS: A sharp increase in the use of fluconazole among critically ill surgical patients has occurred at both medical centers from 1990-1995. The culture results of most patients treated with fluconazole were negative for fungi (73% and 63% at the University of Virginia Medical Center and the Hospital of the University of Pennsylvania, respectively); there was a greater tendency to use fluconazole at the University of Virginia Medical Center compared with the Hospital of the University of Pennsylvania (2.2% vs 1.8% of patients admitted to the SICU received it, respectively; P = .007). There was a significant increase in the proportion of Candida glabrata isolated at the University of Virginia Medical Center (P < .01) from 1990-1995, but a similar change was not detectable at the Hospital of the University of Pennsylvania. CONCLUSIONS: These data justify concern that the increased use of fluconazole in SICUs may be promoting a shift in the fungal flora that cause nosocomial infections toward species that are more difficult to treat. Prospective studies about the use of fluconazole for prophylaxis and empirical therapy among SICU patients are warranted before its widespread use in these settings continues.

Antifungal Agents↗

PubMed2005

Fluconazole distribution in rat dermis following intravenous and topical application: a microdialysis study.

The objective of this study was to investigate the skin distribution of fluconazole, a water-soluble antifungal agent, following intravenous (i.v.) and topical administration in the awake freely moving rat. Following i.v. bolus injection of fluconazole (10 mg/kg), a dual-site microdialysis sampling was performed in jugular vein and dermis in five rats. In addition, cutaneous absorption was studied by dermal microdialysis sampling following topical application of Diflucan Gel 0.5% to 12 rats. Fluconazole microdialysate concentrations were measured by on-line HPLC. To calibrate in vivo the probes, a fluorinated analog (UK-54737) of fluconazole was used as retrodialysis marker after demonstrating that recoveries were no different. Following i.v. bolus injection, fluconazole rapidly penetrates into the dermis. Cutaneous microdialysis sampling provided dermal concentrations of fluconazole, which were very similar to the unbound plasma concentrations determined by vascular microdialysis. The distribution equilibrium was rapidly achieved with a dermis-to-plasma partition coefficient of 1.02+/-0.04 (n=5). Following topical application of 0.5 g of Diflucan Gel containing 0.5% of fluconazole, active unbound concentrations in dermis were measured by cutaneous microdialysis for 11 h after application. The area under the curve (AUC) of fluconazole in dermal dialysate was relatively constant to an implantation depth of approximately 350 microm. Below this depth, the AUC progressively decreased with increasing implantation depth of the probe. Finally, this study shows that cutaneous microdialysis is an effective and minimally invasive tool to evaluate the dermal pharmacokinetics of fluconazole following intravenous or topical administration.

Administration, Topical↗

PubMed2005

Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions.

PURPOSE: To assess the frequency of potential azole-drug interactions and consequences of interactions between fluconazole and other drugs in routine inpatient care. METHODS: We performed a retrospective cohort study of hospitalized patients treated for systemic fungal infections with an oral or intravenous azole medication between July 1997 and June 2001 in a tertiary care hospital. We recorded the concomitant use of medications known to interact with azole antifungals and measured the frequency of potential azole drug interactions, which we considered to be present when both drugs were given together. We then performed a chart review on a random sample of admissions in which patients were exposed to a potential moderate or major drug interaction with fluconazole. The list of azole-interacting medications and the severity of interaction were derived from the DRUGDEX System and Drug Interaction Facts. RESULTS: Among the 4,185 admissions in which azole agents (fluconazole, itraconazole or ketoconazole) were given, 2,941 (70.3%) admissions experienced potential azole-drug interactions, which included 2,716 (92.3%) admissions experiencing potential fluconazole interactions. The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3%), midazolam (17.5%), warfarin (14.7%), methylprednisolone (14.1%), cyclosporine (10.7%) and nifedipine (10.1%). Charts were reviewed for 199 admissions in which patients were exposed to potential fluconazole drug interactions. While four adverse drug events (ADEs) caused by fluconazole were found, none was felt to be caused by a drug-drug interaction (DDI), although in one instance fluconazole may have contributed. CONCLUSIONS: Potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.

Adverse Drug Reaction Reporting Systems↗

PubMed1997

Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Canadian Candidemia Study Group.

A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due to Candida glabrata or Candida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p = 0.39; one-sided 95% CI, -8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p = 0.66: one-sided 95% CI, -12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p = 0.52; chi-square test) and remained similar throughout the course of follow-up, Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.

Adult↗

PubMed1994

A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Multicentre Study Group.

A randomized, comparative study was conducted in 502 patients in 23 centres world-wide to assess the efficacy and safety of fluconazole versus nystatin and amphotericin B for prevention of fungal infection in a severely immunocompromised pediatric population. Patients scheduled within 48 hours to undergo chemotherapy or radiotherapy for hematological or oncological malignancies were randomly allocated to receive 3 mg/kg oral fluconazole once daily, 50,000 U/kg oral nystatin four times daily or 25 mg/kg oral amphotericin B four times daily. Prophylaxis began with the initiation of chemotherapy or radiotherapy and continued throughout a patient's hospital stay or period of neutropenia as necessary. The mean duration of fluconazole prophylaxis was 27.8 days and of the oral polyenes 29.2 days. The outcome of prophylaxis with fluconazole was significantly superior to that with the polyenes (p = 0.01). Mycologically verified infections occurred in 5 patients (2.1%) given fluconazole and in 21 (8.4%) given polyenes (p = 0.002). Clinical evaluation at the end of prophylaxis showed that the clinical outcome was definitely or possibly successful in 87% in the fluconazole group and 82% in the polyenes group with no significant differences between the treatment groups. Mycological evaluation demonstrated reduction or control of colonization in 84% in the fluconazole group and 85% in the polyenes group, again with no significant between-group differences. Possibly drug-related side effects, mainly mild to moderate gastrointestinal disturbances, were reported in 38 patients given fluconazole, with eight subsequent withdrawals, and in 21 patients given oral polyenes, with three subsequent withdrawals. Laboratory test abnormalities occurred in 28 patients given fluconazole and 24 given polyenes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2000

Effect of fluconazole on plasma fluvastatin and pravastatin concentrations.

OBJECTIVE: To study the effects of fluconazole on the pharmacokinetics of fluvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. METHODS: Two separate randomised, double-blind, two-phase, crossover studies with identical study design were carried out. In each study, 12 healthy volunteers were given a 4-day pretreatment with oral fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo, according to a randomisation schedule. On day 4, a single oral dose of 40 mg fluvastatin (study I) or 40 mg pravastatin (study II) was administered orally. Plasma concentrations of fluvastatin, pravastatin and fluconazole were measured over 24 h. RESULTS: In study 1, fluconazole increased the mean area under the plasma fluvastatin concentration-time curve (AUC0-infinity) by 84% (P < 0.01), the mean elimination half-life (t1/2) of fluvastatin by 80% (P < 0.01) and its mean peak plasma concentration (Cmax) by 44% (P < 0.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastatin. CONCLUSIONS: Fluconazole has a significant interaction with fluvastatin. The mechanism of the increased plasma concentrations and prolonged elimination of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism of fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. However, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors.

Adult↗

PubMed1998

Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174.

OBJECTIVE: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. METHODS: A randomised, double-blind, three-phase crossover study design was used. Eleven healthy volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg, fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo (control). On day 4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. RESULTS: The mean peak plasma concentration (Cmax) and area under the curve [AUC(0-infinity)] of E-3174 were significantly decreased by fluconazole to 30% and to 47% of their control values, respectively, and the t1/2 was increased to 167%. Fluconazole caused only a nonsignificant increase (23-41%) in the AUC and t1/2 of the unchanged losartan. Itraconazole had no significant effect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC(0-infinity)(E-3174)/AUC(0-infinity)losartan was 60% smaller during the fluconazole than during the placebo and itraconazole phases. No clinically significant changes in the effects of losartan on blood pressure and heart rate were observed between fluconazole, itraconazole and placebo phases. CONCLUSION: Fluconazole but not itraconazole interacts with losartan by inhibiting its metabolism to the active metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical significance of the fluconazole losartan interaction is unclear, but the possibility of a decreased therapeutic effect of losartan should be kept in mind.

Adult↗

PubMed1999

Increased adherence of fluconazole-resistant isolates of Candida species to explanted esophageal mucosa.

The adherence of fluconazole-resistant and fluconazole-susceptible isolates of Candida albicans to explanted rabbit esophageal mucosa was examined in vivo. Among six Candida albicans isolates collected from HIV-infected patients, three fluconazole-resistant (MIC > 64 microg/ml) isolates attached more avidly than three fluconazole-susceptible strains (MIC < or = 0.5 microg/ml) to esophageal mucosa (P < or = 0.05). When three strains each of six different Candida spp. were compared, the more inherently fluconazole-resistant isolates adhered more avidly in the following order: Candida glabrata>Candida krusei>Candida albicans fluconazole-sensitive>Candida tropicalis>Candida parapsilosis. Nonetheless, fluconazole-resistant Candida albicans demonstrated the greatest degree of adherence in comparison to all fluconazole-susceptible Candida albicans (P<0.001) and to all Candida spp. tested (P<0.001). Thus, the refractoriness of esophageal candidiasis in patients infected with fluconazole-resistant isolates may be related to both in vitro drug resistance and increased mucosal adherence.

Animals↗

PubMed2001

Evaluation of interaction between fluconazole and an oral contraceptive in healthy women.

OBJECTIVE: To evaluate the potential pharmacokinetic interaction between 2 x 150 mg fluconazole administered once weekly and an oral contraceptive (OC) containing ethinyl estradiol and norethindrone. METHODS: A placebo-controlled, double-masked, randomized, two-way crossover study was used to investigate the pharmacokinetic interaction between 300 mg fluconazole once weekly and the OC Ortho Novum 7/7/7 (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) in 26 healthy women, 18-36 years old. In the first cycle (28 days), subjects received OC only. In the second cycle, subjects were assigned randomly to receive OC-fluconazole or OC-placebo. In the third cycle, subjects were crossed over to the opposite treatment. RESULTS: Data for 21 subjects who completed the study were included in the pharmacokinetic analysis; data for all 26 subjects were included in the safety analysis (26 OC only; 24 OC-fluconazole; 23 OC-placebo). Treatment with OC-fluconazole resulted in small but statistically significant increases in 0-24 hour area under the plasma concentration-time curve (AUC(0-24)) for both ethinyl estradiol (mean 24%, 95% confidence interval [CI] 18%, 31%) and norethindrone (mean 13%, 95% CI 8%, 18%) as compared with treatment with OC-placebo. Ethinyl estradiol maximum plasma concentration (C(max)) was slightly (mean 8%, 95% CI 2%, 15%) though statistically significantly higher for OC-fluconazole treatment as compared with OC-placebo treatment. Norethindrone C(max) was not different (95% CI -6%, 11%) between the two treatment groups. No adverse events related to treatment were seen in the fluconazole treatment group. CONCLUSION: The concomitant administration of 300 mg fluconazole once weekly, twice the recommended dose for vaginal candidiasis, to women using OCs results in a slight increase in OC concentrations. Therefore, it appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.

Adolescent↗

PubMed1996

Fluconazole versus oral polyenes in the prophylaxis of immunocompromised patients: a cost-minimization analysis.

This study compares 100 mg daily fluconazole with oral polyenes four times daily in the prophylaxis of fungal infections in immunocompromised patients, to determine a cost-minimization strategy. Data was gathered through a literature survey and clinical interviews conducted in nine different UK hospitals. This was used to construct a decision tree, modelling the drug choices available to a clinician at various stages of a patient's treatment, and assigning probabilities to the different corresponding outcomes. UK cost data were fed into this model to determine the expected cost per patient of the different prophylaxis strategies. Two different patient groups were considered: chemotherapy-only patients, and bone-marrow-transplant (BMT) patients who have higher risks of fungal infection. Probabilities derived from the literature suggest that a cost-minimization strategy to manage both chemotherapy patients and BMT patients is to administer oral fluconazole, both as prophylaxis and as first line treatment, against superficial fungal infection. Probabilities gathered from clinical interviews yield similar results, suggesting that the cost-minimization strategy with chemotherapy-only patients is to administer oral polyenes as prophylaxis, and oral fluconazole in case of superficial fungal infection, while for BMT patients it is a combination of fluconazole and oral polyenes as prophylaxis, with oral fluconazole for the treatment of superficial fungal infections. Using the probabilities from the literature, the lowest cost strategies produce an expected cost of pounds 567.20 for chemotherapy-only patients, and an expected cost of pounds 804.87 for BMT patients for a course of treatment lasting from seven to 28 days. The clinical interview probabilities produce expected costs of pounds 826.48 and pounds 1529.43, respectively. Sensitivity analysis was then conducted, and it was found that in the majority of cases, using the literature probabilities, the cost-minimizing strategy remained prophylaxis with oral fluconazole. The sensitivity analysis for chemotherapy-only patients using the interview probabilities tended to favour oral polyenes as the cost-minimization strategy, whereas for BMT patients the sensitivity analysis favoured a combination of fluconazole and oral polyenes in the majority of cases. The key economic advantage of prophylaxis with fluconazole or a combination of fluconazole with oral polyenes in the prophylaxis of fungal infection in immunocompromised patients, results from the reduction of the expected cost of subsequent fungal infection among those who are most at risk.

Antifungal Agents↗

PubMed2005

Distribution and susceptibility to amphotericin B and fluconazole of Candida spp. isolated from Taiwan.

Susceptibilities to amphotericin B and fluconazole of 628 clinical yeast strains collected from 22 hospitals in Taiwan were determined. A total of 53 isolates (8.4%) were resistant to fluconazole. Each hospital had different resistance rate to fluconazole ranging from 0% to 24%. None of the 186 isolates from eight of the 22 hospitals was resistant to fluconazole. In contrast, isolates from nine of the remaining 14 hospitals had greater than 10% resistance rate to fluconazole. Consistently, 88.9% (8/9) fluconazole-resistant C. albicans isolates were from hospitals having a high resistance rate to fluconazole. The prevalence of various Candida spp. in each hospital was different. A positive association was found between the prevalence of C. tropicalis and the resistance rate to fluconazole for individual hospitals. Although only three isolates (0.5%) were resistant to amphotericin B, a co-resistance to both amphotericin B and fluconazole was observed, which highlights the emerging problem of drug resistance.

Amphotericin B↗

PubMed1995

Fluconazole vs. flucytosine in the treatment of esophageal candidiasis in AIDS patients: a double-blind, placebo-controlled study.

BACKGROUND AND STUDY AIMS: Contrasting opinions exist as to the pharmacological treatment of esophageal candidiasis in human immunodeficiency virus (HIV)-positive patients. The aim of this study has been to evaluate the role, therapeutic efficacy, and the cost-benefit ratio of two antifungal drugs, fluconazole and flucytosine, compared with a placebo, in the treatment of endoscopically-diagnosed esophageal candidiasis in patients with acquired immune deficiency syndrome (AIDS). PATIENTS AND METHODS: The study included 60 HIV-positive patients (38 males and 22 females, mean age 27 +/- 2) with a first episode of esophageal candidiasis diagnosed by endoscopy (grades I-II of Kodsi's endoscopic classification, and grades I-IIa of Barbaro's clinical classification). No other opportunistic infection of the esophagus was detected. In a double-blind procedure, patients were randomized into three groups of 20 patients each, receiving either fluconazole (3 mg/kg/daily per os), flucytosine (100 mg/kg/daily per os) or placebo. After two weeks of treatment, the patients previously assigned to receive the placebo were double-blindly randomized to receive fluconazole (eight patients) or flucytosine (nine patients). In order to evaluate the efficacy of pharmacological therapy, clinical examination was performed at weeks 2 and 5, and then every week up to the end of follow-up (three months); endoscopic examination was performed at weeks 2 and 5, and at the end of follow-up. RESULTS: At week 2, endoscopic cure (grade 0) was observed in 13 patients (65%) of the fluconazole group and in three patients (15%) in the flucytosine group (relative risk ratio: 0.23; 95% C.I.: 0.10-0.48; p < 0.05), and a partial endoscopic response (grade I) was observed in two patients (10%) in the placebo group. Complete clinical remission (grade 0) was observed in 16 patients (80%) in the fluconazole group and 12 patients (60%) in the flucytosine group (relative risk ratio: 0.75; 95% C.I.: 0.42-0.89; p = n.s.), while six patients (30%) in the placebo group presented partial clinical remission (grade I). At the end of follow-up, endoscopic cure was observed in 19 patients (70%) in the fluconazole group and in nine patients (33%) in the flucytosine group (relative risk ratio: 0.47; 95% C.I.: 0.19-0.65; p < 0.05). Complete clinical remission was observed in 21 patients (77.7%) in the fluconazole group and in 17 patients (63%) in the flucytosine group (relative risk ratio: 0.81; 95% C.I.: 0.53-0.92; p = n.s.). No noticeable side-effects were observed in the patients in either treatment group, without a statistically significant difference in comparison with the placebo. CONCLUSIONS: The results of this study have demonstrated that both fluconazole and flucytosine are safe and well tolerated in the treatment of esophageal candidiasis in AIDS patients. Fluconazole showed greater therapeutic efficacy than flucytosine, with a difference that was statistically significant in terms of the rate of endoscopic cure.

AIDS-Related Opportunistic Infections↗