Relationship between fluconazole dosage regimens and the emergence of fluconazole-resistant Candida albicans.
Explore the source record for details and available documents.
Antifungal Agents↗
SEARCH · PubMed Health
Results for “Fluconazole”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Azasordarins: susceptibility of fluconazole-susceptible and fluconazole-resistant clinical isolates of Candida spp. to GW 471558.
The in vitro activity of the azasordarin GW 471558 was compared with those of amphotericin B, flucytosine, itraconazole, and ketoconazole against 177 clinical isolates of Candida spp. GW 471558 showed potent activity against Candida albicans, Candida glabrata, and Candida tropicalis, even against isolates with decreased susceptibility to azoles. Candida krusei, Candida parapsilosis, Candida lusitaniae, and Candida guilliermondii are resistant to GW 471558 in vitro (MICs, >128 microg/ml).
Antifungal Agents↗
A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40.
BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections. METHODS: We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the "continuous fluconazole arm") with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the "episodic fluconazole arm") in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC. The primary study end point was the time to development of fluconazole-refractory OPC or EC, which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days, respectively. RESULTS: A total of 413 subjects were randomized to receive continuous fluconazole, and 416 were randomized to receive episodic fluconazole. After 42 months, 17 subjects (4.1%) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections, compared with 18 subjects (4.3%) in the episodic fluconazole arm, with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months (P=.88, by log-rank test) or before the end of the study (P=.97, by the log-rank test). Continuous fluconazole therapy was associated with fewer cases of OPC or EC (0.29 vs. 1.08 episodes per patient-year; P<.0001) and fewer invasive fungal infections (15 vs. 28 episodes; P=.04, by chi2 test), but not with improved survival, compared with episodic fluconazole therapy. CONCLUSION: Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC, compared with episodic fluconazole therapy, in HIV-infected patients with access to active antiretroviral therapy.
AIDS-Related Opportunistic Infections↗
Effects of fluconazole administration in critically ill patients: analysis of bacterial and fungal resistance.
HYPOTHESIS: The administration of fluconazole in intensive care unit (ICU) patients leads to the emergence of bacterial and fungal resistance. DESIGN: Retrospective analysis of 2 patient cohorts: (1) critically ill patients treated in surgical, trauma, and medical ICUs between June 1997 and January 1999 who did and did not receive fluconazole; and (2) ICU patients with fungal infections and sensitivity testing results from June 1994 to December 1998. SETTING: University-affiliated tertiary care hospital. PATIENTS: The first cohort included 99 ICU patients with documented microorganism culture(s) who were treated with (n = 50) or without (n = 49) fluconazole; the second cohort included 38 patients with Candida species infection, identification, and antifungal susceptibility testing. RESULTS: Mortality (40% vs 20%; P = .03) and hospital length of stay (33.8 vs 25.6 days; P = .04) were higher in the patients treated with fluconazole compared with patients not treated with fluconazole. The ICU length of stay was also higher in patients treated with fluconazole (23.7 vs 15.1 days; P = .009). An increase in bacterial resistance occurred in patients after fluconazole treatment as opposed to bacterial resistance of patients who were treated for bacterial microorganism(s) without fluconazole (16% vs 4%; P = .049). Comparison of patient populations with Candida species identification before and after December 1997 showed an increase in Candida species resistance to fluconazole (11% vs 36%; P = .16), respectively. Fungal strains were dominated by a combination of Candida albicans and Candida glabrata in both populations (60% [before 1998] vs 82% [after 1998]), with an emergence of Candida non-albicans species tolerant to fluconazole. The amount of fluconazole administered and the number of patients receiving fluconazole treatment in the ICUs has also increased when comparing both periods. CONCLUSIONS: Comparison of critically ill patient populations with and without fluconazole treatment found increased mortality and longer hospital and ICU lengths of stay in the fluconazole-treated group. This group also had higher bacterial pathogen resistance to antibiotics after fluconazole administration compared with bacterial resistance of patients without fluconazole treatment. Our results warrant concern regarding worsening bacterial infections, increased mortality, and an increase in Candida resistance to fluconazole from increased use in ICU patients, with a shift in yeast infection that is more difficult to treat.
Antifungal Agents↗
Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail.
BACKGROUND: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. OBJECTIVE: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. METHODS: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. RESULTS: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. CONCLUSION: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.
Antifungal Agents↗
Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial.
BACKGROUND: Among persons who receive solid organ transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective. OBJECTIVE: To evaluate the efficacy and safety of prophylactic fluconazole in liver transplant recipients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-affiliated transplantation center. PATIENTS: 212 liver transplant recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). CONCLUSIONS: Prophylactic fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.
Adolescent↗
Pharmacokinetics of fluconazole in the cerebrospinal fluid of children with hydrocephalus.
BACKGROUND: The aim of this study was to examine the pharmacokinetics of fluconazole in the CSF of children with hydrocephalus during CNS infection treatment after intravenous and/or intraventricular drug administration. Direct fluconazole administration into the ventricular CSF of patients to treat serious CNS infections is an aggressive therapy, and data on the pharmacokinetics of fluconazole in CSF are limited. METHODS: A method of fluconazole quantification in CSF by solid-phase extraction (SPE)-high-performance liquid chromatography (HPLC) was developed to conduct pharmacokinetic studies. The population of patients included 2 children with hydrocephalus. Fluconazole was administered intravenously at average multiple doses of 12.5 mg/kg/24 h and intraventricularly at doses of 4, 5 and 7.5 mg/24 h, and 7.5 and 10 mg/12 h. The CSF samples were taken 2-24 h after administration of fluconazole. The concentrations of fluconazole in CSF specimens were assessed, and after pharmacokinetic studies the fluconazole dosage was modified. RESULTS: The method of fluconazole determination in CSF using the SPE-HPLC method is specific, precise and accurate. After intravenous fluconazole administration, the concentration of this antifungal drug was not detected in the ventricular CSF. The pharmacokinetic parameters determined after intraventricular fluconazole administration were: steady-state peak CSF fluconazole concentration (19.54 +/- 5.63 mg/l); trough CSF fluconazole concentration (0.0-0.3 mg/l); elimination rate constant (0.4654 +/- 0.2097 h(-1)), and half-life (1.84 +/- 0.93 h). CONCLUSIONS: The authors developed a method to determine fluconazole in CSF by SPE-HPLC. After intravenous fluconazole administration, the drug was not detected in the examined CSF samples. The intraventricular multidose pharmacokinetic data suggest the necessity of fluconazole monitoring in children with hydrocephalus during the treatment of shunt infection.
Adolescent↗
Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance.
PURPOSE: To study the epidemiology of oral candidiasis and the effect of treatment of thrush in human immunodeficiency virus (HIV)-infected patients. PATIENTS AND METHODS: We conducted a prospective observational study of 92 patients over 1 year, including a nonblinded, randomized treatment trial of thrush with clotrimazole troches or oral fluconazole. Oral sites were cultured monthly and when thrush occurred. Candida albicans strains were typed by contour-clamped homogeneous electric field (CHEF) electrophoresis. Changes in strains were evaluated over time and in regard to their associations with particular sites, episodes of thrush, relapse after treatment, and colonization of sexual partners. Susceptibility to fluconazole was tested and CHEF analysis was done on these strains to determine the epidemiology of fluconazole resistance. RESULTS: Yeasts colonized 84% of patients. C albicans accounted for 81% of all isolates and was separated into 34 distinct strains. Most patients had persistent carriage of 1 or 2 dominant strains of C albicans. Three couples shared strains. Nineteen different C albicans strains caused 82 episodes of thrush in 45 patients. CD4 < 200/microL was associated with development of thrush. Clinical cure rates were similar with fluconazole (96%) and clotrimazole (91%), but mycologic cure was better with fluconazole (49%) than clotrimazole (27%). Following mycologic cure, colonization recurred with the same strain 74% of the time. Colonization with Torulopsis glabrata and Saccharomyces cerevisiae increased after treatment with either drug, but these organisms were never a sole cause of thrush. In a subset of 35 patients followed for over 3 months in whom fluconazole susceptibilities were performed, minimum inhibitory concentrations (MICs) to fluconazole increased only in those on fluconazole prophylaxis. Clinical failure of fluconazole was associated with an MIC > or = 64 micrograms/mL in 3 patients, and with an MIC of 8 micrograms/mL in 1 patient. In 2 of these 4 patients, the prior colonizing strain developed fluconazole resistance. In the other 2, new resistant strains were acquired. CONCLUSIONS: Many different strains of C albicans colonize and cause thrush in patients infected with HIV. Patients are usually persistently colonized with a single strain, and recurrences following treatment are usually due to the same strain. Transmission of strains may occur between couples. Fluconazole and clotrimazole are equally effective in treating thrush, but mycologic cure occurs more often with fluconazole. Fluconazole resistance in C albicans occurs most often in patients who have low CD4 counts and are taking fluconazole prophylactically for recurrent thrush. Fluconazole resistance may occur through acquisition of a new resistant strain or by development of resistance in a previously susceptible strain.
AIDS-Related Opportunistic Infections↗
Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques.
AIMS: To investigate uptake of fluconazole into the interstitial fluid of human subcutaneous tissue using the microdialysis and suction blister techniques. METHODS: A sterile microdialysis probe (CMA/60) was inserted subcutaneously into the upper arm of five healthy volunteers following an overnight fast. Blisters were induced on the lower arm using gentle suction prior to ingestion of a single oral dose of fluconazole (200 mg). Microdialysate, blister fluid and blood were sampled over 8 h. Fluconazole concentrations were determined in each sample using a validated HPLC assay. In vivo recovery of fluconazole from the microdialysis probe was determined in each subject by perfusing the probe with fluconazole solution at the end of the 8 h sampling period. Individual in vivo recovery was used to calculate fluconazole concentrations in subcutaneous interstitial fluid. A physiologically based pharmacokinetic (PBPK) model was used to predict fluconazole concentrations in human subcutaneous interstitial fluid. RESULTS: There was a lag-time (approximately 0.5 h) between detection of fluconazole in microdialysate compared with plasma in each subject. The in vivo recovery of fluconazole from the microdialysis probe ranged from 57.0 to 67.2%. The subcutaneous interstitial fluid concentrations obtained by microdialysis were very similar to the unbound concentrations of fluconazole in plasma with maximum concentration of 4.29 +/- 1.19 microg ml(-1) in subcutaneous interstitial fluid and 3.58 +/- 0.14 microg ml(-1) in plasma. Subcutaneous interstitial fluid-to-plasma partition coefficient (Kp) of fluconazole was 1.16 +/- 0.22 (95% CI 0.96, 1.35). By contrast, fluconazole concentrations in blister fluid were significantly lower (P < 0.05, paired t-test) than unbound plasma concentrations over the first 3 h and maximum concentrations in blister fluid had not been achieved at the end of the sampling period. There was good agreement between fluconazole concentrations derived from microdialysis sampling and those estimated using a blood flow-limited PBPK model. CONCLUSIONS: Microdialysis and suction blister techniques did not yield comparable results. It appears that microdialysis is a more appropriate technique for studying the rate of uptake of fluconazole into subcutaneous tissue. PBPK model simulation suggested that the distribution of fluconazole into subcutaneous interstitial fluid is dependent on tissue blood flow.
Adult↗
Fluconazole-resistant candidosis in an HIV cohort.
OBJECTIVES: To report the occurrence of HIV-related mucosal candidosis that fails to respond to fluconazole, to establish the correlation between in vitro susceptibility testing and clinical failure, and to assess the efficacy of alternative treatments. DESIGN: Chart review of all patients with fluconazole failure and all patients with CD4 counts < 50 x 10(6)/l continuing to respond to fluconazole, and prospective in vitro susceptibility testing of Candida. SETTING: A regional treatment centre for HIV-infected individuals in north-west England. PATIENTS: A cohort of 155 HIV-positive individuals with CD4 counts < 300 x 10(6)/l cells. MAIN OUTCOME MEASURES: Clinical fluconazole failure was defined as symptomatic oropharyngeal or oesophageal candidosis despite fluconazole > or = 100 mg per day for 10 days. In vitro susceptibility to fluconazole was determined for Candida isolates. Cumulative 12-month fluconazole dose and time from first fluconazole therapy and prophylaxis were recorded. RESULTS: Nine (5.8%) patients meeting the definition of fluconazole failure were identified. In vitro susceptibility to fluconazole of temporally related oropharyngeal isolates was reduced in all cases. Intravenous amphotericin B was the only effective treatment for these patients when symptoms were severe suggesting azole cross-resistance. One patient, who had received alternative treatments for 9 months, reverted from in vitro and clinical fluconazole sensitivity but relapsed within 6 weeks of resuming fluconazole. The median fluconazole dose over the preceding 12 months for the eight adult cases was 386 mg weekly. The median dose for the same period was 79 mg weekly in 28 patients with CD4 counts < 50 x 10(6)/l but without fluconazole failure (difference, 307; 95% confidence interval, 199-514; P < 0.0001). CONCLUSION: A substantial problem of clinical fluconazole failure has developed among HIV-positive patients who have recurrent problematic mucosal candidosis.
AIDS-Related Opportunistic Infections↗
Identification and expression of multidrug transporters responsible for fluconazole resistance in Candida dubliniensis.
Candida dubliniensis is a recently described Candida species associated with oral candidosis in human immunodeficiency virus (HIV)-infected and AIDS patients, from whom fluconazole-resistant clinical isolates have been previously recovered. Furthermore, derivatives exhibiting a stable fluconazole-resistant phenotype have been readily generated in vitro from fluconazole-susceptible isolates following exposure to the drug. In this study, fluconazole-resistant isolates accumulated up to 80% less [3H] fluconazole than susceptible isolates and also exhibited reduced susceptibility to the metabolic inhibitors 4-nitroquinoline-N-oxide and methotrexate. These findings suggested that C. dubliniensis may encode multidrug transporters similar to those encoded by the C. albicans MDR1, CDR1, and CDR2 genes (CaMDR1, CaCDR1, and CaCDR2, respectively). A C. dubliniensis homolog of CaMDR1, termed CdMDR1, was cloned; its nucleotide sequence was found to be 92% identical to the corresponding CaMDR1 sequence, while the predicted CdMDR1 protein was found to be 96% identical to the corresponding CaMDR1 protein. By PCR, C. dubliniensis was also found to encode homologs of CDR1 and CDR2, termed CdCDR1 and CdCDR2, respectively. Expression of CdMDR1 in a fluconazole-susceptible delta pdr5 null mutant of Saccharomyces cerevisiae conferred a fluconazole-resistant phenotype and resulted in a 75% decrease in accumulation of [3H]fluconazole. Northern analysis of fluconazole-susceptible and -resistant isolates of C. dubliniensis revealed that fluconazole resistance was associated with increased expression of CdMDR1 mRNA. In contrast, most studies showed that overexpression of CaCDR1 was associated with fluconazole resistance in C. albicans. Increased levels of the CdMdr1p protein were also detected in fluconazole-resistant isolates. Similar results were obtained with fluconazole-resistant derivatives of C. dubliniensis generated in vitro, some of which also exhibited increased levels of CdCDR1 mRNA and CdCdr1p protein. These results demonstrate that C. dubliniensis encodes multidrug transporters which mediate fluconazole resistance in clinical isolates and which can be rapidly mobilized, at least in vitro, on exposure to fluconazole.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A retrospective Evaluation of fluconazole for the treatment of Candida glabrata fungemia.
BACKGROUND: Candida glabrata accounts for 21% of Candida bloodstream isolates in the United States and ranges from susceptible-dose-dependent to resistant to fluconazole. A fluconazole dose of 800 mg/d ( approximately 12 mg/kg per day) is predicted to produce peak plasma concentrations that surpass the susceptible-dose-dependent MIC breakpoint of 16 to 32 mug/mL. Accordingly, the Infectious Diseases Society of America treatment guidelines for candidiasis recommend fluconazole 12 mg/kg per day as an alternative option for treatment of C glabrata fungemia. OBJECTIVE: The main objective of this study was to evaluate fluconazole retrospectively as a treatment for C glabrata fungemia. METHODS: Data were collected through a database that stores patient information electronically and can be accessed and queried, and chart review at Barnes-Jewish Hospital (St. Louis, Missouri) from January 1999 to August 2002. Eligible patients who had at least 1 positive blood culture for C glabrata and received at least 1 dose of fluconazole were identified through the electronic query. Chart reviews of these patients followed. The primary outcomes were fungemia eradication and in-hospital mortality. RESULTS: Of the total 124 cases of C glabrata fungemia identified, 54 patient charts were evaluable. Chart review revealed that 65% (17/26) of patients receiving fluconazole as the sole antifungal therapy had successful bloodstream eradication of C glabrata, whereas approximately 54% (15/28) of patients who were changed from fluconazole to an amphotericin B formulation had successful bloodstream eradication. Although no association was found between fluconazole dose and fungemia eradication in the entire study population, higher doses of fluconazole (> or =400 mg/d) were more likely to achieve fungemia eradication than lower doses (< or =400 mg/d) in the subset of patients who received only fluconazole (P = 0.042). Mortality rates were approximately 24% (4/17) and 40% (6/15) in patients having successful bloodstream eradication with fluconazole alone and with fluconazole followed by amphotericin B, respectively, compared with 38% (3/8) in patients with persistent fungemia who received fluconazole alone. CONCLUSIONS: Fluconazole was a viable therapy for C glabrata fungemia, with bloodstream eradication in 65% of patients and mortality rates of 24% to 40% in this retrospective chart review.
Algorithms↗
The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil.
UNLABELLED: The azole antimycotic fluconazole inhibits cytochrome P450 enzymes. We studied the possible interaction of alfentanil with oral and i.v. fluconazole in a three-phase, double-blind, placebo-controlled, randomized, cross-over study at intervals of 4 wk. Nine healthy volunteers were given a single oral dose of either fluconazole 400 mg or placebo, followed within 60 min by either i.v. fluconazole 400 mg in saline or saline only. The dose of 20 micrograms/kg of alfentanil was given i.v. 1 h after the fluconazole/placebo. Venous plasma samples were collected, and pharmacodynamic measurements were performed for 10 h. Alfentanil clearance was decreased from 3.1 +/- 1.1 mL.min-1.kg-1 to 1.3 +/- 0.3 mL.min-1. kg-1 after i.v. fluconazole and to 1.4 +/- 0.4 mL.min-1. kg-1 after oral fluconazole (P < 0.001). The mean elimination half-life of alfentanil was almost doubled after both oral and i.v. fluconazole (P < 0.001). Fluconazole increased the subjective effects of alfentanil as quantified on visual analog scales (P < 0.01). Correspondingly, both i.v. and oral fluconazole also increased the alfentanil-induced respiratory depression by decreasing the respiratory rate by 10%-15% (P < 0.05). We conclude that metabolism of alfentanil is inhibited by oral and i.v. fluconazole and that caution should be exercised when alfentanil is given to patients receiving fluconazole. IMPLICATIONS: We studied the interaction of cytochrome P450 3A4 enzyme inhibitor fluconazole with alfentanil. Nine volunteers were given placebo or fluconazole 400 mg orally or i.v. Alfentanil 20 micrograms/kg was given i.v. 1 h after pretreatment. Fluconazole decreased the clearance of alfentanil by 55% and increased the alfentanil-induced subjective effects.
Administration, Oral↗
Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance.
Fluconazole-susceptible Candida albicans strains accumulated [3H]fluconazole at a rate of approximately 2 pmol/min per 10(9) cells. Fluconazole accumulation was not affected by the pretreatment of cells with sodium azide or with 2-deoxyglucose. The rate of fluconazole accumulation became saturated at high fluconazole concentrations and was not affected by the addition of ketoconazole, and there was no fluconazole accumulation in cells incubated at 4 degrees C. A fluconazole-resistant mutant of C. albicans SGY-243 was isolated following growth enrichment in fluconazole-containing medium. Cells of the mutant strain, designated FR2, showed a reduced rate of fluconazole accumulation compared with SGY-243 and were not resistant to other azole antifungal agents. The rates of fluconazole accumulation by C. albicans FR2 and the other azole-resistant strains, B59630, AD, and KB, were increased in the presence of sodium azide, suggesting that fluconazole resistance in these strains may be associated with an energy-dependent drug efflux. Fluconazole-resistant C. albicans strains all contained elevated amounts (2- to 17-fold) of mRNA encoding Cdr1, and an ATP-binding cassette-type transporter. In addition, C. albicans FR2 also contained increased amounts of mRNA encoding Benr, a major facilitator superfamily transporter. These results suggest that fluconazole enters C. albicans cells by facilitated diffusion and that fluconazole resistance may involve energy-dependent drug efflux associated with increased expression of Benr and/or Cdr1.
Antifungal Agents↗
Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis.
Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC. MICs of fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, </=0.125 microgram/ml) and three fluconazole-resistant (FR) (MIC, >/=64 microgram/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied. FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P < 0.001) and tissue burden of C. albicans in tongue, soft palate, and esophagus (P < 0.001). In comparison, rabbits infected with FR isolates were unresponsive to fluconazole and had no reduction in oral mucosal quantitative cultures or tissue burden of C. albicans versus untreated controls. We conclude that there is a strong correlation between in vitro fluconazole susceptibility by NCCLS methods and in vivo response to fluconazole therapy of OPEC due to C. albicans.
Animals↗
A randomized controlled trial assessing the efficacy of fluconazole in the treatment of pediatric tinea capitis.
BACKGROUND: Griseofulvin is considered first-line therapy for tinea capitis, and the Physician's Desk Reference currently recommends 11 mg/kg per day microsize formulation for use in children. Diverse selective pressures have resulted in waning clinical efficacy of griseofulvin, such that higher doses and longer courses of treatment are required. These events have prompted the search for therapeutic alternatives. Fluconazole is one such treatment option, and a variety of studies using this drug have shown promise in the treatment of pediatric tinea capitis. OBJECTIVE: We sought to assess the efficacy, safety, and optimal dose and duration of fluconazole therapy compared with standard-dose griseofulvin (11 mg/kg per day microsize formulation) in the treatment of pediatric tinea capitis. METHODS: This randomized, multicenter, third-party-blind, 3-arm trial was designed as a superiority study to identify a therapeutically superior agent/regimen from the 3 treatment arms: (1) fluconazole 6 mg/kg per day for 3 weeks followed by 3 weeks of placebo, (2) fluconazole 6 mg/kg per day for 6 weeks, and (3) griseofulvin 11 mg/kg per day for 6 weeks. Efficacy variables included mycological, clinical, and combined outcomes. The primary efficacy variable was the combined outcome of the modified intent-to-treat population at week 6. Patient safety was assessed throughout the study. Statistical analysis of the efficacy variables was conducted by means of the Cochran-Mantel-Haenszel test. RESULTS: At the end of treatment, mycological cures were present in 44.5%, 49.6%, and 52.2% of the fluconazole 3-week, fluconazole 6-week, and griseofulvin groups, respectively. Analysis of the primary efficacy variable failed to identify any superior agent, and differences between the combined outcomes of the fluconazole 6-week and griseofulvin groups at week 6 were not significant (P = .32). Regarding mycological, clinical, and combined outcomes, no significant differences between the fluconazole 6-week and griseofulvin groups were detected at any time point in the study. No new safety concerns were raised by this trial, and the incidence of treatment-related adverse events noted in this study is concordant with previous reports. Patients in the fluconazole arms of the study fared similarly. At the end of the trial, the difference in mycological cures between the fluconazole arms was only 7.5%, and increases in the incidence of certain treatment-related adverse events were observed in the fluconazole 6-week group. LIMITATIONS: Adjunctive topical therapies and the impact of infected contacts were not assessed in this trial. CONCLUSION: Systemic therapy with fluconazole 6 mg/kg per day and standard-dose griseofulvin produces comparable but low mycological and clinical cure rates. The limited efficacy of standard-dose griseofulvin and the lack of consensus regarding dose and duration of griseofulvin therapy in tinea capitis emphasize the need for controlled trials to identify optimal treatment parameters. Although the efficacy of fluconazole is no better than that of standard-dose griseofulvin, it may still be useful in select patients with a contraindication or intolerance to high-dose griseofulvin. The outcomes observed in this trial highlight the need to more clearly define the relative importance of adjunctive topical therapies and the evaluation and treatment of infected contacts as factors affecting cure rates.
Antifungal Agents↗
Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail.
BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS: In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS: At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION: The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.
Adolescent↗
Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis.
OBJECTIVE: To evaluate the impact of fluconazole prophylaxis on the incidence of fungal infections and on mortality among critically ill surgical patients. DESIGN: Meta-analysis of randomized, placebo-controlled trials of fluconazole prophylaxis. PATIENTS: Subjects participating in the clinical trials in this area. MEASUREMENTS AND MAIN RESULTS: We identified four randomized studies comparing fluconazole to placebo for prevention of fungal infections in the surgical intensive care unit (SICU). The studies enrolled 626 patients and used differing dosing regimens of fluconazole. All trials were double-blind and two were multicenter studies. Fluconazole administration significantly reduced the incidence of fungal infections (pooled odds ratio, 0.44; 95% confidence interval, 0.27-0.72; p < .001). However, fluconazole prophylaxis was not associated with a survival advantage (pooled OR for mortality, 0.87; 95% confidence interval, 0.59-1.28; p = NS). Fluconazole did not statistically alter the rate of candidemia, as this was low across the studies and developed in only 2.2% of all participants. Performing a sensitivity analysis and including two additional studies that indirectly examined fluconazole prophylaxis in the critically ill did not change our observations. Data from the reports reviewed were insufficient to allow comment on the impact of fluconazole prophylaxis on resource utilization, the distribution of non-albicans species of Candida, and the emergence of antifungal resistance. Generally, fluconazole appeared to be safe for SICU patients. CONCLUSIONS: Prophylactic fluconazole administration for prevention of mycoses in SICU patients appears to successfully decrease the rate of these infections, but this strategy does not improve survival. The absence of a survival advantage may reflect the few studies in this area and the possibility that this issue has not been adequately studied. Because of the potential for both resistance and emergence of non-albicans isolates, clinicians must consider these issues when evaluating fluconazole prophylaxis in the SICU. Future trials should focus on more precisely identifying patients at high risk for fungal infections and on determining if broader use of fluconazole alters the distribution of candidal species seen in the SICU and impacts measures of resource utilization such as length of stay and duration of mechanical ventilation.
Antifungal Agents↗