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PubMed1999

Efficacies of high-dose fluconazole plus amphotericin B and high-dose fluconazole plus 5-fluorocytosine versus amphotericin B, fluconazole, and 5-fluorocytosine monotherapies in treatment of experimental endocarditis, endophthalmitis, and pyelonephritis due to Candida albicans.

We compared the efficacies of fluconazole (Flu), amphotericin B (AmB), and 5-fluorocytosine (5FC) monotherapies with the combination of Flu plus 5FC and Flu plus AmB in a rabbit model of Candida albicans endocarditis, endophthalmitis, and pyelonephritis. The dose of Flu used was that which resulted in an area under the concentration-time curve in rabbits equivalent to that seen in humans who receive Flu at 1,600 mg/day, the highest dose not associated with central nervous system toxicity in humans. Quantitative cultures of heart valve vegetations, the choroid-retina, vitreous humor, and kidney were conducted after 1, 5, 14, and 21 days of therapy. All untreated controls died within 6 days of infection; animals treated with 5FC monotherapy all died within 18 days. In contrast, 93% of animals in the other treatment groups appeared well and survived until they were sacrificed. At day 5, the relative decreases in CFU per gram in the vitreous humor were greater in groups that received Flu alone and in combination with 5FC or AmB than in groups receiving AmB or 5FC monotherapies (P < 0. 005) but were similar thereafter. In the choroid-retina, 5FC was the least-active drug. However, there were no differences in choroidal fungal densities between the other treatment groups. On days 5 and 14 of therapy, fungal densities in kidneys of AmB recipients were lower than those resulting from the other therapies (P < 0.001 and P < or = 0.038, respectively) and AmB-plus-Flu therapy was antagonistic; however, all therapies for fungal pyelonephritis were similar by treatment day 21. While fungal counts in cardiac valves of Flu recipients were similar to those of controls on day 5 of therapy and did not change from days 1 to 21, AmB therapy significantly decreased valvular CFUs versus Flu at days 5, 14, and 21 (P < 0.005 at each time point). 5FC plus Flu demonstrated enhanced killing in cardiac vegetations compared with Flu or 5FC as monotherapies (P < 0. 03). Similarly, the combination of AmB and Flu was more active than Flu in reducing the fungal density in cardiac vegetations (P < 0.03). However, as in the kidney, AmB plus Flu demonstrated antagonism versus AmB monotherapy in the treatment of C. albicans endocarditis (P < 0.05, P = 0.036, and P < 0.008 on days 5, 14, and 21, respectively).

Amphotericin B↗

PubMed1998

Fluconazole-resistant Candida species in the oral flora of fluconazole-exposed HIV-positive patients.

The purpose of this study was to examine the effect of preceding fluconazole treatment on the oral mycologic flora and on the sensitivity of oral Candida albicans isolates to fluconazole. Saline oral rinses were collected from 89 HIV-positive patients, of whom 48 had been exposed to fluconazole and 41 were fluconazole-naive. The rinses were cultured on Sabouraud's and Pagano Levin agars, and yeasts were identified by standard methods. Fluconazole sensitivity of C. albicans isolates was measured by disk diffusion assay. C. albicans was isolated from 69% of patients who had received fluconazole and from 93% of the patients who were fluconazole-naive (p < 0.05). Nine other species of yeasts were also isolated, most commonly C. glabrata. Five patients previously exposed to fluconazole harbored fluconazole-resistant C. albicans, whereas no resistance was detected among the patients who were fluconazole-naive (p < 0.01). Sixteen of the patients who were fluconazole-exposed carried yeasts other than C. albicans, compared with only five patients in the fluconazole-naive group (p < 0.01). All of the fluconazole-resistant strains were isolated from patients with low CD4 counts (less than 100 cells/ml) and after lengthy fluconazole exposures. Nevertheless, patients in Charlotte, N.C., who had a greater mean fluconazole exposure time (10.25 +/- 1.41 months) than patients in Glasgow, UK, (0.65 +/- 0.18 months; p < 0.005), did not develop significantly more in vitro resistance or species diversity. This study indicates that long-term fluconazole treatment can have significant effects on the yeast flora of the mouth, particularly in a patient with a CD4 count of less than 100 cells/ml.

Adult↗

PubMed2000

In vivo activity of amphotericin B lipid complex in immunocompromised mice against fluconazole-resistant or fluconazole-susceptible Candida tropicalis.

We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.

Amphotericin B↗

PubMed1996

Effect of fluconazole dose on the extent of fluconazole-triazolam interaction.

1. Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases. 2. Eight healthy volunteers received either 50 mg, 100 mg or 200 mg (400 mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25 mg oral dose of triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18 h. 3. The mean area under the triazolam concentration-time curve (AUC) was increased 1.6-, 2.1- and 4.4-fold (P < 0.001) by fluconazole 50 mg, 100 mg and 200 mg, respectively. The increase in the elimination half-life of triazolam (t1/2,z) varied from 1.3-fold (fluconazole 50 mg, P < 0.05) to 2.3-fold (fluconazole 200 mg, P < 0.001). The peak concentration of triazolam was also increased significantly during all fluconazole phases; more than twofold by fluconazole 200 mg (P < 0.001). 4. The pharmacodynamic effects of triazolam were increased significantly (P < 0.05) by fluconazole 100 mg and 200 mg. 5. Even a small 50 mg daily dose of fluconazole can interact with triazolam and the extent of the interaction increases with increasing fluconazole dose. When triazolam is used concomitantly with fluconazole 50-200 mg, the dose of triazolam should be reduced, accordingly. Simultaneous use of triazolam with higher fluconazole doses should be avoided.

Adult↗

PubMed2000

Amphotericin B vs fluconazole for controlling fungal infections in neutropenic cancer patients.

BACKGROUND: Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever. OBJECTIVES: To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia. SEARCH STRATEGY: MEDLINE and Cochrane Library (March 2000). Letters, abstracts, and unpublished trials. The industry and authors were contacted. SELECTION CRITERIA: Randomised trials comparing fluconazole with amphotericin B. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by both authors independently. MAIN RESULTS: Thirteen trials (2977 patients) were included. In 3 large 3-armed trials, which comprised 43% of the patients, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is an ineffective drug in theses circumstances, this approach creates a bias in favour of fluconazole. Furthermore, 79% of the patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or the manufacturer of fluconazole. There was no significant difference in effect between fluconazole and amphotericin B. Apart from the "polyene" trials, more patients dropped out of the study when they received amphotericin B. REVIEWER'S CONCLUSIONS: Amphotericin B had been disfavoured in most of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent with a documented effect on mortality and is considerably cheaper than fluconazole, it should be preferred.

Amphotericin B↗

PubMed2004

Cross-resistance between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict susceptibility and resistance to ravuconazole among 12,796 clinical isolates of Candida spp.

Cross-resistance within a class of antimicrobial agents is a problem that is often encountered with antibacterial agents, and it is also an issue with antifungal agents. A current example is ravuconazole, a new triazole antifungal with an expanded spectrum and potency against Candida spp., Aspergillus spp., and other opportunistic fungal pathogens. The present study addresses the issue of cross-resistance between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict the susceptibility of Candida spp. to ravuconazole. Reference broth microdilution MIC results for 12,796 strains of Candida spp. isolated from more than 200 medical centers worldwide were used. Ravuconazole MICs and tentative interpretive categories (susceptible, </=1 microg/ml; resistant, >/=2 microg/ml) were compared with those of fluconazole by using regression statistics and error rate bounding analyses. For all 12,796 isolates, the absolute categorical agreement rate was 92.5% (rate of false-susceptible results, or very major errors [VME], 0.1%). Ravuconazole was active (MIC, </=1 microg/ml) against 99.9% of the fluconazole-susceptible isolates, 96% of the fluconazole-susceptible dose-dependent isolates, and 49% of the fluconazole-resistant isolates, including 99% of the Candida krusei isolates. Since ravuconazole is 16- to 32-fold more potent than fluconazole, the performance of fluconazole as a surrogate marker for ravuconazole susceptibility was improved by designating those isolates with fluconazole MICs of </=32 microg/ml susceptible to ravuconazole, resulting in a categorical agreement rate of 98.3%, with a VME rate of 0.3% (99 and 0.4%, respectively, when C. krusei was omitted). Cross-resistance between fluconazole and ravuconazole applies most directly to fluconazole-resistant Candida glabrata and is variable among other species of Candida. Fluconazole may serve as a surrogate marker to predict the susceptibility of Candida spp. to ravuconazole.

Antifungal Agents↗

PubMed1996

Oropharyngeal yeast flora and fluconazole resistance in HIV-infected patients receiving long-term continuous versus intermittent fluconazole therapy.

OBJECTIVE: To examine the impact of continuous versus intermittent fluconazole therapy on fungal colonization and fluconazole resistance in the oropharynx of HIV-infected patients. DESIGN: Case-control study. SETTING: Duke University Adult Infectious Diseases Clinic, a tertiary referral center in North Carolina which provides care for 700 HIV-infected persons. PATIENTS: Nineteen HIV-infected patients on daily continuous fluconazole for a minimum of 6 months and eleven HIV-infected patients on intermittent fluconazole for a minimum of 6 months were matched by sex and CD4 cell count to HIV-infected patients who had not received fluconazole in the preceding 6 months. MAIN OUTCOME MEASURES: Fungal isolation and fluconazole susceptibility testing were performed on oral saline rinses from each patient. RESULTS: The patients taking continuous fluconazole were more likely than matched controls to have had sterile mouth rinses (14 out of 19 versus five out of 19; P < 0.001), and the yeasts that were isolated were more likely than matched controls to be non-Candida albicans species and to have minimum inhibitory concentrations (MIC) to fluconazole > or = 16 micrograms/ml. None of these isolates were associated with symptoms. In contrast, none of the patients in the intermittent fluconazole group had sterile cultures. When this group was compared to controls, they were more likely to have had non-C. albicans species, and the C. albicans isolates obtained had higher MIC to fluconazole. CONCLUSIONS: Long-term continuous therapy with fluconazole may prevent the appearance of Candida in the oral cavity. This finding may reduce recurrence rates and might favorably impact on the clinical appearance of mucosal candidiasis with resistant C. albicans.

Adult↗

PubMed2003

Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter.

An unusual interaction between flucytosine and fluconazole was observed when a collection of 60 Candida lusitaniae clinical isolates was screened for cross-resistance. Among eight isolates resistant to flucytosine (MIC >/= 128 micro g/ml) and susceptible to fluconazole (0.5 < MIC < 2 micro g/ml), four became flucytosine-fluconazole cross resistant when both antifungals were used simultaneously. Fluconazole resistance occurred only in the presence of high flucytosine concentrations, and the higher the fluconazole concentration used, the greater the flucytosine concentration necessary to trigger the cross-resistance. When the flucytosine- and fluconazole-resistant cells were grown in the presence of fluconazole alone, the cells reversed to fluconazole susceptibility. Genetic analyses of the progeny from crosses between resistant and sensitive isolates showed that resistance to flucytosine was derived from a recessive mutation in a single gene, whereas cross-resistance to fluconazole seemed to vary like a quantitative trait. We further demonstrated that the four clinical isolates were susceptible to 5-fluorouracil and that cytosine deaminase activity was unaffected. Kinetic transport studies with [(14)C]flucytosine showed that flucytosine resistance was due to a defect in the purine-cytosine permease. Our hypothesis was that extracellular flucytosine would subsequently behave as a competitive inhibitor of fluconazole uptake transport. Finally, in vitro selection of spontaneous and induced mutants indicated that such a cross-resistance mechanism could also affect other Candida species, including C. albicans, C. tropicalis, and C. glabrata. This is the first report of a putative fluconazole uptake transporter in Candida species and of a possible resistance mechanism associated with a deficiency in the uptake of this drug.

Antifungal Agents↗

PubMed2001

Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses.

OBJECTIVE: To determine the pharmacokinetics of fluconazole in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Fluconazole (10 mg/kg of body weight) was administered intravenously or orally with 2 weeks between treatments. Plasma fluconazole concentrations were determined prior to and 10, 20, 30, 40, and 60 minutes and 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after administration. A long-term oral dosing regimen was designed in which all horses received a loading dose of fluconazole (14 mg/kg) followed by 5 mg/kg every 24 hours for 10 days. Fluconazole concentrations were determined in aqueous humor, plasma, CSF, synovial fluid, and urine after administration of the final dose. RESULTS: Mean (+/- SD) apparent volume of distribution of fluconazole at steady state was 1.21+/-0.01 L/kg. Systemic availability and time to maximum plasma concentration following oral administration were 101.24+/-27.50% and 1.97+/-1.68 hours, respectively. Maximum plasma concentrations and terminal half-lives after IV and oral administration were similar. Plasma, CSF, synovial fluid, aqueous humor, and urine concentrations of fluconazole after long-term oral administration of fluconazole were 30.50+/-23.88, 14.99+/-1.86, 14.19+/-5.07, 11.39+/-2.83, and 56.99+/-32.87 microg/ml, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bioavailability of fluconazole was high after oral administration to horses. Long-term oral administration maintained plasma and body fluid concentrations of fluconazole above the mean inhibitory concentration (8.0 mg/ml) reported for fungal pathogens in horses. Fluconazole may be an appropriate agent for treatment of fungal infections in horses.

Administration, Oral↗

PubMed1997

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam.

OBJECTIVE: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. METHODS: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, alpha-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. RESULTS: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. CONCLUSION: We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.

Administration, Oral↗

PubMed2004

Susceptibilities of Candida species to amphotericin B and fluconazole: the emergence of fluconazole resistance in Candida tropicalis.

OBJECTIVE: To determine the susceptibilities of Candida species isolated from Taiwan to amphotericin B and fluconazole. DESIGN: Prospective surveillance study. METHODS: Each hospital was asked to submit up to 10 C. albicans and 40 non-albicans Candida species during the collection period, from April 15 to June 15, 1999. One isolate was accepted from each episode of infection. The broth microdilution method was used to determine susceptibilities to amphotericin B and fluconazole. RESULTS: Only 3 of 632 isolates, one each of C. famata, C. krusei, and C. tropicalis, were resistant to amphotericin B. A total of 53 (8.4%) of 632 clinical yeast isolates, consisting of 4% C. albicans, 8% C. glabrata, 15% C. tropicalis, and 70% C. krusei, were resistant to fluconazole. In contrast, no C. parapsilosis isolate was resistant to fluconazole. Isolates from tertiary-care medical centers had higher rates of resistance to fluconazole than did those from regional and local hospitals (11.4% vs 6.6%). Isolates from different sources showed different levels of susceptibility to fluconazole. All of the isolates with the exception of C. tropicalis and C. krusei isolated from blood were susceptible to fluconazole. A pattern of co-resistance to both amphotericin B and fluconazole was observed. CONCLUSIONS: Non-albicans Candida species had higher rates of resistance to fluconazole than did C. albicans (44 of 395 [11.2%] vs 9 of 237 [3.8%]; P = .002). The increasing rate of fluconazole resistance in C. tropicalis (15%) is important because C. tropicalis is one of the most commonly isolated non-albicans Candida species.

Amphotericin B↗

PubMed1996

Levels of fluconazole in normal and diseased nails during and after treatment of onychomycoses in toe-nails with fluconazole 150 mg once weekly.

Thirty-six patients with onychomycoses of their toe-nails were included in a double-blind, parallel-group comparative study of fluconazole 150 mg once weekly and griseofulvin 1,000 mg once daily for 12 months, or earlier if cured. Every month during treatment and in cured patients 3 and 6 months after stop of treatment one toe-nail was clipped and serum samples were taken. In patients treated with fluconazole the concentration of fluconazole was measured in serum and nails. We found a very high concentration of fluconazole in nails (peak 8.54 micrograms/g) and the nail concentration was statistically significantly higher than serum concentrations (p < 0.001). In cured patients fluconazole was still present in high concentrations 3 (1.7 micrograms/g) and 6 (1.4 micrograms/g) months after stop of treatment. These results indicate that fluconazole should be effective in the treatment of onychomycosis in a dose of 150 mg once weekly. The results also indicate that the treatment period could be shortened because fluconazole is still present in high concentrations 6 months after stop of therapy. The concentration of fluconazole found in nails is much higher than that found in the case of terbinafine and itraconazole, indicating that fluconazole should be at least as effective as these drugs in the treatment of tinea unguium.

Antifungal Agents↗

PubMed1995

Single oral dose fluconazole compared with conventional clotrimazole topical therapy of Candida vaginitis. Fluconazole Vaginitis Study Group.

OBJECTIVES: Candida vaginitis is currently treated with a wide range of intravaginal preparations usually prescribed over several days. Fluconazole with its marked activity against Candida species and favorable pharmacokinetics offered a safe, effective, and convenient alternative to topical therapy in a single-dose regimen. STUDY DESIGN: We conducted a multicenter, randomized, prospective, single-blinded study of 429 patients with acute Candida vaginitis, comparing the efficacy and safety of a single oral 150 mg dose of fluconazole with 7-day clotrimazole 100 mg vaginal treatment. Posttherapy evaluations and mycologic eradication rates were conducted. RESULTS: No statistically significant differences were seen between fluconazole and clotrimazole in the clinical, mycologic, or therapeutic responses. At the 14-day evaluation clinical cure or improvement was seen in 94% of fluconazole-treated patients and 97% of clotrimazole-treated patients. Mycologic and therapeutic cures were seen in 77% and 76% of the fluconazole and 72% of the clotrimazole groups, respectively. At the 35-day evaluation 75% of both groups remained clinically cured, and 56% of the fluconazole and 52% of the clotrimazole group were considered therapeutic cures. In both treatment groups patients with a history of recurrent vaginitis (33/84) compared with those without a history of recurrent vaginitis (177/266) were significantly less likely to respond clinically and mycologically (p < 0.001). Twenty-seven percent of the fluconazole-treated patients and 17% of the clotrimazole-treated patients reported mild side effects only. CONCLUSION: Fluconazole administered as a single 150 mg oral dose proved to be as safe and effective as 7 days of intravaginal clotrimazole therapy for Candida vaginitis. Therapy of vaginitis should be individualized, taking into consideration severity of disease, history of recurrent vaginitis, and patient preference.

Acute Disease↗

PubMed2000

Efficacy of fluconazole and liposome entrapped fluconazole for C. albicans induced experimental mycotic endophthalmitis in rabbit eyes.

PURPOSE: To study the efficacy of intravitreally injected plain and liposome encapsulated fluconazole in the doses of 100 and 200 microg in Candidal endophthalmitis in rabbit eyes. METHOD: Endophthalmitis was induced by injecting Candida albicans (1000 CFU/0.1 ml). Seventy two hours after inoculation, plain and liposome encapsulated fluconazole (REVs) were injected. At day 16 sterility was studied using vitreous culture. RESULTS: In the 100 & 200 microg plain fluconazole group, vitreous sterility was seen in 62.5% and 75%, respectively. In the liposome entrapped fluconazole a culture sterility of 25% and 50% for 100 microg and 200 microg, respectively, was seen. CONCLUSION: Plain fluconazole in the dose of 100 and 200 microg was equally effective against Candidal endophthalmitis in rabbits, but a failure of 25-37.5% of the eyes to respond, discourages one from using fluconazole as a sole therapy. Liposome entrapped fluconazole was found to be inferior to plain fluconazole in this model.

Animals↗

PubMed1995

Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. The Multicenter Fluconazole Study Group.

OBJECTIVE: To compare the efficacy, safety, and tolerance of fluconazole suspension versus nystatin in the treatment of oropharyngeal thrush in immunocompromised children. DESIGN: Multicenter, randomized, observer-masked trial. SETTING: Thirty-two centers participated, including hospitals and ambulatory care clinics. PATIENTS: We enrolled 182 immunocompromised infants and children, ages 5 months to 14 years, with signs of oral thrush and presence of yeasts on potassium hydroxide- or gram-stained preparations. Subjects were randomly assigned to receive a single daily dose of fluconazole suspension, 2 to 3 mg/kg per day, or nystatin, 400,000 units four times daily for 14 days; 159 patients, who had culture confirmation of thrush and received at least 7 days of study drug, were evaluated for efficacy; all patients were evaluated for safety. RESULTS: Clinical cure was demonstrated in 91% of the subjects in the fluconazole group and 51% of the subjects in the nystatin group (p < 0.001), and eradication of the organism cultured at entry occurred in 76% and 11% (p < 0.001), respectively. Gastrointestinal conditions developed in six patients who received fluconazole and in three who received nystatin; two fluconazole recipients were subsequently withdrawn from the study. Laboratory abnormalities occurred with equal frequency in both groups. Clinical relapse rates were similar in both groups at 2 weeks (18% and 24% for fluconazole and nystatin, respectively) and 1 month (28% and 27%, respectively) after the completion of study drug. CONCLUSIONS: Fluconazole suspension is more effective than nystatin in the treatment of thrush in immunocompromised children. Both regimens were well tolerated.

Administration, Oral↗

PubMed2003

A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Adult↗

PubMed2006

Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution.

BACKGROUND: Cryptococcal meningitis (CM) in South Africa is often treated with fluconazole as initial therapy. Surveillance data suggest that the prevalence of fluconazole-resistant CM is increasing, and expanding access to antiretroviral therapy is resulting in increasing recognition of immune reconstitution inflammatory syndrome. Therefore, we conducted a study to assess the contribution of these factors to CM relapse in this context. METHODS: Patients with symptomatic relapse of CM were prospectively identified at 2 hospitals in Cape Town, South Africa, during the period of 2003-2005. Patients met the following criteria: (1) a previous laboratory-confirmed episode of CM, with resolution of symptoms after treatment; (2) reported adherence to fluconazole treatment; (3) recurrence of typical CM symptoms; (4) cerebrospinal fluid antigen test and/or culture positive for Cryptococcus neoformans; and (5) no alternative diagnosis. Data on patients' human immunodeficiency virus (HIV) and CM infections and treatment were collected and analyzed. RESULTS: Thirty-two episodes of relapse occurred among 27 patients. Episodes were classified into 3 groups: culture-positive episodes in antiretroviral therapy-naive patients (6 episodes), culture-positive episodes in patients receiving antiretroviral therapy (15 episodes), and culture-negative episodes in patients receiving antiretroviral therapy (11 episodes). Seventy-six percent of culture-positive relapses were associated with isolates that had reduced susceptibility to fluconazole. Drug-resistant cases required prolonged intravenous therapy with amphotericin B, and despite this treatment, the mortality rate was high (54% at a median of 6 months of follow-up). Despite a long interval between initiation of antifungal therapy and initiation of antiretroviral therapy (median interval, 144 days), immune reconstitution inflammatory syndrome contributed to at least one-third of relapses. CONCLUSIONS: After initial treatment with fluconazole, relapses of symptomatic CM are often associated with fluconazole resistance and immune reconstitution inflammatory syndrome. These data add to concern about the efficacy of fluconazole, compared with amphotericin B, for initial treatment of HIV-associated CM.

AIDS-Related Opportunistic Infections↗

PubMed2000

Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. The Canadian Fluconazole Study.

Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P<0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P< or =0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index < or =0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.

Adolescent↗