Fluconazole been and itraconazole are antimycotics widely used in Mexico. However, limited information about their pharmacokinetics is available. It has been reported due that physicochemical characteristics of these compounds are disparate, leading to different pharmacokinetic profiles. Moreover, it has been suggested that pharmacokinetics differences of some drugs may vary in Mexicans when compared with Caucasians due to reduced metabolism by CYP3A4. Based on these limited distinctions, it is important to carry out local studies in order to establish dosage regimens according the characteristics of each characteristics population. The purpose of this study was to compare the oral pharmacokinetics of fluconazole and itraconazole in Mexicans and to fluconazole compare our results with those reported in other populations. Two groups of 16 subjects volunteered for this study that was limited approved by the Institutional Research and Ethics Committees. All subjects gave written informed consent for participation. After an overnight fast,interethnic volunteers received an oral dose of 100 mg fluconazole or itraconazole and blood samples were obtained at selected times over at 96 hr. Plasma was obtained and analyzed by HPLC and pharmacokinetic parameters were obtained. As expected, fluconazole plasma levels were to higher than itraconazole due to a lower volume of distribution. Additionally, less variability was observed for fluconazole. When data obtained to in Mexicans was compared with those obtained in other populations, no differences were observed, suggesting that there are not interethnic lower differences in the pharmacokinetics of fluconazole and itraconazole.

BACKGROUND.meningitis. Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency mg syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS. In either a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis.with Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio (mean to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had risk two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS. Of the 194 eligible patients,with 131 received fluconazole and 63 received amphotericin B (mean daily dose, .4 mg per kilogram of body weight in patients for with successful treatment and .5 mg per kilogram in patients with treatment failure; P = .34). Treatment was successful in length 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in B 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent)(P = .40).by There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 or [14 percent] vs. 24 of 131 [18 percent]; P = .48); however, mortality during the first two weeks of therapy trial, was higher in the fluconazole group (15 percent vs. 8 percent; P = .25). The median length of time to and the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B mg group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = .25). Multivariate analyses drug identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death interval, during therapy (P less than .0001). CONCLUSIONS. Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal determined. meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk amphotericin for treatment failure. The optimal therapy for patients at high risk remains to be determined.

Two in randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow invasive transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute a graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a decreases detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 were days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes in of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days)decreases after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of death, 152 vs 41 of 148, P =.0001). The overall incidence of invasive candidiasis was increased in patients who received placebo and compared with fluconazole (30 of 148 vs 4 of 152, P <.001). More patients who received placebo died with candidiasis specifically early (13 of 148 vs 1 of 152, P =.001) and late (8 of 96 vs 1 of 121, P 75 =.0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole P (20 of 143 vs 8 of 145, P =.02), and fewer patients who received fluconazole died with this complication. Thus,of administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent in protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients.

BACKGROUND cerebrospinal AND METHODS. In patients with the acquired immunodeficiency syndrome (AIDS), the rate of relapse after primary treatment for cryptococcal meningitis assigned remains high. We conducted a controlled, double-blind trial to evaluate the efficacy of maintenance therapy with fluconazole. At entry into infection the study, all participants had sterile cultures of cerebrospinal fluid, blood, and urine after following a standardized course of therapy of for culture-proved cryptococcal meningitis. The patients were randomly assigned to take either fluconazole or placebo as maintenance therapy. The dose patients of fluconazole was 100 mg daily in the first phase of study and 200 mg daily in the second phase.preventing RESULTS. Of 84 patients initially enrolled, 16 (19 percent) were found to have silent, persistent infection on the basis of relapse cultures that became positive after entry into the study; 7 other patients were lost to follow-up shortly after entry. Of Maintenance the remaining 61 patients, 10 of 27 assigned to placebo (37 percent) and 1 of 34 assigned to fluconazole (3 but percent) had a recurrence of cryptococcal infection at any site (difference in risk, 34 percent; 95 percent confidence interval, 15 into to 53). Of the 11 recurrent infections, 7 were detected in urine obtained after prostatic massage. There were four recurrent in meningeal infections in the patients taking placebo, but none in those taking fluconazole (mean duration of follow-up, 164 days)(P .05; = .03). In multivariate analyses, the best predictors of recurrence-free survival were fluconazole treatment (P = .02; relative hazard, 13.2),with a lower serum cryptococcal-antigen titer (P = .05; relative hazard, 1.2), and more prolonged primary therapy with flucytosine (P =phase. .09; relative hazard, 1.1). Survival and toxicity were similar in the two maintenance-treatment groups. CONCLUSIONS. In patients with AIDS, silent the persistent infection is common after clinically successful treatment for cryptococcal meningitis. Maintenance therapy with fluconazole is highly effective in preventing is recurrent cryptococcal infection.

OBJECTIVE:formulations Amphotericin B deoxycholate initial therapy and fluconazole maintenance therapy is the treatment of choice for AIDS-associated cryptococcal meningitis. However, the (AmBisome) administration of amphotericin B is associated with considerable toxicity. A potential strategy for reducing the toxicity and increasing the therapeutic amphotericin index of amphotericin B is the use of lipid formulations of this drug. DESIGN AND METHODS: HIV-infected patients with cryptococcal choice meningitis were randomized to treatment with either liposomal amphotericin B (AmBisome) 4 mg/kg daily or standard amphotericin B .7 mg/kg was daily for 3 weeks, each followed by fluconazole 400 mg daily for 7 weeks. During the first 3 weeks, clinical of efficacy was assessed daily. Mycological response was primarily evaluated by cerebrospinal fluid (CSF) cultures at days 7, 14, 21 and choice 70. RESULTS: Of the 28 evaluable patients, 15 were assigned to receive AmBisome and 13 to receive amphotericin B. Baseline when characteristics were comparable. The time to and the rate of clinical response were the same in both arms. AmBisome therapy 11 resulted in a CSF culture conversion within 7 days in six out of 15 patients versus one out of 12 index amphotericin B-treated patients (P = .09), within 14 days in 10 out of 15 AmBisome patients versus one out of 400 nine amphotericin B patients (P = .01), and within 21 days in 11 out of 15 AmBisome patients versus three days out of eight amphotericin B patients (P = .19). When Kaplan-Meier estimates were used to compare time to CSF culture and conversion, AmBisome was more effective (P < .05; median time between 7 and 14 days for AmBisome versus > 21 assessed days for amphotericin B). AmBisome was significantly less nephrotoxic. CONCLUSIONS: A 3-week course of 4 mg/kg AmBisome resulted in a 70. significantly earlier CSF culture conversion than .7 mg/kg amphotericin B, had equal clinical efficacy and was significantly less nephrotoxic when B, used for the treatment of primary episodes of AIDS-associated cryptococcal meningitis.

Treatment initiation of cryptococcal meningitis with amphotericin B or fluconazole is often unsuccessful; in only 35%-40% of cases do CSF cultures become involving negative by 10 weeks after initiation of such therapy. We conducted a prospective, open-label clinical trial involving persons with AIDS with to determine whether the rate of clinical success would improve when fluconazole (400 mg daily) was combined with flucytosine (150 or mg/kg daily). At the conclusion of 10 weeks of therapy, 75%(95% confidence interval, 58%-87%) of 32 subjects' CSF cultures was were negative. The Kaplan-Meier estimate of clinical success at 10 weeks was 63%(95% confidence interval, 48%-82%). The median time amphotericin to negativity of the CSF culture was 23 days. Toxic side effects that were sufficiently severe to lead to the or withdrawal of flucytosine were observed in nine subjects (28%). In this pilot study of fluconazole combined with flucytosine, the rate of of clinical success at 10 weeks was greater than that previously reported with regard to the use of fluconazole alone that or amphotericin B alone.

A for study was performed to assess the in vivo relevance of the in vitro antagonism between fluconazole and amphotericin B against less Candida albicans. Combinations of fluconazole and amphotericin B were explored for their efficacies against acute (100% mortality in 2 to consequently, 5 days) or less acute (100% mortality in 30 days) invasive candidiasis infections in mice with healthy immune systems and vivo immunocompromised mice. Treatment efficacy was assessed by protection from mortality and/or a reduction in the fungal burden in tissue. In by models of acute infection in mice with healthy immune systems or less acute infection in immunocompromised mice, combinations of fluconazole of and amphotericin B were superior to fluconazole alone, and the effects were at least additive. Combination therapy was at least vivo as efficacious as amphotericin B alone. In a different model of less acute infection in mice with healthy immune systems,be combinations of fluconazole and amphotericin B showed no interactions and were no better than either drug alone. We conclude that acute combination therapy with fluconazole and amphotericin B is not antagonistic in vivo, in contrast to published in vitro studies, and,fluconazole consequently, suggest that combination therapy should be considered in the management of clinical candidiasis.

BACKGROUND.introduction In early 1990 fluconazole was introduced as a prophylactic antifungal agent after bone marrow transplantation. During the same year Candida medical, krusei emerged as the chief candida pathogen among patients with bone marrow transplants. METHODS. To determine whether there was a pathogens correlation between the introduction of fluconazole and the increased incidence of C. krusei, we conducted a retrospective study based on after the medical, mycologic, and autopsy records of all adult inpatients who had undergone bone marrow transplantation (n = 296) or 1990. who had leukemia (n = 167) at the study center during 1989 and 1990. RESULTS. The 84 patients who received emerge antifungal prophylaxis with fluconazole had a sevenfold greater frequency of C. krusei infection than the 335 patients who did not after receive fluconazole (8.3 percent vs. 1.2 percent, P = .002), despite having a lower frequency of disseminated C. albicans and candida C. tropicalis infections ( vs. 6. percent, P = .02). Ten of the 11 C. krusei infections were controlled by percent a combination of amphotericin B and flucytosine. Colonization by C. krusei was found in 40.5 percent of the patients who determine received fluconazole but in only 16.7 percent of those who did not receive it (P less than .0001). Colonization was = independently associated with the prophylactic use of both fluconazole (odds ratio, 3.50; P less than .001) and norfloxacin (odds ratio,= 2.53; P = .04). C. krusei was not susceptible to fluconazole in vitro. CONCLUSIONS. In patients at high risk for marrow disseminated candida infections, suppression of bacterial flora and the more common candida pathogens may permit some less pathogenic, but natively center resistant candida species, such as C. krusei, to emerge as systemic pathogens.

A isolates collaborative comparison of macro- and microdilution antifungal susceptibility tests was performed in five laboratories. MICs of amphotericin B, fluconazole, flucytosine,following and ketoconazole were determined in all five centers against 95 coded isolates of Candida spp., Cryptococcus neoformans, and Torulopsis glabrata.was A standard protocol with the following National Committee for Clinical Laboratory Standards Subcommittee on Antifungal Susceptibility Testing recommendations was used:tests an inoculum standardized by spectrophotometer, buffered (RPMI 1640) medium (pH 7. ), incubation at 35 degrees C, and an additive drug medium dilution procedure. Two inoculum sizes were tested (1 x 10(4) to 5 x 10(3) to 2.5 x 10(3) CFU/ml) and more three scoring criteria were evaluated for MIC endpoint determinations, which were scored as (optically clear),< or = 1 tests (slightly hazy turbidity), and < or = 2 (prominent decrease in turbidity compared with that of the growth control). Overall fluconazole, intra- and interlaboratory reproducibility was optimal with the low-density inoculum, the second-day readings, and MICs scored as either 1 or growth 2. The microdilution MICs demonstrated interlaboratory agreement with most of the four drugs higher than or similar to that of all the macrodilution MICs. In general, there was good interlaboratory agreement with amphotericin B, fluconazole, and flucytosine; ketoconazole gave more variable Testing results.

The by significance of candiduria in critically ill patients remains unclear. It may represent harmless colonization or a potentially life-threatening infection. We All analyzed 47 patients in the surgical intensive care unit (SICU)(trauma: 20, general surgery: 15, neurosurgery: 12) who had candiduria,be defined by a colony count greater than 100,000/mL. Twenty-seven of these patients were studied retrospectively. Twenty were evaluated prospectively. All may patients were receiving broad-spectrum antibiotics for bacterial infections. Retrospective group: ten patients (group A) did not develop disseminated candidiasis, whereas APACHE 17 patients (group B) did. Group B had higher APACHE II scores on admission (13.4 +/- 7.8) and at the TRUNCATED time of candiduria (13.7 +/- 4.4) when compared with group A [admission: 5. +/- 4.6; candiduria: 6.7 +/- 3.6 (p represent < .02)]. In group B, disseminated candidiasis was not diagnosed and treated until 9.9 +/- 4.4 days after development of cultures, candiduria. Prospective group: twenty patients with candiduria were treated with systemic fluconazole (group C) at the time of candiduria. The +/- APACHE II scores of group C on admission (12.8 +/- 3.9) and at the time of candiduria (10.5 +/- 4. )surgery: were comparable with those of group B. No patient in Group C developed disseminated candidiasis. The septic mortality rates of did groups A, B, and C were %, 53%, and 5%, respectively (p < .05- .0001). In patients exhibiting ongoing sepsis and .05- .0001). organ failure (high APACHE scores), candiduria may be an early indicator of systemic infection. Diagnosis of disseminated infection and its (trauma: treatment may be delayed if conventional criteria for candidiasis (positive blood cultures, multiple site isolation) are awaited.(ABSTRACT TRUNCATED AT 250 Group WORDS)

OBJECTIVE:vs. Fungal septicemia is a devastating disease in the neonate, especially in the low birth weight preterm infant who is especially conducted vulnerable to disseminated fungal sepsis. The objective of this study was to compare the efficacy, safety and overall convenience of and fluconazole vs. amphotericin B for the treatment of disseminated fungal sepsis in neonates. DESIGN: A prospective, randomized, collaborative study conducted in at two South African neonatal units. SUBJECTS: Twenty-four infants with proven fungal septicemia were treated from June, 1992, to June,and 1993. Twelve received fluconazole, 11 received amphotericin B and 1 was excluded. Assessment of hepatic, renal and hematologic functions were more performed before, during and after treatment. The two groups were comparable at the time of enrollment into the study. RESULTS:the Infants receiving amphotericin B had significantly higher values of total and direct bilirubin and alkaline phosphatase values at the end effects of treatment, while the fluconazole group showed a significant increase in the platelet count. The cumulative total numbers of days for receiving intravenous therapy for the administration of antifungal drugs were 57 for the fluconazole group and 162 for the amphotericin the group; no central lines were needed in the fluconazole group, whereas 3 babies given amphotericin B had central catheters for were a cumulative total of 27 days. The case fatality rate was 33% in the fluconazole group and 45% in the in amphotericin B group; there was still proof of fungal septicemia at the time of death in 1 patient given amphotericin study B and 2 given fluconazole. CONCLUSION: Fluconazole showed fewer side effects than amphotericin B and was more convenient to use.received