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PubMed2006

Efficacy of amphotericin B in combination with flucytosine against flucytosine-susceptible or flucytosine-resistant isolates of Cryptococcus neoformans during disseminated murine cryptococcosis.

Whether or not flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 microg/ml) to flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the flucytosine-susceptible isolate and in brain and spleen for the flucytosine-resistant isolate. For the flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to flucytosine.

Amphotericin B↗
PubMed2006

Combination of amphotericin B with flucytosine is active in vitro against flucytosine-resistant isolates of Cryptococcus neoformans.

The combination of flucytosine and amphotericin B was tested against 10 flucytosine-resistant isolates of Cryptococcus neoformans by checkerboard, killing curves, and Etest. Although differences were observed depending on the technique used, antagonism was never observed. The synergistic interaction was related to the mechanism of flucytosine resistance of the isolates.

Amphotericin B↗
PubMed1997

Comparison of amphotericin B, flucytosine and itraconazole with amphotericin B and flucytosine in the treatment of cryptococcal meningitis in AIDS.

We compared amphotericin B (0.3 mg/kg/d) plus flucytosine (150 mg/kg/d) plus itraconazole (400 mg/d) (study group) with amphotericin B plus flucytosine (control group) by an open-randomized trial. In the study group, after CSF mycological cultures disclosed nothing, itraconazole was administrated alone through six weeks of treatment. Treatment was considered successful if the patient had two consecutive negative CSF cultures by the end of the 6-week treatment period. Fifty patients were enrolled in each group. There were significant differences between the study group and the control group in the successful treatment (100% vs 90%; P = 0.03), the mean length of time until normal body temperature after treatment (5.9 +/- 3.7 days vs 8.8 +/- 5.1 days; P = 0.02) and the adverse effects. The mean length of time to the first negative CSF culture was 13.9 +/- 6.1 days in the study group and 13.3 +/- 6.5 days in the control group (P = 0.66). Relapse rate with itraconazole 200 mg/day was higher in the study group.

AIDS-Related Opportunistic Infections↗
PubMed2003

An in vitro study on the active conversion of flucytosine to fluorouracil by microorganisms in the human intestinal microflora.

BACKGROUND: Investigation of the rate of active conversion of flucytosine to fluorouracil by microorganisms in the intestinal microflora. METHODS: Active conversion of flucytosine was investigated using viable and nonviable Escherichia coli at different flucytosine concentrations. Additionally, flucytosine conversion was studied in fecal specimens from 3 neutropenic patients at the start of the antimicrobial/antifungal prophylaxis (C/A regimen) and 1 week later. RESULTS: Flucytosine levels decreased by an average of 72, 71 and 72% flucytosine after incubation for 48 h of 10(10) viable E. coli /ml suspension in broth containing 13, 130 and 1300 mg/l flucytosine, respectively. The decreasing flucytosine levels corresponded approximately to an identical increase in fluorouracil levels. Also, a 44% decrease of flucytosine levels occurred when nonviable E. coli were used, indicating that bacterial viability is not necessary for this conversion. When fecal specimens of 2 patients were investigated prior to the C/A regimen, significant flucytosine conversion occurred, whereas this conversion was not observed in the corresponding fecal specimens after 1 week of C/A regimen. CONCLUSION: These in vitro experiments showed that extensive flucytosine conversion can occur in the human intestinal microflora by E. coli. Consequently, fluorouracil exposure and fluorouracil-related toxicity may occur in the flucytosine-treated patient.

Antifungal Agents↗
PubMed1992

Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy.

Flucytosine is an antifungal agent useful in combination with amphotericin B in the treatment of several deeply invasive mycoses. The potentially dose-limiting, hematologic, gastrointestinal, and hepatic toxicities of flucytosine lead to a reluctance to use it in myelosuppressed patients. To investigate the safety and tolerability of flucytosine in this setting, we evaluated its use in 17 patients with cancer or aplastic anemia during a 2 1/2-year period at our institution and reviewed the literature describing mechanisms of action, resistance, in vitro and in vivo antifungal activity, clinical antifungal activity, pharmacokinetics, and toxicity. The combination of amphotericin B plus flucytosine eradicated the mycosis in 12 (71%) of 17 patients, whereas 3 (18%) of 17 died of progressive fungal infection. Serial serum levels of flucytosine measured by a creatinine iminohydrolase assay permitted reliable dosage adjustment. During therapy, only 2 (12%) of 17 patients had elevated mean serum levels of flucytosine (> 100 micrograms/mL) and 3 (18%) other patients had transiently elevated levels. Paired serum samples (n = 45) obtained at steady state during therapy with orally administered flucytosine showed similar peak and trough levels. Adverse effects of flucytosine therapy included one case each of reversible nausea, diarrhea, elevated transaminase levels, and thrombocytopenia. No cases of bone marrow aplasia, enterocolitis, hepatitis, or death due to flucytosine toxicity were encountered. We conclude that flucytosine in combination with amphotericin B is well tolerated in myelosuppressed patients when serum flucytosine levels are serially monitored.

Adolescent↗
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↗
PubMed1995

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

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

AIDS-Related Opportunistic Infections↗
PubMed1996

Fluconazole vs itraconazole-flucytosine association in the treatment of esophageal candidiasis in AIDS patients. A double-blind, multicenter placebo-controlled study. The Candida Esophagitis Multicenter Italian Study (CEMIS) Group.

STUDY OBJECTIVE: To assess the role and the therapeutic efficacy of fluconazole and itraconazole-flucytosine association compared with placebo, in the treatment of endoscopically diagnosed esophageal candidiasis in a selected population of AIDS patients. DESIGN: Double-blind, placebo-controlled study. SETTING: University Hospitals and AIDS Centers. PATIENTS: Eighty-five HIV-positive patients (53 men and 32 women; mean age, 28 years) at first episode of esophageal candidiasis diagnosed by endoscopy (grades I to II of Kodsi's endoscopic classification and grades I to IIa of Barbaro's clinical classification). All the patients selected for the study provided informed consent. INTERVENTIONS: The patients have been double blindly randomized in 3 groups of patients in relation to pharmacologic therapy: (1) the patients of the first group (n = 30) received fluconazole (3 mg/kg daily orally) and placebo (100 mg/kg/daily orally); (2) the patients of the second group (n = 30) received itraconazole (3 mg/kg daily orally) and flucytosine (100 mg/kg daily orally); and (3) the patients of the third group (n = 25) received placebo (3 mg/kg daily orally) and placebo (100 mg/kg daily orally). After 2 weeks of treatment, the patients previously randomized to receive placebo only were double blindly randomized to receive fluconazole+placebo or itraconazole+flucytosine. To evaluate the efficacy of pharmacologic therapy, clinical and endoscopic examinations were performed at weeks 2 and 4 and at the end of follow-up (3 months). RESULTS: At week 2, endoscopic cure (grade 0) was observed in 68.9% of the fluconazole+placebo group and in 72.4% of the itraconazole+flucytosine group (relative risk, 0.95; 95% confidence interval [CI], 0.68 to 1.33; p = 0.772); partial endoscopic response (grade I) was observed in 22.7% of the placebo group. Clinical cure (grade 0) was observed in 75.8% of fluconazole+placebo group and in 72.4% of itraconazole+flucytosine group (relative risk, 1.05; 95% CI, 0.77 to 1.42; p = 0.764), with a difference statistically significant for both treatments in comparison to placebo group (p < 0.001). Partial clinical response (grade I) was observed in 27.3% of the placebo group. At the end of follow-up, endoscopic cure was observed in 89.8% of the fluconazole+placebo group and in 94.8% of the itraconazole+flucytosine group (relative risk, 0.97; 95% CI, 0.83 to 1.08; p = 0.695). Clinical cure was observed in 94.8% of the fluconazole+placebo group and in 97.3% of the itraconazole+flucytosine group (relative risk, 0.97; 95% CI, 0.89 to 1.07; p = 0.981). CONCLUSIONS: The results of this study have demonstrated that both fluconazole and itraconazole+flucytosine association are efficacious in short-term treatment of esophageal candidiasis in AIDS patients with a statistically significant difference in comparison to placebo. Both therapeutic regimens demonstrated a good therapeutic efficacy, without statistically significant difference, between them, in the rate of endoscopic and clinical cure. Itraconazole+flucytosine association may represent an alternative therapeutic regimen for patients with fluconazole-resistant Candida esophagitis.

AIDS-Related Opportunistic Infections↗
PubMed1996

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily).

Animals↗
PubMed1987

Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis.

A multicenter prospective randomized trial of four versus six weeks of amphotericin B, 0.3 mg/kg per day, plus flucytosine, 150 mg/kg per day, was performed with 194 patients with cryptococcal meningitis. One or more toxic drug reactions developed in 103 patients: azotemia (51), renal tubular acidosis (two), leukopenia (30), thrombocytopenia (22), diarrhea (26), nausea/vomiting (10), and hepatitis (13). The four- and six-week regimens were complicated by toxicity in 44 percent and 43 percent of cases, respectively. Toxicity appeared during the first two weeks of therapy in 56 percent and during the first four weeks in 87 percent. Azotemia did not occur more frequently in renal transplant recipients or diabetic patients. Cytopenias did not appear more often in patients with hematologic malignancies or those receiving immunosuppressive therapies. Toxic reactions that contributed to death developed in five patients (two with azotemia, one with pancytopenia, one with hepatitis, one with ileus). Amphotericin B-induced azotemia was not a significant risk factor for the subsequent development of bone marrow, gastrointestinal, or hepatic toxicity attributable to flucytosine. Flucytosine toxicity was associated with peak serum flucytosine levels of 100 micrograms/ml or more during two or more weeks of therapy (p = 0.005). Peak 5-fluorouracil levels were not predictive of toxicity. An initial dose of flucytosine is recommended based on the creatinine clearance: 150 mg/kg per day at a creatinine clearance above 50 ml/minute, 75 mg/kg per day at a creatinine clearance of 26 to 50 ml/minute, and 37 mg/kg per day at a creatinine clearance of 13 to 25 ml/minute. The serum creatinine level should be monitored twice weekly and the creatinine clearance weekly during therapy in order to anticipate changes in serum flucytosine concentration. In addition, it is recommended that the serum flucytosine level be determined two hours after an oral dose once a week, and that the dose be adjusted to maintain a level of 50 to 100 micrograms/ml.

Adolescent↗
PubMed1996

Suspected drug eruption in seven dogs during administration of flucytosine.

7 of 8 dogs receiving combination drug therapy consisting of flucytosine together with amphotericin B and/or a triazole for cryptococcosis or aspergillosis developed cutaneous or mucocutaneous eruptions during the course of treatment. Lesions resolved in all cases following discontinuation of flucytosine despite continued administration of other antifungals, suggesting the eruption was referable primarily to the flucytosine component of therapy. Lesions developed 13 to 41 days (median 20 days) after commencing flucytosine (105 to 188 mg/kg/day divided and given every 8 h; median dose rate 150 mg/kg/day). The cumulative dose of flucytosine given prior to the first signs of the drug eruption ranged from 1.7 to 6.8 g/kg (median 2.3 g/kg). The eruptions consisted of depigmentation, followed by ulceration, exudation and crust formation. The scrotum was affected in all 4 male dogs, the nasal plane in 6 of 7 cases, while the lips, vulva, external ear canal and integument were involved in a smaller number of cases. There was considerable variation in the severity of lesions, with changes being most marked when flucytosine was continued for several days after lesions first appeared. Some dogs experienced malaise and inappetence in association with the suspected drug eruption. Healing took a variable period, typically in excess of 2 weeks after discontinuing flucytosine, with up to 2 months being required for total resolution of the lesions. All lesions resolved eventually without scarring or permanent loss of pigment.

Amphotericin B↗
PubMed2006

Oral versus intravenous flucytosine in patients with human immunodeficiency virus-associated cryptococcal meningitis.

In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.

Administration, Oral↗
PubMed1995

In vitro evaluation of combination of fluconazole and flucytosine against Cryptococcus neoformans var. neoformans.

Amphotericin B and fluconazole are current acceptable therapies for cryptococcal meningitis; however, their effect remains suboptimal. The combination of fluconazole and flucytosine has yielded encouraging clinical results in human immunodeficiency virus patients with cryptococcal meningitis. To investigate the biological basis of this finding, we performed in vitro combination testing of fluconazole and flucytosine against 50 clinical strains of Cryptococcus neoformans var. neoformans. Synergy (fractional inhibitory concentration index of < 1.0) was observed in 62% of cases, while antagonism (fractional inhibitory concentration index of > 2.0) was not observed. For cases in which synergy was not achieved (autonomous or additive effects), the beneficial effect of the combination was still seen (i.e., there was still a decrease, although not as dramatic, in the MIC of one or both drugs when used in combination). The in vitro inhibitory action of flucytosine was greatly enhanced by the addition of fluconazole; the flucytosine MICs for Cryptococcus isolates were markedly decreased to concentrations which were severalfold lower than the achievable cerebrospinal fluid flucytosine concentration. On the other hand, the addition of flucytosine did not greatly enhance the in vitro activity of fluconazole if the initial fluconazole MIC for the isolate was > or = 8 micrograms/ml. Controlled clinical studies are warranted to further elucidate the potential utility of fluconazole-flucytosine combination therapy.

Antifungal Agents↗
PubMed1998

Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis.

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.

Amphotericin B↗
PubMed1979

Pharmacokinetics of amphotericin B and flucytosine.

The absorption of flucytosine from the digestive tract is very good but minimal with amphotericin B. For this reason, amphotericin B has to be injected intravenously. Fungistatic levels are achieved rapidly with flucytosine and slowly with amphotericin B, since the dose has to be increased slowly. Distribution of flucytosine in other body fluids is high, whereas with amphotericin B it is poor. Flucytosine is excreted mainly via the kidney without metabolism, whereas amphotericin B is eliminated mainly by metabolism. Therefore, amphotericin B dosage does not have to be adapted to kidney function, which is the case for flucytosine. The half-life of flucytosine is short (hours), that of amphotericin B is long (days); flucytosine is haemodialysable, whereas amphotericin B, probably owing to the high protein binding, is not.

Amphotericin B↗
PubMed1995

Elimination of flucytosine by continuous hemofiltration.

Flucytosine is effective in the treatment of serious fungal infections. Some of the patients might have acute renal failure requiring continuous hemofiltration as renal replacement therapy. We evaluated the removal of flucytosine in a patient who received the drug for systemic Candida infection while undergoing continuous hemofiltration for acute renal failure. Arterial, venous, and ultrafiltrate sample pairs were collected to evaluate flucytosine removal. Ultrafiltrate/arterial drug concentration ratios and sieving coefficients obtained with the polysulfone membrane were higher than those obtained with the polyacrylonitrile membrane. Between 2.54 and 22.56 mg of flucytosine was removed from the patient per hour when the serum drug concentrations were 21.1-126.5 mg/l. The amount of hemofiltration flucytosine removal was related to ultrafiltration flow rate, serum drug concentration, and hemofilter type. The mean continuous arteriovenous hemofiltration flucytosine clearance for the polysulfone membrane was 77.0 +/- (SD) 15.6% of the ultrafiltrate flow rate, while the clearance for the polyacrylonitrile membrane was 51.0 +/- (SD) 5.7%. In patients with renal failure, continuous hemofiltration can remove an appreciable quantity of flucytosine when the ultrafiltrate flow rate is high. Serum drug concentration determination is necessary to devise an optimal dosage regimen for the patient.

Acute Kidney Injury↗
PubMed1998

Successful treatment of disseminated cryptococcosis in a liver transplant recipient with fluconazole and flucytosine, an all oral regimen.

Amphotericin B, with or without 5-flucytosine, is currently the therapy of choice for cryptococcal infections. However, amphotericin B, is nephrotoxic and requires long-term venous access for parenteral administration. The combination of fluconazole and flucytosine is synergistic in vitro against Cryptococcus. To date, however, the efficacy of fluconazole and flucytosine for cryptococcosis in liver transplant recipients has never been reported. We report a 66-year-old liver transplant recipient with disseminated invasive cryptococcus (presenting as cryptococcal subcutaneous abscess, osteomyelitis, and serum cryptococcal antigen titer of 1:32). The administration of amphotericin B for 3 weeks led to nephrotoxicity without any clinical response (persistent abscess without change in serum cryptococcal antigen titer). Fluconazole, at a dosage equivalent to 800 mg/day administered orally, and flucytosine, also given orally, led to a clinical response and a steady decline in serum cryptococcal antigen titer, which became negative at 6 weeks of therapy. The patient remains well 18 months after therapy. No adverse effects have been attributed to fluconazole or flucytosine. This combination obviates the nephrotoxicity and the need for parenteral access required for amphotericin B infusion, and it can be administered orally. The combination of fluconazole and flucytosine warrants future controlled trials for the treatment of cryptococcal infection in liver transplant recipients.

Administration, Oral↗
PubMed2000

In vitro pharmacodynamic characteristics of flucytosine determined by time-kill methods.

Two Candida albicans isolates, three non-albicans Candida isolates (Candida glabrata, Candida krusei, and Candida tropicalis), and one Cryptococcus neoformans isolate were evaluated by time-kill methods to characterize the relationship of flucytosine concentrations to antifungal activity and the duration of the post-antifungal effect (PAE). Against Candida and Cryptococcusisolates, flucytosine at concentrations > 1 x MIC exhibited fungistatic (</=99% reduction in CFU) activity over a 24-h time-period. The rate and extent of fungistatic activity of flucytosine against all isolates was generally not increased when 5-FC concentrations exceeded 4 x MIC. A notable PAE was detected for flucytosine against both Candida and Cryptococcus species that persisted 2 to 4 h. These in vitro data suggest that flucytosine is predominately a concentration-independent fungistatic agent at clinically achieved serum concentrations. This pharmacodynamic characteristic coupled with the persistent PAE and the relatively long half-life of flucytosine in humans (> 5 h), suggests lower daily dosing may possible without loss of antifungal efficacy.

Antifungal Agents↗