- Cryptococcal and Candida endocarditis (in addition to amphotericin B ).
- Cryptococcal meningitis (in addition to amphotericin B or liposomal amphotericin).
- Cryptococcal and Candida pneumonia (in addition to amphotericin B).
- Cryptococcal and Candida septicemia (in addition to amphotericin B).
- Cryptococcal and Candida urinary tract infections (in addition to amphotericin B).
*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.
USUAL ADULT DOSING
25 mg/kg q6h.
- Therapeutic monitoring recommended with renal insufficiency to limit toxicity. Goal peak: 70-80 mcg/mL drawn 2 hrs post-dose after 3-5 days. Peak serum concentrations >100 mcg/mL associated with increased toxicity.
- Dosing in obesity: Consider IBW for dosing of non-life threatening infections. For severe infections, consider using adjusted body weight and monitor serum concetrations.
DOSING FOR GLOMERULAR FILTRATION OF 50-80
25 mg/kg q6h.
DOSING FOR GLOMERULAR FILTRATION OF 10-50
CrCl 20-40 mL/min: 25 mg/kg q12
CrCl 10-19 mL/min: 25 mg/kg q24h (monitor CBC and serum levels with appropriate dose adjustments).
DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN
25 mg/kg q48h (monitor CBC serum levels closely with appropriate dose adjustments).
DOSING IN HEMODIALYSIS
25 mg/kg q24-48h. Dose post-dialysis on days of dialysis (monitor CBC and serum levels w/ appropriate dose adjustment).
DOSING IN PERITONEAL DIALYSIS
0.5-1.0 gm q24h (monitor CBC and serum levels w/ appropriate dose adjustments).
DOSING IN HEMOFILTRATION
CVVH and CVVHD: Limited data. Consider 25 mg/kg q24 for dialysis rate of 1L/hr and 25 mg/kg q12h for dialysis rate ≥1.5 L/hr (monitor CBC and serum levels with appropriate dose adjustments).
ADVERSE DRUG REACTIONS
- GI intolerance: diarrhea, dyspepsia, and abdominal pain
- Marrow suppression w/ leukopenia or thrombocytopenia (with levels >100 mcg/mL)
- Taste perversion
- Hepatitis (hepatic necrosis has been reported)
- Peripheral neuropathy
- Drugs that cause bone marrow suppression (i.e. AZT, ganciclovir, and interferon): increased bone marrow suppression.
Flucytosine interferes with protein synthesis by incorporation into fungal RNA after being converted to 5-FU intracellularly.
Metabolism and Excretion
Minimal metabolism; principally excreted unchanged in the urine. Unabsorbed drug excreted in feces.
Cmax, Cmin, and AUC
Cmax: 60-80 mcg/mL, Cmin: 20-40 mcg/mL after 37.5 mg/kg/dose.
2.5-6 hrs (normal renal function). Half-life may be up to 250 hrs in patients with ESRD.
Widely distributed into body tissues and fluids such as liver, kidney, spleen, heart, aqueous humor and bronchial secretion. Good CNS penetration (70-85% of serum concentration attained in the CSF).
DOSING FOR DECREASED HEPATIC FUNCTION
No data. Usual dose likely.
Category C. Crosses placental barrier. Teratogenicity reported in animal studies. Three case reports of second and third exposure found no defects in infants.
BREAST FEEDING COMPATIBILITY
No data. Breast feeding during flucytosine therapy not recommended.
- Recommended in combination with amphotericin or liposomal amphotericin for treatment of cryptococcal meningitis for at least 2 weeks. Combination therapy with flucytosine results in more rapid CSF sterilization and improved mortality when compared to amphotericin alone. When compared to amphotericin plus fluconazole, there was no difference in survival outcomes but combination with flucytosine resulted in more rapid CSF sterilization.
- Levels should be considered for patients with renal insufficiency to minimize toxicity. Levels >100 ng/mL for >2 weeks have been associated with increased risk of toxicity. Levels < 25 ng/mL have been associated with emergence of resistance in vitro.
- Close monitoring of renal function and serum level may prevent bone marrow suppression.
Basis for recommendation
- Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50(3):291-322. [PMID:20047480]
Comment: 5FC plus amphotericin B, liposomal amphotericin, or amphotericin lipd complex (for ≥2 wks) is recommended for treatment of cryptococcal meningitis. Without 5FC, recommended amphotericinB treatment duration is 4-6 weeks. Fluconazole 1200 mg/day plus 5FC x 6 wks is alternative in pts unable to tolerate amphotericin.
- Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291-302. [PMID:23550668]
Comment: Amphotericin B (1 mg/kg/day) plus flucytosine (100 mg/kg/day) was associated with improved survival at day 70 as compared with amphotericin B (1 mg/kg/day) alone. Combination therapy with flucytosine also resulted in more rapid yeast clearance from CSF when compared to amphotericin monotherapy or amphotericin B plus fluconazole (800 mg/kg/day). There was no survival benefit found for those treated with amphotericin B plus fluconazole.
- Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1999;28(2):291-6. [PMID:10064246]
Comment: Fluconazole superior to itraconazole for maintenance therapy of cryptococcal meningitis. Factor best associated with relapse was having not received flucytosine during the initial 2 wks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; p=0.04).
- van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337(1):15-21. [PMID:9203426]
Comment: Addition of 5FC to amphotericin resulted in faster CSF sterilization but did not improve clinical outcome.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
- Gillum JG, Johnson M, Lavoie S, et al. Flucytosine dosing in an obese patient with extrameningeal cryptococcal infection. Pharmacotherapy. 1995;15(2):251-3. [PMID:7624273]
Comment: A case report of a morbidly obese patient who received 150 mg/kg/day IBW for treatment of extrameningeal cryptococcal infection. Pharmacokinetic parameters were similar as those reported in non-obese patients receiving the same dose.
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