- Cryptococcal and Candida endocarditis (in addition to amphotericin B).
- Cryptococcal meningitis (in addition to amphotericin B).
- 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 PO q6h in combination with amphotericin B products
- Sole exception: monotherapy can be used for Candida UTI, e.g. azole-resistant candiduria (e.g., C. glabrata).
- Dosing in special populations:
- Obesity: consider IBW for dosing of non-life-threatening infections.
- Meningitis: consider using adjusted body weight and monitor serum concentrations.
- Therapeutic drug 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.
ADULT RENAL DOSING
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: no 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)
USUAL PEDIATRIC DOSING
- 25 mg/kg PO q6h
- Adjust dose to maintain flucytosine concentrations (2-hour post-dose) between 40-60 mcg/mL.
- Obtain drug levels after 3-54 days of continuous dosing.
PEDIATRIC RENAL DOSING
- 20-40 mL/min: 25 mg/kg q12h
- 10-20 mL/min: 25mg/kg q24 h
- < 10 ml/min: 25mg/kg q24-48h
- Important to adjust dose to maintain 2-hour post-dose between 40-60 mcg/mL.
- Supplemental dose needed after hemodialysis or peritoneal dialysis.
Pediatric Dosing Author: George K Siberry, MD, MPH
ADVERSE DRUG REACTIONS
- GI intolerance: diarrhea, dyspepsia, and abdominal pain
- Marrow suppression: leukopenia or thrombocytopenia (with concentrations >100 mcg/mL)
- Taste perversion
- Hepatitis (hepatic necrosis has been reported)
- Peripheral neuropathy
- Fatal bone marrow aplasia
- Drugs that cause bone marrow suppression (e.g., AZT, ganciclovir, and interferon): increased risk of 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 (60-100% of serum concentration attained in the CSF).
DOSING FOR DECREASED HEPATIC FUNCTION
No data. Usual dose likely.
Category C: Teratogenicity reported in animal studies. Partially metabolized to 5-fluorouracil, a known human teratogen. Avoid use in first trimester.
BREAST FEEDING COMPATIBILITY
No data. Breast feeding during flucytosine therapy not recommended because of concern for potential adverse effects.
- 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.
- May be considered in combination with amphotericin (and surgery) in the treatment of candidal endocarditis.
- Flucytosine should never be used as monotherapy due to the rapid development of resistance, with the exception of candiduria without systemic infection.
- Coelho C, Casadevall A. Cryptococcal therapies and drug targets: the old, the new and the promising. Cell Microbiol. 2016;18(6):792-9. [PMID:26990050]
Comment: Authors highlight difficulties with cryptococcus and that emergence of resitance occurs so frequently with 5-FC monotherapy, hence why it is not used except in compination.
- Yao ZW, Lu X, Shen C, et al. Comparison of flucytosine and fluconazole combined with amphotericin B for the treatment of HIV-associated cryptococcal meningitis: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2014. [PMID:24550039]
Comment: Group exmained primary outcomes using mortality d14 and d70 with secondary outcome as early fungicidal activity (EFA) at 2 weeks. Four trials were identified. Meta-analysis found lower mortality in patients given AmB + 5-FC at the 2 weeks point--combination group 44% [risk ratio (RR) 0.56, 95% confidence interval (CI) 0.33-0.95, p = 0.03]. EFA was significantly shorter in patients receiving AmB plus 5-FC [mean difference (MD) -0.10 log10 colony-forming units (CFU) per day, 95 % CI -0.11-0.09, p < 0.00001]. Mortality was no different between the 5-FC and fluconazole groups at the 3 months time point (p = 0.15) Adverse events occurred with similar frequency between the two treatment groups. There was no statistically significant difference in the survival rate between AmB in combination with high-dose fluconazole and the current standard of AmB plus 5-FC therapy for HIV-associated cryptococcal meningitis.
- 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.
- 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: Flucytosine plus AmphoB, liposomal AmB, or AmB lipid complex (for a minimum of 2 weeks) is recommended for the treatment of cryptococcal meningoencephalitis. Without flucytosine, the recommended amphoB treatment duration is 4-6 weeks. Fluconazole 1200 mg/day plus flucytosine x 6 weeks can be considered as an alternative in patients unable to tolerate amphoB.
- Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46(2):171-9. [PMID:10933638]
Comment: Focused review on pharmacological aspects of this antifungal drug, originally developed in 1957 as an antimetabolite
- 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.
- 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.
- Pappas PG, et al: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50.
Comment: Updated IDSA guidelines on the treatment of candidiasis.
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