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^Dosage is indicated in mg unless otherwise noted.
25 mg/kg q6h
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)
25 mg/kg q48h (monitor CBC serum levels closely with appropriate dose adjustments)
25 mg/kg q24-48h
Dose post-dialysis on days of dialysis (monitor CBC and serum levels w/ appropriate dose adjustment)
0.5-1.0 gm q24h (monitor CBC and serum levels w/ appropriate dose adjustments)
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)
Pediatric Dosing Author: George K Siberry, MD, MPH
Flucytosine interferes with protein synthesis by incorporation into fungal RNA after being converted to 5-FU intracellularly.
Minimal metabolism; principally excreted unchanged in the urine. Unabsorbed drug excreted in feces.
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).
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.
No data. Breast feeding during flucytosine therapy not recommended because of concern for potential adverse effects.
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.
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.
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.
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.
Comment: Focused review on pharmacological aspects of this antifungal drug, originally developed in 1957 as an antimetabolite
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).
Comment: Addition of 5FC to amphotericin resulted in faster CSF sterilization but did not improve clinical outcome.
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.
Comment: Updated IDSA guidelines on the treatment of candidiasis.
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