Evolving Role of Flucytosine in Immunocompromised Patients: New Insights into Safety, Pharmacokinetics, and Antifungal Therapy

Abstract

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.

Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia

“…Itraconazole and amphotericin B, either as desoxycholate or encapsuled in liposomes, poorly penetrate across the brain-blood barrier (Como & Dismukes, 1994;Collette et al, 1989Collette et al, , 1991. Flucytosine may be recovered in high concentrations from the CSF, but aspergilli frequently show resistance to this drug (Francis & Walsh, 1992). There is a lack of clinical data on an improved efficacy of combining flucytosine with amphotericin B in cerebral aspergillosis (Denning & Stevens, 1990).…”

Current Concepts in Antifungal Pharmacology

“…28,38 However, resident intestinal bacterial flora in the human gut can convert 5-FC to 5-fluorouracil, resulting in nausea, vomiting, diarrhea, and bone marrow suppression. 28,39 Flucytosine is primarily active against yeasts but must be given in combination with other drugs to avoid resistance that arises with mutations in cytosine permease and cytosine deaminase, resulting in decreased importation and conversion of the drug to its active form (Figure 3). 39 Griseofulvin is a systemic antifungal agent that binds to tubulin, interfering with microtubule formation.…”

“…28,39 Flucytosine is primarily active against yeasts but must be given in combination with other drugs to avoid resistance that arises with mutations in cytosine permease and cytosine deaminase, resulting in decreased importation and conversion of the drug to its active form (Figure 3). 39 Griseofulvin is a systemic antifungal agent that binds to tubulin, interfering with microtubule formation. Because the drug concentrates in keratinocytes, it is only used for noninvasive dermatophyte infections.…”

Systemic Antifungal Therapy: Past, Present and Future

“…Two-hour post-dose levels are usually maintained at 50-75 μg/mL, as levels above 100 μg/mL are associated with a higher incidence of bone marrow suppression and enterocolitis. [52][53][54][55][56][57] Francis and Walsh concluded that flucytosine in combination with amphotericin B is well tolerated in myelosuppressed patients when serum flucytosine levels are serially monitored and maintained at 50-75 μg/mL. 53 Flucytosine is contraindicated in pregnancy because of its teratogenic effects in rats.…”

“…74 Francis and Walsh investigated the safety and tolerability of flucytosine in myelosuppressed patients and conclude that flucytosine in combination with amphotericin B is well tolerated when serum flucytosine levels are serially monitored. 53 The combination of amphotericin B plus fluconazole has been reviewed recently by Sugar. 70 Ramani et al found that no antagonism between amphotericin B and fluconazole occurs using 50% inhibitory endpoints with C. albicans.…”