Pharmacology of flucytosine (5-FC)

INTRODUCTION — Flucytosine (5-fluorocytosine, 5-FC) is an antifungal agent originally developed in 1957 as an antimetabolite. Although it has found no role as an anti-tumor agent, it is used for the treatment of certain fungal infections. Combination therapy of 5-FC with amphotericin B is recommended for the initial management of severe cryptococcal pneumonia and meningoencephalitis and, less frequently, for select invasive candidal infections. Due to a high incidence of primary and/or acquired resistance, use of flucytosine as monotherapy is significantly restricted.

Hematologic and hepatic toxicities may occur with 5-FC administration but can be reduced by monitoring serum concentrations and by adjusting the dose empirically in patients with renal dysfunction. When serum concentration testing is not available, careful monitoring for cytopenias will be necessary.

The pharmacology of flucytosine will be discussed here. The clinical use of flucytosine is discussed separately. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV" and "Candida endocarditis and suppurative thrombophlebitis" and "Candida infections of the central nervous system".)

MECHANISMS OF ACTION — 5-FC exerts its antifungal effects by interfering with both deoxyribonucleic acid (DNA) and protein synthesis. 5-FC is transported into susceptible fungi by cytosine permease then deaminated to 5-fluorouracil (5-FU) by cytosine deaminase [1]. The absence of cytosine deaminase in mammalian cells allows selective effects on fungal cells [1].

●Following incorporation into DNA, 5-FU is converted to 5-fluorodeoxyuridylic acid monophosphate, which interferes with DNA synthesis [1].

●5-FC inhibits protein synthesis by a separate mechanism; 5-FU is converted through 5-fluorouridine monophosphate and 5-fluorouridine diphosphate into 5-fluorouridine triphosphate, which is incorporated into fungal ribonucleic acid (RNA), thereby disturbing the amino acid pool and preventing protein synthesis [2].

The net result antifungal activity may be static or cidal, depending upon the organism. Flucytosine has demonstrated a prolonged post-antifungal effect (up to four hours) and concentration-independent pharmacodynamic activity [3,4].

CLINICAL USE — Combination therapy of 5-FC with amphotericin B is recommended for the initial management of severe cryptococcal pneumonia and meningoencephalitis and, less frequently, for select invasive candidal infections [5,6]. 5-FC is also used as part of an all-oral regimen in combination with fluconazole for cryptococcal meningoencephalitis in countries where it is difficult to give amphotericin B.

Due to a high incidence of primary and/or acquired resistance, use of flucytosine as monotherapy is significantly restricted. Monotherapy with 5-FC may be considered in selected cases of chromoblastomycosis/phaeohyphomycosis and genitourinary candidal infections that are not life-threatening and for which treatment alternatives, such as azoles, are not possible.

The clinical uses of flucytosine are discussed in more detail elsewhere. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV" and "Candida endocarditis and suppurative thrombophlebitis" and "Candida infections of the central nervous system".)

MECHANISMS OF RESISTANCE — Resistance to 5-FC can result from primary (intrinsic) or acquired resistance. Intrinsic resistance is due to impaired cellular uptake secondary to a mutation in cytosine permease. Acquired resistance results from defects in 5-FC metabolism through mutations in cytosine deaminase or uracil phosphoribosyl transferase and is thought to be a result of either failure of the organism to metabolize the agent or loss of pyrimidine biosynthesis feedback control [7]. The rate of mutation is frequent enough that a resistant mutant strain could be selected during high-burden infections (≥10⁶ colony-forming units).

In vitro data from clinical isolates do not always accurately reflect the incidence of resistance to 5-FC. As an example, Candida albicans demonstrating heterozygous resistance traits are frequently seen among clinical strains. These isolates demonstrate only slight increases in minimum inhibitory concentrations in vitro. However, under clinical conditions of drug exposure, selection of organisms that are more resistant may lead to treatment failure [1,8].

ANTIMICROBIAL ACTIVITY — The Clinical and Laboratory Standards Institute has established methods to standardize in vitro testing against Candida spp [9]. Minimum inhibitory concentration <1 mcg/mL by broth microdilution for most yeasts are considered susceptible, while those >2 mcg/mL are considered resistant.

Cryptococcus neoformans — The in vitro activity of flucytosine against Cryptococcus spp varies significantly among reports. Primary resistance rates have been reported to have ranged from 1 to 25 percent of C. neoformans isolates [10-12]. Non-neoformans strains of Cryptococcus may exhibit higher minimum inhibitory concentrations (MICs) to 5-FC [13].

The in vitro activity of the combination of 5-FC with amphotericin B against cryptococcal isolates is generally at least additive in 5-FC–susceptible isolates. (See "Pharmacology of amphotericin B".)

Candida — Reports of in vitro activity of 5-FC against Candida spp have varied by geographic location and species [14-16]. The reported incidence of resistance of Candida albicans to 5-FC ranges from 4 to 15 percent. Most strains of C. glabrata are susceptible to 5-FC. In one report, over 8800 Candida isolates obtained globally were tested for intrinsic resistance to 5-FC [15]. Overall, 95 percent of the isolates evaluated demonstrated in vitro susceptibility. With the exception of C. krusei (only 5 percent susceptible), resistance among a variety of Candida spp tested was uncommon. A later study that tested the in vitro activity of 5-FC against 254 clinical isolates of C. krusei collected worldwide found a similar rate of susceptibility (8 percent) [16].

Although infrequent, clonal outbreaks of 5-FC resistance in select Candida spp have been reported. In one such report, 45 (35 percent) of 130 C. tropicalis bloodstream isolates over a four-year period were reported to be 5-FC resistant [17]. The resistant clone was seen more commonly in patients with malignancies, particularly hematologic malignancies.

When 5-FC is tested in vitro in combination with amphotericin B against Candida spp, an additive effect or synergy was reported in 35 of 40 (85 percent) of isolates [18].

Since 2016, outbreaks of infection due to multidrug-resistant Candida auris have been reported [19]. In one report that evaluated 15 isolates, 5-FC potentiated most of the alternate antifungal agents (including amphotericin B, various echinocandins, and voriconazole) in vitro [19]. Others have reported no evidence of synergy or antagonism between 5-FC and other antifungals [20].

Other fungi — 5-FC demonstrates activity in vitro against less pathogenic fungi including Rhodotorula spp and Saccharomyces cerevisiae [21,22]. In addition, most organisms responsible for chromoblastomycosis and some dematiaceous fungi (Cladophialophora spp, Phialophora spp) are susceptible to 5-FC in vitro [2].

The endemic mycoses (Histoplasma, Blastomyces, Coccidioides species), most Aspergillus species, zygomycetes, and most dermatophytes are resistant in vitro to 5-FC.

PHARMACOKINETICS — 5-FC is available only as an oral capsule in the United States, although an intravenous formulation is available in Europe [23]. Approximately 80 to 90 percent of 5-FC is absorbed following oral administration [24]. Peak serum levels of 30 to 45 mcg/mL occur one to two hours after a single oral dose of 150 mg/kg. Oral absorption of 5-FC may be reduced in patients with advanced acquired immunodeficiency syndrome (AIDS) [23].

5-FC is widely distributed due in part to a low degree of protein binding (approximately 4 percent) [7]. The volume of distribution ranges from 0.6 to 0.9 L/kg [7]. Favorable penetration into bone, vertebral discs, and peritoneal and synovial fluid has been documented. Drug concentrations achieved in the spleen, heart, liver, kidney, and lung are equal to those found in the serum. 5-FC concentrations in the cerebrospinal fluid are approximately 60 to 80 percent of simultaneous serum concentrations, whereas urine concentrations are generally several-fold higher than simultaneous serum concentrations [7].

Up to 96 percent of the total dose of 5-FC is eliminated as unchanged drug in the urine, primarily by glomerular filtration [7]. The elimination half-life of 5-FC ranges from three to eight hours (average six hours) in patients with normal renal function but may extend for up to 60 to 250 hours in patients with end-stage kidney disease. Both hemodialysis and peritoneal dialysis remove significant amounts of 5-FC [7].

PHARMACODYNAMICS — Animal studies suggest that lower peak concentrations (between 40 and 60 mcg/mL) can improve safety while achieving (or exceeding) target exposure [4,25]. In an animal model of disseminated candidiasis, optimal efficacy of 5-FC was achieved when drug concentrations exceeded the organism’s minimum inhibitory concentration for more than 40 percent of the dosing interval [4]. However, studies in humans are lacking and findings may vary between pathogen and with use of combination drug therapy.

DOSING

Usual dosing in adults and children — 5-FC should be given orally in four divided doses (25 mg/kg at six-hour intervals) in both adult and pediatric patients. Because of the commercial availability of a 250 mg capsule, individual oral doses are usually rounded to the nearest 250 mg, especially in adults.

Although the published dose range of 5-FC in adults with normal renal function is 100 to 150 mg/kg per day, we recommend that a total dose of 100 mg/kg per day not be exceeded. There is rarely an indication for doses higher than 100 mg/kg per day and the risk of toxicity is significant.

Excessive serum concentrations of 5-FC have been reported in children (especially neonates) even with standard dosing of 100 mg/kg per day [26], so careful serum concentration monitoring is particularly important in such patients.

Special populations

Renal dysfunction — Dose modification is necessary in patients with renal dysfunction. Empiric oral dose adjustments can be based on measured or estimated creatinine clearance [27]:

●>40 mL/minute: 25 mg/kg every 6 hours

●20 to 40 mL/minute: 25 mg/kg every 12 hours

●10 to ≤20 mL/minute: 25 mg/kg every 24 hours

●<10 mL/minute: 25 mg/kg every 48 hours

It is particularly important to monitor the 5-FC serum concentration in patients with renal impairment, as discussed below. (See 'Serum concentration monitoring' below.)

Renal replacement therapy — Patients undergoing intermittent hemodialysis should receive a 5-FC dose of 25 to 50 mg/kg every 48 to 72 hours after hemodialysis. In patients with significant fluid overload, use of ideal body weight (IBW) may reduce the risk of excessive serum concentrations.

Limited data exist on the removal of 5-FC from the serum from continuous forms of renal replacement therapy. In one case report of a patient receiving 5-FC while undergoing continuous venovenous hemofiltration (CVVH), supratherapeutic 5-FC concentrations were observed despite reducing the dose up to 50 percent beyond the routine dose reduction of 5-FC made for intermittent hemodialysis [28]. Another case report involving administration of 5-FC in a patient undergoing CVVH recommended a dose of 25 mg/kg daily with a low fluid replacement rate [29].

Hepatic insufficiency — Dosing adjustment is not necessary in patients with hepatic insufficiency.

Obesity — We use IBW for dosing of 5-FC in obese patients. This is based on a single case report in which pharmacokinetic estimates were closer to published population estimates when IBW was used in a morbidly obese patient [30].

Pregnancy — Because of the in vivo conversion of 5-FC to 5-fluorouracil (5-FU), 5-FC should be avoided during pregnancy if possible. 5-FU is suspected of producing congenital anomalies in humans and 5-FC has been shown to be teratogenic in rats [31]. However, some cases report 5-FC use during pregnancy without complications [32,33]. Data are lacking on optimal dosing of 5-FC during pregnancy.

It may be necessary to use 5-FC with amphotericin B in some pregnant patients with cryptococcal meningitis, but the potential risks and justification to use this agent during pregnancy should be discussed with the patient and the appropriate consent obtained whenever possible.

ADVERSE EFFECTS — The most significant toxicities of 5-FC are hematologic, hepatic, and gastrointestinal. In particular, leukopenia and thrombocytopenia can limit its use.

Most of the hematologic toxicity associated with 5-FC is thought to result from the in vivo conversion of 5-FC to fluorouracil (5-FU) even though studies have correlated bone marrow toxicity more with 5-FC than 5-FU levels [34]. 5-FC may convert to 5-FU spontaneously or under the influence of Escherichia coli in the gut [35]. Although the enzymes responsible for this conversion are thought to be induced by chronic exposure, toxicity most often occurs during the first two weeks of treatment. Renal dysfunction caused by the concomitant administration of nephrotoxic agents, such as amphotericin B, can lead to 5-FC accumulation and further contribute to dose-related toxicity [36].

Approximately 5 percent of patients develop elevations in serum aminotransferases or alkaline phosphatase, and hepatic necrosis has been reported. As a result, a strong indication must be present to justify administration of 5-FC to patients with severe liver dysfunction. These hematologic and hepatic abnormalities are seen primarily in patients whose peak serum 5-FC concentrations exceed 100 mcg/mL [37]. Gastrointestinal complaints such as nausea, vomiting, and diarrhea occur in up to 6 percent of patients. However, such reactions are less clearly related to serum concentrations.

SERUM CONCENTRATION MONITORING — Monitoring of serum 5-FC concentrations is performed in order to reduce the risk of toxicity, particularly hematologic toxicity [38,39]. It is particularly important to monitor the 5-FC concentration in patients with renal dysfunction, since the drug accumulates in this setting, which can lead to toxicity. In a retrospective study that included 53 intensive care unit patients, patients with serum concentrations >100 mg/L were significantly more likely to develop thrombocytopenia and hepatotoxicity than those with lower serum concentrations [37].

Serum 5-FC concentrations should be measured after approximately three to five doses and should be obtained two hours after a dose has been administered [40]. Serum drug concentrations should be repeated following dose adjustment if renal function worsens or if leukopenia or thrombocytopenia occurs.

All patients receiving 5-FC should undergo regular monitoring of the complete blood count (CBC). In settings in which serum 5-FC concentrations are not available, CBC monitoring two to three times per week provides an indirect method of screening for excessive dosing. An otherwise unexplained reduction in the neutrophil or platelet count may reflect 5-FC toxicity and either the drug should be stopped or the dose reduced.

MANAGEMENT OF TOXICITIES — Dose reductions in patients with preexisting renal dysfunction or in those with excessive serum concentrations may help to reduce hematologic and hepatic toxicities resulting from 5-FC administration. While further dose reductions (resulting in reductions in serum concentrations) may permit the continuation of therapy, it would generally not be advisable to reduce serum concentrations below target. In most clinical scenarios, alternate therapies exist, which facilitate the ability to discontinue therapy in patients for whom toxicity is severe.

DRUG INTERACTIONS AND CONTRAINDICATIONS — Concomitant aluminum hydroxide or magnesium hydroxide delays absorption of 5-FC. The effect of other drugs that raise gastric pH (such as other antacids, histamine-2 antagonists, or proton pump inhibitors) has not been reported. 5-FC is not known to affect the hepatic cytochrome P450 system [24,41].

Concomitant administration of agents with toxicities similar to 5-FC should be approached with caution. As an example, patients with AIDS who are treated with 5-FC for cryptococcal meningitis may be receiving other agents with hematologic toxicities, such as zidovudine, ganciclovir, or trimethoprim-sulfamethoxazole. In addition, drugs known to cause renal dysfunction (such as amphotericin B and foscarnet) may alter the elimination of 5-FC and predispose to toxicities related to excessive 5-FC concentrations.

Although the product information document states that the antifungal activity of 5-FC can be competitively inhibited by cytarabine [37], there are no published data to support this.

5-FC is contraindicated in patients with known complete dihydropyrimidine dehydrogenase enzyme deficiency due to increased risk of severe drug toxicity [42].

DRUG COST AND AVAILABILITY — 5-FC availability and costs vary widely. In a survey of 125 countries worldwide, 5-FC was unavailable in 89 (71.2 percent) [43]. Furthermore, in most African and Asian countries, despite the high incidence of cryptococcal diseases, 5-FC is not available despite ongoing advocacy [44-46]. In addition, a wide variability in drug costs for 5-FC exists, ranging from USD $4.60 to $1409 per day.

In one report, a two-week course was estimated to cost $22,000 in the United States compared with $22 in the United Kingdom, using 2015 US prices [47]. However, the US Food and Drug Administration subsequently approved three generic formulations of 5-FC, which has resulted in significant reductions (up to a 78 percent decrease) in the cost of therapy [48].

SUMMARY

●Mechanism of action − Flucytosine (5-FC) exerts its antifungal effects by interfering with both DNA and protein synthesis. (See 'Mechanisms of action' above.)

●Clinical use

•5-FC (in combination with amphotericin B deoxycholate or a lipid formulation of amphotericin B) is the induction therapy of choice for cryptococcal meningoencephalitis and severe cryptococcal pneumonia. It is used less commonly as part of a combination regimen for select invasive candidal infections. (See 'Clinical use' above.)

•Due to a high incidence of primary and/or acquired resistance, use of flucytosine as monotherapy is significantly restricted. Select cases of chromoblastomycosis/phaeohyphomycosis and genitourinary candidal infections that are not life threatening and for which treatment alternatives, such as azoles, are not possible may be considered for monotherapy. (See 'Clinical use' above.)

●Mechanisms of resistance − Resistance to 5-FC is thought to be a result of either failure of the organism to metabolize the agent or loss of pyrimidine biosynthesis feedback control. (See 'Mechanisms of resistance' above.)

●Antimicrobial activity − 5-FC has activity in vitro against Cryptococcus neoformans, many Candida spp, Rhodotorula spp, Saccharomyces cerevisiae, most of the organisms responsible for chromoblastomycosis, and some dematiaceous fungi. (See 'Antimicrobial activity' above.)

●Dosing

•5-FC is available in the United States only as an oral capsule. Approximately 80 to 90 percent of 5-FC is absorbed following oral administration. (See 'Usual dosing in adults and children' above and 'Pharmacokinetics' above.)

•The usual dosing of 5-FC in patients with normal renal function is 25 mg/kg orally every six hours. Because of the commercial availability of a 250 mg capsule, individual oral doses are usually rounded to the nearest 250 mg, especially in adults. (See 'Usual dosing in adults and children' above.)

•Dose modification is necessary in patients with renal dysfunction. (See 'Renal dysfunction' above.)

●Pregnancy − Because of the in vivo conversion of 5-FC to 5-fluorouracil and the possible teratogenicity of both compounds, 5-FC should be avoided during pregnancy if possible. It may be necessary to use 5-FC with amphotericin B in some pregnant patients with cryptococcal meningitis, but the potential risks and justification to use this agent during pregnancy should be discussed with the patient and the appropriate consent obtained whenever possible. (See 'Pregnancy' above.)

●Adverse effects − The most significant toxicities of 5-FC are hematologic, hepatic, and gastrointestinal. (See 'Adverse effects' above.)

●Serum concentration monitoring

•Serum 5-FC concentrations should be monitored to reduce the risk of toxicities, particularly hematologic toxicity. It is particularly important to monitor the 5-FC serum concentration in patients with renal impairment. (See 'Serum concentration monitoring' above.)

•Measurement of serum 5-FC concentrations is recommended after three to five days of therapy, when available, and should be obtained two hours after a dose has been administered. In settings in which serum 5-FC concentrations are not available, complete blood count monitoring two to three times per week provides an indirect method of screening for excessive dosing. (See 'Serum concentration monitoring' above.)