Flucytosine
Encyclopedia
Flucytosine, or 5-fluorocytosine, a fluorinated pyrimidine analogue
, is a synthetic antimycotic
drug
.
It is structurally related to the cytostatic fluorouracil
and to floxuridine
. It is available in oral and in some countries also in injectable form. A common brand name is Ancobon. Flucytosine was first synthesized in 1957 but its antifungal properties discovered in 1964. The drug is dispensed in capsules of 250 mg and 500 mg strength. The injectable form is diluted in 250 mL saline solution to contain 2.5 g total (10 mg/mL). The solution is physically incompatible with other drugs including amphotericin B
.
Flucytosine is active in vitro as well as in vivo against some strains of Candida
and Cryptococcus
. Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus
, Cladosporium
, Exophila, and Phialophora
.
Resistance is quite commonly seen as well in treatment naive patients and under current treatment with flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.
. Intake with meals slows the resorption, but does not decrease the amount resorbed. Following an oral dose of 2 grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impaired renal function higher serum levels are seen and the drug tends to cumulate in these patients. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100 mcg/ml. Serum levels in excess of 100mcg are associated with a higher incidence of side-effects. Periodic measurements of serum levels are recommended for all patients and are a must in patients with renal damage.
on the bone marrow
, gastrointestinal tract, liver
and kidney
function. Vigorous hydration and hemodialysis
may be helpful to remove the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.
. The issue has been raised because traces of 5-fluorouracil, which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.
antifungals such as fluconazole
or itraconazole
. Minor infections such as candidal cystitis
may be treated with flucytosine alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a therapeutic option, particular if the disease is life-threatening.
It is not known if flucytosine is distributed in human breast milk. Given the potential risk to the child, the patient should not breastfeed
during treatment with flucytosine.
and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., cryptococcal meningitis
). The cytostatic cytarabine
inhibits the antimycotic activity of flucytosine.
alopecia (fall of hairs)
-infected) patients. These patients benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher than in immunocompetent patients.
, flucytosine has been licensed to treat cats, dogs and birds (in most cases together with amphotericin B) for the same indications as in humans.
Pyrimidine analogue
Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines.-Examples:Examples include:* 5-fluorouracil which inhibits thymidylate synthase.* Floxuridine * Cytosine arabinoside...
, is a synthetic antimycotic
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
.
It is structurally related to the cytostatic fluorouracil
Fluorouracil
Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...
and to floxuridine
Floxuridine
Floxuridine is an oncology drug that belongs to the class known as antimetabolites. The drug is most often used in the treatment of colorectal cancer.-Mechanism of action:...
. It is available in oral and in some countries also in injectable form. A common brand name is Ancobon. Flucytosine was first synthesized in 1957 but its antifungal properties discovered in 1964. The drug is dispensed in capsules of 250 mg and 500 mg strength. The injectable form is diluted in 250 mL saline solution to contain 2.5 g total (10 mg/mL). The solution is physically incompatible with other drugs including amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
.
Mechanisms of action
Two major mechanisms of action have been elucidated:- One is that the drug is intrafungally converted into the cytostatic fluorouracil that undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis and disturbs the building of certain essential proteins.
- The other mechanism is the conversion into 5-fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis.
Spectrum of susceptible fungi and resistance
Flucytosine is active in vitro as well as in vivo against some strains of Candida
Candida (genus)
Candida is a genus of yeasts. Many species are harmless commensals or endosymbionts of animal hosts including humans, but other species, or harmless species in the wrong location, can cause disease. Candida albicans can cause infections in humans and other animals, especially in immunocompromised...
and Cryptococcus
Cryptococcus
Cryptococcus is a genus of fungus. Species grow in culture as yeasts. The perfect forms or teleomorphs of Cryptococcus species are filamentous fungi in the genus Filobasidiella...
. Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus
Aspergillus
Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide. Aspergillus was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli...
, Cladosporium
Cladosporium
Cladosporium is a genus of fungi including some of the most common indoor and outdoor molds. Species produce olive-green to brown or black colonies, and have dark-pigmented conidia that are formed in simple or branching chains....
, Exophila, and Phialophora
Phialophora
Phialophora is a form genus of fungus with short conidiophores, sometimes reduced to phialides; their conidia are unicellular. They may be parasites, or saprophitic.Genetic analysis of Phialophora shows that it is a paraphyletic grouping....
.
Resistance is quite commonly seen as well in treatment naive patients and under current treatment with flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.
Pharmacokinetic data
Flucytosine is well absorbed (75 to 90%) from the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. Intake with meals slows the resorption, but does not decrease the amount resorbed. Following an oral dose of 2 grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impaired renal function higher serum levels are seen and the drug tends to cumulate in these patients. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100 mcg/ml. Serum levels in excess of 100mcg are associated with a higher incidence of side-effects. Periodic measurements of serum levels are recommended for all patients and are a must in patients with renal damage.
Human overdose
Symptoms and their severities are unknown, because flucytosine is used under close medical supervision, but expected to be an excess of the usually encountered side effectsAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
on the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, gastrointestinal tract, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
function. Vigorous hydration and hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
may be helpful to remove the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.
Human carcinogenity
It is not known if flucytosine is a human carcinogenCarcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
. The issue has been raised because traces of 5-fluorouracil, which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.
Indications
Oral flucytosine is indicated for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus neoformans. It can also be used for the treatment of chromomycosis (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance, but rather in combination with amphotericin B and/or azoleAzole
An azole is a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of either nitrogen, sulfur, or oxygen. The parent compounds are aromatic and have two double bonds; there are successively reduced analogs with fewer...
antifungals such as fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
or itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
. Minor infections such as candidal cystitis
Cystitis
Cystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
may be treated with flucytosine alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a therapeutic option, particular if the disease is life-threatening.
Contraindications and cautions
- All patients receiving flucytosine should be under strict medical supervision.
- Hematological, renal and liver function studies should be done frequently during therapy (initially daily, twice a week for the rest of treatment).
- Patients with preexisting bone marrow depression and liver impairment should be treated with caution.
- Concomitant treatment with brivudineBrivudineBrivudine is an antiviral drug used in the treatment of herpes zoster.-History:Brivudine is a similar drug to acyclovir. The compound was first synthesized by scientists at the University of Birmingham in the UK in the 1970s...
is an absolute contraindication. - Patients treated with drugs compromising bone marrow function (e.g. cytostatics) should be treated carefully. Blood cell counts should be taken very frequently.
- Patients with renal disease should receive flucytosine cautiously and in reduced doses. Guidelines for proper dosing exist. Serum level determinations are mandatory in these patients.
- HypersensitivityHypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
to flucytosine is an absolute contraindication.
Pregnancy and lactation
In animal models (rats), flucytosine has been found to be teratogenic. Sufficient human data does not exist. Pregnant women should be given flucytosine only if the potential benefits exceed the potential harm to the fetus.It is not known if flucytosine is distributed in human breast milk. Given the potential risk to the child, the patient should not breastfeed
Breastfeeding
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...
during treatment with flucytosine.
Pediatric patients
The efficacy and safety in patients under 18 years of age has not been determined.Side effects
- Antiproliferative actions on bone marrow and GI tissue: Due to the drug's preference to affect rapidly proliferating tissues, bone marrow depression (anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, pancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
, or even rarely agranulocytosisAgranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
) may occur. Aplastic anemiaAplastic anemiaAplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
has also been seen. Bone marrow toxicity can be irreversible and may cause death, particular in immunocompromised patients. GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, abdominal painAbdominal painAbdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, and ulcerative colitisUlcerative colitisUlcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
.
- Liver function: Elevations of liver enzymes and bilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
, hepatic dysfunction, jaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and, in one patient, liver necrosis have all been seen. Some fatal cases have been reported, however the majority of cases was reversible.
- Renal function: Increased BUNBlood urea nitrogenThe blood urea nitrogen test is a measure of the amount of nitrogen in the blood in the form of urea, and a measurement of renal function. Urea is a by- product from metabolism of proteins by the liver and is removed from the blood by the kidneys.-Physiology:The liver produces urea in the urea...
and serum creatinineCreatinineCreatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
have been noted. CrystalluriaCrystalluriaCrystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered as one of the side effects of sulphonamides.-Clinical significance:It can be an indication of urolithiasis.It can be associated with cysteinuria....
(formation of crystals and excretion in the urine) and acute renal failure have also been seen.
- Adverse central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
effects are frequent and include confusion, hallucinationHallucinationA hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s, psychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, hearing loss, headache, paresthesiaParesthesiaParesthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
, parkinsonismParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
, peripheral neuropathyPeripheral neuropathyPeripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, vertigo and sedation.
- Skin reactions: Rash, pruritus, and photosensitivityPhotosensitivityPhotosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
have all been noticed. Toxic epidermal necrolysis (Lyell's syndrome) may also be encountered and may be life-threatening.
- AnaphylaxisAnaphylaxisAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed.
Interactions
For details see Contraindications and Cautions. Flucytosine may increase the toxicity of amphotericin BAmphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., cryptococcal meningitis
Cryptococcus neoformans
Cryptococcus neoformans is an encapsulated yeast that can live in both plants and animals. Its teleomorph is Filobasidiella neoformans, a filamentous fungus belonging to the class Tremellomycetes. It is often found in pigeon excrement....
). The cytostatic cytarabine
Cytarabine
Cytarabine, or cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia and non-Hodgkin lymphoma. It is also known as Ara-C...
inhibits the antimycotic activity of flucytosine.
alopecia (fall of hairs)
Dosage
The recommended daily dose is 50 to 150 mg/kg of bodyweight orally, divided in four equal doses every six hours. If problems exist to swallow a complete single dose, the dose may be given in several partial amounts over 15 minutes. The dose for intravenous infusions is 50 mg/kg infused over 20 to 40 minutes every six hours. The duration of treatment depends on the clinical situation, but generally does not exceed seven days.Use in immunocompromised patients
Serious fungal infections often occur in immunocompromised (e.g. HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-infected) patients. These patients benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher than in immunocompetent patients.
Veterinary uses
In some countries, such as SwitzerlandSwitzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....
, flucytosine has been licensed to treat cats, dogs and birds (in most cases together with amphotericin B) for the same indications as in humans.