Flucytosine, also known as 5-fluorocytosine (5-FC), is an

antifungal medication An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypt ...

. It is specifically used, together with

amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis. Fo ...

, for serious ''Candida'' infections and

cryptococcosis Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the ...

. It may be used by itself or with other antifungals for chromomycosis. Flucytosine is used by mouth and by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. Common side effects include bone marrow suppression, loss of appetite,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

, vomiting, and

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

Anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

and other allergic reactions occasionally occur. It is unclear if use in

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

is safe for the baby. Flucytosine is in the fluorinated

pyrimidine analogue Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines. Examples * Nucleobase analogues **Fluorouracil (5FU), which inhibits thymidylate synthase **Floxuridine (FUDR) ** 6-azauracil (6-AU) *Nucleoside analogue ...

family of medications. It works by being converted into

fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreat ...

inside the fungus, which impairs its ability to

make Make or MAKE may refer to: *Make (magazine), a tech DIY periodical *Make (software), a software build tool *Make, Botswana, in the Kalahari Desert *Make Architects Make Architects is an international architecture practice headquartered in London ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

. Flucytosine was first made in 1957. It is on the World Health Organization's List of Essential Medicines. As of 2016, in the United States the medication cost about US$2,000 per day while in the United Kingdom it is about US$22 per day. It is not available in much of the

developing world A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...

Medical uses

Flucytosine by mouth is used for the treatment of serious infections caused by susceptible strains of '' Candida'' or ''

Cryptococcus neoformans ''Cryptococcus neoformans'' is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to ''Filobasidiella 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 azole antifungals such as

fluconazole Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prevent ...

or itraconazole. Minor infections such as candidal cystitis may be treated with flucytosine alone. In some countries, treatment with slow

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

s for no more than a week is also a therapeutic option, particular if the disease is life-threatening. Serious fungal infections may occur in those who are immunocompromised. These people benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher.

Pregnancy and breastfeeding

In animal models (rats), flucytosine has been found to be

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...

. Sufficient human data does not exist.

Pregnant Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

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, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that brea ...

during treatment with flucytosine.

Children

The efficacy and safety in patients under 18 years of age has not been determined.

Side effects

* Patients treated with drugs compromising bone marrow function (e.g.

cytostatic Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Cytostasis is an important prerequisite for structured multic ...

s) should be treated carefully.

Blood cell count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and pl ...

s 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 for these patients. * 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. * Antiproliferative actions on bone marrow and GI tissue: Due to the drug's preference for rapidly proliferating tissues, bone marrow depression (

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

pancytopenia Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.). If only two parameters from the complete blood coun ...

, or even rarely

agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...

) may occur.

Aplastic anemia Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood ...

has also been seen. Bone marrow toxicity can be irreversible and may cause death, particularly in immunocompromised patients. GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating,

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...

, dry mouth,

duodenal ulcer Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines ...

, GI hemorrhage, nausea, vomiting, and ulcerative colitis. * Liver function: Elevations of liver enzymes and

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

, hepatic dysfunction,

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

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

BUN A bun is a type of bread roll, typically filled with savory fillings (for example hamburger). A bun may also refer to a sweet cake in certain parts of the world. Though they come in many shapes and sizes, buns are most commonly round, and are ...

and serum creatinine have been noted. Crystalluria (formation of crystals and excretion in the urine) and acute kidney injury have also been seen. * Adverse

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

effects are frequent and include confusion, hallucinations,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

hearing loss Hearing loss is a partial or total inability to Hearing, hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to Language ...

, headache,

paresthesia Paresthesia is an abnormal sensation of the skin (tingling, pricking, chilling, burning, numbness) with no apparent physical cause. Paresthesia may be transient or chronic, and may have any of dozens of possible underlying causes. Paresthesias ar ...

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...

, peripheral neuropathy, vertigo and sedation. * Skin reactions: Rash, pruritus, and photosensitivity have all been noticed. Toxic epidermal necrolysis ( Lyell's syndrome) may also be encountered and may be life-threatening. *

: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed. It is not known if flucytosine is a human

carcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...

. The issue has been raised because traces of

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...

, which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.

Interactions

Flucytosine may increase the toxicity of

and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., cryptococcal meningitis). The cytostatic

cytarabine Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by in ...

inhibits the antimycotic activity of flucytosine.

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 effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

on the

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

, gastrointestinal tract,

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

function. Vigorous hydration and hemodialysis may be helpful in removing the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.

Pharmacology

Mechanisms of action

Two major mechanisms of action have been elucidated: * Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis thus disturbing the building of certain essential proteins. * Flucytosine also undergoes 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'' and '' Cryptococcus''. Limited studies demonstrate that flucytosine may be of value against infections with ''

Sporothrix ''Sporothrix'' is a ubiquitous genus of soil-dwelling fungus discovered by Schenck in 1898 and studied in more detail by Hektoen and Perkins. The first described and best known species is ''Sporothrix schenckii ''Sporothrix schenckii'', a fun ...

'', '' Aspergillus'', ''

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. Many species ...

'', ''

Exophiala ''Exophiala'' is a genus of anamorphic fungi in the family Herpotrichiellaceae. The widespread genus contains 28 species. The genus was formally described by J. W. Carmichael in 1966. ''Exophiala'' has been implicated in causing 'saxophone lung ...

'', and ''

Phialophora ''Phialophora'' is a form genus of fungus with short conidiophores, sometimes reduced to phialides; their conidia are unicellular. They may be parasites (including on humans), or saprophytic (including on apples). Genetic analysis of ''Phialop ...

''. 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 tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

. Intake with meals slows the absorption, but does not decrease the amount absorbed. 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 accumulate. 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 μg/ml. Serum levels in excess of 100 μg 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.

Economics

Although a generic, off patent medication in the U.S., as of January 2016, there was only one FDA-approved pharmaceutical supplier,

Valeant Pharmaceuticals Bausch Health Companies Inc. (formerly Valeant Pharmaceuticals International, Inc.) is a Canadian multinational specialty pharmaceutical company based in Laval, Quebec, Canada. It develops, manufactures and markets pharmaceutical products and ...

. Due to this monopoly, the cost per 250 mg tablet was $70.46 per tablet for a daily treatment cost of ~$2110/day for a 75 kg adult (165 pounds) adult and $29,591 for a two-week treatment course as of December 2015. This cost of flucytosine is more than 100-fold higher in the U.S. than in the United Kingdom and Europe via Meda AB Pharmaceuticals. Flucytosine tablets are available in India for US$2.00 per tablet via Jolly Healthcare Pvt. Ltd. and are available in 100 tablet packs.

Other animals

In some countries, such as

Switzerland ). Swiss law does not designate a ''capital'' as such, but the federal parliament and government are installed in Bern, while other federal institutions, such as the federal courts, are in other cities (Bellinzona, Lausanne, Luzern, Neuchâtel ...

, flucytosine has been licensed to treat cats, dogs and birds (in most cases together with amphotericin B) for the same indications as in humans.

References

External links

* {{portal bar, Medicine Antifungals for dermatologic use Nucleobases Organofluorides Pyrimidones World Health Organization essential medicines Wikipedia medicine articles ready to translate Orphan drugs