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 cry ...

. 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 cryptococ ...

, for serious ''Candida'' infections and

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

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

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

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 nutr ...

. Common side effects include

bone marrow suppression Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting ( ...

, loss of appetite,

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, vomiting, and

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

Anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

and other

allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

occasionally occur. It is unclear if use in

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

is safe for the baby. Flucytosine is in the fluorinated pyrimidine analogue family of medications. It works by being converted into

fluorouracil Fluorouracil (5-FU, 5-fluorouracil), 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, stoma ...

inside the fungus, which impairs its ability to make

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

. Flucytosine was first made in 1957. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. 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 less-developed industrial base and a lower Human Development Index (HDI) relative to developed countries. However, this definition is not universally agreed upon. There is also no clear agreeme ...

Medical uses

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

Candida Candida, or Cándida (Spanish), may refer to: Biology and medicine * ''Candida'' (fungus), a genus of yeasts ** Candidiasis, an infection by ''Candida'' organisms * Malvasia Candida, a variety of grape Places * Candida, Campania, a ''comu ...

'' or ''

Cryptococcus neoformans ''Cryptococcus neoformans'' is an encapsulated basidiomycetous 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 ''Filob ...

''. 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 Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e. nitrogen, sulfur, or oxygen) as part of the ring. Their names originate from the Hantzsch–Widman nomenclature. Th ...

antifungals such as

fluconazole Fluconazole is an antifungal medication used for a number of fungal infections. These include candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor. It is also used to pr ...

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...

. Minor infections such as candidal

cystitis A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra ( urethritis) while upper urinary tract infections affect the kidney (py ...

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 nutr ...

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 caused by ...

. Sufficient human data does not exist.

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

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, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a pump and then fed to the infant. The World Health Organization (WHO ...

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 and induce cell death. Cytostasis is an important prerequisite ...

s) 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 for these patients. * All patients receiving flucytosine should be under strict medical supervision. *

Hematological Hematology ( spelled haematology in British English) is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to blood. It involves treating diseases that affect the production ...

renal In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrop ...

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 (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

leukopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...

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 cou ...

, 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 neutropenia in the circulating blood. I ...

) may occur.

Aplastic anemia Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Normally, blood cells are produced in the bone marrow by stem cells that reside there, but patients with aplastic anemia ...

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 associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

, dry mouth,

duodenal ulcer Peptic ulcer disease is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...

, GI hemorrhage, nausea, vomiting, and

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

. * Liver function: Elevations of

liver enzymes Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial t ...

and

bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...

, hepatic dysfunction,

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, 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 ...

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 that is round and small enough that it can generally be eaten hand-held. Whether a bun is considered sweetened or unsweetened differs between countries: it is considered sweetened in the United Kingdom, a savory bread in ...

and serum

creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...

have been noted.

Crystalluria Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered often as a benign condition and as one of the side effects of sulfonamides and penicillins. The main reason for the identification of urin ...

(formation of crystals and excretion in the urine) and

acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in renal function, kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. ...

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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

effects are frequent and include confusion,

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

hearing loss Hearing loss is a partial or total inability to 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 acquire spo ...

, headache,

paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

, vertigo and sedation. * Skin reactions: Rash, pruritus, and

photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxicit ...

have all been noticed. Toxic epidermal necrolysis (

Lyell's syndrome Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu- ...

) 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 agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...

. The issue has been raised because traces of

5-fluorouracil Fluorouracil (5-FU, 5-fluorouracil), 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, stoma ...

, 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 b ...

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 of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

on the

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, 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 i ...

, gastrointestinal tract,

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

function. Vigorous hydration and

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

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 ''

'' and ''

Cryptococcus ''Cryptococcus'' is a genus of fungi in the family Cryptococcaceae that includes both yeasts and filamentous species. The filamentous, sexual forms or teleomorphs were formerly classified in the genus ''Filobasidiella'', while ''Cryptococcus' ...

''. Limited studies demonstrate that flucytosine may be of value against infections with '' Sporothrix'', ''

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. Viewing the fungi under a microscope, Miche ...

'', ''

Cladosporium ''Cladosporium'' is a genus of fungi including some of the most common indoor and outdoor molds. Some species are endophytes or plant pathogens, while others parasitize fungi. Description Species produce olive-green to brown or black colonie ...

'', ''

Exophiala ''Exophiala'' is a genus of Teleomorph, anamorph and holomorph, anamorphic fungus, fungi in the family Herpotrichiellaceae. The widespread genus contains 28 species. The genus was formally described by J. W. Carmichael in 1966. ''Exophiala'' ha ...

'', 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 Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

. 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. is a global, diversified American-Canadian pharmaceutical company. Its global corporate headquarters are located in Laval, Quebec, Canada, and its U.S. headquarters are in Bridgewater, New Jersey. It develops, manufa ...

. 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 Meda AB is a specialty pharmaceutical company, headquartered in Solna, Sweden. Meda imports and markets pharmaceuticals, nutritional, and health-care products, and offers services including clinical research, registration, and logistics. At the ...

Pharmaceuticals.

Other animals

In some countries, such as

Switzerland Switzerland, officially the Swiss Confederation, is a landlocked country located in west-central Europe. It is bordered by Italy to the south, France to the west, Germany to the north, and Austria and Liechtenstein to the east. Switzerland ...

, 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