An antimycotic ( Greek ἀντί anti 'against' and μὑκης mykes ' fungus ' with the Latin ending ; plural: antimycotics, adjective: antimycotic , adjective English antifungal ) is an antimicrobial substance that acts against diseases ( mycoses ) caused by fungi .
A distinction is made between fungicides , which can be effective as biocides or disinfectants against fungi and are used in agriculture, technology, the food industry, health care or other areas of life, but not disease-related (pathogen-specific) on humans or animals.
An effective therapy with few side effects requires the most selective effect possible against the pathogen . Because of the molecular biological similarity between the cells of the fungi and those of humans and animals, only unspecific and insufficiently effective agents were available for a long time. Beginning with the introduction of griseofulvin and polyene antimycotics in the 1960s, there are now a number of effective drugs, not least due to the - relatively still young - azole type antimycotics.
- depending on the mode of action in fungicidal (killing) or fungistatic (reproduction-inhibiting, called fungistatic ) substances
- by type of application in local or topical (on the skin or mucous membrane ) or systemically (via the blood circulation in the whole organism distributed) administrable substances
- according to the spectrum of activity in broadband and narrow-gauge antimycotics.
It was not until the second half of the 19th century that medicinal treatment of fungal diseases began to gain acceptance. At first it was limited to the use of the pitch cap (la calotte) for hair removal in the case of mycosis. In 1897 thallium compounds were used as an epilation agent by the French dermatologist Raymond Jaques Adrien Sabouraud (1864-1938). Since the etiology of fungal skin diseases was still unknown at the beginning of the 19th century, various preparations of metal salts such as copper and lead compounds were also used for the local treatment of the diseased areas of the skin. Based on the observation that chimney sweeps almost never suffered from skin diseases, the French doctor Pierre Blaud (1774–1858) used soot decoctions in 1834 to treat skin diseases. Resorcinol has also been used as an antifungal agent since the 1880s . Some antibiotics later proved to be particularly effective antimycotics. In 1958 Gustav Riehl (1894–1975) recommended griseofulvin for the treatment of skin, nail and hair mycosis. The nystatin isolated by Elizabeth Lee Hazen (1885–1975) and Rachel Fuller Brown (1898–1980) from the ray fungus Streptomyces noursaei has proven to be a classic agent in yeast infections. The fungistatic Trichomycin was marketed by Grünenthal as Trichosept . Amphotericin , obtained for the first time by W. Gold in 1955, was considered the drug of choice, especially for systemic mycoses. In 1962, J. Berger and Duschinsky established the fungistatic effect of fluorocytosine on yeasts and molds . The clotrimazole , synthesized by Karl Heinz Büchel in 1967 , entered the pharmaceutical market in 1973 as Canesten . Naftifin , an allylamine derivative, was manufactured by D. Berney and K. Schuh and found its way into the medical treasury as an exoderil in 1985 due to its effectiveness against molds and dermatophytes .
Inhibitors of ergosterol biosynthesis
The mode of action of modern antimycotics is based in many cases on the inhibition of the biosynthesis of ergosterol (ergosterol), an essential component for the cell membrane of fungi that does not occur in the mammalian organism . The inhibition can take place in different steps of the biosynthesis. Active ingredient examples:
- Allylamines or squalene epoxidase inhibitors
- Naftifine for topical use as a cream , gel or solution and terbinafine for topical use as a cream, gel or for oral use as tablets; Tolnaftate for topical use as a cream or solution.
- Amorolfin for topical application as a cream or nail polish .
- Pyrrole nitrine is also used locally.
- Azole antifungal agents ( imidazoles and triazoles )
Azoles contain an N -substituted imidazole or triazole as a common feature . Examples are: Clotrimazole , Bifonazole , Econazole , Isoconazole , Tioconazole and Sertaconazole are only used locally. There are creams, gels, solutions and sprays for the skin, but also creams, tablets and suppositories for treating the vaginal mucosa .
The substances ketoconazole and miconazole can be used locally or systemically. Also for systemic therapy as tablets or capsules are itraconazole and fluconazole are available. Voriconazole is intended for systemic use as juice , tablets, or solution for infusion , as is posaconazole . Voriconazole and posaconazole are relatively new substances in antifungal therapy. Voriconazole, posaconazole-containing drugs and are used to treat serious fungal infections (such as in patients with cancer with continuous chemotherapy or patients with severe AIDS admitted disease infection), posaconazole so far only as a second-line therapy with resistance or intolerance to standard therapy. Fosfluconazole is currently not available in Germany.
Azole antimycotics have a broad spectrum of activity and have a predominantly fungistatic effect, with the effect starting relatively slowly. While the locally active representatives are generally well tolerated, with those used systemically, a possible liver-damaging effect and the teratogenic effect must be taken into account.
Polyene antifungal agents (pore formers)
Another mechanism of action results from the increase in the permeability of the membrane of the fungal cell ( formation of pores , “perforation”) and, as a result, from the loss of cell components. This is made possible by the amphiphilic character of the macromolecules that interact with the sterol compounds in the cell membrane. Since there is also an affinity for sterols (e.g. cholesterol ) in the host organism, these drugs are relatively toxic when administered parenterally . Active ingredient examples:
Amphotericin B , for topical treatment as a suspension or tablets to be sucked or ingested; for the systemic treatment of severe infections as an infusion preparation.
Nystatin for the local treatment of fungal infections of the skin, mucous membranes and the gastrointestinal tract .
Natamycin for local use
Cell wall synthesis inhibitors
By inhibiting the biosynthesis of the cell wall component chitin and by disrupting the function of the microtubules, griseofulvin acts , which is only effective against dermatophytes . It is used in tablet form (e.g. Likuden ® ) when local therapy is not sufficiently effective.
Caspofungin also has an inhibitory effect on cell wall synthesis . It is only given by infusion.
The active ingredient cilofungin did not come on the market due to side effects .
DNA synthesis inhibitors
5-fluorocytosine acts as an antimetabolite in the DNA synthesis of the fungus . It is used, mostly in combination with amphotericin B, against the most severe organ mycoses.
Formation of reactive oxygen compounds
Ciclopirox (or its ethanolamine salt, ciclopiroxolamine ) acts as a fungicide through the formation of reactive oxygen compounds that are toxic to the fungus . It comes in many dosage forms for local application on the skin, mucous membranes and nails .
Choosing an appropriate antifungal drug depends on
- the resistance of the pathogen and
- the type and severity of the infection ( opportunistic , generalized , systemic, local, cutaneous , subcutaneous ).
The benefit-risk assessment is made accordingly.
- Joachim Morschhäuser: Resistance and Resistance Mechanisms: How Do Fungi "Escape" Therapy? In: Pharmacy in our time . Vol. 32, No. 2, 2003, pp. 124-129, doi : 10.1002 / pauz.200390029 .
- Werner Heinz: Fungal infections. In: Marianne Abele-Horn (Ed.): Antimicrobial Therapy. Decision support for the treatment and prophylaxis of infectious diseases. With the collaboration of Werner Heinz, Hartwig Klinker, Johann Schurz and August Stich, 2nd, revised and expanded edition. Peter Wiehl, Marburg 2009, ISBN 978-3-927219-14-4 , pp. 269-287.
- ↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition, ibid. 1961, pp. 9–223, here: p. 55.
- ^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 213-215 .