Treatment

Treatment for fungal diseases

An antifungal medication is a medication used to treat fungal infections such as athlete’s foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such medicines are usually obtained by a clinician’s prescription or for less serious infections of the nail and skin, over-the-counter from a pharmacy.

Apart from side-effects like liver-damage or affecting oestrogen levels, many medicines can cause allergic reactions in some people including rashes.

There are also many drug interactions and foods which must be avoided. Patients must read in detail the enclosed data sheet(s) called a patient information leaflet (PIL) of the medicine (also see our antifungal PIL collection). For example, the azole antifungals such as itraconazole can be both substrates and inhibitors of the P-glycoprotein, which (among other functions) excretes toxins and drugs into the intestines. For detailed patient information leaflets (PIL) and information on antifungal medication please visit the Aspergillus website here.

The treatment of fungal infections can broadly be described in terms of five classes of antifungal medicines; the triazole, echinocandins, polyenes, flucytosine and terbinafine. These are described more fully here,. A brief description of antifungal medication is given here.

Antifungals marked with an * are World Health organisation recognised Essential Medicines.

Triazoles

Triazoles – itraconazole*, fluconazole*, voriconazole*, posaconazole and isavuconazole – the mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol.

Fluconazole is active against most Candida species, with the absolute exception of Candida krusei and Candida auris and partial exception of Candida glabrata and a small number of isolates of Candida albicans, Candida tropicalis, Candida parapsilosis and other rare species. It is also active against the vast majority of Cryptococcus neoformans isolates. It is active against many other yeasts including Trichosporon beigelii, Rhodotorula rubra, and the dimorphic endemic fungi including Coccidioides immitis but less active than itraconazole against Blastomyces dermatitidis, Histoplasma capsulatum and Paracoccidioides brasiliensis. It is not active against Aspergillus or Mucorales. It is active against skin fungi such as Trichophyton.

Itraconazole is one of the most broad-spectrum antifungals available and includes activity against Aspergillus, Blastomyces, Candida (all species including many fluconazole resistant isolates) Coccidioides, Cryptoccocus, Histoplasma, Paracoccidioides, Scedosporium apiospermum and Sporothrix schenkii. It is also active against all skin fungi. It is not active against Mucorales or Fusarium and a few other rare fungi. It is the best agent against black moulds, including Bipolaris, Exserohilum etc. Resistance to itraconazole is described in Candida, although less often than with fluconazole, and also in Aspergillus.

Voriconazole also has a broad-spectum activity. It is active against the vast majority of Candida species, Cryptococcus neoformans, all Aspergillus species, Scedosporium apiospermum, some isolates of Fusarium and a multitude of rather rare pathogens. It is not active against Mucorales species such as Mucor spp, Rhizopus spp, Rhizomucor spp, Absidia spp and others. Voriconazole has become invaluable in the treatment of invasive aspergillosis.

Posaconazole has an extremely wide spectrum of action. The fungi whose growth are inhibited by posaconazole include Aspergillus, Candida, Coccidioides, Histoplasma, Paracoccidioides, Blastomyces, Cryptococcus, Sporothrix, various species of Mucorales (causing Zygomyetes) and numerous other black moulds such as Bipolaris and Exserohilum.  The majority of Aspergillus isolates are killed by posaconazole at clinically relevant concentrations. Acquired resistance to posaconazole does occur in Aspergillus fumigatus and Candida albicans but is otherwise rare.

Isavuconazole was approved for use in 2015. It has activity against most clinically important yeasts and molds, including Candida spp, Aspergillus spp, Cryptococcus neoformans, and Trichosporon spp and variable activity against Mucorales spp. It is also very active against many rare pathogens including those that cause chromoblastomycosis. A large randomized study (>500 patients) demonstrated equivalent efficacy to voriconazole in invasive aspergillosis with less toxicity.

Isavuconazole is provided as a highly water soluble pro-drug allowing a simple intravenous formulation and excellent oral bioavailability. Loading doses are required due largely to its slow elimination. Its drug interaction potential appears to be less than other azole antifungals – also beneficial.

The side effects of azole drugs are well characterised and there are also some important drug-drug interactions which exclude the use of prescribing certain drugs at the same time. For a more comprehensive understanding of these issues please visit the Aspergillus Website and view individual patient information (PIL) leaflets for each drug.

Terbinafine

Terbinafine is active against all the skin fungi, including Epidermophyton floccosum, Microsporum species and Trichophyton species. It is also active against Malassezia furfur which causes pityriasis tinea (versicolor). It is active against most Candida species, athough it may not be fungicidal in some species such as Candida albicans. There is some activity demonstrated against Aspergillus, but in combination with amphotericin B was antagonistic in invasive aspergillosis. It has limited activity against other organisms. It is only available orally and topically. It has a low number of side effects and few drug interactions.

Polyenes

Amphotericin B* is often used intravenously to treat systemic fungal infections. It works by binding to a fungal cell wall component called ergosterol. Amphotericin B is a broad-spectrum intravenous antifungal available. It has activity against Aspergillus, Blastomyces, Candida (all species except some isolates of Candida krusei and Candida lusitania), Coccidioides, Cryptococcus and Histoplasma and most of the agents of mucormycosis, Fusarium and other rarer fungi. It is not adequately active against Scedosporium apiospermum, Aspergillus terreus, Trichosporon spp., most of the species causing mycetoma and systemic infections due to Sporothrix species. Acquired resistance to amphotericin B has been described in occasional isolates, usually after long term therapy in the context of endocarditis, but is rare. Amphotericin B can cause many side effects which in some cases can be very severe. The side effect profile is less with liposomal formulations, but 3 times the dose is required for the same antifungal effect. Most of its drug interactions relate to kidney dysfunction.

Natamycin eye drops are the most effective therapy for fungal keratitis.

Echinocandins

Echinocandins are often used to treat systemic fungal infections in immune deficient patients – these medicines inhibit the synthesis of glucan which is a specific component of the fungal cell wall. They include micafungin, caspofungin and anidulafungin these are best administered by intravenous means because of poor absorption.

All three echinocandins are active against all Aspergillus species and most Candida species. They kill most Candida strains but not Aspergillus completely in the laboratory. There is a very limited amount of activity against Coccidioides, Blastomyces, Scedosporium species, Paecilomyces and Histoplasma capsulata but it is likely that the activity is not sufficient for clinical use. It is not active against fungal infections in the CNS. They are only available intravenously. They have very few drug interactions.

Flucytosine

Flucytosine* is generally active against the medically important yeasts Cryptococcus neoformans and Candida spp. Occasional outbreaks of resistant isolates of Candida spp. have been described. Flucytosine is active against Phialophora spp, Cladosporium spp and Exophiala spp. Flucytosine is not active against Aspergillus and most other filamentous fungi. It can be given orally or intravenously, and usually with amphotericin B or fluconazole for cryptococcal disease (~20% improved survival). There are few drug interactions.

New Medicines

There is no doubt with increasing rates of resistance to antifungal medicines that research into effective and cost-effective antifungal drugs is a high priority. There are now numerous candidate drugs in development, several novel drug classes. The first inhaled antifungals are also in development. See the Aspergillus Website for latest developments.

WHO Model List of Essential Medicines 21st edition 2019