Antifungals for aspergillosis

Image showing pills falling out of a pot. Antifungals are one of the key treatments for aspergillosis.

The treatment of fungal infections can broadly be described in terms of three classes of antifungals. The echinocandins, the azoles and the polyenes.

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 probably the most 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,Histoplasma, Paracoccidiodes and most of the agents of zygomycosis (Mucorales), 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 schenkii. 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.

Amphotericin can also be dispensed via a nebuliser. View video here.

Echinocandins

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

Caspofungin is very active against all Aspergillus species. It does not kill Aspergillus completely in the test tube. There is a very limited amount of activity against Coccidioides immitis, Blastomyces dermatitidis, Scedosporium species, Paecilomyces varioti and Histoplasma capsulata but it is likely that the activity is not sufficient for clinical use.

Triazoles 

Itraconazole, fluconazole, voriconazole and posaconazole – 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 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 Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatumand Paracoccidioides brasiliensis. It is less active than itraconazole against these dimorphic fungi. It is not active against Aspergillus or Mucorales. It is active against skin fungi such as Trichophyton.

Increasing resistance in Candida albicans in patients with AIDS has been reported. Typical rates of resistance in Candida albicans in a general hospital are 3-6%, in Candida albicans in AIDS 10-15%, in Candida krusei 100%, in Candida glabrata ~50-70%, in Candida tropicalis 10-30% and in other Candida species less than 5%.

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 has an extremely broad spectum. It is active against the vast majority of Candida species, Cryptococcus neoformans, all Aspergillus species, Scedosporium agiospermum, 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.

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 view individual patient information (PIL) leaflets for each drug (at the bottom of the page).

Absorption

Some of the antifungal drugs (e.g. itraconazole) are taken orally and can be difficult to absorb, particularly if you are on antacid medication (medicine used to treat indigestion, stomach ulcers or heartburn). This is because some acid in the stomach is needed to dissolve the capsules and allow absorption.

In the case of itraconazole the standard advice is to ensure that there is plenty of acid in the stomach by taking a fizzy drink such as cola with the medication (the carbon dioxide that causes the fizz also makes the drink quite acidic). Some people dislike fizzy drinks so substitute a fruit juice eg. orange juice, however this is now NOT recommended:

  • Grapefruit juice is known to increase the blood levels of several drugs including itraconazole. In some cases (not with itraconazole) that has lead to potentially dangerous overdosing – for example in blood pressure drugs
  • There has also been a second report that several fruit juices can block absorption of some antifungal drugs (and others), potentially leading to a lowering of blood drug levels.
  • All taken together it is probably best to take your itraconazole with a cola drink, avoiding fruit juices altogether

Itraconazole capsules are taken after a meal and 2 hours before taking antacids. Itraconazole solution is taken one hour before a meal as it is more easily absorbed.

It is well worth reading the Patient Information Leaflet packed with your medication as this gives you all the information you need to store and use it. We provide a list of the most common medications at the bottom of this page, and links to their respective PILs.

Even after following all of the manufacturers’ instructions, absorbance of some drugs is unpredictable. You may find that your doctor will take blood samples to check how well your body is absorbing an antifungal.

Side Effects

All drugs have side effects (‘adverse effects’) and drug manufacturers are required to list them in the Patient Information Leaflet (PIL). The majority are minor, but all are worthwhile mentioning to your doctor at your next visit. Side effects can be very diverse and often completely unexpected. If you are feeling unwell it is always worth checking the list of side effects on the PIL as it may be that the drug you are taking is causing a problem. If in doubt always seek your doctor’s advice.

Steroids are particularly prone to causing many unpleasant side effects. There is information that is specific to steroid side effects and how to best take steroids here.

Patients experiencing side effects are given a range of advice – it may be that persevering in taking the drug causes the problem to disappear, or it may be that the patient should be stopped from taking the drug. Occasionally another drug will be prescribed to counteract the side effect.

Except in the most severe cases it is not advisable for the patient to stop taking a drug without consulting their doctor.

There are many interactions between the different drugs many people have to take that can cause severe side effects. Check the interactions between antifungal drugs and any other medications you may take by searching for them on our Antifungal interactions database.

Voriconazole and squamous cell carcinoma: A 2019 review of 3710 individuals who had received either a lung transplant or hematopoietic cell transplant found a significant link between voriconazole use and squamous cell carcinoma in these patients. Longer duration and higher doses of voriconazole were associated with an increased risk of SCC. The study supports the need for regular dermatologic surveillance for LT and HCT patients on voriconazole, and the suggestion that alternative treatments be taken, especially if the patient is already at an increased risk of SCC. The authors note that the data was rather limited and more research is needed to further explore this connection. Read the paper here.

Reporting drug side effects:

UK: In the UK, the MHRA have a Yellow Card scheme where you can report side effects and adverse incident of medications, vaccines, complementary therapies and medical devices. There is an easy online form to fill in – you do not need to do this via your doctor. If you need help with the form, reach out to someone at NAC or ask someone in the Facebook support group.

US: In the US, you can report side effects directly to the FDA via their MedWatch scheme.

Antifungal Availability:

Unfortunately not all antifungal drugs are available in every country around the world and, even if they are, the price can vary massively from country to country. Global Action Fund for Fungal Infections (GAFFI) has produced a set of maps showing the availability of the key antifungal drugs across the world.

Click here to view the GAFFI antifungal availability map

Further information

The most common drugs prescribed for long-term use for people with aspergillosis are listed with detailed information below. There is also a listing of simplified information for most of these drugs here.

It is well worth reading the patient information leaflets (PIL) for the medication you are about to start taking and noting any warnings, side effects and the list of incompatible medicines. This is also a great place to read specific guidance on how to take your medication. We supply up-to-date copies below:

(PIL – Patient Information Leaflet)