How do we treat fungal disease?

Antifungals are antimicrobials too

Antimicrobials are drugs aimed at killing non-human organisms within the body. Antibiotics are used against bacteria and are subject to wide-reaching stewardship programmes.

Antifungals are also antimicrobials and antifungal stewardship shares many challenges with antibiotic stewardship: inappropriate usage, drug toxicity and emerging resistance amongst the common fungal pathogens are increasing problems in patient care.

Antifungals can be classified based on their spectrum of activity as yeast, dermatophyte or mould-active drugs. Mould-active drugs can also be called broad-spectrum antifungals as they are active against most yeasts and dermatophytes in addition to moulds.

Treatment options for fungal diseases are still limited to a few classes of drugs. Until recently, antifungal resistance has not been a significant problem. Therefore, antifungal stewardship has not been in the focus of most antimicrobial stewardship programmes. If included the main concern has mostly been their high cost.

Invasive fungal infections are medical emergencies with very poor outcomes if the initiation of effective treatment is delayed. In patients at risk, the use of antifungal prophylaxis is recommended and antifungal treatment should be started on clinical suspicion. Patient risk assessment is key in preventing overuse of antifungals in ICUs and haematology. Serious fungal infections rarely occur in the otherwise healthy patient.

It is important to remember that most fungi form biofilms readily, which are highly resistant to antifungal drugs and cannot be treated without physical disruption or removal of the biofilms. First, we need to understand the main groups of antifungals.

The azoles

Azole antifungals are a large group of antifungals and the mainstay of oral treatment for many fungal diseases. Some azole antifungals have a narrow spectrum of activity (e.g. fluconazole is active against yeasts only but not all species) whereas some have a very broad spectrum of activity including yeasts, Aspergillus and most other clinically relevant moulds including those in the Mucorales group (isavuconazole). Azoles have no activity against fungal biofilms.

They function by inhibiting a fungal CYP450 enzyme that converts lanosterol to ergosterol. Ergosterol is a key component of fungal cell membranes. Reduced ergosterol in the fungus disrupts the cell membrane.

Due to their activity as inhibitors of the CYP450 enzyme family, all azole antifungals have a large potential for drug-drug interactions.

Examples include: fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole. Azoles can be administered via the topical, oral and intravenous route. All azoles except for fluconazole have unpredictable pharmacokinetics and pharmacodynamics in unwell patients and children, and should not be used without therapeutic drug monitoring.

The polyenes

Polyene antifungals are large molecules that bind to the fungal cell membrane. This leads to disruption of the membrane and cell death.

The most commonly used polyene is amphotericin B. It has a broad spectrum of activity including most yeasts, Aspergillus species and most other clinically relevant moulds including those in the Mucorales group. It has some activity against fungal biofilms.

Various formulations have been developed to overcome issues with kidney toxicity and its liposomal formulations are safest in systemic use. It can be administered via the topical and intravenous route. Occasionally, it is given in a nebulised form.

Intravenous amphotericin B (even its liposomal formulations) has a significant potential for infusion reactions and adverse effects. It is therefore given with monitoring and expert advice is recommended.

The echinocandins

These drugs are a newer generation of antifungals. They inhibit β-1-3-D-glucan synthase, an enzyme essential for the fungal cell wall. This leads to cell lysis and death. Echinocandins are fungicidal against most yeasts (excluding Cryptococcus species) and fungistatic against most moulds. They have some activity against fungal biofilms and are the first line therapy for candidaemia also for fluconazole susceptible species.

Echinocandins can only be administered via the intravenous route. The available drugs in this group are anidulafungin, caspofungin and micafungin.

Generally, the echinocandins are safer and better tolerated than amphotericin B and, therefore, at risk for being overused.

Others

There are a few other antifungals in clinical use.

Flucytosine disrupts the metabolism of fungal cells by impairing their RNA, DNA and protein synthesis. Its spectrum is broad (several species of yeasts and moulds) but due to a significant risk of acquired resistance, flucytosine is rarely given alone. It is usually used as an adjunct treatment. It is given in combination with amphotericin B when treating cryptococcal meningitis or invasive candidosis. Flucytosine can be given via the oral or intravenous route. As it is well absorbed, the oral route is preferred.

Terbinafine acts by inhibiting ergosterol biosynthesis causing fungal cell membrane disruption. Despite its wide use, terbinafine is still highly active against most dermatophytes but has variable activity against yeasts, Aspergillus species and dimorphic fungi. It is typically given for superficial infections such as onychomycosis (fungal nail infection). Terbinafine is also gaining a role as adjunct treatment in conditions such as azole-resistant chronic pulmonary aspergillosis (but only based on susceptibility testing). Terbinafine can be given in oral or topical preparations.