Side effects and toxicity

Systemic antifungals often cause side effects that range from unpleasant to dangerous (or even life-threatening), but there are ways to prevent or minimise many of these.

Lipid formulations of amphotericin B have milder side effects than the deoxycholate form but are more expensive. Inhaled formulations (e.g. Abelcet) are available but less commonly used. Nebulised forms of voriconazole have shown promise in clinical trials.

Antifungals interact with many other classes of drugs, and in some cases they should not be prescribed together. In particular, drugs affecting CYP enzymes can cause serum levels of antifungals to vary, leading to toxicity.

If you have a patient who is finding it difficult to cope with the side effects of their treatment, they may find it helpful to join a patient support group.

For more information please see reviews by Chaudhary et al (2019)

Notable examples

N.B. this is not an exhaustive list – please refer to the SPCs of individual drugs and consult the recent scientific literature.

AntifungalTarget concentrationSide effectsPreventionDrug interactions
VoriconazoleVisual disturbances
Peripheral neuropathy
UV sensitivity
n/a resolves within a few days
Factor 50 sunscreen
PPIs, benzodiazepines,
ItraconazoleUpset stomach
Inhaled steroids

TDM and pharmacogenomics

In many cases, toxicity is linked to unexpectedly high blood concentrations of the antifungal, in which case a dose adjustment may be required. This can be due to nonlinear pharmacokinetics, underlying conditions such as liver disease, or drug interactions.

Therapeutic drug monitoring (TDM) is recommended for several antifungals, especially in certain patient groups. Watch our webinar on TDM of itraconazole/voriconazole/flucytosine on our YouTube channel.

Some antifungals are substrates or inhibitors of the cytochrome P450 (CYP) enzymes. Genetic polymorphisms in these genes can cause a patient to be a rapid or poor metaboliser of the drug, leading to reduced or raised serum concentrations respectively. In future, the widespread adoption of pharmacogenomics may allow clinicians to select a suitable starting dosage based on a patient’s genetic makeup. For example, some genetic variants of the CYP2C19 gene can cause a 5-fold difference in trough concentrations of voriconazole, and testing for the *17 variant may have clinical utility (Dorado et al, 2019). However, other antifungals such as itraconazole/fluconazole and the echinocandins currently appear less suitable for this approach (Obeng et al, 2015; Amsden & Gubbins, 2017).

Reporting side effects

Clinical trials report the rate of adverse events in a standardised way:

  • Very common = more than 1 in 10 people are affected
  • Common = between 1 in 10 and 1 in 100 people are affected
  • Uncommon = between 1 in 100 and 1 in 1,000 people are affected
  • Rare = between 1 in 1,000 and 1 in 10,000 people are affected
  • Very rare = fewer than 1 in 10,000 people are affected

However, the side effects profile in the real world may be different, especially in groups of patients that are dissimilar to the trial participants. It is important for clinicians and patients to report side effects using the MHRA Yellow Card scheme (UK) or the FDA Voluntary Reporting Form (USA).

Drug Interactions Pro

Our team has produced a free specialist app for checking the drug interactions of many commonly-used drugs with 11 major antifungals (fluconazole, itraconazole, voriconazole, isavuconazole, posaconazole, amphotericin B, AmBisome (liposomal), caspofungin, micafungin, anidulafungin, terbinafine).

Visit Drug Interactions Pro or look for it in the Play Store or Apple Store.

Supported by the Fungal Infection Trust and the National Aspergillosis Centre.

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