The significance of fungal infection is often neglected in society. However, fungal infections affect more than a billion people, resulting in approximately 11.5 million life-threatening infections and more than 1.5 million deaths annually.1  

The antifungals, used to treat fungal infections, are a diverse group of drugs that include inhibitors of membrane and cell wall synthesis, as well as compounds that cause alterations of fungal membranes, effects on microtubules, and inhibition of nucleic acid synthesis. These drugs can be given topically or systemically depending on the disease.2 

There are three main classes of systemic antifungals; polyenes (amphotericin B), imidazoles, and triazoles, and allylamines. Topical antifungals include imidazoles, tolnaftate, terbinafine and the polyenes nystatin and amphotericin.2 

The clinical outcomes for most invasive fungal infections are far from ideal and even non-invasive infections can take months, if not years, to treat. One of the main challenges to current treatment options is the emergence of antifungal drug resistance. Examples of this include azole resistance among non-Candida albicans isolates, azole resistance in Aspergillus fumigatus, and echinocandin resistance in C. glabrata.  

Some fungal species demonstrate resistance to all clinically available antifungals.3 Patients who have infections caused by such species have very few remaining treatment options. 

The treatment of non-invasive fungal infections is limited by poor penetration of topical antifungals. This limitation is particularly evident in the treatment of onychomycosis. Current topical antifungal formulations for nails often do not achieve adequate therapeutic concentrations in the deeper layers of the nail.4 This means they suffer from low efficacy and long treatment regimes. 

Other obstacles to the successful treatment of onychomycosis arise from limitations imposed by side effects and drug-drug interactions of oral antifungals.5 Despite being the drug of choice for the management of onychomycosis, oral terbinafine is associated with a range of adverse effects including hepatotoxicity which requires monitoring before and during treatment. Other adverse effects include severe taste and smell disturbance, neutropenia, depressive symptoms ,skin disorders, lupus erythematosus and thrombotic microangiopathy.6 In addition, drug-drug interactions of oral terbinafine, such as its interactions with itraconazole, mean it is unsuitable for some patients such as the elderly where onychomycosis and polypharmacy are common.7   

Fortunately, the pharmaceutical industry is now looking into new strategies to tackle fungal infection through an increased understanding of fungal metabolic pathways and cell structure, reformulation of excellent existing antifungals to avoid safety issues through reduced dose and screening of drug libraries to identify drugs with antifungal activity. 

 

References 

  1. The Lancet Infectious Diseases. Fungal Infections – Executive Summary. Available from: https://www.thelancet.com/series/fungal-infections [Accessed 24 Jul 2019]
     
  2. Scholar, E. Antifungal Agents. In: Enna, S. J. Bylund, D. B. (eds.) Elsevier. 2007. P. 1-3. Available from: https://doi.org/10.1016/B978-008055232-3.61020-7 

  3. Wierderhold, N. P. Antifungal resistance: current trends and future strategies to combat. Infection and Drug Resistance. 2017. 10: 249–259. Available from: https://www.dovepress.com/antifungal-resistance-current-trends-and-future-strategies-to-combat-peer-reviewed-article-IDR [Accessed 24 Jul 2019]
     
  4. Zane, L. T. Chanda, S. Coronado, D. Del Rosso, J. Antifungal agents for onychomycosis: new treatment strategies to improve safety. Dermatology Online Journal. 2016. 22(3). Available from: https://escholarship.org/uc/item/8dg124gs#main [Accessed 24 Jul 2019]
     
  5. Scher, R.K. Tosti, A. Joseph, W.S. Vlahovic, T.C. Plasencia, J. Markinson, B.C. Pariser, D.M. Onychomycosis Diagnosis and Management: Perspectives from a Joint Dermatology-Podiatry Roundtable. Journal of Drugs in Dermatology. 2015. 14(9): 1016-21. Available from: https://jddonline.com/articles/dermatology/S1545961615P1016X/ [Accessed 6 Aug 2019]
     
  6. Novartis Pharmaceuticals. LAMISIL Tablets Highlights of Prescribing Information. Available from: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/Lamisil_tablets.pdf [Accessed 6 Aug 2019]

  7. LaSenna, C. E. Tosti, A. Patient considerations in the management of toe onychomycosis – role of efinaconazole. Patient Preference and Adherence. 2015. 9: 887–891. Available from: https://doi.org/10.2147/PPA.S72701