Why is onychomycosis so difficult to treat?
Fungal nail infection, as we all know, is a difficult problem to manage. Invasion from chronic fungal skin infection into the nail is a slow, insidious process but until that point it often remains invisible to the patient. As the fungus spreads under the nail, it becomes shielded by the overlying nail plate making it more difficult to treat by any means. Under the nail it is able to form a thriving mass of hyphae which have been termed by Roberts as the “dermatophytoma” (1). This is essentially a large, adherent collection of fungal mass.
Above: Biofilm of E Coli (Creative Commons Licence)
In biological terms, such a collection should be termed a “biofilm”. If you visualise organisms such as bacteria and fungi, you may view them as free-floating structures but in reality, they are not. Biofilms are collections of micro-organisms encased in a tough extra-cellular polysaccharide matrix which is produced by the organisms themselves (2). Biofilms are known to be highly adherent to biological (and non-biological surfaces). Ultimately, this shield increases the organisms resistance to standard treatments acting as a both a physical and chemical barrier. Biofilms have been identified on many structures including dental appliances and catheters, for example, and can be difficult to remove both physically and chemically.
Within the biofilm, you may have a collection of organisms, of the same or differing species. Moreover, organisms residing in the biofilm may exhibit various behaviours - different parts maybe performing different functions at the same time i.e. some fungi maybe resting whilst others reproducing or feeding. Consequently, this may explain why treatments may fail as resting fungi, for example, are not so susceptible to antifungal treatments as they often only target cells which are growing or reproducing.
Why and how biofilms form is still a mystery, but research is uncovering more about them and their behaviour. Biofilms may form due to environmental conditions such as availability of nutrients, moisture or temperature. Interestingly, in bacterial biofilms, it has shown that exposure to some antibiotics may induce biofilm formation whilst other antibiotic drugs may reduce it.
It has been previously established that dermatophytes, like so many other organisms are capable of forming biofilms under certain circumstances. In a recently published paper, researchers have looked at biofilms in amongst common dermatophytes and how they respond to different antifungal agents (3). What the work was able to show was that after 72 hours, all the common infecting fungal agents including T interdigitale and T rubrum, were able to construct biofilms. When tested against various anti-fungal agents they found terbinafine to give the overall best performance particularly against the common dermatophytes.
The authors conclude that future research into anti-fungal drugs should take into account the presence of biofilms which may respond differently than simple colonies in the lab for example. In addition, drugs which are able to dissolve or disrupt the film may enhance effectiveness and subsequently improve cure rates.
As podiatrists, the message is still the same. Removal of the intact nail barrier is the key to improving outcomes in onychomycosis (4). The effect maybe two-fold – not only exposing the hidden fungus on the nail bed to treatment but also removal of the nail keratin removes the surface on which the fungal biofilms may attached.
1. Roberts DT, Evans EGV. Sub-ungual dermatophytoma complicating dermatophyte onychomycosis. Br J Dermatol. 1998;138:189-90.
2. Vlassova N, Han A, Zenilman JM, James G, Lazarus GS. New horizons for cutaneous microbiology: the role of biofilms in dermatological disease. Br J Dermatol. 2011;165(4):751-9.
3. Nourchéne T, Serena C, Marie-Elisabeth B, Dalenda EE, Najla S-Z, Giovanna S. In vitro biofilms and antifungal susceptibility of dermatophyte and non-dermatophyte moulds involved in foot mycosis. Mycoses. 2018;61(2):79-87.
4. Malay DS, Yi S, Borowsky P, Downey MS, Mlodzienski AJ. Efficacy of debridement alone versus debridement combined with topical antifungal nail lacquer for the treatment of pedal onychomycosis: a randomized, controlled trial. J Foot Ankle Surg. 2009;48(3):294-308.