Why do antifungal nail treatments fail?

Fungal nail infection is a common problem we encounter in practice. In a previous blog, I looked at the prevalence and have covered many other aspects of the disease. A recent email from a colleague prompted me to write this blog. They were asking why their patient had not responded to a course of topical amorolfine and asked the question - “Could this represent a resistant strain of fungus?” Treatment failure is the all-encompassing term used to describe non-response, and it has many facets which I will explore here.

Treatment failure may arise for numerus reasons

Treatment Failure - Reinfection or Relapse?

There are two terms frequently used in the literature to describe treatment failure in onychomycosis – relapse and reinfection:

Relapse is the incomplete eradication of fungal nail infection, leading to recurrence of the same infection.

Reinfection is the recurrence of the same or similar infection, following a period of time after a complete cure.

Haneke [1] explains it with more depth, proposing that with relapse, there is visual improvement in the nail appearance during treatment (“clinical cure”) however viable infection may still exist in the nail, as it is not totally eradicated. Reactivation of this causes the infection to return.

Whereas reinfection occurs after a clinical (visual improvement) and mycological cure (negative lab findings) having occurred after a period of time when new infection may be acquired. A paper I published on this subject in more detail is available here.

How big is the problem?

Treatment failures in onychomycosis do arise, but owing to the multifactorial nature of the disease, we can only estimate. Two papers suggest that it may lie anywhere between 10% to over 50% within a few years [2, 3].

So why does the treatment frequently fail?

Over the years there have been several papers examining this. I have categorised them under the headings below.

Is the diagnosis correct?

If it’s not onychomycosis to begin with, treatment will inevitably fail! There is a commonly statistic stating that 50% of nail dystrophies are not fungal. So, it’s important to consider other causes. What they could be I have covered in another blog which you can read here.

It is a good reminder for practitioners that a solid diagnosis for onychomycosis is important – particularly if you want an antifungal treatment to work. Guidelines emphasize that nail infection should always been confirmed before treating [4]. This is to avoid needless oral medications and their rare, but possible side effects. Moreover, even if a topical treatment is being employed, the treatment time can be 12-18 months of weekly applications and so the patient may be investing a lot and time and energy into treatment as well so it’s only ethical that the condition should be properly confirmed.

Accurate diagnosis is ideally confirmed by immunochromatography [5, 6], microscopy, culture or polymerase chain reaction (PCR) is essential before initiating antifungal therapy [2]. However, studies indicate that diagnostic testing is often not undertaken [7] and diagnosis on visual examination alone risks misdiagnosis [8, 9].  

The antifungal treatment does not address the causative organism.

For the vast majority of fungal nail infections of the foot, the culprits are typically dermatophytes – a group of fungi adapted to living on the skin. So, a dermatophyte diagnosis will suggest the normal antifungal agents will be effective. However, yeasts and non-dermatophyte molds [NDMs] (such as Fusarium, Scopulariosis and Aspergillus) can occasionally be identified in the diagnostic process.

Their appearance can complicate matters as these can often be contaminants. Consequently, to be sure they are likely to be a causative organism they typically require at least two separate samples at separate timepoints with confirmatory lab results [10]. Moreover, many NDMs have a lower susceptibility to the available antifungal agents, making them more difficult to treat. In such cases, mycological advice and testing can be vital in establishing which organism is responsible and identifying which drugs it may be susceptible to [11].  Also, NDM’s may be hitching a ride with dermatophytes. Eradication of the primary infection by the dermatophyte, often clears the NDM infection as well.

The active infection is treated but fungal elements remain.

Fungi, including dermatophytes, can form biofilms on and under the nail plate.  Biofilms are structured communities of microorganisms encased in a self-produced extracellular polymeric substance (EPS) matrix [12]. This matrix acts as a physical barrier, significantly reducing the penetration and efficacy of antifungal drugs. Fungi within biofilms also exhibit altered metabolic states and gene expression profiles that can confer increased tolerance to antifungals [13]. The presence of biofilms is increasingly recognized as a major contributor to the chronicity and recurrence of onychomycosis.  

In addition, dermatophytes can produce arthroconidia (spores). These dormant fungal elements are notoriously resistant to current antifungals and these fomites can survive adverse environments for many months such on floors, carpets, and in socks and shoes [14, 15]. Incomplete eradication of arthroconidia during treatment can lead to germination and subsequent relapse when conditions become favourable.  

Resistant Strains of Fungi

In the last few years, we have seen the rise of antifungal resistance emerging from Asia. Mutations in the gene encoding squalene epoxidase, the target enzyme for terbinafine, have been identified in resistant T. rubrum and T. indotineae (previously T. mentagrophytes complex) strains [16]. This resistance may lead to complete treatment failure despite adequate drug administration. Azole resistance, although less characterized in onychomycosis-causing dermatophytes, is also a concern [11]. The widespread and sometimes inappropriate use of steroid creams is thought to be the driver [17].

Identification of terbinafine and azole resistant strains requires specialist PCR and susceptibility testing which is both costly and not routinely available in the UK. Estimates on the extent of such strains in the UK and Europe is currently limited, along with published strategies and guidelines on their management.

Patient Factors

Patient-specific factors play a substantial role in treatment outcomes.

Patient Compliance

Patient participation is important for any medicament selected - whether topical or oral.  For example, amorolfine treatment can take up to 18 months of regular nail lacquer application to be effective. Slow perceived progress and adherence by patients may lead to premature treatment discontinuation causing relapse.  

Anatomy and Physiology

The dense keratin of the nail in health offers a formidable barrier to microbes, and consequently drug penetration. Toenail growth is slow (approximately 1 mm per month) and even slower when infected with dermatophytes [18]. This means that prolonged treatment durations (often 6-12 months or more) are necessary for the newly formed, uninfected nail to replace the diseased portion. Evidence shows that nails which are thickened, have a larger extent of nail infection (more than 50% of the nail surface area) or lateral nail “spikes” are likely to have a poorer response [19].   

In addition, factors such as reduced peripheral circulation may affect the delivery of drugs to the nail unit [20]. Patients with diabetes are also recognised as being less likely to clear fungal nail infection – the reasons are unclear but this may represent reduced circulation or impaired immune function, leading to relapse or reinfection [21]. Similarly, increasing age has shown to be a predictor of lower cure and higher relapse rates. This is possibly due to the presence of co-morbidities such as diabetes and peripheral vascular disease, but older patients exhibit slower nail growth and higher rates of tinea pedis which can contribute to reduced outcomes.

Individuals with compromised immune systems due to conditions like HIV/AIDS, organ transplantation, or immunosuppressive therapies are more susceptible to severe and recalcitrant onychomycosis [22]. Their diminished immune response makes it difficult to eradicate the fungal infection even with aggressive antifungal therapy.  

One final consideration is whether the patient has a genetic predisposition to dermatomycosis. First proposed by Zaias & Rebell [23] and latterly by others [24] there is a suggestion that predisposition to fungal infection is an autosomal dominant trait causing  to a defect in cell mediated immunity. If correct, it may suggest why treatment relapse and failure is recurrent in some individuals.

 

Implications for Podiatrists

The treatment of toenail onychomycosis is fraught with challenges leading to high rates of failure and relapse. These issues stem from a complex interplay of pathogen virulence and defence mechanisms (including resistance and biofilm formation), host-specific vulnerabilities (such as impaired immunity and nail characteristics), limitations in drug efficacy, and the persistent threat of reinfection. Before giving a treatment failure a label of “fungal resistance”, it is important to evaluate the many other factors that may contribute. Strategies to improve outcomes, based on these factors include:

1.      Ensure it has been properly diagnosed using confirmatory tests.

2.      Consider the organism, severity of the infection and any patient factors.

3.      Be mindful of resistance.

4.      Consider adjunctive therapies (combination therapy, nail reduction with a drill, use of hypochlorous solution to remove arthroconidia and biofilms).

5.      Patient education and adherence

6.      Preventative measures for reinfection (see my blog which covers this).

7.      Longer term prophylaxis – intermittent nail lacquer or topical treatment of feet.

References

1.            Haneke E: Prevention of Relapse and Re‐Infection: Prophylaxis. In Onychomycosis Diagnosis and Management. Edited by Rigopoulos D, Elewski B, Richert B. Chichester: Wiley; 2018: 162–171

2.            Gupta AK, Stec N, Summerbell RC, Shear NH, Piguet V, Tosti A, Maria Piraccini B: Onychomycosis: a review. J Eur Acad Dermatol Venereol 2020, 34:1972–1990.

3.            Piraccini B, Alessandrini A: Onychomycosis: A Review. Journal of Fungi 2015, 1:30.

4.            Ameen M, Lear JT, Madan V, Mohd Mustapa MF, Richardson M: British Association of Dermatologists' guidelines for the management of onychomycosis 2014. Br J Dermatol 2014, 171:937–958.

5.            Mareschal A, Scherer E, Lihoreau T, Bellanger AP, Millon L, Aubin F: Diagnosis of toenail onychomycosis by an immunochromatographic dermatophytes test strip. J Eur Acad Dermatol Venereol 2021, 35:e367–e369.

6.            Tsunemi Y, Takehara K, Miura Y, Nakagami G, Sanada H, Kawashima M: Diagnosis of tinea pedis by the Dermatophyte Test Strip. Br J Dermatol 2015, 173:1323–1324.

7.            Lipner SR, Scher RK: Onychomycosis: Clinical overview and diagnosis. J Am Acad Dermatol 2019, 80:835–851.

8.            Fletcher CL, Hay RJ, Smeeton NC: Observer agreement in recording the clinical signs of nail disease and the accuracy of clinical diagnosis of fungal and non-fungal nail disease. Brit J Dermatol 2003, 148:558–562.

9.            Tsunemi Y, Takehara K, Oe M, Sanada H, Kawashima M: Diagnostic accuracy of tinea unguium based on clinical observation. The Journal of Dermatology 2015, 42:221–222.

10.         Gupta AK, Wang T, Cooper EA, Summerbell RC, Piguet V, Tosti A, Piraccini BM: A comprehensive review of nondermatophyte mould onychomycosis: Epidemiology, diagnosis and management. J Eur Acad Dermatol Venereol 2023, n/a.

11.         Martinez-Rossi NM, Peres NTA, Rossi A: Antifungal Resistance Mechanisms in Dermatophytes. Mycopathologia 2008, 166:369–383.

12.         Shi D, Zhao Y, Yan H, Fu H, Shen Y, Lu G, Mei H, Qiu Y, Li D, Liu W: Antifungal effects of undecylenic acid on the biofilm formation of Candida albicans. Int J Clin Pharmacol Ther 2016, 54:343–353.

13.         Nett JE, R. Andes D: Fungal Biofilms: In Vivo Models for Discovery of Anti-Biofilm Drugs. Microbiology Spectrum 2015, 3.

14.         Yazdanparast SA, Barton RC: Arthroconidia production in Trichophyton rubrum and a new ex vivo model of onychomycosis. J Med Microbiol 2006, 55:1577–1581.

15.         Ghannoum MA, Isham N, Long L: Optimization of an infected shoe model for the evaluation of an ultraviolet shoe sanitizer device. J Am Podiatr Med Assoc 2012, 102:309–313.

16.         Bristow IR, Joshi LT: Dermatophyte resistance – on the rise. J Foot Ankle Res 2023, 16:69.

17.         Verma S, Madhu R: The Great Indian Epidemic of Superficial Dermatophytosis: An Appraisal. Indian J Dermatol 2017, 62:227–236.

18.         Na G, Suh M, Sung Y, Choi S: A decreased growth rate of the toenail observed in patients with distal subungual onychomycosis. Annals of dermatology 1995, 7:217–221.

19.         Gupta AK, Versteeg SG: A critical review of improvement rates for laser therapy used to treat toenail onychomycosis. J Eur Acad Dermatol Venereol 2017, 31:1111–1118.

20.         Gupta AK, Gupta MA, Summerbell RC: The epidemiology of onychomycosis: Possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol 2000, 14:466–469.

21.         Gupta A, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW, McManus R, Summerbell RC: Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Brit J Dermatol 1998, 139:665–671.

22.         Gupta AK, Taborda P, Taborda V, Gilmour J, Rachlis A, Salit I, Gupta MA, MacDonald P, Cooper EA, Summerbell RC: Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol 2000, 39:746–753.

23.         Zaias N, Rebell G: Chronic dermatophytosis caused by Trichophyton rubrum. J Am Acad Dermatol 1996, 35:S17–S20.

24.         Hay RJ: Genetic Susceptibility to Dermatophytosis. Eur J Epidemiol 1992, 8:346–349.