Given the prevalence of onychomycosis and its varied clinical presentation, this author discusses the evolution of diagnostic testing and offers insights on the roles of various modalities in the treatment of severe onychomycosis.
Onychomycosis is a common infection that is increasing in incidence. Meissner (of Meissner’s corpuscle fame) first described onychomycosis in 1895.1 The most frequent culture cause of onychomycosis is Trichophyton rubrum, which has evolved over time to become more pathogenic. The previous thinking was that T. rubrum was just a contaminant but since the Vietnam War, it has become the dominant causative organism.
In addition, Zaias and colleagues have reported that patients are genetically susceptible to dermatophyte infections in an autosomal dominant pattern.2 This helps to explain the rising incidence and recurrence rates of onychomycosis.
The clinical types of onychomycosis have been updated to better categorize the wide variety of clinical presentations. Hay and Baran categorized the clinical growth patterns of onychomycosis as distal lateral subungual onychomycosis, white superficial onychomycosis, proximal subungual onychomycosis, endonyx onychomycosis and Candidal onychomycosis.3 Patients may have a combination of these subtypes simultaneously.
Total dystrophic onychomycosis or severe onychomycosis refers to the most advanced form of any of the subtypes. This form of onychomycosis is a later stage of the chronic subungual dermatophyte infection that may take 10 to 15 years to develop. It is not only the most difficult stage to clear but is also the type with the highest risk of associated subungual ulceration, secondary bacterial infection and possible gangrene.
The incidence of onychomycosis is increasing in the United States, reportedly affecting 6 to 12 percent of the population.4 There has been a sevenfold increase in cases over the last 20 years.
Severe onychomycosis in patients with diabetes and patients with peripheral arterial disease increases the risk of secondary bacterial infection, nail bed ulceration and subsequent amputation.5,6 Onychomycosis and concurrent diabetes triple a patient’s risk of toe ulceration, infection and gangrene.
As McCarthy points out, severe onychomycosis poses the greatest problem in patients with diabetic peripheral neuropathy.7 Just as constrictive footwear can cause pressure necrosis of the skin in patients with improperly fitting shoes, thickened, mycotic nails can cause pressure necrosis of the nail bed in those with diabetes. Sharp, brittle, infected nails can also abrade or gouge skin on the adjacent toes, and may even pierce the skin.
In both cases, patients with diabetes often do not recognize these minor ulcerations because of decreased sensation. These ulcerations, if left untreated, have the potential to lead to secondary bacterial infection.7-10 The photo at the bottom on the right illustrates a foot with severe onychomycosis that developed a nail-induced ulceration.
One generally determines clinical severity by the infection’s duration, degree of involvement and thickness of the fungally infected nail plate. Additionally, host resistance, genetic susceptibility and the pathogenicity of the particular fungal strain help account for a particular patient’s overall infection severity and helps predict the likelihood of cure.
We can better define the clinical severity of onychomycosis in terms of area of involvement, proximity to the nail root and thickness in a standardized scoring system called the Onychomycosis Severity Index.11 This parallels the Psoriasis Severity Index that clinicians have long used to compare patient responses to various therapeutic methods in a standardized way.
One can determine the Onychomycosis Severity Index score by multiplying the score for the area of involvement (range, 0-5) by the score for the proximity of disease to the matrix (range, 1-5). Add 10 points for the presence of a longitudinal streak or a patch (dermatophytoma) or for greater than 2 mm of subungual hyperkeratosis. Mild onychomycosis corresponds to a score of 1 through 5, moderate onychomycosis would have a score of 6 through 15 and severe onychomycosis would range between 16 and 35.11
Most importantly, the Onychomycosis Severity Index criteria have been validated.11 Using the Onychomycosis Severity Index scoring system, clinicians are likely to determine the same severity score given the same patient. This methodology is particularly important in diseases like onychomycosis in which there is a wide degree of severity among individual patients.
It also helps to quantify the varying difficulties of clearing cases with nail root involvement or when the nail plate is thicker. For example, one can easily clear white superficial onychomycosis with topical medications and simple debridement while total dystrophic onychomycosis seldom clears without oral therapy.
Severity indices are more economical and better benchmarks to monitor treatment progress rather than expensive mycological tests or just proximal clear zones. The Onychomycosis Severity Index numerically estimates the severity factors that limit the potential for clearing. Using this validated method, we can define cases of severe onychomycosis as those with scores from 16 through 35.
Schemer states that the evaluation of the outcome of clinical cure, mycological cure and total cure should be based on the well-defined worldwide criteria.12 Otherwise, a comparison of results is impossible due to a lack of uniformity in different studies.
Diagnostic testing has evolved over time. It used to be that we could culture suspected cases of onychomycosis with dermatophyte test media, incubate the specimens in desk drawers and speciate the results using a color chart. Interpretation could be difficult with many phenotypic variations. No two fungi look exactly alike. The KOH wet mount preparation of subungual debris is not a very sensitive method and clinicians seldom perform it on nail specimens.13
Currently, the most sensitive test is a pathologist read biopsy of nail clippings stained with periodic acid Schiff (PAS) and or Grocott’s methenamine silver. A mycologist interprets fungal culture testing, which is very specific but not as sensitive as PAS. Fungal cultures are relatively slow growing, adding weeks and more cost to the workup. Fungal culturing is appropriate for atypical cases or when one suspects primary saprophytic infections. In that case, it is recommended that two subsequent cultures of the same saprophytic mold be in evidence before concluding that the saprophyte is the primary pathogen and not a contaminant.
A new development has demonstrated the usefulness of dermoscopy in clinical differentiation of onychomycosis from common nail dystrophies. Piraccini and colleagues observed a characteristic of jagged proximal edges with spikes and longitudinal striations in patients with culture-proven onychomycosis while mycologically negative cases of traumatic onycholysis all have linear transverse edges without spikes.14 A dermatoscope is basically a handheld 10X polarized magnifying lens illuminated with 11 small halogen lamps. It allows the examiner to easily look through a translucent nail plate and visualize the nail bed directly.
Due to an increased risk of subungual ulceration, one should consider oral antifungal therapy for onychomycosis of moderate to severe severity. The gold standard treatment for onychomycosis is basically systemic. Combination therapy with topical agents, such as nail lacquer and/or chemical nail avulsion, may produce better results than systemic treatment alone. Excluding minor cases, topical treatment as monotherapy is not efficient.12
Oral therapy is the most effective treatment, especially in severe onychomycosis. In addition, studies have shown that patients with diabetes tolerate oral terbinafine (Lamisil, Novartis) just as well as other patients.15 Hall and coworkers reviewed over 25,000 patients taking terbinafine with the oldest patient being 78.15 They found no increased risk of adverse drug reactions, regardless of age. The authors also found that in their experience in Europe, there was no increase in adverse drug reactions that required terbinafine cessation. The incidence of adverse events was 10.5 percent with the majority involving the gastrointestinal system (4.9 percent) or skin (2.3 percent). These adverse events tended to be mild, transient and reversible. Researchers considered terbinafine as a possible or probable cause of 11 (0.04 percent) serious adverse events.
Continuous therapy with cephalexin (Keflex, Eli Lilly) and naproxen can cause hepatic elevations at similar rates as terbinafine. Cephalexin can commonly cause mild elevations (less than two- to threefold) in serum transaminases but severe hepatocellular injury is very rare.14,16 Although the liver metabolizes terbinafine like most medications, terbinafine is not intrinsically hepatotoxic like acetaminophen.17
It is important to carefully review the patient history for alcohol abuse and hepatitis. Ordering alanine aminotransferase and aspartate aminotransferase hepatic function tests before the beginning of continuous therapy establishes a baseline. If there is a history of living overseas where hepatitis is endemic, one can add a hepatitis antigen screening panel to the workup. Follow-up hepatic function tests at five weeks serve to detect the less than 2 percent of idiosyncratic responders. If the follow-up tests are significantly elevated, one can stop the drug and retest.
Concurrent medications may preclude the use of oral antifungals. Terbinafine may alter the metabolism of a number of drugs so monitoring is appropriate. There is controversy regarding the risk of terbinafine with concurrent warfarin (Coumadin, Bristol-Myers Squibb) as there have been reports of elevated international normalized ratios.18-20 It is wise to monitor the international normalized ratio if it is necessary to use the drugs concurrently. There has been some controversy with concurrent statin therapy. Concerns regarding drug-to-drug interactions with statin therapy and systemic antifungal therapy are actually with the azole class of antifungals and not terbinafine.21 It might be best to avoid systemic therapy in patients on psychotropic medications. Terbinafine carries a contraindication for concurrent use with the phenothiazines and pimozide (Orap, Teva) for increased risk of QT prolongation.22
Gupta reports one can use terbinafine safely in children and the elderly.23 However, clinicians should always exercise caution in patients with major polypharmacy. It may be best to use alternate therapy in these cases to avoid adverse drug reactions in patients with an essentially benign disease.
Oral therapy is the most effective therapy for severe onychomycosis but for some patients, it is medically inappropriate. Additionally, for many patients, there is a strong personal preference for a non-systemic approach.24 Topical therapy would seem to be a good solution to the problem if only the efficacy rates were better. Many OTC and prescription products are available, hinting that there is no clearly effective topical choice. So what does the best evidence tell us?
Ciclopirox 8% lacquer (Loprox, Medicis) is the best topical available in the U.S. for onychomycosis.25 Despite this, it achieves less than a 9 percent complete clearing rate and is only indicated for cases of mild to moderate severity without lunula involvement. This certainly leaves out severe, thick onychomycosis.25 In a yearlong study, the complete cure rate for terbinafine solution was no better than vehicle and nail thickness naturally impeded any improvement.26
Since the market for an effective topical therapy for onychomycosis is large, researchers are currently studying many drugs and modalities. The most notable new topical drugs are tavaborole (AN2690, Anacor Pharmaceuticals), which belongs to the benzoxaborole class of drugs, and efinaconazole (Valeant Pharmaceuticals) and luliconazole (Topica Pharmaceuticals), which belong to the azole class of drugs.27
In topical drug delivery, the vehicle seems to make the difference. The active ingredient in ciclopirox lacquer goes to the site of the infection in the nail bed by using an occlusive surface sealant of hair spray (Gantrez). It seals the nail plate, slowing the evaporation of water and establishing a diffusion gradient to facilitate the passage of ciclopirox through the hydrophilic nail plate to the nail bed.
Many available topical therapies contain agents that are fungistatic in vitro but offer no evidence demonstrating penetration to the site of the infection in the nail bed. Companies often market topicals with anecdotal reports of effectiveness and illustrated with before and after images, but these agents lack controlled efficacy studies. Typically, topicals contain a tried and true antifungal agent dissolved in alcohol or vegetable oil vehicles to attempt nail plate penetration. Some commonly recommended topical antifungal solutions even lack an indication for onychomycosis but nonetheless come with a convenient brush applicator for nails.28,29
To control symptoms and reduce the risks of subungual ulceration and secondary bacterial infection, clinicians can use periodic debridement to successfully manage severe onychomycosis in patients who are unable to benefit from oral therapy or unable to apply topicals. Unfortunately, debridement is unlikely to clear fungal infections.30
Debridement techniques may vary but the goals of symptom control and risk reduction are the same. One successful method is to prepare the nail with a softening agent like diluted antimicrobial soap solution or a wetting agent. One can reduce the bulk of the nail plate with a large nail nipper and subsequently thin and smooth the nail plate with a 25,000 rpm rotary instrument. Use a coarse, fluted, pear-shaped rotary burr with firm, proximal to distal longitudinal and transverse strokes. A continuous spray of alcohol solution cools the digit and sequesters the fine nail debris. Pressure, pain and discomfort often immediately resolve.
In severe cases of onychomycosis in which there is a history of significant recurrent pain or bacterial infection, one can attempt temporary surgical removal of the entire nail plate. A complete medical history and review of systems with ankle brachial indices can be useful to document healing capacity. Total nail plate avulsion typically heals within a few weeks. One would prescribe topical antifungals throughout the nail plate regeneration phase of treatment.
Depending on the duration and severity of onychomycosis, deviation or scarring of the nail matrix may have taken place, permanently altering the nail plate alignment and nail matrix orientation. This leaves the new nail plate to regrow in a still thickened form that is dystrophic and non-adherent to the nail bed. There is also a risk with surgical avulsion of permanent nail plate loss. Patients should be aware of this potential complication.
In some cases of severe, chronic onychomycosis combined with onychogryphosis, one may consider permanent nail removal. The bulk of the problem is typically reduced but often residual nail matrix produces partial nail plate or spicule that can be annoying to the patient who expects a normal nail bed.
Grover and colleagues in 2007 reported on surgical avulsion of single, moderate to severe onychomycosis followed by twice daily topical ketoconazole (Nizoral, Janssen Pharmaceuticals) or oxiconazole cream (Oxistat, PharmaDerm) in 40 patients.31 One-third of the patients dropped out of the study. Of the remainder, 43 percent were cured. None of the severe cases were cured. They concluded that surgical avulsion followed by topical antifungal therapy could not be generally recommended treatment.
Pandhi and Verma recently detailed a topical technique for nail removal utilizing 40% urea. South and Farber first described this technique in 1980, and Averill and Scher subsequently modified it in 1986.32-34
Urea ointment paste is formulated to include 40% urea, 5% white beeswax or paraffin, 20% anhydrous lanolin and 35% white petrolatum.32 One can use a 1/8-inch felt oval aperture pad to build a wall around the entire nail plate. This creates a shallow well that one packs with the urea paste and secures with occlusive tape. Patients keep the dressing dry and in one week, simple debridement can remove the nail plate.32
In the past, ablative lasers like the carbon dioxide laser have permanently removed severely mycotic nail roots.35 Recently, Landsman and Robbins have been able to demonstrate the effectiveness of a dual band non-ablative laser therapy in mild, moderate and severe onychomycosis.36 At nine months, about one-third of their treated population achieved both negative cultures and negative microscopy, qualifying as “mycological cures.”
The FDA has approved non-ablative lasers for temporary clearing of mild to moderate onychomycosis.37 These lasers do not destroy mammalian tissue. They selectively deactivate fungus, bacteria plasma and mitochondria by endogenously generating radical oxygen species, causing photoinactivation and photodamage.38
Preliminary 1064 nm laser study data on several patients from the Cleveland Foot and Ankle Clinic with moderate to severe infections have shown improved proximal clear zones and reduced Onychomycosis Severity Indices by 22 percent.39 Quality of life scores have improved 20 percent. Non-ablative lasers seem to hold promise as adjunctive cosmetic clearing approaches but do not appear to be magic wands to cure onychomycosis.40,41
Gupta and Simpson report that device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of any of these devices.42
Despite the advances in oral, topical and now device-based therapies, manual and electric debridement remains the most commonly employed treatments for severe onychomycosis.43 Better benchmarks for clinical success may be improved with quality of life surveys and reduction in validated severity scores. These measurements may be more relevant to patients than complete mycological cures for a typically chronic and recurrent disease.
Dr. Bodman is an Associate Professor at the Kent State University College of Podiatric Medicine. He is a Diplomate of the American Board of Podiatric Medicine. Dr. Bodman is in private practice in Ohio.
1. Haas N, Sperl H. A medical student discovers onychomycosis. Hautarzt. 2001; 52(1):64-7.
2. Zaias N, Tosti A, Rebell G, et al. Autosomal dominant pattern of distal subungual onychomycosis caused by Trichophyton rubrum. JAAD 1996; 34(2 Pt 1):302-4.
3. Hay RJ, Baran R. Onychomycosis: a proposed revision of the clinical classification. J Am Acad Dermatol. 2011;65(6):1219-27.
4. Gräser Y, Czaika V, Ohst T. Diagnostic PCR of dermatophytes--an overview. J Dtsch Dermatol Ges. 2012;10(10):721-6.
5. Levy LA. Epidemiology of onychomycosis in special-risk populations. J Am Podiatr Med Assoc. 1997; 87(12):546-50.
6. Mayser P, Freund V, Budihardja D. Toenail onychomycosis in diabetic patients: issues and management. Am J Clin Dermatol. 2009;10(4):211-20.
7. McCarthy DJ, Boyko EJ, Smith DG. Cutaneous manifestations of the lower extremities in diabetes mellitus. In: Kominsky S (ed). Medical and Surgical Management of the Diabetic Foot. Mosby, St. Louis, 1994, pp. 191-222.
8. Rich P. Special patient populations: onychomycosis in the diabetic patient. J Am Acad Dermatol. 1996;35(3 Pt 2):S10-2.
9. Gulcan A, Gulcan E, Oksuz S, et al. Prevalence of toenail onychomycosis in patients with type 2 diabetes mellitus and evaluation of risk factors. JAPMA. 2011; 101(1):49-54.
10. Rich P. Onychomycosis and tinea pedis in patients with diabetes. J Am Acad Dermatol. 2000; 43(5):S130.
11. Carney C, Tosti A, Daniel R, et al. A new classification system for grading the severity of onychomycosis: Onychomycosis Severity Index. Arch Dermatol. 2011;147(11):1277-82.
12. Shemer A. Update: medical treatment of onychomycosis. Dermatol Ther. 2012;25(6):582-93.
13. Alberhasky RC. Laboratory diagnosis of onychomycosis. Clin Podiatric Med Surg. 2004; 21(4):565-578.
14. Piraccini BM, Balestri R, Starace M, Rech G. Nail digital dermoscopy (onychoscopy) in the diagnosis of onychomycosis. J Eur Acad Dermatol Venereol. 2013; 27(4):509-13.
15. Hall M, Monka C, Krupp P, O’Sullivan D. Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients. Arch Dermatol. 1997;133(10):1213-9.
16. Singla A, Hammad HT, Hammoud GM. Uncommon cause of acute drug-induced liver injury following mammoplasty. Gastroenterology Research Volume 3.
17. McGill MR, Sharpe MR, Williams CD, et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574–1583.
18. Gantmacher J, Mills-Bomford J, Williams T. Interaction between warfarin and oral terbinafine. Manufacturer does not agree that interaction was with terbinafine. BMJ. 1998;317(7152):205; author reply 205.
19. Gupta AK, Ross GS. Interaction between terbinafine and warfarin. Dermatology. 1998;196(2):266-7.
20. Clarke MF, Boardman HS. Interaction between warfarin and oral terbinafine. Systematic review of interaction profile of warfarin is needed. BMJ. 1998 Jul 18;317(7152):205-6.
21. Jennings MB, Pollak R, Harkless LB, et al. Treatment of toenail onychomycosis with oral terbinafine plus aggressive debridement: IRON-CLAD, a large, randomized, open-label, multicenter trial. J Am Podiatr Med Assoc. 2006; 96(6):465-73.
22. Epocrates online, 2012. Available at https://online.epocrates.com/u/104851/terbinafine/Drug+Interactions  .
23. Gupta AK, Ryder JE, Lynch LE, Tavakkol A. The use of terbinafine in the treatment of onychomycosis in adults and special populations: a review of the evidence. J Drugs Dermatol. 2005;4(3):302-8.
24. Stier DM, Gause D, Joseph WS, et al. Patient satisfaction with oral versus non-oral therapeutic approaches in onychomycosis. J Am Podiatr Med Assoc. 2001;91(10):521-7.
25. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000;43(4 Suppl):S70-80.
26. Elewski BE, Ghannoum MA, Mayser P, et al. Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs. J Eur Acad Dermatol Venereol. 2011 Dec 20. Epub ahead of print.
27. Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother. 2012 Jun;13(8):1131-42.
28. Formula-3 PI. Available at http://thetetracorp.com/services-view/formula3/  .
29. Fungoid Tincture PI. Available at http://www.pedinol.com/product_detail.php?id=27 .
30. Malay DS, Yi S, Borowsky P, et al. 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.
31. Grover C, Bansal S, Nanda S, et al. Combination of surgical avulsion and topical therapy for single nail onychomycosis: a randomized controlled trial. Br J Dermatol. 2007;157(2):364-8.
32. Pandhi D, Verma P. Nail avulsion: Indications and methods (surgical nail avulsion). Indian J Dermatol Venereol Leprol. 2012;78(3):299-308.
33. South DA, Farber EM. Urea ointment in the nonsurgical avulsion of nail dystrophies: A reappraisal. Cutis. 1980; 25(6):609-12.
34. Averill RW, Scher RK. Simplified nail taping with urea ointment for nonsurgical nail avulsion. Cutis. 1986;38(4):231-3.
35. Neev J, Nelson JS, Critelli M, et al. Ablation of human nail by pulsed lasers. Lasers Surg Med. 1997;21(2):186-92.
36. Landsman AS, Robbins AH. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure: some follow-up observations at 270 days. J Am Podiatr Med Assoc. 2012; 102(2):169-71.
37. United States Food and Drug administration medical device approval (K103626). Available at http://www.accessdata.fda.gov/cdrh_docs/pdf10/K103626.pdf  .
38. Hees H, Raulin C, Bäumler W. Laser treatment of onychomycosis: an in vitro pilot study. J Dtsch Dermatol Ges. 2012 Dec;10(12):913-7.
39. Bodman MA, Blazer M, Caldwell, B. Unpublished data, Cleveland Foot and Ankle Clinic of the Kent State University College of Podiatric Medicine, Independence, Ohio.
40. Kimura U, Takeuchi K, Kinoshita A, et al. Treating onychomycoses of the toenail: clinical efficacy of the sub-millisecond 1,064 nm Nd: YAG laser using a 5 mm spot diameter. J Drugs Dermatol. 2012;11(4):496-504.
41. Zhang RN, Wang DK, Zhuo FL, et al. Long-pulse Nd:YAG 1064-nm laser treatment for onychomycosis. Chin Med J. 2012;125(18):3288-91.
42. Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother. 2012;13(8):1131-42.
43. Warshaw EM, Bowman T, Bodman MA, et al. Satisfaction with onychomycosis treatment. Pulse versus continuous dosing. J Am Podiatr Med Assoc. 2003;93(5):373-9.
For further reading, see “Roundtable Insights On Treating Onychomycosis” in the May 2011 issue of Podiatry Today or “Could Efinaconazole 10% Have An Impact For Onychomycosis?” in the February 2013 issue.