Terbinafine: 250 mg/day for 12 weeks
Itraconazole Continuous: 200 mg/day for 12 weeks
Itraconazole Pulse: 200 mg twice daily, given for one week on and three weeks off, repeated for a total of three pulses*
Fluconazole: 50 mg once weekly given until the abnormal-appearing nail has grown out*
* Not indicated for use in the United States
Ten Pearls For Treating Difficult Nails
Onychomycosis is a common nail infection, which is often chronic, difficult to eradicate and tends to recur.1 Current therapeutic approaches include mechanical or chemical avulsion, topical therapy, oral therapy or a combination of one or more of these treatment modalities. Treatment of onychomycosis has improved greatly with the addition of broad-spectrum oral antifungal agents and topical nail lacquers. However, even with the therapeutic advances, onychomycosis continues to increase in prevalence, treatment is not always successful, and relapse and reinfection may occur even after successful therapy.
With this in mind, here are 10 key tips for recognizing and treating difficult nail conditions.
1. Ensure A Correct Diagnosis Of Onychomycosis
Fungal infections of the nail apparatus may be classified as distal-lateral onychomycosis (DLSO), proximal subungual onychomycosis (PSO), superficial white onychomycosis (SWO), total dystrophic onychomycosis (TDO) and, more recently, endonyx onychomycosis (EO). The clinical presentation of the infection may provide you with information for identifying the causative organism. For instance, Candida infections are generally confined to the fingernails. Subungual hyperkeratosis with onycholysis is a common feature of dermatophyte infections.2
When diagnosing a fungal infection, you should not rely solely on the clinical presentation. Laboratory testing is an essential component in ensuring proper diagnosis. Performing microscopic examination of nail material, for example, subungual debris, involves treatment with potassium or sodium hydroxide to determine the identity of the causative organism. In addition, nail material and subungual debris should be planted on Sabouraud’s agar with and without cycloheximide. Keep in mind the cycloheximide may inhibit potential pathogens (e.g., some non-dermatophytes).
Performing a histological examination of the nail plate may be necessary to demonstrate whether a fungus is invasive into the nail plate or is simply colonizing subungual debris.2 It is also useful to confirm the results of routine microscopy and culture tests when results are repeatedly negative, although clinically, you would have a high suspicion of onychomycosis.3,4 You can stain nail specimens with the following: haematoxylin and eosin or Periodic Acid Schiff (PAS) and toluidine blue. You may also use calcofluor and Grocott’s stain.2 Histopathologic examination of nail clippings may reveal morphological aspects of the mycetes, which could enable you to make a distinction between dermatophytes, yeasts and molds.3 Generally, however, histopathological examination of the nail alone does not enable the identity of the causative organism to be determined.
Stringent criteria are required when you’re diagnosing a fungal infection caused by non-dermatophytes. English proposed the following criteria to determine whether a fungus is a commensal or if it is the true pathogen.5 First, if you find an isolated dermatophyte, it is usually the likely pathogen. Secondly, a direct examination (i.e. potassium or sodium hydroxide or alternatively histopathology) that yields a positive microscopic result showing fungal filaments/hyphae or pseudohyphae consistent with the isolated organism is needed. It is also required to do a repeat culture where at least five out of 20 inocula—planted on two or more separate occasions—demonstrate that the mold is the sole etiologic agent.
However, it is not always possible to carry out repeated sampling. Gupta, et. al., found that when only one sample is available and the light microscopic examination is positive, a strong statistical correlation occurs between high inoculum counts (a count of 11 or more culture-positive inocula out of 15 planted) and true opportunistic onychomycosis.
It should be noted that not all abnormal appearing nails have onychomycosis. In fact, approximately 50 percent of nails that appear to be abnormal may have documented onychomycosis.7 When onychomycosis is suspected, you should also inquire about a family history of fungal infections, particularly onychomycosis, in order to determine whether trauma has occurred. You should also look for other fungal infections (e.g., tinea pedis).
Keep in mind that several nail presentations mimic onychomycosis. Your differential diagnosis should include psoriasis, eczema, trauma, lichen planus and yellow nail syndrome.8,9 Also be aware that onychomycosis may co-exist with another nail disease, such as psoriasis.10
2. What Is The Identity Of The Organism?
Determining the identity of the causative organism of onychomycosis is essential to choosing the most appropriate therapy. For instance, griseofulvin is ineffective in treating onychomycosis caused by non-dermatophyte molds or Candida species. The newer antifungal agents (e.g., terbinafine, itraconazole, and fluconazole) are broad-spectrum agents with activity against dermatophytes, some non-dermatophyte molds, and Candida species. However, their effectiveness may vary. For example, using terbinafine is effective in treating yeast infections, although studies have reported C. parapsilosis responds better than C. albicans, possibly due to the fungicidal activity of the allylamine towards the former and fungistatic activity towards the latter.11,12
In regard to fluconazole, terbinafine and itraconazole, there is limited data regarding their effectiveness in treating non-dermatophyte mold onychomycosis.13 Certain organisms, such as Scytalidium dimidiatum and Onychocola canadensis, may be poorly responsive or unresponsive to therapy.14-16 Furthermore, non-dermatophyte organisms, such as Scytalidium species, may
clinically mimic the signs and symptoms seen in dermatophyte infections.17
3. Optimizing Bioavailability And Being AwareOf Potential Drug Interactions
The bioavailability of oral antifungal agents may be enhanced when patients administer the agents with a meal or beverage. For instance, patients can improve the absorption of griseofulvin if they take it after a meal with a high fat content.18 Similarly, itraconazole bioavailability is maximal when patients take it with a full meal.19 In addition, patients with relative or absolute achlorhydria or those taking gastric acid suppressors (e.g., H2 receptor antagonists) can increase the absorption of itraconazole when they take it with an acidic drink, such as a cola beverage.19 Terbinafine and fluconazole do not appear to be influenced markedly by concomitant food intake.
Drug interactions may also affect the effectiveness of treatment. Griseofulvin is an antibiotic derived from a species of Penicillium. It is contraindicated in individuals with porphyria, hepatocellular failure and those with a history of hypersensitivity to the antifungal agent.18 You may need to adjust the dosage for patients who are on warfarin-type anticoagulant therapy.18 If you’re treating patients who are using barbiturates, you may need to increase the dosage of griseofulvin.18
The azoles, ketoconazole, fluconazole and itraconazole, are inhibitors of the cytochrome P450 3A4 enzyme system. Ketoconazole is not recommended for the treatment of onychomycosis due to the potential of hepatotoxicity.
Fluconazole is contraindicated with cisapride. Also, coadministration of fluconazole, at multiple doses of 400 mg or higher, is contraindicated with terfenadine.20 Itraconazole is contraindicated with dofetilide and quinidine (antiarrhythmics), pimozide (antipsychotic), oral midazolam and triazolam (benzodiazepines), cisapride (gastrointestinal motility agent), and lovastatin and simvastatin (HMG CoA-Reductase inhibitors).19
Few drug interactions have been reported with the use of terbinafine, an allylamine, although it may affect metabolism of CYP2D6 substrates.21,22 No drugs are contraindicated with terbinafine.
4. How To Address Unusual Nail Presentations
Several presentations of onychomycosis may be more difficult to treat. Examples include slow nail outgrowth, severe onychomycosis (e.g., 75 percent nail plate/bed disease or proximal involvement), lateral nail involvement (see photo on left), longitudinal streak onychomycosis (see photo on bottom), a thickened nail (greater than 2 mm) and a dermatophytoma.23-26
A thickened nail plate with underlying subungual debris may have a higher chance of cure if you debride it.23,27,28 Those with lateral nail plate involvement or dermatophytoma, including longitudinal spike, may benefit from partial nail avulsion in addition to antifungal therapy.25 Studies have demonstrated the combination of griseofulvin with a keratolytic increases the cure rates and may decrease relapse rates.29,30
5. When You Should Consider Booster Therapy
When you’re treating difficult cases of onychomycosis, you should consider booster or supplemental therapy. Booster therapy consists of extra antifungal therapy and may improve cure rates of onychomycosis in some instances.27 Pharmacokinetic data suggest there is a “window of opportunity” for booster therapy following administration of the standard indicated doses of terbinafine and itraconazole for toenail onychomycosis.25 You would emphasize an extra four weeks of terbinafine or an extra pulse of itraconazole between month six and nine from the start of therapy.27 Beyond that time, drug concentrations within the nail may fall to such an extent that a short burst of extra therapy may not be sufficient to effect a cure.25
Gupta, et. al., have previously reported booster therapy may be of value when there is less than 3 mm of outgrowth of normal appearing nail within six months of starting therapy; if the decrease in affected nail plate area is less than 50 percent compared to that at baseline; and if the culture at month six is still positive.31
6. What About Adjuvants To Antifungal Therapy?
You may find that using topical or oral antifungals alone may not be sufficient. In some instances, mechanical or chemical therapy in some patients may be necessary to improve cure rates. Various procedures have been effectively used and include: (a) mechanical removal by cutting, filing or abrading, (b) surgical removal by total or partial nail avulsion and (c) chemical removal by keratinolysis.2
Dominguez-Cherit, et. al., evaluated 11 patients with onychomycosis.32 Patients were treated with terbinafine pulse (500 mg/day for seven days). Subsequently, the clinicians surgically removed the affected area of the nails. Rapid growth of a thin and transparent nail plate occurred after surgery. The clinicians found that the addition of surgical treatment improved cure rates and allowed for a shorter course of oral treatment.32
7. Be Aware Of Different Oral Regimens
When employing oral modalities for treating onychomycosis, there are preferred regimens (see “Preferred Dosing Regimens For Oral Antifungals” on page 35). However, there have been studies that evaluated the use of alternative regimens in treating fungal infections of the nail.
Zaias, et. al., reported using itraconazole 200 mg twice daily for one week of every month or terbinafine 250 mg/day in 40 patients.33 Patients used the drug for 11 or more months until the mycotic nail bed had been completely replaced by new non-mycotic nail bed. Seventy-five percent of patients treated with itraconazole and 90 percent of patients treated with terbinafine were cured.33
Studies have also evaluated the use of terbinafine via a pulse regimen. Other regimens that have been investigated include sequential therapy (two pulses of itraconazole followed by one or two pulses of terbinafine) and combination therapy with terbinafine and itraconazole.34-35 Further studies are required. We recommend the use of the standard regimens (approved regimens) when using, whenever possible, terbinafine and itraconazole to treat onychomycosis.
8. Should You Combine Oral And Topical Antifungal Agents?
The combination of oral and topical antifungal agents for onychomycosis may result in increased efficacy, a broader spectrum of action, improved patient tolerability, reduced time to onset of action and reduced patient exposure to each drug. These benefits can be the result of drug synergy.36-40 In addition, the combination of topical and oral antifungals may result in drug penetration from both “inside out” and “outside in.” Topical agents directly and rapidly enter the nail plate, including the lateral margins, while oral agents rapidly accumulate in the nail bed.36
The combined use of ciclopirox nail lacquer with terbinafine is currently being evaluated in a multinational, multicenter, randomized and evaluator-blinded study.38 The combination of amorolfine nail lacquer with griseofulvin, itraconazole or terbinafine has improved cure rates compared to monotherapies with oral antifungal agents.37,39-41 In one study, researchers found that employing amorolfine increased the fungistatic activity of griseofulvin against three strains of Trichophyton mentagrophytes (449, D, and 6).41 Several studies suggested the treatment of severe onychomycosis might be improved with the combination of oral and topical agents.37,39,40,42 Further data are required where combination therapy is used in onychomycosis.
9. Try To Ensure Patient Compliance
Patient compliance with the drug regimen is an important factor in determining the outcome of therapy. Therefore, it is important to carefully monitor your patients since the lack of compliance may result in inadequate drug levels and subsequent failure to eradicate the fungus. For instance, the length of treatment, ease of swallowing medication, frequency of daily intake and the number of oral drugs per intake are features of an oral medication that may affect compliance.43 Patients may also vary in their attitudes about applying a topical nail lacquer daily for one year.
10. Emphasize Preventive Measures
You should educate your patients on proper nail care to help prevent relapse or reinfection of onychomycosis after successful treatment.14, 25 For instance, patients should keep their nails cut short and clean, wear proper footwear when walking in communal areas (e.g., public baths, gymnasiums, health spas, etc.), and dry their feet completely following a bath or shower. Patients may benefit from wearing socks made out of absorbent material, such as cotton.
Dr. Gupta is an Associate Professor in the Division of Dermatology, Department of Medicine at the Sunnybrook and Women’s College Health Science Center and at the University of Toronto in Toronto, Canada. He is also the Laboratory Director at Mediprobe Laboratories, Inc. in Toronto. Ms. Ryder is also affiliated with Mediprobe Laboratories, Inc.
1. Gupta AK, Baran R. Ciclopirox nail lacquer solution 8% in the 21st century. J Am Acad Dermatol 2000;43:S96-S102.
2. Hay RJ, Baran R, Haneke E. Fungal (onychomycosis) and other infections involving the nail apparatus. In: Baran R, Dawber RPR, de Berker DAR, Haneke E, Tosti A. Baran and Dawber’s Diseases of the Nails and their Management. 3rd Ed. Blackwell Science, 2001:129-171.
3. Gianni C, Morelli V, Cerri A, Greco C, Rossini P, Guiducci A, Braidotti P, Calcaterra R, Papini M. Usefulness of histological examination for the diagnosis of onychomycosis. Dermatol 2001;202:283-288.
4. Scher RK, Ackerman AB. Subtle clues to diagnosis from biopsies of nails. The Am. J. Dermatopathol. 1980;2(1):55-56.
5. English MP. Nails and fungi. Br J Dermatol 1976;94:697-701.
6. Gupta AK, Cooper EA, MacDonald P, Summerbell RC. Utility of inoculum counting (Walshe and English criteria) in clinical diagnosis of onychomycosis caused by nondermatophytic filamentous fungi. J Clin Microbiol 2001;39:2115-2121.
7. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physician’s offices: A multicenter survey of 15,000 patients. J Am Acad Dermatol 2000;43:244-248.
8. Schlefman BS. Onychomycosis: a compendium of facts and a clinical experience. The J Foot Ankle Surg 1999;38(4):290-302.
9. Rogers P, Bassler M. Treating onychomycosis Am Fam Physician 2001;63(4):663-672.
10. Gupta AK, Lynde CW, Jain HC, et. al. A higher prevalence of onychomycosis in psoriatics compared with non-psoriatics: a multicenter study. Br J Dermatol 1997;136:786-789.
11. Segal R, Kritzman A, Cividalli L, et. al. Treatment of Candida nail infection with terbinafine. J Am Acad Dermatol 1996;35:958-961.
12. Nolting S, Brautigam M, Weidinger G. Terbinafine in onychomycosis with involvement by non-dermatophytic fungi. Br J Dermatol 1994;130(Suppl. 43):16-21.
13. Gupta AK, Gregurek-Novak T, Konnikov N, et. al. Itraconazole and terbinafine treatment of some nondermatophyte molds causing onychomycosis of the toes and a review of the literature. J Cutan Med Surg 2001;5(3):206-210.
14. Gupta AK, Shear NH. A risk-benefit assessment of the newer oral antifungal agents used to treat onychomycosis. Drug Safety 2000;22:33-52.
15. Gupta AK, Horgan-Bell CB, Summerbell RC. Onychomycosis associated with Onychocola canadensis: ten case reports and a review of the literature. J Am Acad Dermatol 1998;39:410-417.
16. Gupta AK, Elewski BE. Nondermatophyte causes of onychomycosis and superficial mycoses. Curr Top Med Mycol 1996;7:87-97.
17. Elewski BE, Greer DL. Hendersonula toruloidea and Scytalidium hyalinum: Review and update. Arch Dermatol 1991;127(7):1041-1044.
18. Grifulvin V package insert. Ortho Pharmaceutical Corp, New Jersey, USA. (1997 January).
19. Sporanox package insert. Janssen Pharmaceutica, New Jersey, USA. (2001 April).
20. Diflucan prescribing information. Pfizer. www.diflucan.com/pi.htm. (1998 June).
21. Abdel-Rahman SM, Gotschall RR, Kauffman RE, et. al. Investigation of terbinafine as a CYP2D6 inhibitor in vivo. Clin Phamacol Ther 1999;65(5):465-472.
22. Kaplan DL. Terbinafine and potential drug interactions. J AM Acad Dermatol 2000;43(5 Pt 1):882-884.
23. Gupta AK, Daniel III CR. Factors that may affect the response of onychomycosis to oral antifungal therapy. Aust J Dermatol 1998;39:222-224.
24. Baran R, De Doncker P. Lateral edge nail involvement indicates poor prognosis for treating onychomycosis with the new systemic antifungals. Acta Derm Venereol (Stockh) 1996;76(1):82-83.
25. Gupta AK, Daniel III CR. Onychomycosis: strategies to reduce failure and recurrence. Cutis 1998;62:189-191.
26. Roberts DT, Evans EG. Subungual dermatophytoma complicating dermatophyte onychomycosis. Br J Dermatol 1998;138:189-190.
27. Gupta AK, Konnikov V, Lynde CW. Single-blind, randomized, prospective study on terbinafine and itraconazole for treatment of dermatophyte toenail onychomycosis in the elderly. J Am Acad Dermatol 2001;44:479-484.
28. Markinson BC, Monter SI, Cabrera G. Traditional approaches to treatment of onychomycosis. J Am Pod Med Assoc 1997;87(12):551-556.
29. Friedman-Birnbaum R, Cohen A, Shemer A, et. al. Treatment of onychomycosis: a randomized, double-blind comparison study with topical bifonazole-urea ointment alone and in combination with short-duration oral griseofulvin. Int J Dermatol 1997;36:67-69.
30. Arenas R, Fernández G, Dominguez L. Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent. Int J Dermatol 1991;30(8):586-589.
31. Gupta AK, Ryder J. How to improve cure rates for the management of onychomycosis. Derm Clin. Submitted 2002.
32. Dominguez-Cherit J, Teixeira F, Arenas R. Combined surgical and systemic treatment of onychomycosis. Br J Dermatol 1999;140:749-782.
33. Zaias N, Rebell G, Zaiac MN, et. al. Onychomycosis treated until the nail is replaced by normal growth or there is failure. Arch Dermatol 2000;136(7):940.
34. Gupta AK, Lynde CW, Konnikov N. Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared with terbinafine pulse for the treatment of toenail onychomycosis. J Am Acad Dermatol 2001;44:485-91.
35. Gupta A. Combination therapy with terbinafine and itraconazole for the treatment of toenail onychomycosis. Ann Dermatol Venereol 2002;129:1S662. (Abstract)
36. Hay RJ. The future of onychomycosis therapy may involve a combination of approaches. Br J Dermatol 2001;145(Suppl.60):3-8.
37. Lecha M. Amorolfine and itraconazole combination for severe toenail onychomycosis; results of an open randomized trial in Spain. Br J Dermatol 2001;145(Suppl. 60):21-26.
38. Gupta A. Exploring regimens to improve efficacy in the treatment of onychomycosis. Ann Dermatol Venereol 2002;129:1S665. (Abstract)
39. Baran R, Feuilhade M, Datry A, et. al. A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycosis affecting the matrix region. Br J Dermatol 2000;142:1177-1183.
40. Baran R. Topical amorolfine for 15 months combined with 12 weeks of oral terbinafine, a cost-effective treatment for onychomycosis. Br J Dermatol 2001;145(Suppl. 60):15-19.
41. Lauharanta J, Zaug M, Polak A, et. al. Combination of amorolfine with griseofulvin: in vitro activity and clinical results in onychomycosis. JAMA SEA 1993;9(Suppl. 4):23-27.
42. Gupta AK, Hamel L, Baron F, et. al. Onycho tree study: cost-effectiveness analysis for the treatment of toenail onychomycosis. Ann Dermatol Venereol 2002;129:1S517. (abstract)
43. Nolting SK, Carazo JS, De Boulle K, et. al. Oral treatment schedules for onychomycosis: a study of patient preference. Int J Dermatol 1998;37:454-456.