Onychomycosis: Therapy Directed by Morphology and Mycology

K. Barber, MD¹ and J. Barber^2
1Department of Medicine, University of Calgary, Calgary, AB, Canada
²Royal College of Surgeons, Dublin, Ireland

ABSTRACT

Onychomycosis is one of the most common nail disorders. Despite recent therapeutic advances with the introduction of effective systemic agents and transungual drug delivery systems, the incidence of onychomycosis is increasing. This is of concern, as the morbidity related to this infection also increases as our population ages with associated conditions, such as diabetes and immunosuppression from illness and medical therapy. Rational and effective treatment plans are needed.

Key Words: itraconazole; morphology; mycology; onychomycosis; nail disorders; terbinafine

In a multicenter survey about the incidence of onychomycosis in 15,000 consecutive patients, Gupta et al.¹ reported that this condition affects 6.5% of Canadian adults. These patients visited their clinical physicians for any reason and consented to an examination of their fingernails and toenails, and to fungal cultures of any nail plates that appeared abnormal. The nail plate cultures were positive in 1,199 (8%) patients, and 1,137 (7.6%) of them had only pedal onychomycosis. This confirmed the work of other investigators by showing that the most common organisms responsible for >90% of onychomycosis involving the toenails are the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes.

Baran et al.² proposed a morphological classification based on the portal of entry, which has proven very useful in the clinical setting. Clinical presentations may combine features of basic morphologic patterns. Three basic clinical presentations include:

A fourth clinical presentation is total dystrophic onychomycosis (TDO), which may be considered secondary to severe DLSO, SWO, PSO, or primary when associated with severe immunodeficiency.

Gupta et al.¹ noted in their review that the relative frequency of presentation was 360:59:1 for DLSO:SWO:PSO when the toenails were involved. They also noted that in the DLSO group, the percentage of the nail plate involvement could be categorized as mild (<25%), moderate (26%-74%) and severe (>75%) with relative incidences of 27.6%, 39.9%, and 32.5%, respectively.

The morphological presentation of the infection within the nail plate aids in the choice of treatment agents and in determining prognosis and the need for adjunctive therapy. The involvement of the lunula appears to be the critical morphologic criteria that establishes the need to consider systemic therapy in the management of onychomycosis. Therefore, in most clinical settings, when <75% of the nail plate surface area is involved and the lunula is spared, topical therapy may be considered as monotherapy. The number of nails involved may also contribute to this decision. Most authorities recognize that they should consider the addition of systemic therapy when a patient presents with the involvement of more than 5 infected nails.

The morphology of the nail plate infection at the time of presentation may also help determine the need for adjunctive therapy. These presentations are:

• Dermatophytoma/longitudinal streaking with nail plate changes that are produced by keratin debris and filled with dermatophytes, which produce a relatively inaccessible foci of infection.


• Lateral nail plate involvement/onycholysis, whereby seperation of the nail plate from the nail bed reduces the vascular access to the plate and limits the penetration of systemic therapy.


• Thick nail (>2mm), which may indicate matrix involvement, and keratinaceous debris can limit drug diffusion regardless of the delivery system.

These presentations all limit the access of pharmaceutical agents to the site of the dermatophyte infection and all require adjunctive therapy that is directed to the physical removal of the keratinaceous debris. Mechanical or chemical debridement is essential for effective therapy.

Scher et al.⁴ discuss the difficulties in assessing the results of randomized controlled trials (RCTs) to aid in the selection of specific treatment modalities. The trials are not consistent in their design or in their use of criteria to determine the relative effectiveness of treatment modalities. Scher proposes definitions for clinical cure in RCTs, which are either 100% morphologic cure, or mycological cure of <10% of the nail plate with morphologic disturbance or thickening of the plate related to comorbidity. Mycological cure rates, however, appear to be the most consistent criteria as they can be objectively determined and compared. Gupta5 provided a meta-analysis of published studies from 1966 through 1999, which recorded mycological cure rates for terbinafine (3 months continuous), itraconazole (3 pulses) and griseofulvin (daily) as 77%, 70%, and 41% respectively. Topical therapy with 8% ciclopirox, when used in mildto- moderate onychomycosis without lunular involvement, produced a mycologic cure of 52.6%.

Chang et al.,⁶ using a meta-analysis of 122 studies with 20,000 patients, reviewed the safety of oral anti-fungal treatments in immunocompetent patients. The risk of treatment discontinuation as a result of an adverse event was 3.4% for continuous terbinafine (250mg/day for 3 months) and 2.58% for pulse itraconazole (400mg/day for 1 week). Transaminase elevations requiring treatment termination occurred in 0.34% of patients receiving continuous terbinafine and 0.39% of patients on pulse itraconazole. Transaminase elevations not requiring treatment termination occurred in 0.70% and 1.04% of patients, respectively. These treatment regimens did not reveal the risk of an adverse event to be any greater than the placebo groups in those studies that were placebo controlled.

Baran et al.^7,8 proposed a severity index for assessing the responses to treatment of onychomycosis. The index assigns a numerical value to the morphological presentation, to the mycology, and to host factors, which would influence the outcome of treatment. The values are added together to assign a prognosis that could then be discussed with patients. This index would provide an indication of which patients would be likely to fail therapy, so that a rational treatment program could be developed that might also include mechanical or chemical intervention. The concept of a booster dose, which is another cycle of systemic therapy delivered for 1 month at approximately 6 to 9 months from the start of therapy, is also supported for patients who are likely to fail therapy.

The recurrence of onychomycosis (relapse or reinfection) is a significant challenge in the management of patients with this infection. The LION study group9 documented mycological cure at 72 weeks in 75%-80% of terbinafine treated patients and 38%-49% of itraconazole treated patients. However, a 5 year follow-up study of 151 of these patients revealed that only 46% of terbinafine- and 13% of itraconazole-treated patients were disease free. These patients were treated with systemic monotherapy. There is a discussion in the literature suggesting that topical therapy, both concomitantly and intermittently, may improve these results by providing a longer treatment period for slow growing nails, and offering treatment for individuals prone to reinfection due to genetics or comorbidities.

Conclusion

The goal of treatment is to completely eradicate the infection and return the nail plate to its normal appearance. Unfortunately, the eradication of the dermatophyte does not routinely result in a normal nail plate. The changes related to chronic infection, repeated trauma, and other disease processes, such as psoriasis, may all predispose the patient to a dermatophyte infection and not allow for a return to a normal nail plate. Reviewing the information that is presented in this paper with the patient will help to develop a rational treatment, manage expectations, and encourage compliance.

References

1. Gupta AK, Jain HC, Lynde CW, et al. Prevelance and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicentre Canadian survey of 15,000 patients. J Am Acad Dermatol 43(2 Pt 1):244-8 (2000 Aug).
2. Baran R, Hay RJ, Haneke E, et al. Onychomycosis: the current approach to diagnosis and therapy. 2nd edition (2006).
3. Gupta AK, Cooper EA. A simple alogrithm for the treatment of dermatophyte toenail onychomycosis. Skin Therapy Lett Family Practice Ed. 4(3):1-3 (2008 Jun).
4. Scher RK, Tavakkol AT, Sigurgeirsson B, et al. Onychomycosis: diagnosis and definition of cure. J Am Acad Dermatol 56(6):939-944 (2007 Jun).
5. Gupta AK. Pharmacoeconomic analysis of ciclopirox nail lacquer 8% and the new oral antifungal agents used to treat dermatophyte to onychomycosis in the United States. J Am Acad Dermatol 43(4 Suppl):S81-95 (2000 Oct).
6. Chang CH, Young-Xu Y, Kurth T, et al. The safety of oral antifungal treatments for superficial dermatophytosis and onychomycosis: a meta-analysis. Am J Med 120(9):791-8 (2007 Sep).
7. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy and the severity index for assessing onychomycosis: part I. J Dermatolog Treat 19(2):72-81 (2008).
8. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: treatment rationale, including specific patient populations. J Dermatolog Treat 19(3):168-75 (2008).
9. Sigurgeirsson B, Olafsson JH, Steinsson JP, et al. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch Dermatol 138:353-7 (2002 Mar).

In this issue:

1. Onychomycosis: Therapy Directed by Morphology and Mycology
2. Many Common Drugs in Dermatology are Light, Temperature, or Moisture-Sensitive
3. Update on Drugs and Drug News - February 2009