Unanswered Questions in Antifungal Therapy for Onychomycosis

ABSTRACT

Onychomycosis affects about 7–8% of the North American population¹ and having significant social, psychologic, health, and occupational effects³, is more than a cosmetic issue², it is a clinical and economic problem. However, with three new, orally effective, antifungal agents, we have for the first time effective treatment that can provide benefit for a high percentage of patients. This review examines some of the areas of uncertainty and controversy.

Key Words:
Onychomycosis, Antifungal, dermatophytoma, itraconazole, terbinafine, fluconazole, griseofulvin

Recurrence and relapse in onychomycosis

There is a difference between “re-infection” and “relapse”. Relapse, or “delayed failure” refers to recurrence of the original infection that was clinically and mycologically cured at one time-point following therapy. Reinfection is a new infection resulting from exposure to a fungus in shoes, floors or fomites. In many cases when there is a recurrence of infection, it may be difficult to distinguish between relapse and reinfection.⁴ Some have suggested that the recurrence of toenail onychomycosis, once complete clinical and mycological cure has occurred, is more likely to be due to relapse if it has developed within 18 months of starting oral antifungal therapy4, and reinfection when toenail onychomycosis recurs 18 months or more beyond the start of therapy.⁴ The time-point of 18 months is an arbitrary choice; others have suggested 24 months from the start of therapy. It should be kept in mind that the terms relapse and recurrence have been used interchangeably in the literature.

Dermatophytoma complications may be a leading cause of treatment failure

In a significant number of cases of dermatophyte onychomycosis, a dense white linear area or a round white area is seen. When the overlying nail is cut back, a densely packed clump of thick walled, somewhat abnormal looking dermatophyte hyphae is revealed. It is probable that antifungal drug penetration into such lesions does not achieve adequate concentrations and nail removal is necessary in order for antifungal drugs to prove effective. The dermatophytoma is not particularly adherent and can be readily removed.⁵

What roles do increasing age, disease duration or ethnic origin play in re-infection or relapse?

Older people have a higher prevalence of nail disease. They also respond less well to treatment,^6,7 as do patients with more severe nail involvement.⁶ Since nail growth slows with increasing age, and local trauma increases, the elderly are more likely to develop nail infections and more likely to have reinfections. The decrease in T cell function associated with aging may be the primary reason for the increased recurrence rates⁸, although patients with long-standing onychomycosis may have nails that grow relatively more slowly compared to the usual growth rates of nails in those of a similar age and gender.⁴ Because the newer antifungal drugs require new growth of nail to replace the old infected portions, growth of nail is a necessary feature to effect a cure. Therefore, a long disease duration and a slow rate of nail outgrowth are associated with a poorer response to treatment with the new oral antifungal agents.

Another reason that disease duration and increasing age may impede cure rates, is the fact that the infections may become more complicated and other non-dermatophyte moulds and/or yeasts and/or bacteria may become secondary pathogens.⁹ There is no evidence for ethnic differences in re-infection or relapse rates.^4,6,7,10

In onychomycoses, what is the incidence of recurrence and relapse following treatment with itraconazole or terbinafine?

Currently, it is not possible to distinguish between relapse and reinfection.^4,6 Used in their currently recommended regimen, until recently there was thought to be no clear difference between the drugs.⁶ However, in the L.I.ON. double-blind, double-dummy study, continuous terbinafine for 12 weeks and 16 weeks resulted in statistically significantly superior mycological and clinical cure rates as compared to intermittent itraconazole given for one in every four weeks for 12 and 16 weeks.¹¹ Estimated rates of recurrence/relapse following treatment with itraconazole or terbinafine range from 15–30% depending on the patient population under study.^2,7,10,12 Following pulse therapy with itraconazole for toenail onychomycosis, after 1 year, the incidence of relapse/ recurrences is on average 10% based on a number of clinical trials, including more than 1300 patients treated with 3 pulses for toenail onychomycosis.⁷ There is relatively little information on the rate of recurrence/relapse of toenail onychomycosis in special populations treated with the newer antifungal agents.⁴

Is there evidence of resistance emerging to itraconazole, terbinafine, fluconazole or griseofulvin?

• For superficial fungal skin/nail or hair infections there is as yet no evidence for dermatophyte resistance emerging to itraconazole, terbinafine or fluconazole.^2,6,7,9 Usually, failures can be attributed to a wrong diagnosis, poor compliance and less than optimal absorption with itraconazole capsules not being taken with a fatty meal.⁷ Why some patients under optimal conditions still fail to respond to treatment with itraconazole or terbinafine is not fully understood. It seems that some of the fungal elements (e.g. with dermatophytes) are present as arthrospores in the nail unit. These arthrospores have thicker cell walls than hyphal elements and are encapsulated in such a way that drug penetration becomes difficult or perhaps impossible.⁷ In onychomycosis, especially in those patients with longstanding disease, fungal organisms protect themselves in this way so that they can better survive in their environment. Surviving arthrospores may also be the reason for more frequent relapses in patients with long standing disease. This should not be termed resistance as there is some evidence that when these fungi are transformed to a hyphal phase, they are once again very sensitive to treatment. In fact, we might consider stimulating the conversion of their arthrospore phase into a hyphal phase before commencing with antifungal agents.^4,7
• For superficial Candida infections in the immunocompetent host/healthy patient, again there is no evidence supporting the emergence of resistance.^6,7,9
• In the immunocompromised host, induced resistance to fluconazole has been identified in Candida. Recently, Candida albicans isolates resistant to fluconazole have been reported with increasing frequency in oral infections in HlV-positive patients. This was mostly observed during long-term treatment. So far, ketoconazole resistance has only been described in Candida albicans following chronic use in chronic mucocutaneous cadidiasis patients. Even though the use of ketoconazole in HIV infected patients has increased, acquired resistance has not been reported. Acquired and intrinsic resistance to Candida spp has not been documented.⁷

“ In vitro” cross resistance between different azoles has been documented by some laboratories but not by others. Crossresistance evidenced by some labs, has not been confirmed by other laboratories studying these same strains.

What is the importance or significance of agents being fungicidal rather than fungistatic?

Clinically, the difference is not important.^7,9 It is more important to get the appropriate concentration of oral antifungal agent at the site of the infection (e.g. nail unit, hair or the skin).

Are moulds increasing?

Dermatophytes are the prime pathogens in onychomycosis.⁴ Non-dermatophyte moulds may occur from time to time, but are generally not a problem and their appearance is generally an incidental finding as a laboratory contaminant.⁹ In young adults and adults up to 65 years of age, non-dermatophyte moulds may be more likely to be saprophytes than true invaders, although in some cases they do cause an invasive toenail infection. In patients older than 65, nail growth declines further and non-dermatophytic moulds may find it easier to penetrate the nail unit and cause invasive nailplate infection.⁷ If this hypothesis is correct, we will see more nondermatophyte infections as the average age of the population increases.⁷ The incidence of moulds is significantly higher in the tropics and moulds are more likely in patients returned from the tropics.⁸

Do some individuals have an “inherited predisposition” to severe forms of fungal infections?

Fungal infections of the feet and toenails are transmitted via infected fungal elements or arthrocondidia. People who are at highest risk include those who have sweaty feet, and individuals such as army recruits, athletes, etc. who walk over surfaces which are heavily contaminated with fungus, such as in gyms and locker rooms. A genetic predisposition may explain why some people who are exposed get an infection and others don’t.^4,9 There is some evidence to suggest that atopic patients may have a more chronic form of fungal infection.⁷ However, this observation has not been substantiated.

Treatment of Onychomycoses of the toenails

* Based on the Average US Wholesale Price (Red Book, January, 1999) and Average Canadian Wholesale Price to Pharmacies, January 1999.
**Itraconazole pulse therapy for onychomycoses of the fingernails, but not the toenails, has been approved by the US FDA. The pulse regimen is approved in Canada.

Now that we have improved means of treating toenail onychomycosis, it is even more important to pay attention to ways of reducing the recurrence (relapse and reinfection) of toenail onychomycosis. Patient education is one way in which we can reduce the potential for reinfection. Some strategies include avoidance of facilities with a high level of dermatophyte contamination (communal swimming pools, showers, changing facilities) discarding old shoes that may have a high density of fungal spores, and the judicious use of topical antifungal agents.² This is especially important in at risk populations, for example, those with a genetic predisposition and immunocompromised individuals.⁴
Dr. Aditya Gupta⁴

References

1. Gupta AK, Jaine HC, Lynde CW et al. Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists’ offices in Ontario, Canada – a multicenter survey of 2001 patients. Int J Dermatol 1997; 36: 783–787.
2. Gupta AK, Scher RK. Oral antifungal agents for onychomycosis. Lancet 1998; 351: 541–2.
3. Drake LA, Scher RK, Smith EB et al. Effect of onychomycosis on quality of life. J Am Acad Dermatol 1998; 38: 702 – 704.
4. Gupta AK. Personal communication December, 1998.
5. Roberts DT, Evans EGV. Subungual dermatophytoma complicating dermatophyte onychomycosis. Brit J Derm 1998; 138: 189–190.
6. Hay RJ. Personal communication November, 1996.
7. De Doncker PGR Personal communication December, 1996.
8. Millikan LE. Personal communication November, 1996.
9. Elewski BE. Personal communication May, 1997.
10. Scher RK. Personal communication October, 1996.
11. Evans EGV, Sigurgeirsson B, Billstein S. An analysis of the efficacy, safety, and tolerability of terbinafine versus intermittent itraconazole in the treatment of toenail onychomycosis (L.I.O.N Study). Presented at the 7th Congress of the European Academy of Dermatology and Venereology, October 7–11, 1998, Nice, France.
12. Ogawa H. Personal communication November, 1996.