treating onychomycosis - american family physicianfeb 15, 2001 · about one half of nail...

FEBRUARY 15, 2001 / VOLUME 63, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 663

Classification of OnychomycosisDISTAL SUBUNGUAL ONYCHOMYCOSIS

The most common form of tinea unguiumis distal subungual onychomycosis, which canalso be distal and lateral (Figures 1 and 2).

Onychomycosis (tinea un-guium) is a fungal infectionof the nail bed, matrix orplate. Toenails are affectedmore often than finger-

nails.1,2 Onychomycosis accounts for onethird of integumentary fungal infections andone half of all nail disease.1 Tinea unguiumoccurs primarily in adults, most commonlyafter 60 years of age. The incidence of thisinfection is probably much higher than thereported 2 to 14 percent.1 Occlusive footwear,locker room exposure and the disseminationof different strains of fungus worldwide havecontributed to the increased incidence ofonychomycosis.3

Tinea unguium is more than a cosmeticproblem, although persons with this infectionare often embarrassed about their nail disfig-urement. Because it can sometimes limitmobility, onychomycosis may indirectlydecrease peripheral circulation, thereby wors-ening conditions such as venous stasis anddiabetic foot ulcers.4 Fungal infections of thenails can also be spread to other areas of thebody and, perhaps, to other persons.

Dermatophytes, yeasts and nondermato-phytic molds can infect the nails.1 The clinicalsignificance of molds is uncertain, becausethey may be colonizing organisms that arenot truly pathogenic.3,5

Onychomycosis accounts for one third of fungal skin infections. Because onlyabout one half of nail dystrophies are caused by fungus, the diagnosis should beconfirmed by potassium hydroxide preparation, culture or histology before treat-ment is started. Newer, more effective antifungal agents have made treating ony-chomycosis easier. Terbinafine and itraconazole are the therapeutic agents ofchoice. Although the U.S. Food and Drug Administration has not labeled flucona-zole for the treatment of onychomycosis, early efficacy data are promising. Con-tinuous oral terbinafine therapy is most effective against dermatophytes, whichare responsible for the majority of onychomycosis cases. Intermittent pulse dosingwith itraconazole is as safe and effective as short-term continuous therapy butmore economical and convenient. With careful monitoring, patients treated withthe newer antifungal agents have a good chance of achieving relief from ony-chomycosis and its complications. (Am Fam Physician 2001;63:663-72,677-8.)

Treating OnychomycosisPHILLIP RODGERS, M.D., and MARY BASSLER, M.D.University of Michigan Medical School, Ann Arbor, Michigan

PRACTICAL THERAPEUTICS

Members of variousmedical facultiesdevelop articles for“Practical Therapeu-tics.” This article is onein a series coordinatedby the Department ofFamily Medicine at theUniversity of MichiganMedical School, AnnArbor. Guest editor ofthe series is Barbara S.Apgar, M.D., M.S.,who is also an associ-ate editor of AFP.

O A patient informa-tion handout oninfected fingernailsand toenails, writtenby the authors of thisarticle, is provided onpage 677.

FIGURE 1. Distal and lateral subungual ony-chomycosis.

FIGURE 2. Fissure formation (arrow) in distalsubungual onychomycosis.

Distal subungual onychomycosis may developin the toenails, fingernails or both. Somedegree of tinea pedis is almost always present.The infection is usually caused by Trichophy-ton rubrum, which invades the nail bed andthe underside of the nail plate, beginning at the hyponychium and then migrating proxi-mally through the underlying nail matrix2,3

(Figure 3). Susceptibility to distal superficialonychomycosis may occur in an autosomaldominant pattern within families.1

WHITE SUPERFICIAL ONYCHOMYCOSIS

White superficial onychomycosis accountsfor only 10 percent of onychomycosis cases.3

The toenails are usually affected (Figure 4).White superficial onychomycosis is caused bycertain fungi that directly invade the superfi-cial layers of the nail plate and form well-delineated opaque “white islands” on theplate. As the disease progresses, these patches

coalesce to involve the entire nail plate. The nailbecomes rough, soft and crumbly. The mostcommon causative agent is Trichophytonmentagrophytes.1-3

PROXIMAL SUBUNGUAL ONYCHOMYCOSIS

Proximal subungual onychomycosis is theleast common form of tinea unguium inhealthy persons (Figure 5). It occurs when theinfecting organism, usually T. rubrum,invades the nail unit through the proximalnail fold, penetrates the newly formed nailplate and then migrates distally. Fingernailsand toenails are equally affected.1 This formof onychomycosis usually occurs in immuno-compromised persons and is considered aclinical marker of human immunodeficiencyvirus infection.1 Proximal subungual ony-chomycosis can also arise secondary to localtrauma.1-3

664 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 63, NUMBER 4 / FEBRUARY 15, 2001

The most common cause of subungual onychomycosis is Trichophyton rubrum.

FIGURE 4. White superficial onychomycosis(arrow).

FIGURE 5. Proximal subungual onychomycosis(arrow).FIGURE 3. Anatomy of the toenail, showing the right large toe.

ILLU

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BY

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ON

Cuticle

Nail plate

Proximal nail fold

Nail matrix

Cuticle

Nail bed

Nail plate

Hyponychium

Nail root

Lunula

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.

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.

. . . . ..

CANDIDAL ONYCHOMYCOSIS

Patients with chronic mucocutaneous can-didiasis may develop candidal infection of thenails. Candida species may invade nails previ-ously damaged by infection or trauma.1,3

Candidal paronychia more commonly affectsthe hands and usually occurs in persons whofrequently immerse their hands in water.5

TOTAL DYSTROPHIC ONYCHOMYCOSIS

Total dystrophic onychomycosis may be theend result of any of the four main forms ofonychomycosis. This condition is character-ized by total destruction of the nail plate.3

DiagnosisBecause fungi are responsible for only

about one half of nail dystrophies, the diag-nosis of onychomycosis may need to be con-firmed by potassium hydroxide (KOH)preparation, culture or histology. Psoriasis,lichen planus, contact dermatitis, trauma, nailbed tumor and yellow nail syndrome may bemistakenly diagnosed as onychomycosis.1,2 Afungal etiology is unlikely if all fingernail ortoenails are dystrophic.3

OBTAINING A SPECIMEN

The technique used to collect specimensdepends on the site of the infection.1,3

In distal subungual onychomycosis, theconcentration of fungus is greatest in the nailbed. Therefore, the nail should be clippedshort, and a small curette or number-15scalpel blade should be used to obtain a spec-imen from the nail bed as close to the cuticleas possible. A specimen should also be takenfrom the underside of the nail plate.

In white superficial onychomycosis, a num-ber-15 blade or curette can be used to scrapethe nail surface or the white area, and removeinfected debris.

In proximal superficial onychomycosis, thehealthy nail plate should be gently pared awaywith a number-15 scalpel blade. A sharpcurette can be used to remove material from

the infected proximal nail bed as close to thelunula as possible.

In candidal onychomycosis, infected ma-terial should be collected from the proximaland lateral nail edges.

TreatmentHistorically, the treatment of onychomyco-

sis has been challenging. Orally administeredgriseofulvin (Grisactin, Gris-Peg) has beenavailable for many years, but its use is limitedby a narrow spectrum, the necessity for longcourses of treatment and high relapse rates.The oral form of ketoconazole (Nizoral) ismuch more effective but carries a risk ofhepatotoxicity.6

Onychomycosis has long been treated withtopical antifungal preparations. However,these agents are inconvenient to use, andresults are often disappointing. Treatmentusing nail avulsion in combination with topi-cal therapy has been somewhat more success-ful, but this approach can be time-consuming,temporarily disabling and painful.

The U.S. Food and Drug Administration(FDA) has labeled ciclopirox (Penlac) naillacquer for the treatment of mild to moderateonychomycosis caused by T. rubrum withoutinvolvement of the lunula. Although safe andrelatively inexpensive, ciclopirox therapy isseldom effective.7

In recent years, treatment outcomes inpatients with onychomycosis have improvedsubstantially, primarily because of the intro-duction of more effective oral antifungal med-ications.8 Current evidence supports the useof these newer agents as part of individualizedtreatment plans that consider patient profiles,nail characteristics, infecting organism(s),

Onychomycosis


Because fungi are responsible for only about one half of naildystrophies, the diagnosis of onychomycosis may need tobe confirmed by potassium hydroxide preparation, cultureor histology.

potential drug toxicities and interactions, andadjuvant treatments.9

Triazole and allylamine antifungal drugshave largely replaced griseofulvin and keto-conazole as first-line medications in the treat-ment of onychomycosis. These agents offershorter treatment courses, higher cure ratesand fewer relapses.10 Of the newer drugs,terbinafine (Lamisil) and itraconazole (Spora-

nox) are the most widely used, with flucona-zole (Diflucan) rapidly gaining acceptance.These medications share characteristics thatenhance their effectiveness: prompt penetra-tion of the nail and nail bed,3,11 persistence inthe nail for months after discontinuation oftherapy12,13 and generally good safety profiles.Published studies measuring “mycologic cure”(negative KOH preparation or negative cul-


TABLE 1

Common Drug Interactions with Selected Antifungal Agents

Drug or drug class Terbinafine (Lamisil) Itraconazole (Sporanox) Fluconazole (Diflucan)

Benzodiazepines Concomitant use of midazolam Avoid concomitant use (Versed) and triazolam (Halcion) because of increased contraindicated; use of other risk of sedation.benzodiazepines not recommended

Cimetidine (Tagamet) Increased terbinafine Decreased itraconazole absorption Decreased fluconazole levels possible levels possible

Gastric pH neutralizers (histamine H2 Monitor for treatment failure because blockers, proton pump inhibitors, of decreased itraconazolesucralfate [Carafate]) absorption with increased gastric pH.

HMG-CoA reductase inhibitors Concomitant use contraindicatedbecause of reported rhabdomyolysis

Hydrochlorothiazide (Esidrix) and Increased fluconazole hydrochlorothiazide combinations levels possible

Oral hypoglycemics (all classes) Increased hypoglycemia possible Risk of significant hypoglycemia

Quinidines Concomitant use contraindicatedbecause of reported ventriculararrhythmias

Pimozide (Orap) Concomitant use contraindicatedbecause of reported ventriculararrhythmias

Rifampin (Rifadin) Decreased terbinafine Decreased fluconazole levels possible levels possible

Theophylline Increased theophylline levels possible

Warfarin (Coumadin) Bleeding events reported Increased risk of bleeding Increased risk of bleeding

HMG-CoA = 3-hydroxy-3-methylgultaryl coenzyme A.

Information from Katz HI, Gupta AK. Oral antifungal drug interactions. Dermatol Clin 1997;15(3):535-44; Physicians’ desk reference. 54thed. Montvale, N.J.: Medical Economics, 2000; and Sporanox product information update. Titusville, N.J.: Janssen Pharmaceuticals, Decem-ber 10, 1999.

tures) and “clinical cure” (normal nail mor-phology) have demonstrated the effectivenessof all three medications.

TERBINAFINE

Terbinafine is an allylamine antifungalagent that is active against dermatophytes,which are responsible for the majority of ony-chomycosis cases. This agent is notably lesseffective against nondermatophytes, includ-ing Candida species and molds.

Adverse effects, including headache, rashand gastrointestinal upset, are reported moreoften with terbinafine than with placebo. Yetthese side effects are uncommon and resolvewith discontinuation of the drug.14 Because ofits hepatic metabolism, terbinafine has severalimportant drug interactions (Table 1).15-17

Rare but serious complications, such ascholestatic hepatitis, blood dyscrasias andStevens-Johnson syndrome, have beenreported in patients treated with terbinafine.Consequently, liver enzyme levels and a com-plete blood count (including a platelet count)should be obtained before terbinafine is initi-ated and repeated every four to six weeks dur-ing treatment.18 Terbinafine should be dis-continued if the aspartate aminotransferaseor alanine aminotransferase level becomeselevated to two or more times normal.

The FDA-labeled dosage of terbinafine is250 mg per day given continuously for 12 weeks to treat toenail infections and for sixweeks to treat fingernail infections. Studieshave shown that the regimen for toenailsresults in a mycologic cure rate of 71 to 82percent and a clinical cure rate of 60 to 70percent.19,20 Shorter courses and pulse dosingof terbinafine have shown promise in smallstudies, but data are not yet sufficient to sup-port the use of these regimens.21

ITRACONAZOLE

Itraconazole is a newer triazole medicationwith a broad antifungal spectrum thatincludes dermatophytes, many nondermato-phytic molds and Candida species. Headache,

rash and gastrointestinal upset occur in about7 percent of treated patients, but hepatic tox-icity is rare.22

Because itraconazole is metabolized by thehepatic cytochrome P450 system, significantdrug interactions can occur (Table 1).15-17

Notably, concurrent use with quinidines andpimozide (Orap) is contraindicated becauseof the risk of ventricular arrhythmias. Itra-conazole is also contraindicated for concomi-tant use with 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase in-hibitors, such as atorvastatin (Lipitor),because of the increased risk of rhabdomyol-ysis. In addition, itraconazole should not betaken with some benzodiazepines, such asmidazolam (Versed) and triazolam (Hal-cion), because of exaggerated sedation andpotential airway compromise.15

Increased gastric pH decreases the absorp-tion of itraconazole. Therefore, the effective-ness of this antifungal agent can be decreasedby histamine H2 blockers such as ranitidine(Zantac) and famotidine (Pepcid), and byproton pump inhibitors such as omeprazole(Prilosec) and lansoprazole (Prevacid). Forthis reason, itraconazole should be takenwith food.

The FDA-labeled dosage of itraconazole is200 mg once daily taken continuously for 12 weeks to treat toenail infections and for sixweeks to treat fingernail infections. The FDAhas labeled pulse therapy only for the treat-ment of fingernail infections. Pulse treatmentconsists of 200 mg taken twice daily for oneweek per month, with the treatment repeatedfor two to three months (i.e., two to three“pulses”).7,8,22,23 This dosage, given in three tofour pulses, has also been shown to be effec-tive in the treatment of toenail infec-tions.7,8,22,23 Published studies have demon-strated similar success rates for continuousand pulse therapies, with mycologic cure ratesranging from 45 to 70 percent and clinicalcure rates ranging from 35 to 80 percent.22,24,25

Liver enzyme monitoring is recommendedbefore continuous therapy is initiated and

Onychomycosis


every four to six weeks during treatment. Nomonitoring recommendation is given forpulse therapy.26

FLUCONAZOLE

Like itraconazole, fluconazole is activeagainst common dermatophytes, Candidaspecies and some nondermatophytic molds.Adverse effects, including nausea, headache,pruritus and liver enzyme abnormalities, arereported in approximately 5 percent oftreated patients.26 These side effects remitafter the discontinuation of fluconazole. Theabsorption of this drug is not pH sensitiveand is not affected by acid suppression orfood intake. However, fluconazole has impor-tant drug interactions15 (Table 1).15-17

Fluconazole is not currently labeled by theFDA for the treatment of onychomycosis, butearly efficacy data are promising.13,27,28 Atten-tion has focused on once-weekly dosing (450 mg), taking advantage of the drug’spharmacokinetics to reduce treatment costs,decrease rates of adverse effects and poten-tially improve compliance.

In one placebo-controlled study involvingpatients with fingernail onychomycosis,29 flu-conazole in a dosage of 450 mg taken once

weekly for three months was associated with a90 percent clinical cure rate and nearly totalmycologic eradication. Lower dosages wereslightly less effective. No differences in com-plication rates were observed between thetreatment and placebo groups. Published out-comes data27,28 on the use of fluconazole intoenail fungal infections demonstrated “clini-cal improvement” (i.e., less than 25 percent ofthe nail still affected) rates of 72 to 89 percent,compared with 3 percent for placebo.27 Treat-ment duration in these studies varied fromfour to nine months, with a small but measur-able advantage shown for longer courses.27-29

Treatment guidelines for the newer antifun-gal medications are provided in Table 2.

Comparative Clinical TrialsMuch of the published data on the treat-

ment of onychomycosis are of limited clinicaluse. Many studies have been small and obser-vational, and they have lacked randomizationand control subjects. Recently, however, theresults of a handful of larger randomized, con-trolled trials have been published. These stud-ies provide more convincing guidance inchoosing appropriate therapy.

In a 1998 study30 of 378 patients with der-matophytic onychomycosis, continuous ter-binafine therapy was shown to be more effec-tive than continuous itraconazole therapy inpatients with toenail onychomycosis. Inten-tion-to-treat analysis showed nearly 85 per-cent negative cultures in the treatment groupcompared with 55 percent in the placebogroup, and 65 percent clinical improvementin the terbinafine group compared with 37percent in the itraconazole group.

Other studies comparing terbinafine anditraconazole had similar findings.31,32 A recentprospective, double-blind, randomized, con-trolled trial33 compared the use of continuousterbinafine therapy and pulsed itraconazoletherapy in 496 patients with toenail fungalinfection. This well-designed study showed thatterbinafine provided superior clinical andmycologic outcomes up to 15 months after


Comparative trials have shown terbinafine to be superior toitraconazole in the treatment of toenail onychomycosis.

The Authors

PHILLIP RODGERS, M.D., is clinical instructor in the Department of Family Medicine atthe University of Michigan Medical School, Ann Arbor. Dr. Rodgers graduated from theMedical College of Ohio, Toledo, and completed a family practice residency at the Uni-versity of Michigan Medical School.

MARY BASSLER, M.D., is clinical instructor in the Department of Family Medicine atthe University of Michigan Medical School. Dr. Bassler graduated from Saint Louis Uni-versity School of Medicine, St. Louis, and completed a family practice residency atSanta Monica (Calif.) Hospital.

Address correspondence to Phillip Rodgers, M.D., Briarwood Family Practice, Univer-sity of Michigan Health System, 1801 Briarwood Circle, Ann Arbor, MI 48108 (e-mail:[email protected]). Reprints are not available from the authors.

treatment. To date, fluconazole has not beenincluded in published direct-comparison trials.

Most patients in the published studies wereinfected with dermatophytes, against whichterbinafine is most effective. Outcomes datafor the treatment of nondermatophytic andcandidal onychomycosis are limited, butbroader spectrum triazole medications maybe more effective against these pathogens.

CostOnychomycosis is expensive to treat. Costs

include medications, procedures, laboratorytests and health care providers’ time, as well asexpenses associated with the management ofadverse drug effects and treatment failures.

One pharmacoeconomic study34 comparedthe cost-effectiveness of continuously dosedterbinafine and itraconazole in the treatmentof toenail onychomycosis.34 The investigators

concluded that continuous terbinafine ther-apy is less expensive, at a little over one half theprice of continuous itraconazole treatment. Itshould be noted, however, that itraconazolepulse therapy is less expensive than continu-ous treatment (lower overall drug cost and noneed for blood monitoring). Furthermore, thepharmacoeconomic study used national refer-ence pricing and wholesale drug costs. Locallaboratory standards, retail pharmacy costsand increasingly common payor formularyconsiderations may significantly alter individ-ual costs.

Adjuvant TreatmentsIn addition to oral medications, some

patients benefit from other treatments. Surgi-cal or chemical nail avulsion may be useful inpatients with severe onycholysis, extensivenail thickening or longitudinal streaks or

Onychomycosis


TABLE 2

Oral Antifungal Agents for the Treatment of Onychomycosis

Antifungalagent Indication Dosage Monitoring

Terbinafine First-line therapy for dermatophytic 250 mg per day for 6 weeks to treat Complete blood count and(Lamisil) infections (most cases of onychomycosis) fingernails and for 12 weeks to treat ALT and AST levels at

toenails* baseline, then every 4 to6 weeks during therapy

Itraconazole Alternative first-line therapy for Continuous therapy: 200 mg per day for ALT and AST levels at (Sporanox) dermatophytic infections 6 weeks to treat fingernails and for baseline, then every 4 to

Preferred therapy for nondermatophytic 12 weeks to treat toenails* 6 weeks during therapyand candidal infections Pulse therapy: 200 mg twice daily for None recommended

7 days per month, with the treatment repeated for 2 to 3 months (“pulses”) to treat fingernails* and for 3 to 4 months to treat toenails†

Fluconazole First-line therapy for candidal infections 150 mg once weekly until nail is normal None recommended(Diflucan) but also active against dermatophytes or acceptably improved (treatment

Consider for use in patients with often requires 6 to 9 months)†complicated medication regimens

ALT = alanine transaminase; AST = aspartate transaminase; FDA = U.S. Food and Drug Administration.

*—Labeled by FDA.†—Not labeled by FDA.

“spikes” in the nail. These nail changes can becaused by a granulated nidus of infection(dermatophytoma), which responds poorlyto standard courses of medical therapy.35,36

Longer courses of antifungal therapy maybe useful in patients whose nails grow slowly,who have diminished blood supply to the nailbed as a result of conditions such as periph-eral vascular occlusion or diabetes mellitus,or who have total or nearly total nail plateinvolvement.9

Topical antifungal creams or powders mayalso be beneficial, especially in patients withconcomitant tinea pedis.

To improve treatment outcomes and pre-vent recurrence, patients should be counseledabout proper foot hygiene (Table 3). Patientsshould be encouraged to wear breathablefootwear and 100 percent cotton socks whenpossible. They should be advised to keep theirfeet dry throughout the day. Similar infectionpatterns observed in households and patronsof communal bathing facilities suggest a rolefor foot protection in high-risk areas.21

There may be a familial predisposition tosome T. rubrum infections. In such instances,prophylactic treatment of family memberscan be considered.37

Treatment Failure and RelapseRates of treatment failure can be extracted

from published trials, but data on relapse areless readily available. Post-treatment follow-up is long, drop-out rates in many studies aresignificant or unreported, and most studieshave not allowed crossover of treatment regi-mens. Furthermore, especially in outcomes ofclinical improvement (as opposed to cure orfully normal nail appearance), evaluation cri-teria have not been standardized and ofteninclude subjective assessments that are diffi-cult to quantify. Published studies have notspecifically addressed the management oftreatment failures or relapse.

Despite these difficulties, several measuresmay be helpful in managing unsuccessfultreatment or relapse. The first step is to con-

firm mycology. If the initial diagnosis wasbased on a KOH preparation alone, culture ofproperly collected specimens is mandatory.Culture reports often identify multiple organ-isms, including possibly nonpathogenicmolds, and treatment should be directed atthe organism(s) most likely to be causative. Amicrobiology or infectious disease consulta-tion may be valuable in interpreting the cul-ture report.

Of note, there has been some concernabout evolving drug resistance among fungalpathogens, particularly with the widespreaduse of systemic fluconazole therapy to treatoropharyngeal and recurrent vaginal candidi-asis.5 However, the impact of antifungal resis-tance on the treatment of onychomycosis isnot yet clear.

Careful clinical review may identify patientor nail characteristics that are impeding treat-ment. These factors can be addressed withappropriate medication changes or adjuvantmeasures. Because of superior efficacy, con-tinuous antifungal therapy may be consid-ered in patients who fail or relapse after pulsetherapy.

Onychomycosis in ChildrenOnychomycosis in children is rare, with an

estimated prevalence of 0.2 percent.38 Mostoften, onychomycosis develops in children


TABLE 3

Patient Practices That May Aid Treatment and Prevent Recurrence of Onychomycosis

Wearing 100 percent cotton socks and changingthem often

Choosing breathable footwear

Protecting feet in shared bathing areas

Keeping feet dry throughout the day

Recognizing and treating tinea pedis

Maintaining and improving chronic health conditions (e.g., controlling diabetes, quittingsmoking, etc.)

with immunosuppression (e.g., acquiredimmunodeficiency syndrome, chemotherapy,congenital immunodeficiency syndromes), astrong familial history of onychomycosis orextensive cutaneous mycosis (tinea capitis orpedis).

Although griseofulvin remains the main-stay of onychomycosis treatment in children,the efficacy of this drug is variable, and relapseis common. Newly available medications mayimprove the traditionally mediocre treatmentoutcomes in this age group.

The FDA has not yet labeled terbinafine foruse in children. However, some studies haveshown terbinafine to be safe and quite effec-tive in the treatment of tinea capitis, and it islicensed for this purpose in several coun-tries.39 In more limited trials, itraconazole hasalso been shown to be safe and efficacious inthe treatment of tinea capitis.21 If the safetyand effectiveness of terbinafine and itracona-zole are established over the longer coursesneeded to treat nail infections, they maybecome potent first-line therapies for onycho-mycosis in children.

The authors thank Barbara Apgar, M.D., M.S., andStephen A. Swisher, M.D., University of MichiganMedical School, Ann Arbor, for their guidance andsupport.

Figures 1, 2, 4 and 5 were supplied by James E. Ras-mussen, M.D., professor of dermatology and pedi-atrics, University of Michigan Medical School, AnnArbor.

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