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`
`1i.;iN1cAL
`REVIEW
`
`Management of toenail onychomycosis
`
`CATHl;".; NE‘. M. TOM AND MICHAEL P. KANE
`
`Abstract: The treatment of
`toenail mychomycosis is re-
`viewed.
`O11‘;/’€f'~f‘ omycosis contrib-
`utes to 40% of all nail disor-
`ders at: :' appears to be in-
`creasing in frequency. My-
`cotic n.,ii infections are usual-
`ly caused by dermatophytes,
`yeasts, and nondermatophyte
`molds. Most cases of toenail
`onychomycosis are caused by
`derniatnjnhytes. Mycotic nail
`infections do not always re-
`solve sotiritaneously and may
`have a substantial impact on
`the pa'”c.rit's quality of life.
`
`Current treatment modalities
`
`conazole have been oral anti-
`
`for onychomycosis include
`surgery, topical antifungals,
`and oral antifungals. Surgery
`is generally not recommend-
`ed as first-line therapy. Broad-
`spectrum topical and oral an-
`tifungal agents are the most
`frequently used treatments.
`Topical treatment is well tol-
`erated but is usually not ef-
`fective because of poor pa-
`tient compliance and inade-
`quate penetration of the nail.
`Oral antifungals are more
`successful but carry greater
`risks. Griseofulvin and keto-
`
`fungals traditionally used for
`onychomycosis, but these
`agents are associated with rel-
`atively low cure rates. Itra-
`conazole and terbinafine are
`both safe and effective first-
`
`line agents, with reported
`overall cure rates of 50-90%
`
`for dermatophyte-related on-
`ychomycosis. Intermittent
`oral antifungal therapy may
`reduce the risk of systemic
`adverse effects and the cost of
`therapy; more study of this
`approach is needed.
`Oral antifungal agents offer
`
`patients with toenail onycho-
`mycosis greater likelihood of
`a cure than topical antifun-
`gals, but oral therapy carries
`greater risks and requires clos-
`er monitoring.
`
`Index terms: Antifungals;
`Clinical studies; Diagnosis;
`Drug administration routes;
`Drugs; Economics; Itracona-
`zole; Onychomycosis; Sur-
`gery; Terbinafine hydrochlo-
`ride; Topical preparations
`Am J Health-Syst Pharm.
`1999; 56:865-71
`
`;. nychomycosis, or fungal infection of the nail
`bed or nail plate, contributes to 40% of all nail
`disorders} Although the prevalence of onycho-
`mycosis is relatively low, its frequency appears to be
`increasing.“ Contributing to this increase are a grow-
`ing cglerly population, the spread of HIV infection and
`AIDS, the greater frequency of iatrogenic immunosup—
`pression with the use of immunosuppressants, superin-
`fectirrns due to systemic antimicrobials, and lifestyle
`factors, such as wearing tight clothing and shoes and
`using communal bathing facilities, recreational facilities,
`and health clubs.1'3'4 Improved detection and height-
`ened public awareness are also contributing to the report-
`ed i:;‘s;:rease in the frequency of onychomycosis.“
`This article reviews the diagnosis and treatment of
`toenail onychomycosis.
`
`Diagnosis and patient impact
`
`ycotic nail infections are caused most commonly
`
`by dermatophytes (90% Trichophyton, Microsporum, and
`Epidermophyton species), yeasts (7% Candida species),
`and nondermatophyte molds (3% Scytalidium, Fusari-
`um, Acremonium, Aspergillus, and Scopulariopsis spe-
`cies).3«5i5 Four major types of mycotic nail infections
`have been identified: distal subungual onychomycosis
`(the most common type, initially affecting the plantar
`surfaces of the hands and feet), white superficial ony-
`chomycosis (which affects only the toenails), proximal
`subungual onychomycosis (which is often associated
`with immunosuppression), and candidal onychomyco-
`sis.7 These infections vary with respect to the pattern of
`fungal invasion of the nail plate and the causative
`pathogen.“ Clinical symptoms of onychomycosis in-
`clude onycholysis (separation of the nail from its bed),
`hyperkeratosis (calluses, corns), brittleness, paronychial
`inflammation (inflammation due to infection of the skin
`fold at the nail margin), and color change (Figure 1).
`Formal diagnosis of onychomycosis typically in-
`
`is Pharmacy Practice Resident,
`C/\’ii._ ;I~.1NE M. TOM, PHARM.D.,
`Thomas Jefferson University Hospital, Philadelphia, PA. MICHAEL
`P. Kxt.-:13, Pl-[ARM.D., BCPS, is Associate Professor, Division of Phar-
`macy Practice, Albany College of Pharmacy, Albany, NY.
`:‘.Z.'d1‘eSS reprint requests to Dr. Kane at the Division of Phar1na—
`
`cy Practice, Albany College of Pharmacy, 106 New Scotland Ave-
`nue, Albany, NY 12208, or to kanem@panther.acp.edu.
`
`Copyright © 1999 American Society of Health-System Pharma-
`cists, Inc. All rights reserved. 1079-2082/99/0501-086530600.
`
`Vol 56 May 1 1999 Am] Health-Syst Pharm 865
`
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`
`Clinical Review Toenail onychomycosis
`
`volves preparation of nail scrapings in a potassium
`hydroxide solution and examination for hyphal frag-
`ments by direct microscopy; a fungal culture grown in
`a suitable medium for 7-14 days is necessary for specific
`identification of the pathogen.1I6"‘ Depending on the
`pathogen suspected, a cycloheximide-containing me-
`dium can be chosen to inhibit the growth of many
`nondermatophytes, while a cycloheximide—free medi-
`um can be used to isolate yeasts and nondermato—
`phytes.1 Nail biopsies from the nail bed and nail plate
`are warranted when onychomycosis is clinically sus-
`pected but findings from repeated microscopy and
`cultures are negative. In practice, the diagnosis of ony-
`chomycosis is usually based on clinical examination,
`and therapy is often empirical.
`Mycotic nail infections do not always resolve spon-
`taneously and may have serious consequences, includ-
`ing limitation of mobility and dexterity (potentially
`affecting physical work ability), decrease in peripheral
`circulation in the area affected, self-consciousness, and
`avoidance of physical intimacy. Onychomycosis can
`worsen preexisting foot problems, such as diabetic
`foot.-3 Although the frequency of dermatophyte nail
`infections is probably not increased in diabetics, the
`potential for serious complications from such infec-
`tions may be greater in that population.9'1°
`Lubeck et al.“ evaluated the impact of onychomyco-
`sis on quality of life, assessed as general health, bodily
`pain, disease symptoms, social functioning, mental
`health, health concerns, social confidence, and per-
`ceived problems with physical appearance and physical
`activities. Compared with healthy controls, onycho-
`mycosis patients had significantly lower quality-of-life
`scores for all measures except social confidence. The
`disease’s greatest impact was on onychomycosis—specif-
`ic measures like problems with physical activities (e.g.,
`problems with work activities that require being on
`one’s feet or working with one’s fingers).
`
`Treatment
`
`Current treatment modalities for onychomycosis
`include surgical measures, topical antifungals, and oral
`(systemic) antifungals.4v‘°:i2 Surgical treatment consists
`of nail avulsion, in which the nail plate is macerated,
`and nail obliteration with the carbon dioxide laser
`
`(efficacy data on the latter are limited).4 Because of
`patient discomfort and the risk of complications, sur-
`gery is generally not recommended as first-line therapy,
`except for severe or refractory infections.
`Broad—spectrum topical and oral antifungal agents
`are most often used in managing severe toenail onycho-
`mycosis.13v14 Table 1 lists the desirable properties of
`such agents. Three main classes of topical antifungals
`are available: (1) polyenes (e.g., nystatin), (2) imida-
`zoles (clotrimazole, econazole, ketoconazole, micona-
`zole, sulconazole, and oxiconazole), and (3) allyl-
`amines—benzylamines (naftifine,
`terbinafine, and
`
`Figure 1. Typical appearance of severe toenail onychomycosis
`
`Table 1 _
`
`Properties of Ideal Antifungal Agents‘3=“‘
`
`Ideal Oral Agent
`
`Ideal Topical Agent
`
`Incorporated into nail
`matrix
`Diffuses through nail bed
`High clinical cure rate
`High mycologic cure rate
`Low risk of relapse
`Effective when used for
`short—term therapy
`Low risk of adverse
`effects
`Few drug interactions
`Cost-effective
`
`Efficacious at low concen‘*a_-
`tions
`Fungicidal
`Effective with topical
`application
`High affinity for stratum
`corneum
`Well tolerated
`Nonsensitizing
`Low risk of fungal resistar lce
`User—friend|y dosage
`regimen
`
`butenafine). Only imidazoles and ally1amines—benzy—
`lamines are active against dermatophytes; all
`three
`classes are active against Candida species.” Since a
`majority of toenail onychomycosis cases are caused by
`dermatophytes, only imidazoles and allylaminea»-ben-
`zylamines will be discussed here.
`Imidazoles are relatively broad—spectrum, fungistatic
`antifungal agents. They cause fungal cell men lsrane
`defects by inhibiting the synthesis of ergosterol, an essen-
`tial component of the cell wall. This inhibition is accom-
`plished by interference with the conversion of lan:’“:3t€I01
`to ergosterol at the level of the cytochrome P—450 enzyme
`lanosterol 14-demethylase.” Topically applied ..r1ida-
`zoles are generally well tolerated because mammalian
`cytochrome P-450 enzyme systems are not affected.15'16
`Topical administration is also advantageous in ti‘-at the
`drug interactions and endocrine—related adverse effects
`(menstrual irregularities, gynecomastia, sexual dy:~;fuI1C'
`tion, and plasma cortisol suppression) sometimes associ-
`ated with the systemic administration of imidazoles are
`avoided.” ‘ 7
`
`Allylamines—benzy1amines appear to have bOth
`fungistatic and fungicidal effects. They too interfere
`with the production of ergosterol, but through 4-; "iffer-
`ent mechanism. Terbinafine, for example, inhibits the
`activity of squalene epoxidase, which is involved earlier
`
`866 Am] Health-Syst Pharm Vol 56 May 1 1999
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`.. ._...___.
`
`2""-"flu
`
`in the m,l=,osterol metabolic pathway. Consequently,
`Cell death occurs because of a decrease in ergosterol
`Concentration and an accumulation of squalene in the
`fungal
`;:;2!l.13I13 Since terbinafine appears to have a
`lower affinity for mammalian enzymes in vitro,“‘
`Squalenr. epoxidases in mammals are spared.
`Topical antifungal treatment of onychomycosis is
`ineffective in curing most infections. This is probably
`because ::=t‘ inadequate drug penetration of the nail—a
`hardened mass of tightly packed, keratinized cells.”
`Another concern with topical antifungal use is that
`patient compliance is likely to be suboptimal. Medica-
`tion has to be applied two or three times daily for 6-12
`montltu, if not lifelong!‘ Topical treatment may be an
`effective adjunct to systemic therapy, however, and
`adverse effects (itching, burning, and redness at the
`applicgfion site) are generally minor.
`Overall, oral antifungal therapy is more efficacious
`than topical treatment in the management of toenail
`onychomycosis. Traditionally, griseofulvin or ketocon-
`azole has been used. These agents are less than ideal,
`however. Griseofulvin is associated with low clinical
`and mycologic cure rates and a high relapse rate, and
`the duration of therapy is long (at least six months for
`toenai‘; infections). Ketoconazole is only slightly more
`efficacious, and, as with griseofulvin, the potential for
`adverse effects and drug interactions is high. Flucona-
`zole may have a role in toenail onychomycosis manage-
`ment, but there are limited data supporting its use for
`dermaiaiphyte onychomycosis.Z°r21 Although flucona—
`zole has a favorable adverse-effect profile, up to nine
`months of therapy may be needed. Fluconazole cannot
`be recommended as first—line therapy.
`
`Itraerzrlazole and terbinafine
`
`ltraconazole (Sporanox, Janssen), a triazole, and ter-
`binafine (Lamisil, Sandoz) are two newer oral antifun-
`gal agmts that offer improved safety and greater effica-
`cy in managing toenail onychomycosis (Table 2). Both
`drugs are incorporated into the nail via both the nail
`matrix and the nail bed, thereby enhancing mycologic
`and clinical efficacy. They exhibit a broad spectrum of
`activ;;.y against dermatophytes, molds, and yeasts, al-
`though. terbinafine may be less active against Candida
`species. 14 Finally, compared with other agents, the du-
`ratioié. of treatment is much shorter.
`
`ltraconazole accumulates slowly in the nails, and it
`may remain detectable for six months after it is discon-
`tinuetl because of its high affinity for keratinized tis-
`sues.” This affinity results in high nail concentrations
`of the drug. In a nonrandomized, nonblinded study of
`39 patients with onychomycosis, nail clippings were
`Collected during and for three months after a three-
`monfh course of itraconazole 100 or 200 mg orally
`daily.” Toenail itraconazole concentrations were 84-
`149 mg/g for the 100-mg group and 490-990 ng/g for
`the 2.00-mg group. Maximum mean drug concentra-
`
`Toenail onychomycosis Clinical Review
`
`tions (149 and 990 ng/g) were achieved after two
`months of therapy, and drug was detectable in the nails
`for six months after drug discontinuation. ltraconazole
`was actively incorporated into the nail matrix, as well as
`incorporated by passive diffusion from the nail bed into
`the nail plate.
`In a study by Dykes et al.,23 clippings were collected
`from the infected and healthy nails of 12 patients
`receiving a 12-week course of terbinafine hydrochloride
`250 mg orally daily. Drug was detected in nail samples
`at week 4 «(the first sampling time), but concentrations
`were not significantly higher at week 12. Drug concen-
`trations in infected and uninfected nails did not differ
`
`significantly. The authors concluded that diffusion
`through the nail plate is the primary route by which
`terbinafine penetrates nails.
`ltraconazole and terbinafine have both been found
`
`to be more effective than placebo in the treatment of
`toenail onychomycosis. Most studies defined efficacy
`as (1) clinical cure or response (based on a global
`evaluation of nails as cured or markedly improved), (2)
`mycologic cure or response (negative microscopy or
`culture results), or (3) overall cure (a combination of
`clinical cure and mycologic cure). The mycologic cure
`rate is usually used for comparing agents because of its
`greater objectivity.
`Jones and Zaias“ randomly assigned patients with
`toenail onychomycosis to 12 weeks of itraconazole 200
`mg daily (11 = 36) or placebo (11 = 37) taken with a meal.
`Clinical and mycologic evaluations were made at weeks
`4, 8, and 12. At week 12, clinical success was observed in
`77% of patients treated with itraconazole and in 0%
`given placebo, while mycologic success was achieved in
`69% and 6% of patients, respectively. Overall success
`occurred in 51% of the itraconazole-treated group and
`0% of the placebo group. One year after the start of
`therapy, clinical relapse, mycologic relapse, and overall
`relapse rates of 30%, 46%, and 28% were recorded for
`the itraconazole group. An explanation for the high
`relapse rates was not provided by the study’s authors,
`nor is one readily apparent. Adverse events (gastritis,
`headache, sinusitis, rhinitis, and diarrhea) did not dif-
`fer significantly in frequency between the drug and
`placebo groups (53% versus 57%).
`In a randomized, double-blind, multicenter study of
`148 patients with toenail onychomycosis, Svejgaard et
`a1.25 compared terbinafine hydrochloride 250 mg orally
`daily for three months (n = 75) with placebo (11 = 73).
`One hundred twenty-seven patients completed the ini-
`tial three months of the study (12 terbinafine recipients
`and 9 placebo recipients withdrew because of lack of
`efficacy, adverse effects, and various other reasons).
`Twenty-six nonresponders in the terbinafine group and
`57 members of the placebo group then completed an
`additional three-month course of terbinafine therapy. At
`12 months, clinical cure was seen in 44% of the patients
`who received placebo alone, 67% of those given placebo
`
`Vol 56 May 1 1999 Am] Health-Syst Pharm 867
`
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`

`
`Clinical Review Toenail onychomycosis
`
`Table 2.
`
`Comparison of ltraconazole and Terbinafine‘5v‘°’a
`Item
`ltraconazole
`Terbinafine
` ‘_‘
`Synthetic triazole
`Class of drug
`Mechanism of action
`Inhibits cytochrome P-450—dependent synthesis
`of ergosterol
`Cryptococcus neoformans and species of
`Microsporum, Trichophyton, Ep/dermophyton,
`Candida, Pityrosporum, Histop/asma,
`B/astomyces, and Aspergillus
`
`Synthetic allylamine derivative
`Inhibits squalene epoxidase
`
`Trichophyton rubrum, Trichophyfon
`mentagrophytes
`
`Spectrum of activity
`
`250 mg daily for 12 wk
`
`70% absorption, 40% bioavailability
`after first-pass effect
`1000
`
`23
`
`6
`>99
`Hepatic metabolism, with 70% of dc.-.~e
`eliminated in the urine
`
`CLC,, S50 mL/min: clearance decreased
`by 50% (use not recommended)
`Hepatic cirrhosis: clearance decreased
`by 50% (use not recommended)
`Changes in ocular lens and retina E‘a',—‘=v‘e
`occurred (clinical significance
`unknown). Monitor liver function if
`treatment duration is >6 wk. Transient
`decreases in absolute lymphocytz-‘
`count reported (frequency, 1.7%).
`Isolated cases of neutropenia
`History of hypersensitivity
`
`Diarrhea, dyspepsia, abdominal pain,
`nausea, flatulence, elevated liver
`enzymes, taste disturbance. Rareiy:
`visual disturbance, serious rash
`neutropenia
`Cyclosporine, rifampin, cimetidine.
`terfenadine
`
`B 2
`
`50—mg tablets
`598
`502.32
`
`May take with or without food
`
`Regimen for toenail
`onychomycosis
`
`Bioavailability
`
`Mean i S.D. Cmax (ng/mL)
`Mean : S.D. tmax (hr)
`Mean t S.D. t.,, (hr)
`Plasma protein binding (°/o)
`Elimination
`
`Renal impairment
`
`Hepatic impairment
`
`Precautions
`
`Contraindications
`
`Adverse reactions (in treatment
`of onychomycosis)
`
`interacting drugs
`
`Pregnancy category
`
`How supplied
`Cost per unit ($)b
`Cost per 12 wk of continuous
`therapy (8%)
`Cost per regimen of intermittent
`therapy (35)
`Patient information
`
`200 mg daily with full meal for 12 wk or three 1-
`wk courses of 200 mg b.i.d. (with meal), with
`each course separated by 3 wk without
`treatment (intermittent regimen not FDA
`approved)
`55% (with meal)
`
`239 i 85
`4.5 i 1.1
`21 i 5
`99.8
`Hepatic metabolism, with 40% of close renally
`eliminated as inactive metabolites
`No adjustment necessary
`
`Monitor plasma drug concentrations
`
`Monitor liver function if history of hepatic
`disease present, if duration of continuous
`treatment is >1 mo, or if signs or symptoms of
`liver dysfunction arise
`
`Coadministration of terfenadine, astemizole, or
`cisapride; concomitant oral midazolam or
`triazolam therapy; pregnancy (for treatment of
`onychomycosis); history of hypersensitivity
`Reversible hepatitis, elevated liver enzymes,
`nausea, vomiting, diarrhea, rash, hyperten-
`sion. Rarely: orthostatic hypotension,
`headache, malaise, myalgia, vasculitis,
`vertigo
`Warfarin, terfenadine, astemizole, cisapride,
`ritonavir, indinavir, midazolam, triazolam,
`diazepam, lovastatin, simvastatin, cyc|ospo-
`rine, tacrolimus, methylprednisolone, digoxin,
`quinidlne, phenytoin, phenobarbital, carba~
`mazepine, histamine H2-receptor antagonists.
`isoniazid, rifampin, rifabutin
`C (contraindicated for treatment of
`onychomycosis)
`100-mg capsules
`5.82
`977.76
`
`488.88 (three weeks’ doses)
`
`Take with full meal. Report unusual signs of
`fatigue, anorexia, nausea, vomiting, jaundice,
`dark urine, or pale stool
`
`f'l'lE|X
`= maximum plasma drug concentration, I
`50
`IV = elimination half—life, CL” = creatinine clearance.
`= time to reach Cmax,
`“Costs are average wholesale prices (Garrett Hmxed. Red book. Montvale, NJ: Medical Economlcs;A1997).
`
`and then terbinafine, 63% of those given terbinafine for
`3 months, and 81% of those given terbinafine for 6
`months; mycologic cure rates (negative microscopy and
`
`culture results) were 33%, 49%, 40%, and 47%, resp€C'
`cl
`tively, and overall cure rates were 25%, 40%, 33" an
`42%. The high cure rates for placebo reflect the fact that
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`5p0Ht8.",~‘,ll:1 cure may occur in onychomycosis. The
`small number of patients in each group precluded statis-
`tical evtuaarion of drug efficacy. Adverse effects, such as
`gamom»-_ostinal symptoms,‘urt1car1a, erythema multi-
`forme, and taste and smell disturbances, were not signif-
`icantly .Ti."’i'erent between the terbinafine and placebo
`groups (13.5% versus 5.4%).
`Watson et al/2" compared terbinafine with placebo
`in 118 /patients with toenail onychomycosis in a ran-
`domized, double-blind, 48-week, multicenter trial.
`Phase i of the study involved a 12-week regimen of
`terbinafine hydrochloride 250 mg once daily versus
`placebo, with the groups being compared at week 24
`(12 wr::i;s after treatment was discontinued). In phase
`2, nonresponders were offered a 12-week course of
`terbinafine hydrochloride 250 mg once daily, begin-
`ning at week 28 (when the mycology results at week 24
`were available). Treatment responders were observed
`for an additional 24 weeks.
`One hundred eleven patients (56 in the terbinafine
`group and 55 in the placebo group) completed phase 1.
`At we-=~l-; 24, 88% of the terbinafine recipients had
`negative culture results, versus 29% of the placebo
`group (p < 0.001). Eighteen of the 24 nonresponders in
`the terbinafine group and 48 of the 52 nonresponders
`in the placebo group were placed on the second 12-
`week terbinafine regimen. At the study’s end (week 48),
`84% of the responders in phase 1 and 67% of the
`responders in phase 2 had been effectively treated.
`Cultrkes were negative in 97% of the phase 1 terbin-
`afine recipients, 89% of the phase 1 plus phase 2
`terbinafine recipients, 33% of the phase 1 placebo
`recipients, and 77% of the phase 1 placebo plus phase 2
`terbinafine recipients. Eighty-two percent of terbin-
`afirieureated patients and 73% of placebo recipients
`reported adverse effects (central nervous system, gas-
`trointestinal, respiratory, skin, and taste effects), but
`the srffference was not significant.
`
`Intesriuittent therapy
`
`A recent approach to the management of toenail
`onychomycosis is intermittent ("pulse”) administra-
`tion -gel antifungal agents, as opposed to ongoing daily
`administration. A fixed dose of antifun gal is given daily
`for the first week of the month for several consecutive
`
`I110?” hs. Advantages of this regimen include a reduced
`risk of systemic adverse effects,” a lower cost of thera-
`py, aricl enhanced patient compliance.
`P.-avu et al.37 sought to determine whether intermit-
`tent therapy with itraconazole is as effective as contin-
`HOLE: therapy for toenail onychomycosis. In a multi-
`center, double-blind, placebo—controlled, parallel-
`group study, 64 patients were randomly assigned to
`recefire itraconazole 400 mg daily for the first week of
`the month for three consecutive months, while 65
`otlicr patients received 200 mg daily for 12 consecutive
`Weeks. Mycologic cure rates for the intermittent-thera-
`
`Toenail onychomycosis Clinical Review
`
`py and continuous-therapy groups were 56% and 69%,
`respectively, at month 6 and 52% and 66% at month 12
`(not a significant difference). Overall response rates at
`one year were 56% in the intermittent group and 52%
`in the continuous group (also not significant). The
`frequency of adverse events (which were mainly gas-
`trointestinal—nausea, flatulence) was 16.9% in the
`continuous group and 14.1% in the intermittent group.
`The authors concluded that both regimens were effec-
`tive and well tolerated.
`
`DeDoncker and colleagues” randomly assigned 50
`patients in an unblinded manner to an intermittent
`regimen of itraconazole 200 mg twice daily with meals
`for the first week of the month for three months or four
`
`months. At 12 months, 84% of the patients in the three-
`month group had a clinical cure, versus 76% of the
`patients in the four—month group (difference not signif-
`icant) ; 64% and 72%, respectively, had negative micros-
`copy results (difference not significant). Culture results
`were negative in 80% of both groups. The drug was well
`tolerated in each group, with no important adverse
`effects reported.
`Intermittent therapy with terbinafine has also been
`explored. In an unblinded attempt to investigate the
`efficacy of terbinafine for treating dermatophyte-asso-
`ciated toenail onychomycosis, 60 patients were ran-
`domly assigned to receive 250 mg daily for three
`months or 250 mg twice daily for the first week of each
`month for three months.” Toenails were examined
`
`clinically and mycologically at monthly intervals. At 48
`weeks, there was no significant difference in the rate of
`cure (defined as negative microscopy and culture re-
`sults) between the continuous and intermittent groups
`(79.2% versus 73.9%, respectively). In addition, no
`significant difference was found in the time to myco-
`logic cure (22.4 versus 19.8 weeks).
`Comparative studies of terbinafine and itraconazole
`have also been conducted. In a double-blind, random-
`
`ized trial, 372 patients with clinically diagnosed toenail
`onychomycosis were given 12 weeks of terbinafine
`hydrochloride 250 mg daily or itraconazole 200 mg
`daily?“ Intention-to-treat analysis revealed that, at 48
`weeks, mycologic results (microscopy and culture) were
`negative in 73% of the terbinafine group and 45.8% of
`the itraconazole group (p < 0.0001). The report lacks
`important details, however, such as study inclusion
`criteria, a comparison of patient characteristics at base-
`line, the mean duration of onychomycosis before ther-
`apy, and the rate of patient withdrawals.
`In a comparative, open-label trial, Arenas et al.“
`randomized 53 otherwise healthy adults with a clinical
`diagnosis of toenail onychomycosis to receive terbin-
`afine hydrochloride 250 mg (n = 26) or itraconazole 200
`mg (n = 27) daily for three months. Patient age, sex, and
`onychomycosis history were similar in both groups,
`although the duration of the disease before treatment
`was significantly longer in the terbinafine group. Pa-
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`Clinical Review Toenail onychomycosis __
`
`tients were examined clinically and mycologically ev-
`ery four weeks; photographs of each patient’s baseline
`lesion were used as a control. Six months after drug
`therapy ended, the overall rate of cure (clinical plus
`mycologic) in the 43 evaluable patients was 60.9% in
`the itraconazole group and 64.7% in the terbinafine
`group. The difference was not significant. Terbinafine—
`treated patients reported more frequent adverse effects
`(47% versus 21%, no statistical analysis reported),
`which consisted primarily of dysgeusia, facial rash, and
`abdominal pain. The authors concluded that both anti-
`fungal agents are drugs of choice in the treatment of
`onychomycosis.
`In an open—label, randomized study, Tosti et al.”
`compared continuous terbinafine, intermittent terbin-
`afine, and intermittent itraconazole in 60 patients with
`toenail onychomycosis. Patients received terbinafine
`hydrochloride 250 mg daily for four months, terbin-
`afine hydrochloride 500 mg daily for the first week of
`each month for four months, or itraconazole 400 mg
`daily for the first week of each month for four months.
`Six months after treatment ended, the mycologic cure
`rate was 94.1% in the continuous terbinafine group,
`80% in the intermittent terbinafine group, and 75% in
`the intermittent itraconazole group. There were no
`significant differences in efficacy or adverse effects
`among the three regimens.
`
`Cost-effectiveness of oral therapy
`
`Marchetti and colleagues” performed a pharrnaco—
`economic analysis of oral therapy for onychomycosis by
`comparing drug acquisition costs; mycologic cure, fail-
`ure, and relapse rates; physician visit and laboratory test
`costs; and costs of adverse drug reactions. Specific data
`derived from a literature meta-analysis were applied in a
`decision—tree analysis. Daily terbinafine was found to
`have the lowest cost per mycologic cure after one treat-
`ment regimen for both toenail and fingernail onychomy-
`cosis ($791 and $454, respectively). Daily itraconazole
`was the second most cost—effective therapy ($1,535 and
`$767), while griseofulvin ($2,385 and $837) and ketocon-
`azole ($10,025 and $1,512) were less cost-effective. In a
`sensitivity analysis, intermittent itraconazole therapy for
`toenail onychomycosis reduced drug acquisition costs by
`nearly half but was still less cost—effective than daily
`terbinafine therapy. The major limitation of this analysis
`was the lack of a quality-of—life assessment. The results are
`in agreement with two other phannacoeconomic analy-
`ses, however.3‘*'35
`
`Discussion
`
`Terbinafine and itraconazole are both effective first-
`
`line agents for onychomycosis, with mycologic and
`overall cure rates ranging from 50% to 90%. Intermit-
`tent itraconazole therapy and continuous terbinafine
`therapy appear to be cost—effective regimens. The re-
`sults of a 72-week multicenter study of nearly 500
`
`patients comparing continuous terbinafine with inter.
`
`mittent itraconazole in the treatment of toenail my.
`chomycosis (Sigurgeirsson B, Reykjavik City Hosnital,
`Reykjavik, Iceland, 1998 Mar 16) should better eluci.
`date the treatment of choice.
`
`Selection of the appropriate drug and regimen should
`be individualized on the basis of underlying illnesses and
`the potential for drug-drug interactions. For instance,
`terbinafine is not recommended in patients with de-
`creased renal function (creatinine clearance, <50 mL/
`min) or in patients with hepatic cirrhosis. ltraconazole is
`contraindicated in pregnant women and in patients
`receiving medications that may interact with it. Immun-
`osuppressed patients and those with documented can-
`didal infections may benefit from itraconazole. Intermit-
`tent itraconazole therapy may be an option for patients
`expected to have poorer compliance with a standard
`regimen, although drug interactions may limit its u