`
`Onychomycosis
`
`by Boni E. Elewski, MD, University Hospitals of Cleveland
`
`I t has been estiinated dmt only
`
`50% of all dystmphk: nails are
`caused by fimgi~; of these, over
`90% are caused by dermatophytes.2
`Because of these filets, no patient
`with dystrophic nails and suspected
`onychomycosis should be treated
`without first establishing a diagno-
`sis-and, ideally, identifying the
`particular pathogen.
`
`DEFINITION
`O~9,chomyca£~; or ~hngal nail ini{~c-
`tion, refers to fimgal organisms
`invading the nail uuk via the nail
`bed or nail plate. It at~:ects about
`20% of the U.S. population
`between 40 and 60 yea~ of age3--
`an amazing incidence, in that ony-
`chomycosis is a relatively new dis-
`ease, rarely seen in the United
`States prior to the Second World
`~u; Dermatophytes are the most
`common pathogens (q~ble l)...--
`accounting fi)r more dmn 90% of
`the infectious in one large study
`
`Dermatophyte Fungi
`[] Epidermophyton floccosum
`
`[] Trichophyton mentagro-
`phytes
`
`[] Trichophyton rubrum
`
`Nondermatophyte Fungi
`
`[] Aspergilfus spp.
`I~ Acremonium spp.
`
`¯ Fusarium spp,
`~ Scopulariopsis brevicaulis
`[] Scytalidium dimidiatum
`[] Scytalidium hvalinum
`
`Yeast
`
`[] Candida albicans
`
`(involving 2,662 cases).2 The other
`infbctions in that study were
`caused by (.)~mtida albicans
`(5.5%), Scopulariopsa breva’autis
`(1.6%), and miscellaneous organ-
`isms (1.7%).2 As some anrimy-
`cofics used fbr onychomycosis,
`such as griseofhlvin, act only
`against dermamphytes, it is itnpor-
`taut to rule out a nondcrmatophyt-
`ic yeast or mould that may be resis~
`rant to the selected antifimgal.
`Onychomycosis occurs in dis-
`tal subungual, proximal white sub-
`ungual, white superficial, and
`¯
`4
`CTtndida [orms. These tbur vari-
`eties differ by the pattern of fungat
`invasion into the nail unit, which
`directly afl£:cts the clinical appear-
`ance of the diseased nail. ~so,
`each variety is caused by a different
`group of fimgal organisms.
`Distal subungual owchomyco-
`sis, the most commoll form,
`gener;dly caused by dermatophytes.
`The organism is usually established
`in the stratum corneum of the
`adjacent skin bdbre it invades the
`nail unit. The fimgus first invades
`d~e distal nail bed, causing hyper-
`keratosis of the nail bed, onycholy-
`sis, and thickening of the nail
`plate. Both fingernails alld toenails
`can be infected, but toenail
`r]on oCCtll’S [Otlr times inore fie-
`quentl>5 probably because of the
`greater incklence of tinea pedis
`than of tinea manus.
`In proximal ,¢him subungual
`onychomycosis, the organism
`invades under the cuticle and
`infect~s thd proximal rather than
`distal nail bed. The nail plate
`rein ains intact and devdops a
`white color proximally near rl~e
`cuticle. Again, dermamphytes are
`
`the predominant pathogen. The
`clinician shoukl be aware that
`proximal white subungual ony-
`chomycosis is common
`i~nmunocompromised patients,
`particularly in those in~ccted with
`HIV~6 ’I’he condition is rare
`heahhy, immunocompetent indi-
`viduals and is seen in both finger-
`nails and toenails.
`In ~z,hite suF~fi}ial owchomy-
`costs, fhngal organisms invade the
`nail plate directlB prodncing a
`crumbled white suH~tce. The der-
`matophyte 7~’ichwhym~*
`p~yles and a variety of moulds are
`causative pathogens, including
`species of Ac,w,~onium, Fusarium,
`and A.[pe~gillus.4 "Ibenail infection
`is siguificantly more common than
`fingerna!l infectio,~.
`C}~ndida onychomycosis refers
`to a rare syndrome limited
`patients af~icted with chronic
`mucocutaneous caudidiasis; as the
`name stiggests, it is caused only by
`C},ndi&. However, Candida can
`cause chronic paronychia in~ction,
`and can also cause primary ony-
`cholysis, especially in those with
`peripheral vascular disease/’
`
`DIAGNOSIS OF ONYCHOMYCOSIS
`The diagnosis ofor}ychomycosis is
`best established by a fimgal cul-
`ture. In addition, a potassium
`hydroxide preparation (KOH) may
`be helpful in ruling out nonfimgal
`etiologies. Direct microscopy usi~g
`15% t{} 2(}% potassinm hydroxide
`will reveal only the presence or
`absence of fungaI elemcuts, hut
`not the limgal pathogem A fimgal
`cuhure will ascertain du: causative
`organism, and therdbre allow ttae
`clinician to determine an appropri-
`
`48
`
`Fi~zpatrick’s Journal o{:Cliuk:al l)crmamlogy
`
`atth~NLM and mayb~
`
`N(}vvmb~r/I)cccmbvr 199,i
`
`Page 1 of 7
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1501
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`
`
`TI!ERAPEUTICS
`
`Onychomycosis
`
`by Boni E. Elewski, MD, University Hospitals of Cleveland
`
`I t has been estiinated dmt only
`
`50% of all dystmphk: nails are
`caused by fimgi~; of these, over
`90% are caused by dermatophytes.2
`Because of these filets, no patient
`with dystrophic nails and suspected
`onychomycosis should be treated
`without first establishing a diagno-
`sis-and, ideally, identifying the
`particular pathogen.
`
`DEFINITION
`O~9,chomyca£~; or ~hngal nail ini{~c-
`tion, refers to fimgal organisms
`invading the nail uuk via the nail
`bed or nail plate. It at~:ects about
`20% of the U.S. population
`between 40 and 60 yea~ of age3--
`an amazing incidence, in that ony-
`chomycosis is a relatively new dis-
`ease, rarely seen in the United
`States prior to the Second World
`~u; Dermatophytes are the most
`common pathogens (q~ble l)...--
`accounting fi)r more dmn 90% of
`the infectious in one large study
`
`Dermatophyte Fungi
`[] Epidermophyton floccosum
`
`[] Trichophyton mentagro-
`phytes
`
`[] Trichophyton rubrum
`
`Nondermatophyte Fungi
`
`[] Aspergilfus spp.
`I~ Acremonium spp.
`
`¯ Fusarium spp,
`~ Scopulariopsis brevicaulis
`[] Scytalidium dimidiatum
`[] Scytalidium hvalinum
`
`Yeast
`
`[] Candida albicans
`
`(involving 2,662 cases).2 The other
`infbctions in that study were
`caused by (.)~mtida albicans
`(5.5%), Scopulariopsa breva’autis
`(1.6%), and miscellaneous organ-
`isms (1.7%).2 As some anrimy-
`cofics used fbr onychomycosis,
`such as griseofhlvin, act only
`against dermamphytes, it is itnpor-
`taut to rule out a nondcrmatophyt-
`ic yeast or mould that may be resis~
`rant to the selected antifimgal.
`Onychomycosis occurs in dis-
`tal subungual, proximal white sub-
`ungual, white superficial, and
`¯
`4
`CTtndida [orms. These tbur vari-
`eties differ by the pattern of fungat
`invasion into the nail unit, which
`directly afl£:cts the clinical appear-
`ance of the diseased nail. ~so,
`each variety is caused by a different
`group of fimgal organisms.
`Distal subungual owchomyco-
`sis, the most commoll form,
`gener;dly caused by dermatophytes.
`The organism is usually established
`in the stratum corneum of the
`adjacent skin bdbre it invades the
`nail unit. The fimgus first invades
`d~e distal nail bed, causing hyper-
`keratosis of the nail bed, onycholy-
`sis, and thickening of the nail
`plate. Both fingernails alld toenails
`can be infected, but toenail
`r]on oCCtll’S [Otlr times inore fie-
`quentl>5 probably because of the
`greater incklence of tinea pedis
`than of tinea manus.
`In proximal ,¢him subungual
`onychomycosis, the organism
`invades under the cuticle and
`infect~s thd proximal rather than
`distal nail bed. The nail plate
`rein ains intact and devdops a
`white color proximally near rl~e
`cuticle. Again, dermamphytes are
`
`the predominant pathogen. The
`clinician shoukl be aware that
`proximal white subungual ony-
`chomycosis is common
`i~nmunocompromised patients,
`particularly in those in~ccted with
`HIV~6 ’I’he condition is rare
`heahhy, immunocompetent indi-
`viduals and is seen in both finger-
`nails and toenails.
`In ~z,hite suF~fi}ial owchomy-
`costs, fhngal organisms invade the
`nail plate directlB prodncing a
`crumbled white suH~tce. The der-
`matophyte 7~’ichwhym~*
`p~yles and a variety of moulds are
`causative pathogens, including
`species of Ac,w,~onium, Fusarium,
`and A.[pe~gillus.4 "Ibenail infection
`is siguificantly more common than
`fingerna!l infectio,~.
`C}~ndida onychomycosis refers
`to a rare syndrome limited
`patients af~icted with chronic
`mucocutaneous caudidiasis; as the
`name stiggests, it is caused only by
`C},ndi&. However, Candida can
`cause chronic paronychia in~ction,
`and can also cause primary ony-
`cholysis, especially in those with
`peripheral vascular disease/’
`
`DIAGNOSIS OF ONYCHOMYCOSIS
`The diagnosis ofor}ychomycosis is
`best established by a fimgal cul-
`ture. In addition, a potassium
`hydroxide preparation (KOH) may
`be helpful in ruling out nonfimgal
`etiologies. Direct microscopy usi~g
`15% t{} 2(}% potassinm hydroxide
`will reveal only the presence or
`absence of fungaI elemcuts, hut
`not the limgal pathogem A fimgal
`cuhure will ascertain du: causative
`organism, and therdbre allow ttae
`clinician to determine an appropri-
`
`48
`
`Fi~zpatrick’s Journal o{:Cliuk:al l)crmamlogy
`
`atth~NLM and mayb~
`
`N(}vvmb~r/I)cccmbvr 199,i
`
`Page 1 of 7
`
`
`
`ate therapy.7 Although over 90%
`ot: padenrs with onychomycosis are
`inf~:cted by dcrmatophytes, other
`potential pathogens~including
`(~},,dida and nondermatophyre
`mouids~are important ro identi~,
`as in some instances no e~lbctive
`systemic or topical therapy exists.
`Material for culture and KOH
`should be ~aken fi’om the in~bcted
`nail bed and nail plate. In distal
`subungual onychomycosis, the nail
`bed generally has the highest num-
`ber of viable fimgal particles. A
`mm curet is the best device for
`removing in~cred nail particles
`and debris. When nail bed debris
`either unavailable or insufficient,
`nail plate clippings can be used.
`but they must be pulverized prior
`m culturing or direct microscop~
`Material can be sen~ m a reference
`laboratory in a sterile container
`such as a sterile urine cnp, or
`commercially available collection
`devices such as the Detma-Pak.
`search adequately for all pathogens,
`the laboratory stmuld use media
`with and without cycloheximide,
`such as Mycosel and Sabouraud’s
`glucose agar.2’7 C~cloheximide
`an antifimgal added to agar to iso-
`late dermatophytes and other path-
`ogenic fimgi. Ideall> the cuh:ure
`should be perfbrmed when the
`patient has not been nsing topical
`or sysmmic antifimgat drugs fi~r 2
`m 4 weeks.
`If both cuhurc and KOH
`to yield a diagnosis, nail plate clip-
`pings can be sent in a formalin
`container fbr histologic analysis
`fimgal elements.8 Again, as with
`the KOH, only the presence or
`absence of fimgal elements---
`rather than the fimgal patliogen--
`will be determined. This is a help~
`rid technique, howevm; with a
`dystrophic nail that repeatedly has
`been culture-negative and KOH-
`
`Nm~emb~:r/Dccembcr 19!)4
`
`negative. A nail biopsy is a last
`resort.
`
`THERAPY
`After onychomycosis has been
`established by KOH, fimgat cul-
`ture, or histologic analysis, the
`clinician can choose from a wide
`variety of therapeutic options.
`Factors to consider in choosing
`therapy include: causative
`pathogen, potential adverse eft:cots
`and drug interactions, cost: of treat-
`ment, dosage schedule, and patiet~t
`compliance (’E~ble 2).9 When
`being treated with a systemic
`agent, the patient shonld see the
`physician every 1 m 2 months to
`monitor improvement in nail
`growth. Keep in mind that finger-
`nails grow 2 to 3 mm per month
`and toenails about 1 mm per
`month, which also is the amotmt
`of new nail that should grow out
`monthly if the d~erapeutic )’egimen
`is effective. If this amount of new
`nail is not seen, the therapy is
`probably ineffective, and should be
`reevaluated. Factors to consider
`incorrect dosage of andfhngal
`agent, patient compliance, drag
`interaction, and wrong diagnosis.
`
`SYSTEMIC ANTIFUNGALS
`Griseofulvin
`Introduced iu 1958, griseofulvin
`was the first oral antimycotic used
`to treat onychomycosis. Although
`initially heralded as a promisiug
`therap> griseo~dvin has numerous
`limitations that restrict its use in
`onychomycosis,4’9 It is efl~ctive
`only agaiust dermatophytes and
`has no effect: on Guulida or other
`nondermatophyte fungi, CTtndida
`mlg be responsible ~)r one out of
`twenty cases, mostly in fingernails.
`Because of its fimgistatic activitB
`griseofhivin mnst be administered
`daily until the in’bored nail plate
`
`T~is mat~ri~ t w~ c~pie~t
`
`Age and health of patient
`
`Causative pathogen
`
`Dosage schedule
`
`Patient c~mpliance
`
`Cost
`Potential drug interactions
`
`Potential side effects
`
`grows out, which is generally 6 to
`9 months ~br fingernails and 12 to
`18 months for toenails.
`GriseotTulvin appears m be
`delivered to the nail plate via the
`matrix, but the pharmacokiuetics
`of the drug have nor been well
`studied. It is clear, however, that
`the drug does not persist in the
`nail plate more than 1 or 2 weeks,
`anodmr fi~ctor explaining the tong
`course of therapy needed, The
`ultramicrosize ~)rm is best suited
`g,~ ,mvchomvcosis, and mos~
`patients require 750 mg to 1000
`mg daily o~~the ul~ramicrosize form
`to eradicate inf[~ction. This trans-
`lates to Gris-Peg 250 mg three to
`fi:mr times a day or Fulvicin
`330 mg ~wo m three times a day,
`dosed daily until normal nail has
`grown out and replaced the dys-
`trophic nail. it is importan.t to
`suvss that underdosing will not
`yield thvorable results, and may
`account fbr many therapeutic ~hil-
`
`tires.
`Bel:bre griseofulvin is adminis-
`tered, a baseline complete blood
`count, liver profile, and urinalysis
`should be ordered, followed by
`monitoring of these parameters
`every 2 months. Griseofidvin is
`contraindicated in pregnancy,
`lupus, and acute i~termtttent por-
`phyria, In addition, tile drug
`appears to interfere with oral con-
`traceptives, and, given its potential
`fbr prodncing fetal ab~mrmalities,
`
`Page 2 of 7
`
`
`
`I THERAPEUTICS
`
`cat, lion should be exercised in
`women of child-beari ng potential.4
`With long-term regimens, patients
`frequently experience minor
`annoyances, including headaches
`and gastrointestinal disturbances,
`The requirement ~br daily dosing,
`combined with numerous potential
`adverse e[t~bcts (’Ihble 3), restricts
`griseofulvin’s use as an agent fbr
`onychomycosis. Further, cure rates
`are disappointing. Only about 25%
`of patients witlt toenail disease and
`approximately 70% of those wit’h
`fingernail infb.ction are cured,
`despite long-tem~ dosing at appro-
`priate levels.4 ~Ihble 4 presents an
`analysis of comparative cost.
`
`Ketoconazole
`Ketoconazole was the first broad-
`spectrum oral antifhngal and the
`first oral azole. Ketoconazole acts
`against dermatophytes as well as
`Candida, and, like griseofhlvin,
`must be dosed daily in onychomy-
`cosis.4’9-1! It is fimgistatic and has
`no persistent binding to the nail
`plate. Daily dosages of 200 mg are
`
`= Anemia
`
`¯ Headache
`¯ Hepatotoxicity
`¯ Interference with oral contra-
`ceptives
`
`II Leukopenia
`
`III Nausea, gastrointestinal dis-
`turbance
`
`II Photosensitivity
`¯ Precipitation of subacute cuta-
`,neous lupus erythematosus
`¯ Proteinuria
`¯ Thrombocytopenia
`
`generally sufficient. Cure rates in
`onychomycosis are higher with
`ketoconazole than with griscofulvin.
`About 30% to 50% of patients
`with toenail disease and over 70%
`witll fingernail inf’:orion arc report-
`ed cured in clinical trials.4
`Because of its broad spectrum,
`ketoconazole was initially touted as
`the ideal agent fbr onychomycosis,
`but the potential risk of hepatotox-
`icity has severely restricted its use.
`
`The published risk of 1 in 10,000
`to 15,000 patients may be low, as a
`resnh ofnnderreporting, and hepa-
`tomxicity is morn common in
`patients with onychomycosis.4’~ 2
`Caution must be exercised in
`patlents on long-term therap>
`Kemconazole is appropriate for
`patients who are allergic or intoler-
`ant to griseofi~lvin, aud f~r those
`with (,)~mtlda onychomycosis.
`Because an acidic environment
`enhances absorption, ketoconazole
`shonid be taken 2 hotn:s befbre
`antacids or t-1-2 blockers. Pre-
`liminary data suggest, howevm;
`that the newer triazoles and mem-
`bers of the azole £mfil> itracona-
`zole and fluconazole, are saf~r than
`kemconazole, and therefbre more
`suited to onychomycosis therapy.
`BaR)re ketoconazole is admire
`istered, a baseline liver profile
`should be ordered, [{)llowed by
`monitoring of hepadc parameters
`in 2 weeks, then at mouthly inter-
`vals. Patients at highest risk for
`hepatotoxicity are women, persons
`more than 40 years of age, and
`
`Antifungal agent* Unit [mg)
`(ultra-
`microsize)
`
`Cost per
`unit ($)**
`
`Dose range Cost per
`{rag}
`dose
`
`Doses per
`month
`
`Duration
`(months)
`
`Cost per course
`of treatment ($)
`
`G~iseofulvin
`
`Ketoconazole
`
`Itraconazole
`
`Fluconazole
`
`25(}
`
`330
`
`200
`
`100
`
`100
`
`200
`
`1,38
`
`0.96
`
`2.35
`
`4,58
`
`5.82
`
`9.45
`
`750-1000
`
`660~990
`
`4.14-5.52
`
`1,92~2.88
`
`200
`
`200
`
`400
`
`400
`
`150
`
`300
`
`2.35
`
`9,16
`
`18,32
`
`18.32
`
`8.73
`
`14.18
`
`30
`
`30
`
`30
`
`30
`
`7
`
`7
`
`4
`
`4
`
`12
`
`12
`
`12
`
`3
`
`4
`
`3
`
`9
`
`9
`
`1490.40-1987.20
`
`691.20-1036.80
`
`846.00
`
`824.40
`
`5!2,96
`
`384.72
`
`314.28
`
`510.30
`
`~ This table does not include oral tarbinafine, which is not yet available tn the Ut~Red States,
`
`** Cost to patient in retail chain pharmacy, Cleveland, Ohio, July 15, 1994.
`
`Note: This tabte does not take into consideration cost of blood work, physician office visits, or time missed from work.
`
`50
`
`Fitzpatrick’s Journai of Clinical I)ennamlogy Nov,mdx:,’/l)(!cen~l~er 199:
`Subje-~t US C~pvwi~h~ Law~
`
`Page 3 of 7
`
`
`
`those with a history of drug aller-
`gies or hepatotoxicity.
`Kemconazole is also con-
`traindicated ill patients taking ter-
`fenadine or astemizoie.
`
`INVESTIGATIONAL AGENTS
`The newer triazoles, fluconazole
`and itraconazole~ are currently
`investigational agents in the
`United States fbr onycbomycosis,
`as is ketoconazole. I’..Ioweve~; they
`are approved by the FDA (i)r other
`indications. FluconaZole is indicat-
`ed for cryptococcosis and candidia-
`sis and has been used extensively
`worldwide in the AIIDS epidemic.
`Fluconazole is under investigation
`for use in onychomycosis in the
`United States and is currently used
`fbr this indication in other coun-
`tries. Itraconazole is a newer agent
`and is indicated in the United
`States [br histoplasmosis, blasto-
`mycosis, and, more recently,
`aspergillosis. Itraconazole is cur-
`rently being used fi3r onychomyco-
`sis in many other countries.
`The oral allylamine, terbin-
`afine, is being used fbr onychomy-
`cosis in many conntries. It is under
`investigation in the United States
`f~+r onychomycosis i~s welt as other
`indications.
`
`Fluconazole
`Fluconazole is a member of the
`azole fhmily and has activity against
`dermatophytes, Candida, and other
`fungi, 13 This agent has received
`nluch acclaim in the t-IIV-infi~cted
`patient, for whom it is a useful
`prophylactic agent against Candida
`and disseminated (5")~tacoccus,
`Flnconazole has only recently
`been studied as a therapy [br ony-
`chomycosis.~4 As with griseofulvin
`and ketoconazole, long-term dos-
`ing is generally required. The phar-
`macokinetics in the nail bare not
`
`been well studied, but the drug
`reaches the nail plate via the nail
`bed. Dosing at 50 mg or 100 mg
`either daily or on alternate clays
`tmtil normal nail has grown out is
`generally ef}~ctive. A new ,pulse,"
`or intermittent, regimen also
`reported to be effective is 150 mg
`administered once a week ~{~r 9
`months.15 In those patients not
`
`responding, this pulse dose can be
`increased. Patients taking muhiple
`medications may enjoy the flee-
`dom of only 1 day per week
`dosage.
`Fluccmazole has an advantage
`over griseofhlvin in being ef}~ctive
`against dermatophytes and
`Candida, and, unlike griseofidvin,
`it leads to a minimum of gastroin-
`testinal disturbances. Preliminary
`data suggest that it is much safer
`than ketoconazole. "lb date, flu-
`conazole has an excellent sa~ty
`prome,
`requirement
`of an ideal antifimgal [i)r ony-
`chomycosis. Flnconazole can be
`administered with or without food,
`and without regard to gastric acidi-
`ty. Despite its worldwide use in
`HIVdnfected patients, adverse
`events are minima!.~6 In particulm;
`hepamtoxicity is extremely rare.
`Howevm; until more data are avail-
`able, a periodic liver profile, com-
`¯ plete blood count, and platelet
`count should be monitored in
`patients on long-term therap>
`
`Itraconazole
`Itraconazole is the newest member
`of the azole ~}mfily and is currently
`used as firstdine therapy for ony-
`chomycosis in many counn’ies.
`Effective against dermatophytes,
`Candida, and some nondermato-
`phyte moulds, itraconazole has the
`broadest specn’um of all oral anti-
`fhngal drugsJ7~9 In addition, the
`pharmacokinetics in the nail have
`
`Pharmacokinetics
`III Lipophilic
`II Delivered to nail plate with-
`in 7 days
`¯ Delivered to nail plate from
`nail bed
`III The level in the nail plate
`rises 10-fold when the dose
`is increased from 100 mg
`four times a day to 200 mg
`four times a day
`
`¯ Serum levels drop to 0
`within 7 days of discontinu-
`ation
`¯ Persists in nail plate for 6 to
`9 months after therapy is
`discontinued
`
`Potential Adverse Effects
`¯ Nausea, gastrointestinal
`disturbance
`
`¯ Rash
`
`[] Pruritus
`tl Hypokalemia
`
`¯ Reversible telogen
`effluvium
`
`¯ Hepatotoxicity
`
`been well studied,20’21 Itraconazole
`is detected in the nail plate within
`7 days of administration. It pene-
`u’ates the nail plate from the nail
`bed and persists in the nail plate
`for up to 9 months after therapy is
`discontinued, This is probably
`rdated m its lipophilic property,
`causing the drug to adhere to the
`lipophilic cytoplasm of the ker-
`atinocytes in the nail plate (+Ihble
`5),9,20,2l
`
`Based on the nail pharmacold-
`netics, ,:here are two published
`dosage regimens in onydmmycosis.
`The first, or "fixed," dose is 200 mg
`daily for 12 weeks in menait disease
`and for 6 weeks in fingernail dis-
`case.9’21 Cure rates are about 80%.
`tt is important to emphasize to the
`patient that when therapy is discon-
`tinued, the nail appearance is not
`
`Novembertl)eccmbcr 1994
`
`Fitzpat6ck’sJour,ml,d!Clinical Dermatology 51
`
`Page 4 of 7
`
`
`
`ERA P EU’! ’1 CS
`
`normal. Because of the persistence
`of itraconazole in tile nail plate,
`however, the nail grows our fun-
`gus-fi’ee. It is often helpfid to see
`the patient 4 to 5 months post-
`therapy and to re-treat for an addi-
`tional month or 1-week pulse if
`the nail has not grown out as
`scheduled.
`The second dosage schedule is
`the "pnlse," or intennktent, regi-
`men.20 Because of the pharmacoki-
`netic profile of itraconazole, con-
`tinuous therapy is not necessary to
`maintain the drug at therapeutic
`levels in the nail plate. Intermittent
`cycles ofitraconazole, given for the
`
`first week of a period of consecu-
`tive months, have been investigat-
`ed. A dose of 400 mg daily fbr 1
`wee~l week per month [{3r 1 to
`2 months fbr fingernail infection
`and 3 to 4 months ~br toenail
`int~ction~has been shown to be
`effective (Figures I-5). Pilot studies
`report cure rates to be about 80%.
`The nail is not normal when thera-
`py is discontinued, but slow, con-
`tiuued improvement occurs.
`Reevaluation 4 to 5 months a~ier
`therapy is discontinued is helpfiil,
`and another l-week pulse of 400
`mg once a day may be given to
`patients not completely clinically
`
`cured. The advantages of the inter-
`mittcut regimen include lower cost
`than that of the fi~ed regimen and
`fi’eedom fi:om daily medicatkm.
`Both lvgimens have comparahle
`cure rates. The efficacy of intermit-
`tent itraconazote therapy ~br ony-
`chomycosis is under hwestigation
`in the United States.
`Itrac, mazole shoukl be given
`with tbod. A baseline liver profile
`should be ordered, with monitor-
`ing every month or alternate
`month while therapy continues. As
`with fluconazole, hepamtoxicity
`appears to be rare. However, itra-
`conazole has not been used to the
`
`Treatment of
`Onychomycosis with
`Intermittent Itraconazole
`T. rubrum and & brevicatdis were
`
`cultured. Patient was treated with
`intermittent itraconazole therapy,
`3 pulses of 400 mg once a day for
`1 week during each of 3 consecutive
`months:
`
`Figure 1. Onychomycosis, pretreatment. Figure 2. After 2 months, the patient
`begins to improve,
`
`Figure 3. Month 4, 1 month following
`therapy, Note continued improvement.
`
`Figure 4. Month 6, 3 months following
`therapy. Continued improvement.
`
`Figure 5. Month 12, Nail is myco!ogi-
`cally and clinically normal,
`
`5~
`
`Fhzpau’idds Journal of Clinical l)ermamlogy
`
`November/l)ec~mdx, r 19!14
`
`Page 5 of 7
`
`
`
`extent of fluconazo]e, and more
`data are needed m f’ully establish a
`sat~:ry profile. Potential adverse
`effects are listed in "l~d~le 5.
`
`Terbinafine
`Terbinafine is a member of the
`allylamine f~mfily of an tifh ngals
`and is available as an oral agent in
`many countries outside the United
`States, including Canada and
`Mexico. It is also the only fungici-
`dal oral andmycotic, with activity
`against the dermarophytes and
`some species of Gmdida.
`There is considerable world-
`wide experience with this agent in
`onycnomycos~s.-~ -" Also, tl~e
`pharmacokinetics in the nail have
`been well studied (’Ihble 6).26’27
`Like irraconazole, terbinafine is
`lipophilic and persists in the nail
`plate. It is detected in the nail plate
`in 1 to 3 weeks, apparently deliv-
`ered via the llali
`nail concentrations are in the
`fimgicidal range for dermato-
`phytes.-7 Drbmafine persists in the
`nail plate up to 4 months after
`therapy is discontiuued.
`Based on the pl~armacokinetics,
`a 12-week daily dose of250 mg
`once a day is generally effective in
`toenail disease, while 6 weeks is nec-
`essary in fingernail disease.28 Cure
`rates are ahout 80%. Remember
`that the nail is not clinically nor-
`real when the drug is discontin-
`ued, but because of the persistence
`of terbinafine in the nail, and its
`fimgicidal properties, the nail grows
`out fimgus-fi’ee. Adverse e~cts are
`rare, and are listed in ~lhble 6.
`
`MISCELLANEOUS THERAPIES
`’Bvo topical antifimgals currendy
`under investigation in the United
`States, amorolfine and tioconazole,
`are available in other countries for
`onychomycosis.29 These agents
`
`have the greatest potential as pri-
`mary therapy in patients with min-
`imal disease and as prophylactic
`agents in patients a~ highest risk
`l~)r recu trent disease.
`Most other topical antifungal
`agents have little value as primary
`therapy in the majority of patients
`with onychomycosis. A recent
`study, however, showed avnlsio i~ of
`the nail combined with topical 2%
`ketoconazole cream under occlu-
`sion to be effective in selected
`patients.3° However, because of the
`inherent problems of nail avulsion,
`this approach is limited to persons
`with only one or two infbctcd
`nails.
`
`SELECTION OF
`AN ANTIFUNGAL AGENT
`Given the new plethora of excel-
`lent antimycotics suitable fbr ony-
`chomycosis, the selection of a pa,’-
`ticular antifungal ager~t can be a
`difficult decision. As there are cur-
`rently no comparative studies, the
`clinician might choose an agent on
`the basis of cost, potential drug
`interactions, likelihood of adverse
`effects, dosage schedule, patient
`compliance, and the fi.mgal organ-
`ism cultured. Also, performing
`minimum inhibitory conce,m:a-
`tions of the fungal organisms cul-
`tured fi’om the nail may provkte a
`reasonable estimate as m dm most
`suitable drug to use.31 Patients tak-
`ing multiple medications might
`prefer the convenience of once a
`week dosing possible with flucona-
`zole. Others might prefer a 1 week
`per month schedule, with itracona-
`zole, or a fixed 12-week course of
`terbinafine. Cost is also an impor-
`tant issue. As seen in ~lhble 4, the
`cost fbr a treatment course ofgris-
`eofulvin is higher than that of the
`more recent triazoles, tluconazole
`and in:aconazole. Given the low
`
`Pharmacokinetics
`I Delivered to nail plate via
`nail bed
`I Levels in nail plate
`detectable I to 3 weeks
`after initiation of therapy
`I Serum levels may persist in
`srnall quantities 4 to 8
`weeks after drug is discon-
`tinued
`I Levels in nail plate persist 4
`months after therapy
`
`Potential Adverse Effects
`I Nausea, gastrointestinal
`disturbance
`i Taste disturbance~
`reversible upon discontinu-
`ation of therapy
`
`I Hepatotoxicity
`I Rash
`
`cure rate with griseofidvin, it is
`certainly more cost-effective to
`treat with these newer antimy-
`cotics. Keep in mind that the most
`expensive medication is the one
`that does not work. For this rea-
`son, these newer antifimgals are
`likely to replace the use ofgtiseoo
`fillvin in onychomycosis, and
`make it possible to treat a greater
`number of patients with toenail
`disease.
`Identification of the infecting
`fungus provides important data fbr
`selecting a particular antimycotic.
`For example, if C)mdMa is cultured
`or suspected to be pathogenic, gris-
`eofillvin is ineffective. A member
`of the azole family, such as keto-
`conazole, fluconazole, or itracona-
`zole, would be the best choice. Ira
`dermatophyte is cultured, griseo-
`fulvim the azote fimfily, and oral
`terbinafine are ei%ctive. In. circum-
`stances where a nondermatophyte
`filamentous fhngus is isolated, such
`:is Scopulariopsis brevitvndis, the
`best therapy may be surgical.
`
`NovcmbcrtDect’mber 1{)!)4
`
`rhia material was ~:opied
`
`Fitzpatrick’s.bmrmlI of Clinical l)ermatdogy 53
`
`Page 6 of 7
`
`
`
`[ THERAPEUTICS
`
`LONG-TERM MANAGEMENT
`
`In many patients, onychomycosis
`rectlrs af:ter gtiseofulvin therapy. In
`some patients, this may be due to
`an inherited immune defect predis-
`posing susceptibility to infection.
`However, many recurrent bouts of
`onycbomycosis are caused by
`rectlrrence of tinea pedis and rein-
`fection of dae nail bed fi’om the
`stratum corneum of the foot. Keep
`in mind that dermatophytes gene>
`ally infect the stratum corneum of
`the plantar surface or toe webs
`before invading the nail bed and
`nail plate. WeeHy or daily applica-
`tion of a topical andfungal agent
`to the entire plantar sur~hce, toe
`webs, and nails can prevent the
`reestablishment of tinea pedis and
`limit the possibili~ of reinfection.
`Other suggested guidelines
`patients are listed in %ble 7.
`
`CONCLUSION
`With recent advances in antilhngal
`therapy, there is finally hope for
`patients afflicted with onychomyco-
`sis. The triazoles, fluconazx)le and
`itraconazole, and the oral allylamine
`terbinafine offer the most potential
`in treating this stubborn disease.
`These drags appear to be safie and
`wdl tolerated by patients, It is likely
`that our ability to treat patients with
`onychomycosis, and in particular
`toenail disease, will be increased by
`the effectiveness and safety of these
`new antifhngal agents. []
`
`References
`
`1. Sche~: RK. Diseases of’d~e nails. In: Corm II
`(Ed). Curren~ Therapy, Philadelphia:
`Satmdef,% 1990; p 736,
`
`2. Stmmlerbell RC, Kime J, Krajden S.
`Onychomycosis, tinea pedis and tlnea
`manuum caused by non-dermatophyte
`l:lentous fimgi. Mycoses 1989; 32:609o619.
`
`3. Zaias N. Onydmmycosis. In: Daniel CR
`{Ed). Demlamklgic Clinics. Philadelphia:
`Saunders, 1985; p 445.
`
`Never go barefoot.
`
`Wear absorbent, cotton socks
`to prevent moisture accumula-
`tion.
`Discard old shoes.
`Apply a topical antifungal to
`feet and toenails on a regular
`basis--indefinitely,
`
`4. Cohen JL, Sober RK, Pappert AS. The nail
`and fimgus ild~ctions, lm Elewskl BE (Ed),
`Cutaneous Fungal Infections. New York:
`Igaku-Shoin, 1992; pp I {16-123.
`
`5. Andre J, Achen G. Onychomycosis, h’lt J
`Dermatol 1987; 26:481-490.
`
`6. Eiewski BE. Proximal white subungual
`chomycosis in acquired immunodeficiency
`syndrome, J Am Acad I)ermaml 1993;
`29:631-632.
`
`7. Elewski BE, Hazen PG. The superficial
`mycoses and the dermamphytes. J Am Acad
`Dermaml 1989; 21:655-673.
`8. Suarez SM et al. ltismlogic evaluation of nail
`clippings ~br diagnosi~g onychomycoses.
`A mh Dermau.4 1991 ; 127:151
`
`9, Picrard GE, Arresse-Esi:rada J, Pierard-
`Franchimont C. Treatment ofonydmmyco-
`sis: Traditional approaches. J Am Acad
`[)ermatol 1993; 29:541-545.
`10, Galimberti R e~ al, The acdvlty of kemcm~a-
`zole ill the treatment ofonychomycosis, Rev
`infect Dis 1980; 2:596-598,
`
`11. Holub PG, Hubbard ER. Ketoconazo~e
`the treatment ofm’~ychomycosis, J Am
`Podiatr Med Assoc 1987; 77;338-339.
`
`12. Lake-Bakaar G, Scheucr P j, Sherlock
`Hepatic ~eacdons associated wid~ ketocom>
`zole in the United KinDlom. Br Med J
`1987; 294:419-422.
`
`13, Grant SM, Clessok{ SM. Fhmonazole: A
`review of its pham,acodynamic and plmmm-
`cokinetic properties and d~erapeudc pmen~
`dal in superficial and Systemic mycoses.
`Drugs 1990; 39:877-9 t6.
`14. guokkanen K, Alava S. Fluconazole in the
`tream~en~ ofonychomycosls caused by der~
`matophy*es. J Dermaml Treat 1992; 3:115,-
`117,
`15. Nahass GT~ Sism g’l~ Onychomycosis:
`Successful u~atinent with once,.