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`
`luxzu
`
`C-01 ------ --sac: m944ouou
`
`PITAL
`MEDICINE
`
`
`
`New
`treatments for
`onychomycosis
`
`Diarrhea in adults:
`A practical approach
`
`Physician-assisted
`suicide: Where the
`law stands now
`L
`_ {__
`
`NEW DEPARIMENTS
`The Diagnostic X-Ray
`Nutrition in Primary Care
`
`
`
`Earn AMA/AAFP (ME crecit
`
`Page 1 of 9
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`i
`
`Kaken Exhibit 2007
`Acrux v. Kaken
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`IPR2017-00190
`
`

`

`HOSPITAL
`MEDICINE’
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`IRSTEIOIOIV
`MARK J. LEMA. MD, PhD
`Cltttimtztn. Dcpmmcm of
`Artcsthesiology
`Roswell Prrrk Cancer Institute
`A.\\'0Cl3lc Professor and
`Vir:e»Clt:rinnan for Academic
`Department of Anesthesiology
`School 0|‘ Medicine rnd Blottledictll
`Sciences
`SUNY-Bullalo. Buffalo, NY
`GIDIOIOIY
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`Professor of Medicine
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`Umvcrxrry of Pittsbtrgh School ni
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`Cllllfll. (Ill IEIIICIIIE
`THOMAS A. RAFFIN. MD
`A.s<ociate Professor of Medicine
`Chief. Division of Pulmonary and
`Critical Care Medicine
`Stanford Urtivenity School of
`Medicine. CA
`lfiliflfl Ilfltlfl
`DAVID K. WAGNER. MD
`Professor and Chttimtan
`IX.-punnterrt of Ernergency Medicine
`Allegheny University of the I-lealth
`S(.‘iencr.;\'. Pltiladelpltlat
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`I(l7.NNF.'l'H l.. BECKER. Ml). PhD
`Pmfessor of Medicine
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`School of Medicine
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`VA Medical Center
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`III! IKE
`WII‘_Ll/\M A. SCHWER. MD
`Pmlessor ol‘ l-';t1nily Medicine
`Chrtimtztn. Deprrrttnent of
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`Rus.h—Presbyterittr1-St Luke's
`Medical Center
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`Allegheny University of the Hcrrltlt
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`IIIIIODIIIIOIOOY
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`l’rol'c~‘sorof Medicine
`llepttntnent of internal Medicine
`Yrtle University School of Medicine
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`ilfldlolli MIMI
`AARON GLATI". MD
`Chicl. Division of Infectious l)l.\L!tlSCS
`Catholic Medical Center of
`Brooklyn and Queens
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`Albert Einstein College of Medicine
`New York. N Y
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`JOI IN J. CARONN/\. MD
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`Vice-Chuinnrrt. Dcpztnment of
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`The New York Huspit:tl—Comcll
`Medical Cetlcr. NY
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`Chuimtm
`Dcpatrtntcnt of (lbstctrics ltlld
`(iymcology
`Baylor College of Medicine
`Texas Medical Center
`Ilousort. TX
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`OTOIJIIIGOLOOV
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`l’t'0les.\‘or tux! Chztinttztn
`Dcp‘.ututcnl of ()tularryngo|ogy/Hood 5:
`Neck Surgery
`University ul'Color.1do I-lcultlt
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`PIIIIIIIIOIY
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`

`

`INFECTIOUS DISEASES
`
`CME Feature
`
`Advances in the diagnosis and
`treatment of onychomycosis
`
`With a new pharmacologie armamentarium available, you can now cure many fungal
`infections of the fingernail and toenail.
`
`Richard K. Scher, MD, and Lisa Marie coppa, MD
`
`nychomycosis refers to a fungal
`oinfection of the nail unit—the
`nail matrix, bed, or plate. The inci-
`dence of onychomycosis is reported
`to be 2% to l4%,' but the actual in-
`
`cidence is probably much higher.
`Onychomycosis accounts for one-
`third of all fungal skin infections and
`one—lialf of all nail disease. It affects
`
`hallux—mueh
`the
`loes——usually
`more frequently than fingers.
`Fungal infections of the nail are
`notoriously difficult to treat. Spon-
`taneous remission is rare and recur-
`rence after treatment
`is common.
`
`The incidence of onyehomyeosis is
`30 times higher in adults than in
`children, afflicting 15% to 20% of
`adults aged 40 to 6() years and 25%
`to 40% of adults older than 60 years,
`but only up to 2.6% of children un-
`der the age of I8 years? The disease
`occurs worldwide and its incidence
`
`has been steadily increasing. The
`following factors have contributed
`to its proliferationzi‘
`0 Growing elderly population
`0 Spread of HIV infection/AIDS
`0
`Immunosuppicssives and other drugs
`(cg, corticosteroids, antibiotics)
`0 Occlusive footwear
`
`Vigorous physical activity
`° Communal bathing facilities
`
`I"
`
`-
`
`
`
`I.ius1rat.onbyScottBoceli
`
`I)r Sclrc/‘ is I’ro_fe.r.s'or of Clinicul Dernmmlogy and Dr Coppa is a DernIaroplmrmacolo1;v l"¢*lI(m'. l)epm1/ncnr (2/‘I)cI'ImI!ulm;\'.
`Co/um/)iu Univer.t'ily College Q/'PII_\'.s'ician.s' and SlII‘g(.‘()II.S‘. New York. New York.
`
`Page 3 0f 9
`
`il()SPlR\}; MEDICINE / APRIL I998
`u. HINT?
`Jcuptud
`atthe NLM may be
`Subject US Copyright Laws
`
`

`

`
`
`onychomycosis
`
`
`
`KEY PRAGTl—C_E POINTS
`
`
`
`
`
`
`
`
`Characteristic signs of distal
`
`
`subungual onychomycosis
`
`
`
`include nail bed hyperkeratosis,
`
`
`
`nail plate thickening. discol-
`
`
`
`oration. and onycholysis.
`O
`
`
`
`
`
`
`
`
`
`
`In white superficial
`
`
`
`onychomycosis. the nail
`
`
`
`
`
`looks white and crumbly, in
`
`
`
`
`a speckled pattern. but
`
`
`
`the patches may eventually
`coalesce to involve
`
`
`
`the whole nail surface.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Onychomycosis is more thanjust
`
`
`
`
`
`a cosmetic problem. The nail unit
`
`
`
`
`serves many tlilfcrent functions, in-
`
`
`
`
`cluding pincer grasp, scratching, en-
`
`
`
`
`
`hancement of fine touch, and pro-
`
`
`
`
`
`
`tection of the digit. Any disease of
`
`
`
`
`
`
`the nail unit can have a negative im-
`
`
`
`
`
`
`
`pact on quality of life and interfere
`
`
`
`
`
`
`with the activities of daily living.
`
`
`
`
`
`Thickened painful nails may limit
`
`
`
`mobility, affect peripheral circula-
`
`
`
`
`tion, delay healing, exacerbate dia-
`
`
`
`
`
`
`
`betic foot ulcers, and serve as a fitn-
`
`
`gal reservoir.-‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IMMUNOLOGY
`
`
`Deirnatophytc colonization. gener-
`
`
`
`
`
`ally limited to the dead ket'atini'.r.ed
`tissue of the strattirn corneum. re-
`
`
`
`
`
`
`
`
`
`
`sults in an inflammatory reaction of
`
`
`
`
`
`mild to severe intensity. Both hu-
`
`
`moral- and cell-mediated immunity
`
`
`
`
`
`
`and specific and nonspecific host de-
`
`
`
`fense meehaiiisins
`respond
`and
`
`
`
`the
`eventually eliminate
`liiiigiis.
`
`
`
`Htimoral
`immunity is
`responsible
`
`
`
`
`
`
`for producing antibodies, but it is the
`
`
`
`development of cell-mediated ini-
`
`
`
`
`
`munity that is associated with clini-
`
`
`
`
`
`cLii'e and ridding the stratum
`cal
`
`
`
`
`corneuin of the olfendiiig dermato-
`
`
`
`
`
`phyte. Patients with recurrent or
`
`
`
`
`chronic onychomycosis have high
`
`
`
`
`antibody levels but
`impaired cell-
`
`
`mediated immunity.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`O
`
`
`
`
`Before instituting oral antifungal
`
`
`
`
`
`therapy. make sure to confirm
`
`
`
`the diagnosis of onychomyco-
`
`
`
`
`
`sis via KOH. fungal culture,
`
`
`
`and any additional modalities
`
`
`
`that are necessary.
`
`
`
`I
`
`
`
`
`
`
`
`
`
`
`CAUSATWE AGENTS
`
`
`
`
`Onychomycosis is caused by der-
`
`
`
`matophytes, yeast, and nondermato—
`
`
`
`
`
`
`phytic moulds. The incidence of each
`
`
`
`
`
`type of infection varies with geo-
`
`
`
`
`
`graphic region.
`In temperate zones,
`
`CLASSIFICATION
`
`
`
`
`
`the most common causative agents
`
`
`
`
`
`
`
`
`
`
`
`are dermatophytes, a group of closely
`The four clinical types of fungal nail
`
`
`
`
`
`
`
`
`
`related fungi that can invade kerati-
`disease——each with its own host-par-
`
`
`
`
`
`
`
`
`
`nous tissue—skin, hair, nails, or fur.
`asite ielationship—are distal subun-
`
`
`
`
`
`
`
`Tlierefone, deiinatophytes aie primaiy
`guiil onychomycosis (DSO). while
`
`
`
`
`
`
`causative agents of onychoinycosis.
`superficial onychomycosis
`(W50).
`
`
`
`
`
`
`
`The three genera of dermatophytes
`proximal subnngual onychoinycosis
`
`
`
`
`
`
`
`
`
`
`
`(PS0), and C.:inc.-'.r'dri onyclioinycosis
`are Epideiii-i0ph_ytoii, Micro.s'_rmi'aii:,
`invasion into nails has been clearly
`
`
`
`
`
`
`
`
`
`and 7i‘icho,r)hyion.“ Tri'.:'.’icipi'iytr;ii ra-
`Distal subungual onychomyco-
`established.“ In one report, chronic
`briiiri accounts for 80% of all der-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`paronychia and onycholysis { separa-
`sis. DSO. the most common subtype.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`matophyte nail infections and 46% of
`begins with fungal penetrat'ion into
`tion of the nail plate from the nail
`all nail infections?‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`bed) were attributed to trauma or
`the hyponychium (the area just pros-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The incidence of yeast-related
`Contact
`irritants; CLindid.:i only ag-
`imal
`to where the nail plate begins
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to separate from the nail bed) and the
`gravated the problem. In some pa-
`onychoinycosis ranges from 5.4% to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`is most likely to be a
`6.3%. Yeast
`tients with immunodeficiency disor-
`distal or lateral nail bed I Figure I. it
`
`
`
`
`
`
`
`
`
`
`
`
`
`ders and mucocutaneoiis candidiasis,
`causative agent
`in tropical areas.
`I3). Chai'acteristic signs include nail
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Cciiidiclri ai'bi'c.:iii.i', the most common
`bed hyperkeratosis, nail plate thick-
`C cilbic-tins clearly is the primary of-
`
`
`
`
`
`
`
`
`
`
`
`
`isolate. has been cultured in 'i'(}% of
`fending pathogen.
`ening, discoloratioii. and onycholy-
`
`
`
`
`
`
`
`
`
`
`
`leg,
`Nondermatophytic moulds
`cases of onychomyeosis attributed to
`sis. Other derniatologic findings Listi-
`
`
`
`
`
`
`
`
`
`
`
`
`yeast. Candida] infections are more
`i'Jrevicntili's, Aspar-
`.S'co,r)ii£cirio;).i'i.i'
`ally accompany these signs.
`In L]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`gi'i'iiis iiiger) are typically found in
`common in fingernails than toenails
`series of 2,000 patients with disto-
`and in women than in men.“ Yeast as
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lateral
`subungual
`0l‘lyCi1()l"t"lyCU.\'l>~
`subtropical and tropical climates.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a causative agent in onychomycosis
`Like yeast, they are not keratolytic;
`(DLSO), 98% had asymptomatic mi-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`is actually a controversial
`topic;
`instead, they invade nails that have
`crovesicles with little or no eiytlieiiia
`some maintain that Ccii-ididci
`is not
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`oti their soles,“ suggesting that the in-
`suffered prior damage. The usual
`fection was transmitted froiii
`Ilia:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`site is a single toenail.-5 Again, like
`a primary pathogen in healthy pa-
`soles to the nails rather than vice
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`that
`tients, whereas others assert
`yeast, even when grown on culture,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`versa. Transmissioii of DLSO Iltil}
`candidal
`infection is
`the primary
`nondermatophytic moulds are not
`also occur in an autosomal domiiiaiil
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`process. Yeast are not iteratinolytic
`always considered primary caus-
`
`
`
`
`
`
`
`
`
`
`
`ative agents.”
`pattern within families."
`and no mechanism for their primary
`
`
`Page 4 of 9
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`lI()Sl’|’|'r'\L Ml-_iD[f_‘|NE i‘ i'\l’R[l. W98
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`pied
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`
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`atthe NLM anclfiagbe
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`Subject LlSC.up'I(rigl'it Laws
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`Page 4 of 9
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`

`

`
`
`Onychomycosis
`
`Figure 1. Distal subungual onychomycosls
`
`
`
`
`
`¢HOSPI1’N..MEDlC1NE
`
`DSO. the most common subtype of fungal nail disease, begins with fungal
`penetration into the hyponychium and the distal or
`lateral nail bed.
`Characteristic signs include nail bed hyperkeratosis. nail plate thickening,
`diseoioration, and onycholysis
`
`l Figure 2. White superficial onychomV¢°3i3
`
`
`
`
`
`GHOSPITALMEDICINE
`
`In WSO, the fungi directly invade the nail plate and may proceed directly to
`the nail bed and hyponyehium. Initially the nail looks white and crumbly. "1 3
`speckled pattern. but the patches may eventually coalesce to Involve the
`whole nail surface
`W?!
`
`White superficial onychomyco-
`sis. ln cases of WSO, the fungi di-
`rectly invade the nail plate and may
`proceed to the nail bed and hypo-
`nychium (Figure 2, right). Initially,
`the nail looks white and crumbly, in
`a speckled pattern, bttt the patches
`may eventually coalesce to involve
`the whole nail surface. The tnost
`
`is Tri-
`
`common causative agent
`(‘/'l()])/I_\’I()I‘I menIagmp/tyres.
`Proximal
`subungual onycho-
`mycosis. PSO, the least common pre-
`sentation
`of
`onychomycosis
`in
`healthy persons. affects lingemails
`and toenails in similar frequency.
`ll
`is usually caused by Trul)/'ttm.'” The
`fungi
`invade the proximal nail
`fold
`and subsequently penetrate the newly
`fortncd nail plate. The distal portion
`of the nail remains normal until late
`in the course of the disease, when the
`
`entire nail plate is affected." The
`proximal white
`subungual
`ony-
`chomycosis (PWSO) subtype affects
`immunoeotnprotnised persons.
`In a
`recent case series, 87.l% of patients
`with AIDS had PWSO.”
`
`Canditla onychomycosis. Candi-
`(Ia causes three different patterns of
`infection: mucocutancous candidia—
`
`sis. Cumlir/a paronychia, and Can-
`</ic/cr onycholysis. In chronic inuco-
`cutaneous
`candidiasis,
`the yeast
`organism directly invades the nail
`plate, after which the proximal and
`lateral nail
`folds thicken increas-
`
`ingly until the nail becomes totally
`dystrophic." Camlizla paronychia,
`eharaeteri7.cd by swelling and ery-
`thema of the nail folds, usually oc-
`curs in persons who frequently im-
`merse their hands in water. such as
`dishwashers." The seal between the
`
`nail plate and nail fold is broken, al-
`lowing Clllil/fl/(I to secondarily pop-
`ulate the area and retard the "re-
`
`Collecting a specimen. For each
`type of onychomyeosis. collect a
`specimen as follows: For D30, clip
`the distal nail plate and use a curette
`to obtain debris from the nail bed at
`a site as proximal
`to the cuticle as
`sealing” of the nail unit.“’ ln nails
`possible, where the number of viable
`previously damaged by infection or
`trauma, Cumliz/(1 can act as a sec-
`ltyphae is greatest. Nail clippings or
`First, cleanse the nails, using alcohol
`to eliminate bacterial contamination.
`portions of the nail that have been
`ondary pathogen causing onyclto—
`
`mycosis. Cumliz/u onycholysis may
`or may not be a distinct entity; the
`organism may be the cause of the
`onycholysis or it may colonize ony-
`eholytic nails secondarily.
`
`MAKING THE DIAGNOSIS
`
`Page 5 of 9
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`l‘l()Sl’l'l'/\l. Mlil)|(‘|N|i I /\|‘l{|l. |‘)‘)t4
`'l;hi7:rri3’:’ Vi’ inn: copied
`atthe NU art: may he
`Subject US Copyright Laws
`
`

`

`
`
`Onychomycosis
`
`Figure 3. Debridement of the proximal nail bed
`
`
`
`OHOSPITALIEDKJNE
`
`To collect a specimen from the proximal nail bed, use a#15 scalpel or a sharp
`CUrette .
`
`
`
`
`
`OHOSPWAI.MEDICINE
`
`This nail plate was periodic acid Schiff—positive for fungal elements. Note the
`many septate hyphae present.
`
`avulsed have the lowest yield of hy-
`phae, and subungual debris,
`the
`highest. For WSO, use a #lS blade
`or a sharp curette to scrape debris
`from the nail surface. For PS0, clip
`away the overlying healthy nail.
`Then use a sharp curette or a #15
`blade to remove debris from the
`
`proximal nail bed (Figure 3, above).
`For Candida paronychia. try to ex-
`
`press material from the nail folds.
`For Candida onycholysis.
`scrape
`material from the nail bed.”
`
`Preparing the specimen for mi-
`croscopy. Divide the material col-
`lected into two portions—one for di-
`rect microscopy and one for culture.
`If you have obtained nail clippings,
`break them into small pieces.” Soften
`and clean the nail specimen in potas-
`
`Page 6 of 9
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`HOSPITAL MEDICINE / APRIL 1998
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`Subject Uscopv/right Laws
`
`sium hydroxide (KO!-I) 20%—30%.
`alone or with dimethyl sulfoxide. You
`can add a stain such as Chlorazol
`
`black E because it is specific for chitin
`and will accentuate hyphae.
`Demonstrating the specimen.
`Set the microscope on low power
`and reduce the light. Microscopy
`can identify the presence or ab-
`sence of hyphae and spores. You
`will need to obtain a fungal culture
`to identify the genus and species.
`Use Sabouraud‘s glucose agar with
`chloramphenicol
`to inhibit bacte-
`rial overgrowth. and a medium with
`cycloheximide to inhibit growth of
`nondermatophytic moulds. lf KOH
`and culture are unrevealing. send a
`piece of the nail plate for histologic
`analysis (Figure 4, left).'‘’ Obtain a
`nail biopsy when the diagnosis is in
`question and other modalities have
`been unrevealing.
`Confirming the diagnosis. Be-
`fore instituting oral antifungal ther-
`apy, make sure to confimi the diag-
`nosis of onychomycosis via KOH.
`fungal culture, and/or histologic ex-
`amination. Otherwise—since many
`conditions mimic onychomycosis-
`you may be using the wrong treat-
`ment, which could have adverse con-
`
`sequences for the patient.
`
`THE DIFFERENTIAL DIAGNOSIS
`
`Onychomycosis accounts for 50%
`of all nail disorders. Other condi-
`
`tions that may mimic onychomy-
`cosis clinically include psoriasis.
`lichen planus, Contact dermatitis.
`trauma, nail bed tumors, and the yel-
`low nail syndrome.
`Psoriasis. Psoriatic nails
`
`tend
`
`features in
`to have many clinical
`common with onychomycosis.
`in-
`cluding subungual hyperkeratosis,
`onycholysis. splinter hemorrhages.
`and diffuse crumbling. Three clinical
`signs of psoriasis may aid in diagno-
`sis:
`line nail pitting, small yellow-
`(-cmlinuwl on p1rg.,w I7
`
`

`

`
`
`Onychomycosis
`
`
`Figure 5. Yellow nall syndrome
`
`In
`ntn
`
`EQi
`
`5 S 30
`
`This rare disease. which accompanies primary lymphedema and chronic
`obsgucnve pU'm°_”3|'V disease, can be confused with onychomycosis. in this
`Syn fome. the nails lack cuticles, have yellow pigmentation. and show retard-
`ed growth.
`
`Nail bed tumors. Nail bed tu-
`mors can cause separation of the nail
`plate from the nail bed and there-
`fore, in some cases, must be distin-
`guished frotn onychomycosis with a
`biopsy.
`Yellow nail syndrome. This rare
`disease can be confused with onycho-
`mycosis.
`lt accompanies primary
`lymphedema and chronic obsuuctive
`pulmonary disease. Clinically,
`the
`nails lack cuticles, have yellow pig-
`mentation, and exhibit growth rettu'-
`dation (Figure 5, above).
`
`THE OLD THERAPIES
`
`has
`Traditionally, onychomycosis
`been very difficult to treat, with low
`cure rates and high relapse rates.
`Topical
`therapies cannot penetrate
`the nail plate and eradicate the infec-
`tion in the nail bed; they are useful
`only in milder forms of the disease.
`The older oral antifungal medica-
`tions—griseofulvin and ketocona—
`zole——penetrate the nail plate via the
`nail matrix, but both necessitate pro-
`longed treatment courses (4 to 6
`months for
`fingernails,
`l0 to l8
`
`HOSPITAL MEDICINE I APRIL I998
`at the NI.
`may be
`Subject Uscopyright Laws
`
`months for toenails). Mycologic cure
`rates have been as low as 3% for toe-
`nails and 40% for ftngemails."
`
`THE NEW OBAI. ANTIFUNGALS
`The introduction of the allylamine
`and triazole classes of antifungal
`medications has revolutionized the
`treatment of onychomycosis (Table,
`p 18). Three new drugs——terbinafine,
`itraconazole,
`and
`lluconazole—
`have the advantages of shorter treat-
`ment courses, fewer side effects (the
`most common tue gastrointestinal
`upset, headache, and allergic skin
`eruptions), and higher cure rates.
`They also exhibit the “reservoir ef-
`feet”; that is, therapeutic concentra-
`tions of the medication remain in the
`
`distal nail plate weeks after treatment
`has stopped.
`Terbinafine. At a recommended
`
`dosage of 250 mg per day for 6 con-
`secutive weeks for fingernails and
`12 consecutive weeks for toenails,
`
`is fungicidal
`this allylamine agent
`against dermatophytes, C parapst'l0-
`sis.
`and some nondennatophytic
`moulds. It is fungistatic against C ul-
`
`brown areas of discoloration in the
`
`involvement
`nailbed, and frequent
`of nails on both hands." Onycho-
`mycosis in the immunocompetent
`host tends to involve only one hand.
`Psoriasis of the nails occurs in less
`
`than 5% of all cases of psoriasis. Be
`aware, however, that in a small per-
`centage of cases, a fungal
`infec-
`tion—usually Candt'da—may ac-
`company psoriatic nails.
`Lichen planus. An inflammatory
`skin disease, lichen planus is char-
`acterized by wide, flat, violaceous.
`itchy papttles. Nail
`involvement
`may occur in about 10% of patients
`with lichen planus and may appear
`in the absence of skin disease. As
`
`with psoriasis, lichen planus tends to
`involve the nails on both hands and
`
`both feet. Lichen planus may be as-
`sociated with onycholysis, yellow
`discoloration, and subungual liyper-
`keratosis. The most common clini-
`
`cal manifestations that distinguish it
`from onychomycosis
`are Wick-
`ham's striae—typical lesions of the
`skirt or mucous membranes—and
`
`pterygium—destruction of the nail
`matrix with resultant formation of a
`
`scar, causing a break in the nail plate
`connecting the proximal nail and
`nail bed epithelium."
`Contact dermatitis. This condi-
`
`tion, especially when it tuises from
`exposure to acrylic or epoxy resins,
`can cause cczematous lesions in the
`
`periungual area associated with nail
`bed hyperkeratosis and onycholysis.
`Trauma. Repeated trauma to the
`nails can cause onycholysis that re-
`sembles onychomycosis. Pigment-
`producing microorganisms can then
`colonize the onycholytic space. You
`can
`differentiate
`onychomycosis
`from trauma by clipping the nail; in
`cases of trauma, the underlying nail
`bed should be normal, not hyperker-
`atotic, unless the trauma is chronic."
`
`If the underlying nail bed looks ab-
`normal, petfonn a KOH and culture.
`
`Page 7 of 9
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`

`

`
`
`
`Onychonwcosis
`
`
`
`
`
`Table. The new antifungal agents
`
`
`
`
`
`Drug
`
`
`
`Dogage
`
`
`
`Activity
`
`
`
`Contraindications
`
`
`
`
`Terblnaflne
`
`
`
`
`Toenails: 250 mg/d ><
`
`
`
`12 consecutive weeks
`
`
`
`‘
`Fungicidal against
`
`
`dermatoohytes. some Candida
`
`
`
`
`species, and some moulds
`
`
`
`
`
`
`
`
`Fungistatic against 0 aioicans
`Fingernails: 250 mgid x
`and some moulds
`6 consecutive weeks
`
`
`
`
`
`
`
`
`
`
`Hypersensitivity to terbinafine
`
`
`
`
`
`Itraconazole
`
`
`
`
`
`
`
`Toenails: 200 mgid x
`
`
`
`12 consecutive weeks:
`
`
`
`
`
`or 200 mg twice daily
`
`
`
`
`
`x 7 days, followed by
`
`
`
`
`3 weeks of no medicine.
`
`
`
`for 3 pulses"
`
`
`
`
`
`Fungistatio against
`
`
`dermatophytes, yeast, and
`
`
`some nonderrnatophytic
`
`moulds
`
`
`
`
`
`
`
`Hypersensitivity to itraconazole
`
`
`
`or other azoles
`_
`‘
`
`
`
`Concurrent use of cisapride,
`
`
`lovastatin, astemizole.
`
`
`midazolarn. simvastatin.
`
`
`
`terfenadine. or triazolam
`
`
`
`
`
`
`
`Fingernails: 200 mg twice
`daily x 7 days. followed
`
`
`
`
`by 3 weeks of no
`
`
`
`
`
`
`
`
`medicine. lor 2 pulses
`
`
`Fluconazole
`
`
`
`
`
`
`Toenails: 150-800 mg
`
`
`
`
`once weekly, until infection
`clears‘
`
`
`
`
`Fingernaiis: 150-300 mg
`
`
`
`once weekly, until infection
`clears‘
`
`
`
`
`
`
`Fungistatic against
`
`
`derrnatophytes, most
`
`
`
`Candida species, and some
`
`
`nondermatophytic moulds
`
`
`
`
`
`
`Hypersensitivity to fluconazole
`or other azoles
`
`
`
`
`
`
`
`(Use caution with oral
`
`hypoglycemics. coumarin-type
`
`
`anticoagulants. phenytoin,
`
`
`cyclosporine, riiampin,
`
`theophylline, hydrochiorothiazide,
`cimetidine. terfenadine,
`
`
`
`
`
`cisapride. and astemizole)"
`
`
`
`
`
`I
`
`‘Not currently FDA approved for this indication.
`
`
`
`
`
`
`
`rPiaceuticns are based on data from studies using iiuconazoie in a continuous-dosing fashion. iniermmeni dosing regimens for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`onychomycosis may have fewer precautions.
`
`
`
`
`
`Note: Terbinarine and iiuconazoie do not need to be taken with food. itreconazoie should be taken with a full meal.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`were 82% and 83% in patients tak-
`.-'3i.:'aii.s‘.“‘ It works by inhibiting the
`is possible because terbinafine re-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mains in the nail plate for extended
`ing terbinatine 250 or 500 mg/day,
`enzyme squalene epoxidase, thereby
`
`
`
`
`
`
`
`
`
`
`
`
`
`periods. Pulse dosing may also re-
`preventing fungal cell membrane
`respectively,
`to treat
`toenail ony-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`synthesis. It also causes an accumu-
`duce side effects. Although terbin-
`chomycosis, indicating that the two
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`afine does not have many side ef-
`lation of squalene. which is fungici-
`are
`similarly
`effective.
`dosages
`
`
`
`
`
`
`
`
`
`
`
`
`fects,
`its pharmacokinetic profile
`dal. Terbinafine rapidly distributes
`Mycologic cure rates for infections
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`that
`does not
`it
`readily suggest
`into the nail plate via the nail bed
`caused by Candida species are more
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and the nail matrix, reaches mini-
`variable and have been reported as
`should be dosed this way. {It may re-
`52% for toenails and 65% for tin-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mum
`inhibitory
`concentration
`main longer in the blood than do the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`triazoles [see next section].)
`gernails.” Relapse is unlikely after
`{MIC) quickly, and remains in the
`
`
`
`
`
`
`
`
`
`
`The triazoles.
`ltraconazole and
`terbinafine treatment.
`
`
`
`nail plate for up to 10 months.” The
`
`
`
`
`
`
`
`
`
`
`fluconazole are synthetic triazole
`package insert
`reports mycologic
`Pulse closing regimens l typically,
`cure rates of "i'0% for toenails and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`antifungals that
`interfere with the
`1 week on therapy, 3 weeks off ther-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`79% for
`fingernails.
`In a recent
`14-0. deinethylase system,
`thereb)
`apy) are reportedly as effective as
`
`
`
`
`
`
`
`
`
`r.'r)ii.'iitti(’ri’ oi! girrgi’ _’ii
`
`
`
`
`continuous dosing.” Pulse therapy
`study, 2-year mycologic cure rates
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 8 of 9
`
`HOSPITAL MEDICINE i‘ APRIL. I998
`
`
`
`
`
`
`
`This l'I1EtE1'l3l w¥qpI33
`attire NLM andme be
`
`
`
`
`
`
`Subject US Copyright Laws
`
`
`
`
`
`
`Page 8 of 9
`
`

`

`
`onychomycosis
`2
`
`preventing ergosterol synthesis, a
`vital component of fungal cell mem-
`branes. They have a greater affinity
`for
`fungal, as opposed to main-
`malian, cytochrome P-450.
`liramnaznle has maximal oral
`
`bioavailahility when taken with a
`full meal. Absorption is impaired if
`it is taken on an empty stomach or
`with drugs that alter gastric pH (eg,
`antacids, H, blockers). ltraconazole
`undergoes extensive hepatic metab-
`olism, so it should be used with cau-
`tion in patients with hepatic impair-
`ment.” To date,
`three nail matrix
`kinetics studies have measured lev-
`
`els of itraconazole in distal nail clip-
`pings. All of them showed that itra-
`conazole penetrates the nail plate via
`the nail matrix and the nail bed.3°~3'
`
`The drug was detected in nails as
`early as 1 week after oral adminis-
`tration. There was no correlation be-
`tween itraconazolc level in the nail
`clippings and mycologic cure rate,
`however.
`ltraconazole teached the MIC for
`
`is not currently FDA ap-
`cosis
`proved. it is used frequently in the
`clinical
`setting (typically,
`three
`pulses). Pulse dosing with itracona-
`zole has been approved for finger-
`nail onychomycosis.
`Fluconazole, not yet FDA ap-
`proved for the treatment of ony-
`chomycosis, is a bis-triazole which,
`like itraconazole, blocks the enzyme
`14-ot detnethylase. It has low protein-
`binding capacity,
`so it distributes
`quickly into tissues. and it is rapidly
`cleared from plasma. Therapeutic
`levels remain in the nails for up to 6
`months,“ possibly contributing to the
`increase in cure rates after treatment
`is stopped. Fluconazole is well stiited
`for _ intermittent
`(ie, once weekly)
`dosing. Recent studies indicate that
`the optimal regitnen is 150 to 300 mg
`once weekly until the fungal infec-
`tton clcats——appt°oximately 3 months
`for fingernails and 6 months for toe-
`nails?” At this dosage, mycologic
`cure rates are 90% for fingemails and
`59% for toenails.
`
`dermatophytes and most Candida
`species within 7 to 2| days.
`Iti-
`hjbitory concentrations were main-
`tained for up to 6 months in finger-
`nails and for up to 9 months in
`toenails?‘ ltraconazole can be given
`by pulse dosing because it remains in
`the nails but
`is rapidly eliminated
`from the plasma}: Mycologic cure
`rates have ranged from 64% to 72%
`for fingernails and 43% to 95% for
`toenails. A 2-year follow-up study
`showed that the mycologic cure rate
`was 57% in both pulse— and contin-
`uous-dosing groups