FlTZPATRlCK’S
`
`IN G E N E RA L
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`s .x in eb%:T j ow
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`The McGraw-I-Irill Companies
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`Note: Dr. Stephen Katz’s work as editor and author was performed outside the scope
`of his employment as a U.S. government employee. This work represents his personal
`and professional views and not necessarily those of the U.S. government.
`
`FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE
`
`Sixth Edition
`
`'
`
`Copyright © 2003, 1999, 1993, 1987, 1979, 1971 by The McGraw-Hill
`Companies, Inc. All rights reserved. Printed in the United States of America.
`Except as permitted under the United States Copyright Act of 1976, no part
`of this publication may be reproduced or distributed in any form or by any
`means, or stored in a database or retrieval system, without the prior written
`permission of the publisher.
`
`1234567890 KGPKGP 09876543
`
`Set: ISBN 0-07—l38076-0
`Volume 1: ISBN O—07—138066—3
`Volume II: ISBN O-O7-138067-1
`
`This book was set in Times Roman by TechBooks, Inc. The editors were
`Darlene Cooke, Susan R. Noujaim, Lisa Silverman, and Peter J. Boyle; the
`production supervisor was Richard Ruzycka; the cover designer was Elizabeth
`Pisacreta; Barbara Littlewood prepared the index. Quebecor World Kingsport.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`Fitzpatrick’s dermatology in general medicine.—6th ed. /
`Irwin M. Freedberg .
`.
`. [et al.]
`p.
`; cm.
`Includes bibliographical references and index.
`ISBN O-O7-138076—0
`
`3. Cutaneous manifestations
`2. Sl<in—Diseases.
`1. Dermatology.
`1. Fitzpatrick, Thomas B. (Thomas Bernard), 1919-
`of general diseases.
`II. Freedberg, Irwin M.
`[DNLM: 1. Skin Diseases.
`2003]
`RL71.D46
`61 6.5—dc21
`
`2002021932
`
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`2003
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`*
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`

`INDEX
`
`Octreotide (continued)
`for Graves’ disease, 1663
`for scleroderrna, 1716
`Octyl dimethyl paba. See Padimate—O
`Ocular albinism, 826, 8271, 834
`autosomal recessive, 830
`diagnosis of, 834
`type 1 (X—linked recessive), 135t, 834
`molecular pathogenesis of, 834
`phenotypes, 834
`Ocular effects
`of aminoquinolines, 2396, 2396t
`laser safety, 2499
`of PUVA, 2486
`of systemic retinoids, 24l5t, 2416-2417
`Ocular involvement
`in albinism, 826, 827t
`in alkaptonuria, 1424-1425, 1425f
`in ataxia—telangiectasia, 1834, 1834f
`in atopic dermatitis, 1185-1186
`in Behc-et’s disease, 1837, 1838t
`in burns, 1225
`in cicatricial pemphigoid, 582-585
`in congenital rubella syndrome, 2042, 2043t
`in cutaneous T cell lymphoma, 1549, 1549‘:
`in Fabry disease, 1476-1477, 1478f, 1479, 1482
`in Graves’ disease, 1663, 1663f
`in herpes simplex, 2064, 2068t, 2069
`in Kawasald disease, 1983
`in leprosy, 1965
`in loiasis, 2246, 2246f
`in Lyme borreliosis, 1978
`in malignant atrophic papulomatosis, 986
`in Marfau syndrome, 1501-1502
`in neurofibromatosis type 1, 1828, 1831t
`in neurofibromatosis type 2, 1830
`in pseudoxanthoma elasticum, 1504
`in relapsing polychondritis, 1745, 1746f
`in rheumatoid arthritis, 1750t
`in Sjogren’s syndrome, 1758-1759, 1759t, 1761
`in syphilis, 2172, 2177, 2179, 2179f
`in tuberous sclerosis, 1824
`in tyrosinernia type II, 1419-1420, 1419f
`in visceral larva migrans, 2258, 2258f
`in vitamin A deficiency, 1403
`in vitiligo, 842
`in Xeroderma pigmentosum, 1508, 1510f
`Oculocutaneous albinism (OCA), 826, 1811t
`autosomal dominant, 831
`brown, 827t, 829, 829f, 831
`in Chédial:-Higashi syndrome, 1127
`classification of, 827, 827t, 831t
`defect not limited to melanocytes, 831-834
`genetics of, 827, 831t
`prevalence of, 827
`rufous/red, 827t, 830-831, 837t
`squamous cell carcinoma and, 739
`type 1, 135t, 137, 827-828, 827t, 837t
`diagnosis of, 834
`molecular pathogenesis of, 828
`OCA1A, 827, 827t
`OCA1B, 827-828, 827t
`type 2, 135t, 137, 827t, 828-829, 837t. See also
`Angelman’s syndrome; Prader—Willi’s
`syndrome
`diagnosis of, 834
`molecular pathogenesis of, 830, 831t
`phenotypes, 828-829, 829f
`type 3, 135t, 827t, 830, 837t
`molecular pathogenesis of, 830-831, 831t
`phenotypes, 827t, 830
`type 4, 137, 827t, 831, 837t
`Oculodermal melanocytosis. See Nevus of Ota
`Odansetron, for pmritus, 403
`Odds ratios, 2309-2310
`
`Odland bodies. See Lamellar granules
`Odontotrichomelic syndrome, 521
`Oeciacus, 2296
`Ofloxacin, 2432
`cost of, 2427t
`for gonorrhea, 2209
`phototoxicity of, 1301, l302t
`prophylaxis of meningococcal infections,
`1900
`OIF, 212t
`Oil acne, 1321
`Oil of cade, 2364
`Oil folliculitis, l322t
`Oil—in—water vanishing creams, for pruritus, 403
`Oil spot, 414f
`Ointments, 2321
`absorption bases, 2321
`hydrocarbon bases, 2321
`oil-in—water emulsions, 2321
`Water—in—oil emulsions, 2321
`water-soluble bases, 2321
`OKTcdr4a, 2458t
`Olanzapine
`actions of, 393
`adverse effects of, 394
`dosing of, 393
`for trichotillomania, 390-391
`Olaquindox
`photoallergic reactions to, l305t
`phototoxic reactions to, 1305
`Oleic acid, 1410
`Oleoresins, allergic reactions to, 1292
`Olestra, for TCDD exposure, 1322
`Olfactory hyperhidrosis, 700t, 701
`Olmsted syndrome, 510
`Omega—3 fatty acids, 343, 1410
`for atopic dermatitis, 1192
`for polymorphic light eruption, 1284, 1286
`for Raynaud’s phenomenon, 1767
`Omega—6 fatty acids, 343, 1410
`Oinega-9 fatty acids, 1410
`Omenn’s syndrome, exfoliative dermatitis in, 438
`Onchocerca volvulus, 962, 2241t
`'
`Onchocerciasis, 2225t
`acute papular onchodermatitis, 2247-2248
`calcification and, 1493
`chronic papular onchodermatitis, 2248
`clinical manifestations of, 2226t-2228t,
`2247-2249, 2248f
`depigmentation and, 859, 2248, 2249f
`diagnosis of, 2249
`differential diagnosis of, 2235-2237, 2244,
`2249-2.250
`eosinophil granule proteins in, 960t
`eosinophils in, 962-963 ‘
`epidemiology of, 2247
`etiology of, 2246
`geographic distribution of, 2247, 2247f—2248f
`hanging groin, 2249
`hypopigmentation in, 837t
`laboratory findings in, 2249
`lichenified onchodermatitis, 2248
`life cycle of parasite, 2246
`onchocercal nodules, 2248, 2249f
`pathogenesis of, 2247
`prevention of, 2249
`transmission of, 2295
`treatment of, 2230t, 2249
`Oncogenes, 362, 367, 369, 374, 378
`in cutaneous T cell lymphoma, 1539
`Oncosphere, 2237
`Oncostatin M, 292
`in Kaposi’s sarcoma, 1024, 1024f
`in, keratoacanthoma, 762
`ONMR syndrome, 637t
`
`Onychia
`candidal, 2012
`pianic, 2190
`Onychocola czmadensis, onychomycosis, 2001
`Onychodennal band, 160
`Onychodystrophy, 409, 414
`in psoriatic arthritis, 433
`Onychogryphosis, 659, 659f
`Onycholysis, 660-661, 661f
`cherr1otherapy—induced, 1340t, 1341-1342
`photo-onycholysis, 1300
`Onychomadesis, 660-661, 664t
`chemotherapy—induced, 1341-1342
`syphilis and, 2170
`Onychomatricoma, 667, 667f
`Onychomycosis, 163, 662, 2001
`candidal, 2001-2003
`,
`clinical manifestations of, 2002, 2002f
`differential diagnosis of, 662t, 925, 2003
`distal subungual, 2001-2003, 2002f
`in drug abusers, 1357
`in elderly, 1394
`epidemiology of, 2001
`etiology of, 2001-2002, 2001t, 2002f
`HIV infection and, 2145
`laboratory findings in, 2002-2003
`pathogenesis of, 2001-2002, 2001t, 2002f
`pathology of, 2003
`proximal subungual, 2001-2003, 2002f
`subungual, 1156
`treatment of, 2590
`superficial, 661
`treatment of, 2003, 2342, 2443, 2446
`white superficial, 1156, 1156f, 2001-2003, 2002f
`Onychoptosis defluvium, 660
`, Onychorrhexis, 661
`OPECIMPEC regimen, for adult T cell
`leukemia/lymphoma, 2134
`Opera-glass hand, 1600
`Ophiasis, 641-642, 642f
`Ophthalmia neonatorum, gonococcal, 2207
`Ophthalmic rosacea, 689t, 690-691, 690f, 691t, 695
`Ophthalmic zoster, 2076, 2082
`Opiates
`pruritus and, 399
`urticaria/angioedema and, 1135
`Opportunistic infections, in immunosuppressed
`host, 1152
`Oprelveldn, 245 St
`cutaneous reactions to, 1350
`Optical coherence tomography (OCT), 2494,
`25 12-2513
`Optical properties, of skin, 1271-1272,
`1271f-1272f
`Optic atrophy, in neurosyphilis, 2176-2177, 2176t
`Optic glioma, neurofibromatosis type 1 and, 1828
`Optic nerves, routing of, 133
`Oral cavity
`in lipoid proteinosis, 1487, 1487f
`physiology of, 1078-1079
`squamous cell carcinoma of, 741
`syphilitic chancre of, 2166-2167, 2167f
`Oral contraceptives
`acanthosis nigricans and, 1799
`for acne vulgaris, 681
`candidiasis and, 2007t
`cutaneous manifestations of, 1668-1669
`fixed drug eruptions, 1115
`for Fox-Fordyce disease, 710
`hair loss and, 638t
`hirsutism and, 651
`hyperpigmentation and, 873t
`Raynaud’s phenomenon and, 1765t
`Sweet’s syndrome and, 950t
`thrombophlebitis and, 1643, 1643t
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`
`FIGURE 205-18
`
`Tinea manus. Polycyclic pattern of an eruption composed of scaling vesi-
`cles vith involvement of the thumb nail; the nail exhibits destruction of
`the rail plate.
`
`include psoriasis, soft corns, bacterial coinfection, candidiasis, and
`erytiirasnia. The likelihood of candidal and bacterial infection increases
`witlv xhe severity of maceration, denudation, and pruritus.“ Unlike
`tinea pedis, erythrasma fluoresces coral red under a Wood lamp. The
`hypsi.
`l~(€I”£tl;0tlC type must be differentiated from psoriasis, hereditary or
`acquired keratodermas of the palms and soles, dyshydrosis, pityriasis
`rubra pilaris, and Rciter’s syndrome. Contact dermatitis may also be
`C0ns‘iered, although it more commonly affects the dorsal foot than
`tinea pedis. Children are more likely to have peridigital dermatitis or
`atopi
`dermatitis. Vesiculobullous or vesiculopustular presentations
`may be confused with pustular psoriasis, palmoplantar pustulosis, and
`bactcdal pyodcrmas.
`
`PREVENTION AND TREATMENT Minimizing chronic moisture is
`impc ‘iant in preventing tinea pedis. This may be achieved through tal-
`Cllm powder, absorbent socks, nonocclusive shoes, and. occasionally,
`20 tc 35% aluminum chloride hexahydrate powder. Antifungal pow-
`ders such as undecylenic acid and tolnaftate are also beneficial.” Mild
`interdigital tinea pedis without bacterial involvement can be treated top-
`ically with an allylarnine, azole, ciclopirox, tolnaftate, or undecenoic
`acid.“ Topical terbinafine for 1 week is 66 percent effective,53 while
`the 0: er topicals generally require 4 to 6 weeks of application.
`The newer oral antifungals have replaced griseofulvin as the treat-
`ments of choice for severe or refractory ti nea pedis. The dosing schedule
`Of terbinafine is 250 mg daily for 2 weeks. Effective regimens of itra-
`C0I1azole for adults are 200 mg twice daily for 1 week, 200 mg daily for
`3 WCC is, or 100 mg daily for 4 weeks,“ while children should receive
`5 mg/kg per day for 2 weeks.“ Fluconazole 150 mg weekly for 3 to
`4 wee..s or 50 mg daily for 30 days is also cffectivef“ Associated ony-
`°h0ID3'<:osis is common; if present, treatment of the onychomycosis is
`“eC€SSary to prevent recurrence of tinea pedis.
`M: seration, denudation, pruritus, and malodor obligate a Search
`f01‘ bacterial coinfection by Gram stain and culture. Antibiotics should
`
`CHAPTER 205
`
`Superficial Fungal Infections
`
`2001
`
`be started once bacterial infection is documented and chosen based
`
`therapy such as 0.25%
`on sensitivity studies. Adjunetive topical
`acetic acid for Pseudomonas and colorless Castellani’s paint are also
`helpful.
`Finally, because vesiculobullous tinea pedis is the result of a T cell-
`medialed immune reaction, symptomatic relief with topical or systemic
`corticosteroids may be warranted during the beginning of antifungal
`treatment.54
`
`ONYCHOMYCOSIS
`
`Onychomycosis denotes any infection of the nail caused by der1nato-
`phyte fungi, nondermatophyte fungi, or yeasts. Tinea unguium, how-
`ever. refers strictly to dermatophyte infection of the nail plate. The four
`clinical types of onychomycosis are: (1) distal subungual onychomy-
`cosis (DSO), (2) proximal subungual onychomycosis (PS0), (3) white
`superficial onychomycosis (WSO), and (4) candidal onychomycosis.
`
`Epidemiology
`
`Onychomycosis is a common infection, with a prevalence estimated
`at 2 to 18 percent worldwide and up to 48 percent incidence by age
`70.55 Higher rates of onychomycosis are associated with male gender,
`age, smoking, and peripheral arterial disease.“ Finally, 30 percent of
`patients with dermatophytoses elsewhere also have tinea unguium. The
`dermatophytosis commonly begins as tinea pedis before extending to
`the nail bed, where eradication is more difficult. This site then serves as
`a reservoir for recurrent distal infections, particularly in the setting of a
`hot and humid environment created by occlusion or tropical climates}
`
`Etiology and Pathogenesis
`
`The dermatophytes, especially 1". rubrtmr, T. menmgrophytcs Var. inter-
`digirale. 1". ronsurans, and E._fl0cc0sum, cause the great majority of ony-
`chomycosis. Table 205-5 categorizes the most likely causative dermato-
`phytes according to patterns of concurrent infection in other areas.57
`Yeasts arc the source of approximately 5 percent of onychomy-
`cosis, the majority of which is caused by Candida albicarz.s' and oc-
`curs in conjunction with chronic rnucocutaneous candidiasis. The non-
`dcrrnatophyte molds Acremomimt, Aspergillus, Fusarium, Onychocola
`carzadensis, Scapulariopsis brevicaulis, and Scyralidium dimidiatunz
`account for approximately 4 percent of onychomycosis.55 The non-
`dermatophyte molds appear to have a predilection for antecedently
`diseased or aged nails (Fig. 205-19).“
`
`TABLE 205-5
`
`Causative Organisms According to Anatomic Patterns
`of Infection
`
`Tinea unguium -l- tinea pedis and/or tinea corporis
`T. rubrum
`7'. mentagrophytes var. interdigita/e
`E. floccosum
`
`Tinea unguium + tinea capitis or favus
`I tonsurans
`T. vio/aceum
`T, megninii
`T. s('/voenleinii
`
`Tinea unguium + tinea imbricata
`T. concentricum
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`culture on SDA (with and without antimicrobials) are most useful. How-
`ever, microscopy is often negative even when there is a high clinical
`52 spicion of onychomycosis, and nails with positive microscopy often
`yield negative cultures. As most false—negatives are caused by sampling
`at or, the simplest measures to maximize yield are to maximize sample
`size and perform repeat collections.”
`Finally, because of the difficulty in discerning pathogens from con-
`ga-ninants. the following guidelines should be followed: (1) if adermato—
`phyte is isolated on culture, it is a pathogen; (2) if a nondermatophyte
`m ~ld or yeast is cultured, it is considered significant only if hyphae,
`spores, or yeast cells are seen on microscopic examination; and (3)
`ct. ifirmation of an infection by a nondermatophyte requires repeated
`isolation, classically defined as at least 5 of 20 inocula without concur-
`rent isolation of a dermatopbyte."°
`
`Pathology
`
`Hyphae are seen lying between the nail laminae parallel to the surface,
`wit .2 a predilection for the ventral nail and nail bed stratum corneum.‘“
`The epidermis may show spongiosis and focal parakeratosis and there
`is a minimal dermal inflammatory response. In WSO, the organisms
`are present superficially on the dorsal nail and display unique “perfo-
`rating organs” and “eroding fronds.” Candidal onychomycosis displays
`inv sion of pseudohyphae throughout the entire nail plate, adjacent
`cuticle, granular layer and stratum spinosum of the nail bed, and the
`hypanychial stratum corneum.58
`
`Ditferential Diagnosis
`
`A variety of disorders may cause nail changes similar to or1ychomyco-
`sis, ncluding hand eczema, pachyonychia congenita, Daricr’s disease.
`Reiter’s syndrome, lichen planus, exfoliative dermatitis, and Norwe-
`giai scabies. Neither the pitting produced by psoriasis nor the typi-
`callv transverse ridges seen in the dystrophic nails of hand eczema are
`seen with fungal nail infections. Otherwise, most of the above disor-
`derr‘ ire differentiated by related skin findings and history. WSO must
`be distinguished from the acquired and congenital leukonychias. All
`leul
`tnychia of the fingernails not WSO.
`
`Treatment
`
`The only effective topical agent for tinea unguium is cielopirox
`(8% lacquer) applied daily for 48 weeks. When used for mild to
`moderate disease, it is 34 percent effective in achieving mycologic
`cure alone and 7 percent effective in achieving mycologic cure and
`clear nails.“ Despite its poorer efficacy when compared to the newer
`Oral antifungals, topical ciclopirox is more cost effective because of
`its r.e'=atively low cost.“
`Ural anti fungals may be used for refractory, severe, or nondermato-
`phyt : onychomycosis, or when a shorter treatment regimen is desired.
`Selecting an antifungal should be based primarily on the causative
`0rga;.lsm, potential adverse effects, and drug interactions. As potent in-
`hibitors of cytochrome P450 3A4, the azole antifungals are contraindi-
`Gated with drugs such as astemizole, terfenadine, lovastatin, simvas—
`tatin. ‘riazolam, and midazolam. Baseline and interval testing of liver
`enzymes is prudent for each agent discussed below.
`Taxbinafinc is fungicidal against dermatophytes, Aspergilltis, and
`5C0pz!larz'0psis, but demonstrates variable activity against Candida
`Species. A course of 250 mg daily for 6 weeks is effective for most
`_fiHge"'iail infections, while a l2-week course is required for toenail
`infections. Most adverse effects are gastrointestinal, and cytochrome
`P450 hteractions are insignificant.
`ltraconazole is fungistatic against dermatophytes, nondermatophyte
`m0ldc,, and yeasts. Safe and effective schedules include pulse dosing
`at 409 mg daily for 1 week per month or a continuous dose of 200 mg
`daily, both of which require 2 months of treatment for fingernails and
`
`CHAPTER 205
`
`Superficial Fungal Infections
`
`2003
`
`3 months for toenails.“ Children may receive 5 mg/kg daily.45 Elevated
`liver enzymes occur in 0.3 to 5 percent of patients, returning to normal
`within 12 weeks of discontinuation.
`
`Fluconazole is fungistatic against dermatophytes, some nonder-
`matophyte molds, and Candida. The usual dosage is l50 to 300 mg
`once per week for 3 to 12 months, although 450 mg weekly may be
`used in refractory onychomycosis. Adverse effects include gastroin-
`testinal disturbance and elevated liver enzymes.”
`Griscofulvin is no longer considered standard treatment for ony-
`chomycosis because of its adverse effects, drug interactions, prolonged
`treatment course, and low cure rates. Final options for refractory cases
`include surgical avulsion or chemical removal of the nail with 40% urea
`compounds in combination with topical or oral antifungals.“
`
`TINEA NIGRA
`
`Tinea nigra is a rare infection, usually of the palmar stratum corneum,
`caused by the nondermatophyte Phaeoarmellomyces wemeckii (for-
`merly called Exophia/a werneckii).
`
`Epidemiology
`
`Tinea nigra usually occurs in tropical or subtropical areas, including
`Central and South America, Africa, and Asia. Of the approximately
`150 cases reported in North America since 1950, the majority were asso-
`ciated with tropical travel.“ However, endemic foci exist in the coastal
`southeastern United States. Person-to—person transmission is rare.“
`
`Etiology
`
`Nearly always caused by Phaeoannellomyces werneckii, other demati—
`aceous fungi may produce the disease. Szenella aragmzta, for example,
`has been isolated from clinical Linea nigra. Such dematiaceous fungi are
`commonly found in soil, sewage, and decaying vegetation,“ although
`P. werneckii was also recently isolated from the surfaces of rocks in the
`Mediterranean and Northern Europe.“
`
`Clinical Manifestations
`
`Tinea nigra presents as an asymptomatic, mottled brown to greenish-
`black macule with minimal to no scale (Fig. 205-23). The macule is
`often darkest at the advancing border. Although usually seen on the
`palm or ventral surface of the fingers, plantar involvement is possible.
`
`Laboratory Findings
`
`KOH examination of scrapings from the lesion reveals brown to olive-
`colored hyphae and oval to spindle-shaped yeast cells occurring singly
`or in pairs with a central transverse septum. Cultures may be per-
`formed on SDA with cycloheximide and chloramphenicol. Growth is
`initially yeastlike and brown to shiny black, appearing as the typi-
`cal two—celled yeast forms under microscopic examination. With time,
`myeelial growth predominates as aerial hyphae create a fuzzy grayish-
`black colony. Deeply pigmented, thick, septate hyphae 7 to 10 am in
`diameter are seen microscopically.
`
`Pathology
`
`Skin biopsy shows brown, branching hyphae in the upper stratum
`comeum on hematoxylin and eosin stain. Hyperkeratosis is present
`without dermal inflammation.
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`2342
`
`SECTION THIRTY-FIVE
`
`Topical Therapy
`
`of topical terbinaiine with clotrimazole in the treatment of tinea pedis, a
`significantly higher cure rate and lower relapse rate for terbinafine was
`reported.“”” In summary, topical allylamines, especially terbinafine,
`are marginally superior to topical imidazoles in cure rates and probably
`require shorter duration of therapy. Terbinatine is now available over
`the counter.
`
`Butenafine, the newest topical antifungal agent, is the only 1nem-
`ber of the benzylamine class of antifungals. It is structurally similar to
`the allylamines, and like the allylamines. it works by inhibiting squa-
`lene epoxidase. Like the allylamines it is both fungistatic and fungici-
`dal. The minimal fungicidal concentrations for butenafi ne are 4 to 130
`times lower than for naftifine, tolnaftate, clotrimazole, and bifonazole. 18
`Like the allylamines, this drug also demonstrates anti-inflammatory ef-
`fects as measured by reduced cutaneous erythema in response to UVB
`irradiation.” Results in clinical trials suggest that it is very similar to
`the allylamines in terms of clinical responses.
`Tinea unguium is the third major category of superficial dermato-
`phytoses. Although pharmacokinetic studies demonstrate that imida-
`zoles and allylamines are capable of penetrating the nail plate in con-
`centrations sufficient to exceed the MlCs of most dermatophytes,2° they
`typically fail to produce clinical cures. A prescription product composed
`of triaeetin, sodium propionate, benzalkonium chloride, cetylpyridium
`chloride, and chloroxylenol has been marketed in a tincture base (Fun-
`goid) for the treatment of onychomycosis. An uncontrolled study has
`reported a l00 percent cure rate after 12 months of treatment; how-
`ever, treatment also included monthly nail débridement and there was
`only a 2-mo11th follow—up. Because of its excellent penetration of the
`nail plate, ciclopirox nail lacquer 8% solution was developed and intro-
`duced for the topical treatment of onychomycosis. The most commonly
`used treatment regimen is to apply the lacquer to the affected nail once
`per day for 48 weeks. The reported mycologic cure rates have ranged
`from 29 to 85.7 percent with the meta—analytic average cure rate being
`53 percent. The reported relapse rate is 21 percent.“ Ciclopirox nail
`lacquer has an advantage over systemic antifungal agents in that it does
`not require physician monitoring, laboratory testing is not required, and
`it has a reduced cost per mycologic cure.“
`
`rable in efficacy, but more recent studies suggest that imidazole drugs
`are more effective than nystatin in vaginal candidiasis.” This may be
`related to the increased nystatin resistance which is now obserw 3 in
`up to 20 percent of isolates. Nystatin resistance may be encountered in
`wild strains (primary resistance) but may also be induced during .:tet~.
`apy (secondary resistance). Nystatin and amphotericin, while effective
`against candidial infections, are not effective against dermatophytes,
`Topical imidazoles are the mainstay of topical therapy for car;‘idj_
`asis. Imidazoles are available as lotions, creams, and troches (elotri-
`tnazole). Clotrimazole troches are used for the management of oral
`candidiasis, a11d imidazole lotions and creams are used for superficial
`cutaneous candidiasis. The susceptibility of different strains of L. a].
`bicans to imidazolcs is highly variable (MIC of 0.5 to 100 ug/*:tL),
`The implication of this difference in susceptibility to imidazoles has
`not been studied to determine if it is clinically significant in terr s of
`response rates. All of the topical imidazoles are clinically and mvco-
`logically effective in treating superficial candidal infections and Cat‘) be
`used interchangeably. As discussed in the management of derrnatophyte
`infections, there is evidence to suggest that clotrimazole and micona-
`zole are potentially initating and may not be the preferred imida ales
`in sensitive flexural areas infected with Candida.
`
`Ciclopirox olamine, like the imidazoles, is a broad-spectruir». an-
`timycotic drug that is effective against Candida species. Ciclowirox
`olamine is indicated for the management of cutaneous candidial infec-
`tions but it does not come in formulations for oral use. Head-tofilead
`
`studies comparing this drug to the topical imidazoles have not been
`done, but ciclopirox olamine appears to be equivalent to the topical
`imidazoles in terms of clinical efficacy.
`Topical allylamines (naftifine, terbinafinc) demonstrate moderate
`activity against yeast,
`including Candida species. In vitro st" dies
`demonstrate that Candida species are more sensitive to the imidazole
`class of drugs than the allylarrtinesg Despite the higher measur .:l in
`vitro MICs for yeasts, clinical studies have demonstrated that most cases
`of cutaneous candidiasis can be successfully treated with topical ally-
`lamines; they compare with topical imidazoles in terms of mycafrtgic
`cure. Despite the therapeutic efficacy of the allylamines, they should
`not be considered as a primary topical therapy for candidiasis be ruse
`they are expensive, have not received approval for this indication. and
`demonstrate less—favorable MlCs.
`
`CANDIDIASIS (CANDIDOSIS)
`
`PITYROSPORUM (MALASSEZIA) INFECTIO. SS
`
`Candida albicans is the primary pathogen in most cases of superfi-
`cial candidiasis, although other species, such as C. parapsilosis and
`C. guillzerrnondii, may also produce infection (see Chap. 206). Can-
`dida species are commensal organisms that usually require a change in
`the host milieu, usually alterations in nutrition (e.g.. diabetes mellitus),
`microbial flora (e.g., antibiotic therapy), or host immune defenses (e.g.,
`neutropenia) to produce infections. This is an important consideration
`in assessing the efficacy of topical therapies, since the recurrence rate
`is very high if the underlying disease is not corrected.
`Before the advent of the imidazoles, the polyenes were the mainstay
`of topical candidial therapy. There are more than 80 polyene antibiotics.
`but only nystatin and amphotericin B have been used as topical agents.
`Polyene antimycotics are primarily fungistatic at low concentrations
`and fungicidal at high concentrations. They act by binding irreversibly
`with ergosterol in the cell membrane, which leads to altered cellular per-
`meability and leakage of cell contents. Nystatin is available in powder,
`suspension, lozenges. and as creams for topical therapy. The suspension
`and lozenge formulations are used for oral candidiasis, and the powder
`and creams are used for cutaneous infections. Older studies comparing
`topical nystatin with imidazoles suggested that the two were compa-
`
`Piryrosparum orbiculare is a lipophilic yeast that produces superficial
`fungal infections in the form of tinea (pityriasis) versicolor and less
`commonly, as a folliculitis (see Chap. 206). Because these two forms
`of infection respond to the same topical therapies, they are dlSCL.l>Sed
`together. Because this yeast is a normal component of the skin flora,
`its total eradication is usually not possible by using topical therapies.
`The ubiquitous nature of the organism also accounts for the high 7' ‘Cuf-
`rence rate following treatment. For this reason, it is difficult to compare
`different studies since the follow—up periods are usually of difj rent
`lengths. Patients with extensive involvement are usually best treated
`with oral antimycotics, whereas patients with limited involvement may
`be treated with either systemic or topical antimycotics. A num‘t— '11‘ Of
`less—eonventional agents that are notregarded as antimycotics have been
`reported in the literature, including salicylic acid, propylene glycci
`and
`zinc pyrithione. These are not discussed because they do not appear to
`offer significant advantages over specific antimycotic agents.
`Selenium sulfide (2.5%) lotion has been shown in uncontrolled and
`controlled studies to be useful in the management of both tinea VET‘
`sicolor and Pityrospormrz folliculitis. A variety of different me ‘Dds
`and durations of applications have been utilized but one of the 11105‘
`
`CFAD V. Anacor, |PR20’|5-01776 ANACOR EX. 2160 - 7/1 7
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2160 - 7/17
`
`

`

`CHAPTER 261
`
`Nellie Konnikov
`
`Helen Raynham
`
`Oral Antifungal Agents
`
`Oral antifun gal agents are now widely and frequently used for the treat-
`ient of superficial fungal infections} The first and the only synthetic
`agent was griseofulvin. Subsequently, other drugs, including amphe-
`taricin B and ketoconazole, were introduced. As a result of recent
`advances in antifungal chemotherapy, new drugs with a broad spec-
`trum of activity, high efficacy, tolerability, and rare, mild side effects
`4 re now available. The three newer, released oral antifungal agents are
`the first oral allylarnine, terbinafine, and the triazoles fluconazole and
`. raconazole.
`
`ALLYLAMINES
`
`Terbinafine
`
`Terbinafine hydrochloride is a synthetic antimycotic agent that belongs
`t a new family of compounds known as the allylamines. All allylamine
`derivatives possess a tertiary allylamine, a structural component crucial
`for antifungal activity (Fig. 261-l).2 In vitro the drug is primarily a
`f’ ingicidal agent and highly active against dermatophytes, but less active
`against molds, dimorphic fungi, and various yeasts.
`
`PHARMACOLOGY Terbinafine is well absorbed from the gastroin-
`testinal
`tract, mostly in chylomicrons. The distribution half-life is
`l 5 h, and the elimination half-life is approximately 22 h.3 Terbinafine
`is highly lipophilic and keratophilic in nature and,
`therefore,
`is
`\— idely distributed upon absorption throughout skin and adipose tissue.
`Terbinafine is extensively biotransformed by the liver, mostly through
`oxidation by a very small fraction of P450 isoenzymes. More than
`E93 percent of the drug is excreted in urine; the rest is eliminated with
`feces.4
`
`MECHANISM OF ACTION Terbinafine inhibits the enzyme squa-
`lene epoxidase in the fungal membrane, thereby blocking the biosyn-
`
`FIGURE 261-1
`
`Terbinafine.
`
`thesis of ergosterol.5 Squalene epoxidase, a complex, microsomal,
`noncytochrome P450 enzyme, catalyzes the first enzymatic step of
`ergosterol synthesis—the conversion of squalene into squalene epox-
`ide. Consequently, terbinafine causes an abnormal intracellular accu-
`mulation of squalene and deficiency in ergosterol.“ Accumulation of
`squalene accounts for the drug’s fungicidal activity, whereas in vitro
`deficiency of ergosterol
`is associated with the drug’s fungistatic
`activity.“
`
`CLINICAL USES
`
`For the treatment of tinea capitis in children, the dosage
`Pediatric
`guidelines are 3 to 6 mg/kg per day.7 Children weighing 10 to 20 kg
`can be given 62.5 mg/day; children Weighing 20 to 40 kg can be given
`125 mg/day; and those children weighing more than 40 kg can be
`given 250 mg/day.3 The treatment course for Trichophyton infections is
`4 weeks.
`In a study of tinea capitis in children, comparing a
`4-week course of terbinafine with an 8-week course of griseofulvin
`(10 mg/kg day), oral terbinafine was shown to have efficacy similar to
`griseofulvin.” Other studies suggest that for treatment of M. canis with
`terbinafine, 6 or more weeks may be needed.8"°
`Adult Terbinafine is indicated for the treatment of onychomycosis
`of the toenails and fingernails caused by derrnatophytes." In a study
`comparing continuous terbinafine with intermittent itraconazole in the
`treatment of toenail onychomycosis, terbinafine was significantly more
`effective than itraconazole in the treatment of toenail dermatophyte
`onychomycosis.” At week 72, the mycologic cure in those patients
`treated with a 3-month course of terbi nafi ne was 75.5 percent, compared
`with a mycologic cure rate of 38.3 percent in those patients treated
`with a 3-month course of intermittent pulse therapy with itraconazole.
`Terbinafine is superior to itraconazole in maintaining mycologic and
`clinical cure for at least 2 years after completion of therapy.” In a study
`of 22 patients with tinea corporis and tinea cruris who used terbinafine
`250 mg daily for 1 week, l00 percent clinical and mycologic clearing
`was observed at 6 weeks.” In a study of moccasin tinea pedis and tinea
`manuum, after a 2-week c