British Journal of Dermatology 2003; 148: 402–410.
`
`GUIDELINES
`
`Guidelines for treatment of onychomycosis
`
`D . T . R O B E R T S , W . D . T A Y L O R * A N D J . B O Y L E  
`Southern General Hospital, Glasgow G51 4TF, U.K.
`*James Cook University Hospital, Middlesbrough, Cleveland TS4 3BW, U.K.
` Taunton and Somerset Hospital, Taunton TA1 5DA, U.K.
`
`Accepted for publication 9 October 2002
`
`Summary
`
`These guidelines for management of onychomycosis have been prepared for dermatologists on
`behalf of the British Association of Dermatologists. They present evidence-based guidance for
`treatment, with identification of the strength of evidence available at the time of preparation of the
`guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
`
`Disclaimer
`
`These guidelines have been prepared for dermatologists
`on behalf of the British Association of Dermatologists
`and reflect the best data available at the time the report
`was prepared. Caution should be exercised in interpre-
`ting the data; the results of future studies may require
`alteration of the conclusions or recommendations in
`this report. It may be necessary or even desirable to
`depart from the guidelines in the interests of specific
`patients and special circumstances. Just as adherence
`to guidelines may not constitute defence against a
`claim of negligence, so deviation from them should not
`necessarily be deemed negligent.
`
`Introduction
`
`Onychomycosis is one of the commonest dermatolog-
`ical conditions. A large questionnaire survey of 10 000
`people suggested a prevalence of 2Æ71% in the U.K.1,2
`More recent mycologically controlled surveys in Fin-
`land3 and in the U.S.A.4 indicate a prevalence of
`between 7 and 10%. Increasing publicity about disease
`prevalence, and the advent of new and more effective
`antifungal drugs, has led to a greater enthusiasm
`
`Correspondence: D.T.Roberts.
`E-mail: dai.roberts@sgh.scot.nhs.uk
`
`These guidelines were commissioned by the British Association of
`Dermatologists Therapy Guidelines and Audit subcommittee. Mem-
`bers of
`the committee are N.H.Cox (Chairman), A.V.Anstey,
`C.B.Bunker, M.J.D.Goodfield, A.S.Highet, D.Mehta, R.H.Meyrick
`Thomas, A.D.Ormerod, J.K.Schofield and C.H.Smith.
`
`among sufferers to seek treatment and among medical
`practitioners to institute therapy. However, treatment
`is often prescribed without mycological confirmation of
`infection, there may be confusion as to whether fungi
`isolated on culture are primary or secondary patho-
`gens, the relative efficacy of different antifungal agents
`against different fungi
`is not completely understood
`and drugs are often prescribed for inappropriate treat-
`ment durations.
`
`Definition
`
`Onychomycosis is an infection of the nail apparatus by
`fungi that include dermatophytes, nondermatophyte
`moulds and yeasts (mainly Candida species). The
`toenails are affected in 80% of all cases of onychomy-
`cosis; dermatophyte infection, mostly due to Trichophy-
`ton rubrum, is the cause in over 90% of cases.5
`Onychomycosis is classified clinically as distal and
`lateral subungual onychomycosis (DLSO), superficial
`white onychomycosis
`(SWO), proximal
`subungual
`onychomycosis (PSO), candidal onychomycosis and
`total dystrophic onychomycosis.
`
`Distal and lateral subungual onychomycosis
`
`DLSO accounts for the majority of cases and is almost
`always due to dermatophyte infection. It affects the
`hyponychium, often at the lateral edges initially, and
`spreads proximally along the nail bed resulting in
`subungual hyperkeratosis and onycholysis although
`the nail plate is not initially affected. DLSO may be
`
`402
`
`Ó 2003 British Association of Dermatologists
`
`Page 1 of 9
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1503
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`British Journal of Dermatology 2003; 148: 402–410.
`
`GUIDELINES
`
`Guidelines for treatment of onychomycosis
`
`D . T . R O B E R T S , W . D . T A Y L O R * A N D J . B O Y L E  
`Southern General Hospital, Glasgow G51 4TF, U.K.
`*James Cook University Hospital, Middlesbrough, Cleveland TS4 3BW, U.K.
` Taunton and Somerset Hospital, Taunton TA1 5DA, U.K.
`
`Accepted for publication 9 October 2002
`
`Summary
`
`These guidelines for management of onychomycosis have been prepared for dermatologists on
`behalf of the British Association of Dermatologists. They present evidence-based guidance for
`treatment, with identification of the strength of evidence available at the time of preparation of the
`guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
`
`Disclaimer
`
`These guidelines have been prepared for dermatologists
`on behalf of the British Association of Dermatologists
`and reflect the best data available at the time the report
`was prepared. Caution should be exercised in interpre-
`ting the data; the results of future studies may require
`alteration of the conclusions or recommendations in
`this report. It may be necessary or even desirable to
`depart from the guidelines in the interests of specific
`patients and special circumstances. Just as adherence
`to guidelines may not constitute defence against a
`claim of negligence, so deviation from them should not
`necessarily be deemed negligent.
`
`Introduction
`
`Onychomycosis is one of the commonest dermatolog-
`ical conditions. A large questionnaire survey of 10 000
`people suggested a prevalence of 2Æ71% in the U.K.1,2
`More recent mycologically controlled surveys in Fin-
`land3 and in the U.S.A.4 indicate a prevalence of
`between 7 and 10%. Increasing publicity about disease
`prevalence, and the advent of new and more effective
`antifungal drugs, has led to a greater enthusiasm
`
`Correspondence: D.T.Roberts.
`E-mail: dai.roberts@sgh.scot.nhs.uk
`
`These guidelines were commissioned by the British Association of
`Dermatologists Therapy Guidelines and Audit subcommittee. Mem-
`bers of
`the committee are N.H.Cox (Chairman), A.V.Anstey,
`C.B.Bunker, M.J.D.Goodfield, A.S.Highet, D.Mehta, R.H.Meyrick
`Thomas, A.D.Ormerod, J.K.Schofield and C.H.Smith.
`
`among sufferers to seek treatment and among medical
`practitioners to institute therapy. However, treatment
`is often prescribed without mycological confirmation of
`infection, there may be confusion as to whether fungi
`isolated on culture are primary or secondary patho-
`gens, the relative efficacy of different antifungal agents
`against different fungi
`is not completely understood
`and drugs are often prescribed for inappropriate treat-
`ment durations.
`
`Definition
`
`Onychomycosis is an infection of the nail apparatus by
`fungi that include dermatophytes, nondermatophyte
`moulds and yeasts (mainly Candida species). The
`toenails are affected in 80% of all cases of onychomy-
`cosis; dermatophyte infection, mostly due to Trichophy-
`ton rubrum, is the cause in over 90% of cases.5
`Onychomycosis is classified clinically as distal and
`lateral subungual onychomycosis (DLSO), superficial
`white onychomycosis
`(SWO), proximal
`subungual
`onychomycosis (PSO), candidal onychomycosis and
`total dystrophic onychomycosis.
`
`Distal and lateral subungual onychomycosis
`
`DLSO accounts for the majority of cases and is almost
`always due to dermatophyte infection. It affects the
`hyponychium, often at the lateral edges initially, and
`spreads proximally along the nail bed resulting in
`subungual hyperkeratosis and onycholysis although
`the nail plate is not initially affected. DLSO may be
`
`402
`
`Ó 2003 British Association of Dermatologists
`
`Page 1 of 9
`
`

`

`G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S
`
`4 0 3
`
`confined to one side of the nail or spread sideways to
`involve the whole of the nail bed, and progresses
`relentlessly until
`it reaches the posterior nail
`fold.
`Eventually the nail plate becomes friable and may
`break up, often due to trauma, although nail destruc-
`tion may be related to invasion of
`the plate by
`dermatophytes that have keratolytic properties. Exam-
`ination of the surrounding skin will nearly always
`reveal evidence of tinea pedis. Toenail infection is an
`almost inevitable precursor of fingernail dermatophy-
`tosis, which has a similar clinical appearance although
`nail thickening is not as common.
`
`Superficial white onychomycosis
`
`SWO is also nearly always due to a dermatophyte
`infection, most commonly T. mentagrophytes. It is much
`less common than DLSO and affects the surface of the
`nail plate rather than the nail bed. Discoloration is
`white rather than cream and the surface of the nail
`plate is noticeably flaky. Onycholysis is not a common
`feature of SWO and intercurrent foot infection is not as
`frequent as in DLSO.
`
`Proximal subungual onychomycosis
`
`PSO, without evidence of paronychia, is an uncommon
`variety of dermatophyte infection often related to inter-
`current disease. Immunosuppressed patients, notably
`those who are human immunodeficiency virus-posit-
`ive, may present with this variety of dermatophyte
`infection; conditions such as peripheral vascular dis-
`ease and diabetes also may present
`in this way.
`Evidence of
`intercurrent disease should therefore be
`considered in a patient with PSO.
`
`Candidal onychomycosis
`
`Infection of the nail apparatus with Candida yeasts may
`present in one of four ways: (i) chronic paronychia
`with secondary nail dystrophy; (ii) distal nail infection;
`(iii) chronic mucocutaneous candidiasis; and (iv) sec-
`ondary candidiasis.
`Chronic paronychia of the fingernails generally only
`occurs in patients with wet occupations. Swelling of the
`posterior nail fold occurs secondary to chronic immer-
`sion in water or possibly due to allergic reactions to some
`foods, and the cuticle becomes detached from the nail
`plate thus losing its water-tight properties. Microorgan-
`isms, both yeasts and bacteria, enter the subcuticular
`space causing further swelling of the posterior nail fold
`
`and further cuticular detachment, i.e. a vicious circle.
`Infection and inflammation in the area of the nail matrix
`eventually lead to a proximal nail dystrophy.
`Distal nail infection with Candida yeasts is uncom-
`mon and virtually all patients have Raynaud’s phe-
`nomenon or some other form of vascular insufficiency.
`It is unclear whether the underlying vascular problem
`gives rise to onycholysis as the initial event or whether
`yeast
`infection causes
`the onycholysis. Although
`candidal onychomycosis cannot be clinically differen-
`tiated from DLSO with certainty, the absence of toenail
`involvement and typically a lesser degree of subungual
`hyperkeratosis are helpful diagnostic features.
`Chronic mucocutaneous candidiasis has multifacto-
`rial aetiology leading to diminished cell-mediated
`immunity. Clinical signs vary with the severity of
`immunosuppression, but in more severe cases gross
`thickening of the nails occurs, amounting to a Candida
`granuloma. The mucous membranes are almost always
`involved in such cases.
`Secondary candidal onychomycosis occurs in other
`diseases of the nail apparatus, most notably psoriasis.
`
`Total dystrophic onychomycosis
`
`Any of the above varieties of onychomycosis may
`eventually progress to total nail dystrophy where the
`nail plate is almost completely destroyed.
`
`Diagnosis
`
`This section follows the criteria set out by Evans and
`Gentles.6 Treatment should not be instituted on clinical
`grounds alone. Although 50% of all cases of nail
`dystrophy are fungal in origin it is not always possible
`to identify such cases accurately. Treatment needs to be
`administered long-term and enough time must elapse
`for the nail
`to grow out completely before such
`treatment can be designated as successful. Toenails
`take around 12 months to grow out and fingernails
`about 6 months. This is far too long to await the results
`of therapeutic trial and, in any case, treatment is not
`always successful. If the diagnosis is not confirmed, and
`improvement does not occur, it is impossible to tell
`whether this represents treatment failure or an initial
`incorrect diagnosis. Although the cost of diagnostic
`tests may be deemed high at
`times of budgetary
`constraint, the cost is always small relative to inappro-
`priate and unnecessary treatment.
`Laboratory diagnosis consists of microscopy to
`visualize fungal elements in the nail sample and
`
`Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410
`
`Page 2 of 9
`
`

`

`4 0 4
`
`D . T . R O B E R T S et al.
`
`culture to identify the species concerned. The success
`or otherwise of such tests depends upon the quality of
`the sample, the experience of the microscopist and the
`ability of
`the laboratory to discriminate between
`organisms that are likely pathogens, organisms grow-
`ing in the nail as saprophytes, and contamination of
`the culture plate.
`Given that dermatophyte onychomycosis is primarily
`a disease of the nail bed rather than of the nail plate,
`subungual debris taken from the most proximal part of
`the infection is likely to yield the best results. In DLSO
`material can be obtained from beneath the nail: a small
`dental scraper is most useful for this purpose. If the nail
`is onycholytic then this can be cut back and material
`can be scraped off the underside of the nail as well as
`from the nail bed. As much material as possible should
`be submitted to the laboratory because of the relative
`paucity of
`fungal elements within the specimen. In
`SWO the surface of the infected nail plate can be
`scraped and material examined directly. PSO is rare
`and again should be scraped with a scalpel blade.
`However, punch biopsy to obtain a sample of the full
`thickness of nail together with the nail bed may be
`necessary. Some of the material obtained is placed on a
`glass slide and 20% potassium hydroxide added. Fifteen
`to 20 min should be allowed to elapse before examin-
`ing the sample by direct microscopy. The addition of
`Parker’s blue ⁄ black ink may enhance visualization of
`the hyphae. An inexperienced observer may very well
`misdiagnose cell walls as hyphae and care should be
`taken to examine all of the specimen as fungal elements
`within the material may be very scanty.
`The remaining material should be cultured on
`Saboraud’s glucose agar, usually with the addition of
`an antibiotic. The culture plate is incubated at 28 °C
`for at least 3 weeks before it is declared negative, as
`dermatophytes tend to grow slowly.
`Direct microscopy can be carried out by the clinician,
`and higher specialist training includes teaching of this
`technique. However, nail microscopy is difficult and
`should only be carried out by those who do it on a
`regular basis. Fungal culture should always be carried
`out in a laboratory experienced in handling mycology
`specimens, because of potential pitfalls in interpretation
`of cultures. It must be remembered that the most
`common cause of treatment failure in the U.K.
`is
`incorrect diagnosis, which is usually made on clinical
`grounds alone. This should not be further compounded
`by incorrect laboratory interpretation of results.
`Histology is almost never required and its use is
`usually confined to other causes of nail dystrophy.
`
`Such dystrophies, notably psoriasis, regularly yield
`Candida yeasts on culture but they are rarely causal in
`aetiology of fungal nail infection.
`
`Reasons for treatment
`
`Although dermatophyte onychomycosis is relentlessly
`progressive there remains a view among some practi-
`tioners that it is a trivial cosmetic problem that does not
`merit treatment. In the elderly the disease can give rise
`to complications such as cellulitis and therefore further
`compromise the limb in those with diabetes or periph-
`eral vascular disease. While these complications may
`not be common they are certainly serious. The high
`prevalence of
`the disease is the result of heavy
`contamination of communal bathing places7 by infec-
`ted users; disinfecting the floors of such facilities is very
`difficult because fungal elements are protected in small
`pieces of keratin. It is therefore logical to try to reduce
`the number of infected users by effective treatment and
`thus reduce disease prevalence. Finally, onychomycosis
`is a surprisingly significant cause of medical consulta-
`tion and of absence from work.8
`Onychomycosis should not therefore be considered a
`trivial disease, and there is a sound case for treatment
`on the grounds of complications, public health consid-
`erations and effect on quality of life.
`
`Treatment
`
`Introduction
`
`Both topical and oral agents are available for the
`treatment of fungal nail infection. The primary aim of
`treatment is to eradicate the organism as demonstrated
`by microscopy and culture. This is defined as the
`primary end-point in almost all properly conducted
`studies. Clinical
`improvement and clinical cure are
`secondary end-points based on a strict scoring system
`of clinical abnormalities in the nail apparatus. It must
`be recognized that successful eradication of the fungus
`does not always render the nails normal as they may
`have been dystrophic prior to infection. Such dystrophy
`may be due to trauma or nonfungal nail disease; this is
`particularly likely in cases where yeasts or nondermat-
`ophyte moulds (secondary pathogens and saprophytes,
`respectively) are isolated.9
`Invariably mycological cure rates are about 30%
`better than clinical cure rates in the majority of studies,
`the clinical cure rates often being below 50%. Publi-
`cations of clinical trials in onychomycosis are often
`
`Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410
`
`Page 3 of 9
`
`

`

`G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S
`
`4 0 5
`
`criticized for quoting mycological cure rates and thus
`overemphasizing the efficacy of treatment. While it is
`understood that the patient is more concerned with
`improvement in the clinical appearance of the nail
`rather than eradication of the organism, questions
`regarding patients’ satisfaction at the end of a study
`usually mirror very closely the mycological cure rate.
`This suggests that eradication of the organism does
`restore the nail to its previous state prior to infection
`even though that state may not be completely ÔnormalÕ
`as defined by a scoring system.
`Systemic therapy is almost always more successful
`than topical treatment, which should only be used in
`SWO, possibly very early DLSO or when systemic
`therapy is contraindicated.
`
`Topical therapy
`
`topical antifungal preparations
`There are several
`available both as prescription-only medicines and on
`an over-the-counter basis. The active antifungal agent
`in these preparations is either an imidazole, an allyl-
`amine or a polyene, or a preparation that contains a
`chemical with antifungal, antiseptic and sometimes
`keratolytic properties such as benzoic acid, benzyl
`peroxide, salicylic acid or an undecenoate. Products
`that are specifically indicated for nail
`infection are
`available as a paint or lacquer that is applied topically.
`There are four such preparations (Table 1).
`There are no published studies on the efficacy of
`salicylic acid (PhytexÒ; Pharmax, Bexley, U.K.) and
`methyl undecenoate (MonphytolÒ; LAB, London, U.K.)
`in fungal nail
`infection and their use cannot be
`recommended.
`Amorolfine (LocerylÒ; Galderma, Amersham, U.K.)
`nail lacquer has been shown to be effective in around
`50% of cases of both fingernail and toenail infection in
`a large study where only cases with infections of the
`distal portion of the nail were treated.10 There are
`several published studies examining the efficacy of
`tioconazole (TrosylÒ; Pfizer, Sandwich, U.K.) nail solu-
`tion, with very variable results ranging from cure rates
`of around 20% up to 70%.11 While it is clearly possible
`
`to achieve clinical and mycological cure with topical
`nail preparations, these cure rates do not compare
`favourably with those obtained with systemic drugs.
`Currently, topical therapy can only be recommended
`for the treatment of SWO and in very early cases of
`DLSO where the infection is confined to the distal edge
`of the nail.
`A combination of topical and systemic therapy may
`improve cure rates still further or possibly shorten the
`duration of therapy with the systemic agent. Thus far
`the results of such studies are inconclusive. A study
`comparing terbinafine and amorolfine with terbinafine
`alone produced somewhat idiosyncratic results12 and
`was not properly blinded, so further evidence from
`well-controlled double-blind studies is required before
`combination therapy can be advocated.
`Although there are no studies comparing one topical
`preparation with another in a properly controlled
`fashion, it is likely that amorolfine nail lacquer (Loce-
`rylÒ) is the most effective preparation of those avail-
`able.
`
`Systemic therapy
`
`The three drugs currently licensed for general use in
`onychomycosis are listed in Table 2. The two other
`systemic agents available for oral use, ketoconazole and
`fluconazole, are not licensed for nail infection. Ketocon-
`azole may be used in some recalcitrant cases of yeast
`infection affecting the nails but cannot be prescribed for
`dermatophyte onychomycosis because of problems with
`hepatotoxicity. The use of fluconazole thus far has
`concentrated on vaginal candidiasis and systemic yeast
`infections although it is active against dermatophytes.
`There are some published studies of
`its use in nail
`infection but the dose and duration of treatment are
`not yet clear and it is not licensed for this indication in
`the U.K., nor does it appear likely to be so in the near
`future.
`
`Griseofulvin. Griseofulvin (FulcinÒ; GrisovinÒ; Glaxo-
`SmithKline, Uxbridge, U.K.) is weakly fungistatic, and
`acts by inhibiting nucleic acid synthesis, arresting cell
`
`Table 1. Topical agents for onychomycosis, with strength of recommendation and quality of evidence grading
`
`Agent
`Amorolfine (LocerylÒ; Galderma, Amersham, U.K.) nail lacquer
`Tioconazole (TrosylÒ; Pfizer, Sandwich, U.K.) nail solution
`Salicylic acid (PhytexÒ; Pharmax, Bexley, U.K.) paint
`Undecenoates (MonphytolÒ; LAB, London, U.K.) paint
`
`Strength of recommendation and quality of evidence
`
`Strength of recommendation B, Quality of evidence II-ii
`Strength of recommendation C, Quality of evidence II-iii
`Strength of recommendation E, Quality of evidence IV
`Strength of recommendation E, Quality of evidence IV
`
`Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410
`
`Page 4 of 9
`
`

`

`division and inhibiting fungal cell wall synthesis.13–15
`It is available in tablet form and is the only antifungal
`agent licensed for use in children with onychomycosis,
`with a recommended dose for age groups of 1 month
`)1 daily. It requires to be taken
`and above of 10 mg kg
`with fatty food to increase absorption and aid bioavail-
`ability. In adults the recommended dose is 500 mg
`daily given for 6–9 months in fingernail infection and
`12–18 months in toenail infection. Mycological cure
`rates in fingernail infection are reasonably satisfactory
`at around 70% but griseofulvin is a disappointing drug
`in toenail disease where cure rates of only 30–40% can
`be expected.16
`It is generally recognized that 500 mg daily is too
`small a dose for nail infection and 1 g daily is most
`often prescribed, but there is no certain evidence that
`this improves cure rates in toenail infection. Although
`the cost of griseofulvin is very low, its poor cure rate,
`often necessitating further treatment, suggests that its
`cost ⁄ efficacy ratio is relatively high. Both direct and
`historical comparison with studies of the newer anti-
`fungal agents terbinafine17–19 and itraconazole20–22
`suggest that griseofulvin is no longer the treatment of
`choice for dermatophyte onychomycosis.
`Side-effects include nausea and rashes in 8–15% of
`patients. In adults, it is contraindicated in pregnancy
`and the manufacturers caution against men fathering
`a child for 6 months after therapy.
`
`Terbinafine. Terbinafine (LamisilÒ; Novartis, Camber-
`ley, U.K.), an allylamine, inhibits the enzyme squalene
`epoxidase thus blocking the conversion of squalene to
`squalene epoxide in the biosynthetic pathway of
`ergosterol, an integral component of the fungal cell
`wall.23 Its action results
`in both a depletion of
`ergosterol, which has a fungistatic effect, together with
`an accumulation of squalene, which appears to be
`directly fungicidal. The minimum inhibitory concen-
`tration (MIC) of terbinafine is very low, approximately
`)1. This is equivalent to the minimal
`0Æ004 lg mL
`fungicidal concentration (MFC), demonstrating that
`this drug is truly fungicidal in vitro. It is the most active
`currently available antidermatophyte agent in vitro and
`clinical studies strongly suggest that this is also the
`case in vivo.24
`
`Itraconazole. Itraconazole (SporonoxÒ;
`Janssen-Cilag,
`High Wycombe, U.K.) is active against a range of fungi
`including yeasts, dermatophytes and some nonder-
`matophyte moulds. It is not as active in vitro against
`dermatophytes as terbinafine, its MIC being 10 times
`
`4 0 6
`
`D . T . R O B E R T S et al.
`
`A–I
`
`A–I
`
`B–I
`
`aTerbinafinehasbettercurerateandlowerrelapseratethanitraconazolefordermatophytes(A–I).
`
`useofH2blockers,phenytoinandrifampicin
`reducedefficacyofitraconazolewithconcomitant
`andsimvastatin(increasedriskofmyopathy);
`(midazolam),digoxin,cisapride,ciclosporin
`antipsychotics(sertindole),anxiolytics
`antihistamines(terfenadineandastemizole),
`
`Enhancedtoxicityofanticoagulants(warfarin),
`
`increasedbycimetidine
`byrifampicin,
`
`Plasmaconcentrationsreduced
`
`oralcontraceptivepill
`
`Warfarin,ciclosporin,
`
`childrenandcontraindicatedinpregnancy
`than1month;notlicensedforusein
`requiredfortreatmentdurationsoflonger
`thanterbinafine;monitoringofliverfunction
`Lesseffectiveindermatophyteonychomycosis
`
`reversibletastedisturbancein1:400patients
`idiosyncraticliverandskinreactions;
`nosuspensionformulation;
`NoU.K.licenceforchildren;
`
`porphyriaandsevereliverdisease
`contraindicatedinlupuserythematosus,
`nopaediatricformulationcurrentlyavailable;
`highrelapserates;
`toenailinfection;poorcurerates;
`inbothfingernailand
`
`arepossible
`pulsedtreatmentregimens
`
`ItraconazoleaActiveagainstCandidaalbicans;
`
`goodcompliance
`shortdurationoftherapy;
`(comparedwithgriseofulvin);
`
`Fungicidal;highcurerates
`
`Terbinafinea
`
`extensiveexperience
`andchildren,inexpensive,
`
`Lengthytreatmentnecessary
`
`Licensedinbothadults
`
`Griseofulvin
`
`qualityofevidence
`Strengthofrecommendation,
`
`Maindruginteractions
`
`Disadvantages
`
`Advantages
`
`Drug
`
`Table2.Systemicagentsforonychomycosis,withmajoradvantagesanddisadvantages,andstrengthofrecommendationandqualityofevidencegrading
`
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`G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S
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`4 0 7
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`greater. Although it is generally felt to be a fungistatic
`agent
`it
`can achieve
`fungicidal
`concentrations,
`although its MFC is about 10 times higher than its
`MIC.25
`Both terbinafine and itraconazole persist in the nail
`for a considerable period after elimination from the
`plasma.26 This property has given rise to a novel
`intermittent (ÔpulsedÕ) treatment regimen using itrac-
`onazole in nail infection.
`
`Terbinafine vs. itraconazole in dermatophyte onychomyco-
`sis. Both of these drugs have been shown to be more
`effective than griseofulvin in dermatophyte onychomy-
`cosis and therefore the optimum choice of treatment
`lies between terbinafine and itraconazole.
`Terbinafine is licensed at a dose of 250 mg daily for
`6 weeks and 12 weeks in fingernail and toenail infec-
`tion, respectively. Itraconazole is licensed at a dose of
`200 mg daily for 12 weeks continuously, or alternat-
`ively at a dose of 400 mg daily for 1 week per month. It
`is recommended that two of these weekly courses,
`21 days apart, are given for fingernail infections and
`three courses for toenail disease.
`There have been numerous open and placebo-con-
`trolled studies of both drugs in dermatophyte nail
`infection. However, historical comparisons of such
`studies do not provide evidence of equivalent quality
`as that achieved by directly comparative double-blind
`trials, as even in properly conducted studies the results
`can be influenced by variation in the criteria for
`mycological or clinical cure, or by the period of follow-
`up. It is generally accepted that patients entered into
`such studies should be both microscopy- and culture-
`positive for fungus and that mycological cure should be
`defined as microscopy and culture negativity at com-
`pletion. Clinical criteria for cure are difficult to interpret
`as the appearance of the nail prior to infection is
`generally unknown and, especially in the case of
`toenails, because trauma can affect their appearance.
`Short follow-up periods after cessation of therapy are
`unlikely to allow interpretation of which is the superior
`drug; a follow-up period of at least 48 weeks (prefer-
`ably 72 weeks) from the start of treatment should be
`allowed both in order to allow the most effective
`preparation to become apparent and to identify relapse
`as far as possible.
`There are various published studies comparing ter-
`binafine with continuous itraconazole therapy,27–29
`most of which demonstrate terbinafine to be the more
`effective agent. Thus far there are only two studies
`comparing terbinafine with intermittent itraconazole
`
`therapy. The first compared terbinafine 250 mg daily
`for 16 weeks with four ÔpulsesÕ of itraconazole 400 mg
`daily for 1 week in every 4 weeks for 16 weeks and
`also with terbinafine 500 mg daily for 1 week in
`every 4 weeks for 16 weeks.30 As only approximately
`20 patients were recruited in each study group, this
`was a very small study; the regimens used were not
`those of the U.K. product licences, and the results
`comparing the groups were not significantly different.
`A more recent and much larger study has been
`completed comparing terbinafine 250 mg daily for
`both 3 and 4 months with itraconazole 400 mg daily
`for 1 week · 3 and 1 week · 4. One hundred and
`twenty patients were recruited to each group and
`the follow-up period was 72 weeks.31 The study
`was carried out in double-blind, double-placebo fash-
`ion and demonstrated terbinafine 250 mg daily for
`both 3 and 4 months to be very significantly superior
`to both three and four ÔpulsesÕ of itraconazole (Strength
`of
`recommendation A, Quality of
`evidence
`I;
`see
`Appendix 1).
`The 151 patients in the Icelandic arm of this study
`were further studied for long-term effectiveness of
`treatment during a 5-year blinded prospective follow-
`up study.32 At the end of the study mycological cure
`without a second therapeutic intervention was found
`in 46% of the 74 terbinafine-treated subjects but in
`only 13% of
`the 77 itraconazole-treated subjects.
`Mycological and clinical
`relapse was
`significantly
`higher in the itraconazole group (53% and 48%) than
`the terbinafine group (23% and 21%) (Strength of
`recommendation A, Quality of evidence I).
`The superiority of
`terbinafine has recently been
`supported by a systematic review of oral treatments
`for toenail onychomycosis;33 this reference documents
`many additional studies and also the varied and often
`incompletely presented criteria that have been used to
`describe a Ôclinical cureÕ.
`
`Treatment of yeast infections
`
`Most yeast infections can be treated topically, partic-
`ularly those associated with paronychia. Antiseptics
`can be applied to the proximal part of the nail and
`allowed to wash beneath the cuticle, thus sterilizing the
`subcuticular space. Ideally, such antiseptics should be
`broad spectrum, colourless and nonsensitizing. They
`require to be applied until the integrity of the cuticle
`has been restored, which may be several months. An
`imidazole lotion alternating with an antibacterial lotion
`is usually effective.
`
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`D . T . R O B E R T S et al.
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`Itraconazole (SporonoxÒ) is the most effective agent
`for the treatment of candidal onychomycosis where the
`nail plate is invaded by the organism.34 It is used in the
`same dosage regimen as
`for dermatophytes,
`i.e.
`400 mg daily for 1 week per month repeated for
`2 months in fingernail infection. Candida infection of
`toenails is much less common but can be treated as
`above using three or four pulses.
`
`Treatment of nondermatophyte moulds
`
`Many varieties of saprophytic moulds can invade
`diseased nail. Scopulariopsis brevicaulis is the common-
`est of these and may be a secondary pathogen. Its
`response to systemic antifungal agents is variable,
`although terbinafine is probably the drug of choice in
`that the primary nail disease is quite likely to be a
`dermatophyte infection that is masked by the Scopu-
`lariopsis. There is little categorical evidence to support
`the choice of one drug.35 In the U.S.A. and Europe
`cyclopirox nail lacquer has its advocates but it is not
`available in the U.K. Nail avulsion followed by an oral
`agent during the period of regrowth is probably the best
`method of restoring the nail to normal.
`
`Treatment failure
`
`Although terbinafine is demonstrably the most effective
`agent in dermatop