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`British Iournal of Dermatology
`The British Journal of Dermatology is owned by and is the official organ of the British Association of Dermatologists.
`
`EDITORS
`
`=
`
`DR S.M.BREATHNACH
`
`St Thomas’ Hospital, St ]ohn’s Institute of Dermatology, Lambeth Palace Road, London SE1 7l-TH
`DR N.H.COX
`
`Cumberland Infirmary, Department of Dermatology, Newtown Road, Carlisle CA2 7HY
`
`SUPPLEMF.N’J‘ EDITORS
`
`DR D.].GAWKRODGER
`Department of Dermatology, Royal Hallamshire Hospital, Glossop Road. Sheffield S10 2]F
`DR N.H.COX
`
`Cumberland Infirmary, Department of Dermatology, Newtown Road. Carlisle CA2 7HY
`
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`Cover picture: The feet of an entire family with onychomyC0Sl5~
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`
`British Journal of Dermatology
`Volume 141, Supplement 56, November 1999
`
`CONTENTS
`
`Introduction B.E.ELE\/VSKI AND H.OGAWA
`
`Onychomycosis: current treatment and future challenges D.T.ROBERTS
`
`L.l.ON. Study: efficacy and tolerability of continuous terbinafine (Lamisil®)
`compared to intermittent itraconazole in the treatment of toenail
`onychomycosis BSIGURGEIRSSON, S.BILLSTEIN, TRANTANEN.
`'l'.KUZ]CKr\. mm
`FONZO, B.].Vl".RMl£liR, M.j.lJ.GOODF'IELD AND E.G.V.E\/ANS FOR THE L.I.ON. STUDY
`GROUP
`
`Long-term outcomes in the treatment of toenail onychomycosis
`C.DE CUYPER AND P.H.F.B.HINDRYCKX
`
`Terbinafine: tolerability in general medical practice D.P.O'SULLIVAN
`
`Drug interactions of the newer oral antifungal agents HlI.KATZ
`
`Resistance of Candida species to antifungal agents used in the treatment of
`onychomycosis: a review of current problems E.G.v.EVANs
`
`Therapeutic potential of terbinafine in subcutaneous and systemic
`mycoses l{,J.JlAY
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`British Iournal 0fDermatology I999; 141 (Suppl. 56): I4}.
`
`Onychomycosis: current treatment and future challenges
`
`D. T. ROBERTS
`
`Department of Dermatology, Southern General Hospital. 7345 Govan Road, Glasgow, G51 4TF, UK.
`E-mail: 11. t. r0borts@clinmed. gla.ac. uk
`
`II »
`
`Summary
`
`Onychomycosis is a fungal infection of the nails, more often of the toenails. It is a common condition,
`with an estimated overall prevalence of 3—10% in European populations, Dermatophytes, especially
`Trichophyton rubrum and Trichophyton mentagrophytes, are the usual pathogens. Some 50% of infected
`patients fail to seek medical advice. Medically confirmed onychomycosis should be treated. This
`recommendation is based on several disease—specific considerations: cosmetic and functional
`disability, lack of spontaneous remission, impairment of health and wellbeing in elderly patients
`and the need to reduce contamination in communal bathing places. Current treatments for
`onychomycosis include oral antifungal agents such as terbinafine (Lamisil®) and itraconazole
`(Sporanox®). They offer significantly improved rates of cure, shorter treatment regimens and a
`lower level of adverse events than was previously the case. Comparative studies have shown that
`terbinafine is more effective than griseofulvin, fluconazole or itraconazole in the treatment of this
`condition, providing a cure rate of 70-80% and an excellent tolerability profile. Terbinafine is also
`the most cost~effective agent. However. several problems remain that will provide future challenges
`in the treatment of onychomycosis, not least the consistent treatment failure rate of 20%. In many of
`these cases, surgery may need to precede drug therapy in order to maximise the prospects of clinical
`and mycological cure. In addition, duration of treatment also needs to be more closely adjusted to the
`individual case by prior identification of severity and extent of toenail infection, and combined oral
`and topical therapy also requires further investigation.
`
`Onychomycosis comes from the Greek onyx, a nail, and
`' rnykes, a fungus. It is the term used to describe a fungal
`infection of the nails caused predominently (in about
`90 Yo
`of cases)
`by anthropophilic dermatophytes:
`Trirrhophyton rubrum and Trichophyton mentagrophytes
`are the usual pathogens. Yeast and non—dermatophyte
`Inc nld infections are much less common. Toenails are
`
`more often affected than fingernails by a ratio of about
`4: 1.
`
`Infection usually begins in the toe clefts, with sub-
`Seqaent spread to the hyponychium and thence into the
`distal area of the nail bed. The whole width of the nail
`may be affected, but involvement of the lateral edges is
`Inore frequently seen. Subsequent spread of infection is
`Proximal towards the posterior nail fold and medially to
`encompass the whole nail bed. The nail can become
`
`grossly thickened, sometimes completely broken. Invol-
`Vement of the nail plate leads ultimately to complete
`1 <les;ruction of the nail, a process that can take several
`Years from initial infection.
`
`Onychomycosis is common. Prevalence studies”
`hate suggested that 3% of the population in developed
`
`(9 1999 British Association of Dermatologists
`
`3
`
`countries are affected. Both studies also showed that
`
`almost 50% of infected patients had never sought
`medical advice, and that among those who had, few
`had been prescribed systemic therapy. More recently,
`smaller mycologically controlled studies3 have suggested
`a prevalence approaching 10%. These data suggest that
`onychomycosis would constitute a significant healthcare
`challenge, both logistically and financially, if treatment —
`systemic and/or topical — were to be made available to
`all sufferers.
`
`Why onychomycosis should be treated
`
`treating
`for
`An excellent case can be made out
`mycologically confirmed onychomycosis, based on four
`disease—specific considerations. First. fingernail infection
`results in increasing cosmetic and functional disability.
`Second,
`the well-documented lack of spontaneous
`remission totally invalidates any ‘wait and watch’
`policy. Third. no improvement in the contamination
`
`levels of communal bathing places can be envisaged
`unless the general pool of infection is reduced. Last,
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`D.T.ROBERTS
`
`family members can fall easy victim to transmission
`from an infected parent or sib (Fig. 1).
`To these disease—specific considerations can be added
`several general, but in some ways more important.
`reasons. Onychomycosis becomes more common with
`age, and can impair the quality of life and Wellbeing of
`elderly persons. In those with intercurrent diabetes
`mellitus or significant peripheral vascular disease,
`the presence of onychomycosis can aggravate manage
`ment. In these and similar cases it may be more cost
`effective to treat
`the initial disease than the later
`
`complications.
`
`Table 1. Minimum inhibitory concentration (MIC) and minimum
`fungicidal concentration (MFC) values (in p.g/mL), and p<
`‘; Haj]
`levels (in ptg/g) of five agents used orally iii
`the treatment of
`dermatophyte infection. Not all values are provided. Dr
`_
`from
`references 4—8 Courtesy of Dr Neil Ryder, Novartis Research
`Institute, Vienna, Austria
`
`——é_.
`
`Agent
`
`Griseofulvin
`Ketoconazole
`Itraconazole
`Fluconazole
`Terbinafine
`
`MIC
`
`U * 5-2 -0
`O - 04-6 - 0
`0-08
`6-25-200
`0-004
`
`M |~‘C
`
`na
`na
`06
`na
`0-004
`
`Peak nail
`concei. .;ation
`
`2;:
`~
`0‘S—I-0
`.9 ’)
`0- 5—l -5
`
`Currently available drug therapy
`
`na: Not applicable as these drugs are fungistatic only, nr: not "eported
`
`The medical management of onychomycosis has
`improved considerably over the last 10 years. Oral
`antifungal agents now available offer
`significantly
`increased rates of cure, shorter treatment regimens
`and a
`lower
`level of adverse events. Terbinaline
`
`(Lamisil®) and itraconazole (SporanoX®) are now
`available in many countries, and are generally con-
`sidered to be the treatments of choice for this condition.
`
`Is there any evidence to suggest that one or other of
`these agents has greater efficacy?
`
`In vitro evidence
`
`1. compiled from data collected in several
`Table
`studies.4’8
`shows mean inhibitory concentration
`(MIC)
`and mean fungicidal concentration (MFC)
`values and peak nail concentrations for
`terbinafine
`and itraconazole (and for several other drugs where
`values are available). The MIC values for both agents are
`low. The MFC value for itraconazole. though still low,
`is two orders of magnitude higher than that for terbi-
`nafine. The relevance of these figures relates to the data
`in the third column on peak nail concentrations. which
`for maximum efficacy should be consistently higher
`than the MFC value. This status is comfortably achieved
`
`by terbinafine, but is not always achieved by either
`itraconazole or fluconazole. Nails affected by dermato-
`
`phyte infection are not kinetically homogenous, so this
`difference may be crucially important.
`
`In vivo evidence
`
`This is conventionally based on two comparisons of
`efficacy: mycological cure rates at completion of the
`study and relapse rates at long—term follow—up. Nails
`have no power of regeneration, and must therefore be
`
`given the time to grow out completely if cure (abs nee of
`relapse) is to be properly assessed. For a toenail the time
`span can be 12-18 months. Thus a follow—up nine of
`12 months from the start of a study is desira."‘e, but
`12 months from cessation of treatment may be even
`better. Beyond 2 years it
`is difficult
`to distinguish
`between relapse and reinfection.
`Comparative studies have shown that terbinafine is
`more effective
`than griseofulvin,
`fluconazoie and
`itraconazole in the treatment of fungal nail inf “tions.
`Griseofulvin has a low cure rate and high relapse rate
`
`in toenail disease, coupled with a more significant adverse
`event profile than newer agents. Three stus"“és9’”
`comparing griseofulvin with terbinafine have shown
`consistent advantages for
`terbinafine in teens of
`mycological and clinical cure rates, increase ir ength
`of the unaffected nail and number of adverse events.
`Fluconazole has been less well evaluated than either
`
`:= ‘d the
`terbinafine or itraconazole in onychomycosis.
`remain
`optimum dose and duration of
`treatment
`uncertain. To date. only one study (V. Havu, personal
`communication) has directly compared the effl
`<:C}’ Of
`terbinafine with fluconazole. The results in terms Of
`negative microscopy at week 60 were statistically in
`favour of terbinafine. The doses of fluconazo‘
`used
`in this study were probably too low. but the higher
`doses needed would tend to increase terbinafiI1€'S
`
`advantage in terms of cost-effectiveness.
`Terbinafine at a dose of 250 mg daily has been sl10Wn
`to be more effective than continuous itraconazole
`200 mg daily in two studies in toenail infectior
`H1 3
`doub1e—b1ind study12'13 over 3 months and with 3
`follow—up extending to 52 weeks. Brautigam gt al.
`showed that the mycological cure rate for terbi
`ilIIlC
`
`© 1999 British Association of Dermatologists. British Journal of Derlnatology, ]-1-I (Suppl. 5- .- 144
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`MANAGEMENT OF ()NYCH(,)l\/IYCOSIS
`
`3
`
`00O
`
`0')O
`
`J3O
`
`NO
`
`Terb/nafine
`
`ltraconazole
`
`36
`
`Time (weeks)
`
`
`
`
`
`Patientsshowingnegativemycology%
`
`The feet of an entire family (mother. father, and two children)
`Figure
`3 who onychomycosis. In this case there is no doubt that one family
`member was responsible for infecting the others.
`
`, was 81%, significantly better than the 63% seen in
`the itraconazole group, P<0-O1. Mean time to first
`‘ negative culture was 8-52 weeks
`for
`terbinafine,
`5 compared to 11-64 weeks for itraconazole, P<O-05.
`At the end of the follow—up period there was an overall
`
`gr<ater percentage of cures in the terbinafine group,
`and a smaller percentage of unchanged or deteriorated
`nails. In another double—blind study” over 3 months
`with a follow—up of 48 weeks, De Backer et al. recorded
`
`a riycological cure rate of 73% with terbinafine, com-
`zpared to only 438% with itraeonazole, P<O-0001
`(Fig. 2). At the end of the study, 76' 1% of the terbinafine
`‘ group had normal nails (or minimal signs). compared to
`: 58-1% in the itraconazole group: failure of treatment
`I was 12-8% and 29-1%,
`respectively. both findings
`. significantly in favour of terbinafine, P<()~001. These
`i findings, showing terbinafine to be the more effective
`agent, are in keeping with the in vitro data.
`
`Itraconazole is now more usually given in an inter-
`' Inittent fashion, at a dose of 400 mg daily for 7 days
`each month for 3 or 4 months. An open randomised
`, study” in 63 patients compared continuous (250 mg/
`day) and intermittent (500mg/day for 7 days each
`' month)
`terbinafine with intermittent
`itraconazole
`(€lC'>0mg/day
`for 7 days each month) over 16 weeks.
`‘ Mycological cure rates 6 months after completion of
`M therapy were 94-1%, 80% and 755%. respectively. In
`f patients where mycological cure was achieved without
`nail deformities.
`there was a significant difference
`1 between the cure rates
`in favour of continuous
`, terbinafine over
`intermittent
`itraconazole. P<O-O5.
`The results of the L.l.0N. (Lamisil® vs. Itraconazole in
`v 0Nychomyeosis) study, which compared terbinafine
`
`Figure 2. Mycological cure rates (determined by negative mycology on
`culture) during treatment with either terbinafine 250 mg daily or
`itraconazole 200mg daily for 12 weeks and subsequently over a
`follow-up period extending to 48 weeks. The difference at 48 weeks
`between terbinafine (l) (73% culture negative) and itraeonazole (O)
`(45-8% culture negative) is significant. P<U-0001. After de Backer
`et al.”
`
`250 mg/day for 12 or 16 weeks with intermittent
`
`itraconazole 400mg/day for 7 days every 4 weeks for
`12 or 16 weeks, are presented later in this supplement.
`For the present it seems reasonable to conclude that
`terbinafine,
`taken at a dose of 250 mg daily for
`3 months,
`is
`the most effective currently available
`treatment for onychomycosis, with a cure rate of 70-
`
`80% and an excellent tolerability profile.
`
`Reasons for a continuing failure rate
`
`Despite the high cure rates that can now be achieved,
`some 20% of patients still fail to benefit from therapy.
`Leaving aside inadequate compliance. the usual reasons
`are dermatophyte resistance; inadequate drug absorp-
`tion into the affected area, often associated with the
`
`presence of a dermatophytoma; lack of any nail growth:
`and immunosupression. It seems likely that the majority
`of treatment failures are related to kinetic problems
`within the affected nail that prevent adequate penetra-
`tion of drug into the fungal mass or dermatophytoma.
`Surgical removal of such areas prior to drug therapy
`may be the answer. In general, physicians need to identify
`these patients early in the treatment cycle,
`to ensure
`that they receive treatment appropriate to their needs.
`Dystrophic
`nails
`that
`yield
`non—dermatophytc
`moulds in culture are unlikely to respond adequately
`to treatment if the moulds are secondary pathogens of
`previously damaged nail. However,
`the commonest
`
`cause of previous nail damage is primary dermatophyte
`
`: © 1999 British Association of Dermatologists. British Journal 0fDermatology, 141 (Suppl 56): 1—4
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`
`D.T.ROBERTS
`
`leading to outgrowth
`infection, which will respond,
`of saprophytic moulds and restoration of the nail to
`normal. Thus, improvement in cure rates is likely to
`follow a better understanding of treatment failure rather
`than manipulation of drugs and drug regimens.
`
`Economic considerations
`
`Effective
`
`treatment
`
`for onychomycosis has
`
`three
`
`aspects: rapid onset of action, sustained effect and a
`favourable adverse events profile. But economic con-
`siderations cannot be ignored, and several studies have
`attempted to evaluate the cost—effectiveness of
`the
`available agents. Einarson et al. compared terbinafine,
`ketoconazole and griseofulvin, and showed that terbi-
`nafine was the most cost-effective, providing the highest
`
`percentage success rate in both toenail and fingernail
`infection, and the greatest number of disease—free
`days.” Meta—analysis of data from 12 European coun-
`tries and Canada, undertaken by the same group,
`confirmed the findings.” In the USA, a comparison of
`the costs of treatment with terbinafine, griseofulvin,
`itraconazole and ketoconazole - including on this
`occasion costs related to adverse events and relapses
`as well as the drug acquisition and clinical and labora-
`tory costs — showed once again that terbinafine was the
`most cost—effective.1 8
`
`Future challenges
`
`There are several issues in the treatment of onycho-
`
`mycosis that remain to be overcome. First, the con-
`sistent failure rate of some 20% in all studies needs to
`
`be addressed. As suggested above, the most frequent
`explanation is likely to be kinetic: patients with a fungal
`mass effectively impenetrable to an antifungal agent need
`to be offered surgery before medical treatment. Second,
`the duration of treatment needs to be more closely
`
`adjusted to the individual case. Perhaps some 40% of
`those with toenail
`infection require only 6 weeks of
`treatment, but the challenge is to identify this population
`prior to therapy. Third, the combination of oral and topical
`therapy has hardly been investigated, and may be the
`route by which the duration of systemic therapy can be
`reduced. Last, there is the challenge to produce the ideal
`drug, one with a 100% cure rate and no adverse events!
`
`Conflict of interest: Dr Roberts and his department have
`carried out drug studies for, given advice to and received
`educational funding from Novartis Pharma, Janssen
`Pharmaceuticals and Pfizer.
`
`References
`
`I Roberts DT. Prevalence of dermatophyte onychomycosiv '11 the
`United Kingdom: results of an omnibus survey. Br I Dermatoi
`1992; 126 (:Suppl.39): 23-7.
`Sais G. Iuggla A. Peryi J. Prevalence of dermatophyte onychomycosis
`in Spain: a cross-sectional study. Br I Dermatol 1995; 132: Z 8-61_
`Heikkila H. Stubb S. The prevalence of onychomycosis in Finland.
`Br}l)ermat0l1995:133:699—703.
`, Clayton YM. Relevance of broad—spectrum and fungicidal activity
`of antifungals in the treatment of dermatomycoses. Br I I -rmatol
`1994: 130 (Suppl.43): 7-8.
`Troke PF. In vitro and experimental in viva activities of flucenazole
`against some fungi causing cutaneous mycoses. In: CW/ineous
`Antifungal Agents: Selected Compounds in Clinical Practice ant1Devel-
`opment (Rippon IW, Fromtling RA, eds), New York: Marcel ".-eklger,
`1993:i99-214.
`, De Doncker P, Decroix ], Pierard GF. et al. Antifungal pulse ‘ierapy
`for ouyclioniycosis. A pharmacokinetic and pharmacodynamic
`investigation of monthly cycles of 1-week pulse there
`with
`itraconazole. Arr'l1Dermatol I996; 132: 34-41.
`E vels of
`Faergemann J. Zchender H, Denouél I, Millerioux |..
`terbinafine in plasma, stratum corneum. dermis-epidermis (with-
`out stratum corneum) sebum, hair and nails during a.,d after
`250mg terbinafine orally once per day for four weeks. Ami Derm
`Venereol (Stockh) 1993; 73: 305-9.
`Schatz F, Brautigam M, Dobrowolski E et al. Nail incorporation
`kinetics of terbinafine in onychomycosis patients. Clin Exp Derma-
`t0l1995;2U:377-83.
`Faergemann ]. Andresen C, Ilersle K at al. Double-blind, parallel
`group comparison of terbinafine and griseofulvin in the LT
`itment
`of toenail onychomycosis. I/lm Acnrl Dermatol 1995: 32: 750-3.
`Haneke E, Tausch I. Brautigam M et al. Short duration t:
`‘itment
`of fingernail dermatophytosis: a randomized double—blind study with
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