Skin disorders
`
`Fungal toenail infections
`Search date May 2008
`Jill Ferrari
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`ABSTRACT
`INTRODUCTION: Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by dermatologists,
`but are less common in the general population, affecting 3–5% of people. METHODS AND OUTCOMES: We conducted a systematic review
`and aimed to answer the following clinical questions: What are the effects of oral treatments for fungal toenail infections? What are the effects
`of topical treatments for fungal toenail infections? We searched: Medline, Embase, The Cochrane Library, and other important databases
`up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review).
`We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and
`Healthcare products Regulatory Agency (MHRA). RESULTS: We found 11 systematic reviews, RCTs, or observational studies that met
`our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic
`review we present information relating to the effectiveness and safety of the following interventions: amorolfine, butenafine, ciclopirox, flu-
`conazole, griseofulvin, itraconazole, ketoconazole, mechanical debridement, terbinafine, and tioconazole.
`
`QUESTIONS
`What are the effects of oral treatments for fungal toenail infections?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`What are the effects of topical treatments for fungal toenail infections?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`INTERVENTIONS
`TOPICAL TREATMENTS
` Likely to be beneficial
`Ciclopirox (topical) (although benefits are modest, even
`after long-term treatment) . . . . . . . . . . . . . . . . . . . . . 9
`
`ORAL TREATMENTS
` Beneficial
`Oral itraconazole (more effective than placebo, but
`probably less effective than terbinafine) . . . . . . . . . . 3
`Oral terbinafine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`
` Likely to be beneficial
`Fluconazole (oral) (although benefits are modest, even
`after long-term treatment) . . . . . . . . . . . . . . . . . . . . . 6
`
` Unknown effectiveness
`Griseofulvin (oral) . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
`Ketoconazole (oral) . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`
` Unknown effectiveness
`Amorolfine (topical) . . . . . . . . . . . . . . . . . . . . . . . . . 10
`Fluconazole (topical) . . . . . . . . . . . . . . . . . . . . . . . 11
`Ketoconazole (topical) . . . . . . . . . . . . . . . . . . . . . . 11
`Mechanical debridement . . . . . . . . . . . . . . . . . . . . 10
`Terbinafine (topical) . . . . . . . . . . . . . . . . . . . . . . . . 11
`Tioconazole (topical) . . . . . . . . . . . . . . . . . . . . . . . 11
`Topical butenafine . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`Key points
`
`• Fungal toenail infection (onychomycosis) is characterised as infection of part or all of the toenail unit, which includes
`the nail plate, the nail bed, and the nail matrix. Over time, the infection causes discoloration and distortion of part
`or all of the nail unit.
`Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by der-
`matologists, but are less common in the general population, affecting 3–5% of people.
`Infection can cause discomfort in walking, pain, or limitation of activities.
`• People taking oral antifungal drugs reported greater satisfaction, and fewer onychomycoses-related problems,
`such as embarrassment, self-consciousness, and being perceived as unclean by others, compared with people
`using topical antifungals.
`Oral antifungals have general adverse effects including gastrointestinal complaints (such as diarrhoea), rash,
`and respiratory complaints. It was rare for people to withdraw from an RCT because of adverse effects.
`• Both oral itraconazole and oral terbinafine effectively increase cure rates of fungal toenail infection; terbinafine
`seems slightly more effective.
`Adverse effects unique to terbinafine include sensory loss, such as taste, smell, or hearing disturbance.
`• Alternative oral antifungal treatments include fluconazole, which seems to modestly improve cure rates, and keto-
`conazole and griseofulvin, which may be effective; but the evidence is insufficient to allow us to say for certain.
`• Topical ciclopirox seems to modestly improve symptoms of fungal toenail infection compared with placebo.
`We found no evidence examining the effectiveness of other topical agents such as ketoconazole, fluconazole,
`amorolfine, terbinafine, tioconazole, or butenafine.
`© BMJ Publishing Group Ltd 2008. All rights reserved. . . . . . . . . . . . . . . . . . . . . 1 . . . . . . . . . . . . . . . . . . . . Clinical Evidence 2008;12:1715
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`Fungal toenail infections S
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`We don't know whether mechanical debridement has any effect on fungal toenail infection, as we found no adequate
`studies.
`
`DEFINITION
`
`INCIDENCE/
`PREVALENCE
`
`AETIOLOGY/
`RISK FACTORS
`
`PROGNOSIS
`
`Fungal toenail infection (onychomycosis) is characterised as infection of part or all of the nail unit,
`[2]
`which includes the nail plate, the nail bed, and the nail matrix. [1]
`[3] Over time, the infection
`causes discoloration and distortion of part or all of the nail unit. [4] The tissue under and around
`the nail may also thicken. This review deals exclusively with dermatophyte toenail infections (see
`aetiology) and excludes candidal or yeast infections.
`
`Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people
`seen by dermatologists, but are less common in the general population, affecting 3–5% of people.
`[3] The prevalence varies among populations, which may be due to differences in screening tech-
`niques. In a large European project (13,695 people with a range of foot conditions), 35% had a
`fungal infection diagnosed by microscopy/culture. [5] One prospective study in Spain (1000 adults
`aged over 20 years) reported a prevalence of fungal toenail infection as 2.7% (infection defined
`as clinically abnormal nails with positive microscopy and culture). [6] In Denmark, one study (5755
`adults aged over 18 years) reported the prevalence of fungal toenail infection as 4.0% (determined
`by positive fungal cultures). [7] The incidence of mycotic nail infections may have increased over
`the past few years, perhaps because of increasing use of systemic antibiotics, immunosuppressive
`treatment, more advanced surgical techniques, and the increasing incidence of HIV infection. [8]
`However, this was contradicted by a study in an outpatient department in Eastern Croatia, which
`compared the prevalence of fungal infections between two periods (1986–1988, 47,832 people;
`1997–2001, 75,691 people). [9] It found that the prevalence of fungal infection overall had increased
`greatly over the 10 years, but that the percentage of fungal infections affecting the nails had de-
`creased by 1% (fungal infections overall: 0.26% in 1986–1988 v 0.73% in 1997–2001; nail: 10.31%
`in 1986–1988 v 9.31% in 1997–2001).
`
`Fungal nail infections are most commonly caused by anthropophilic fungi called dermatophytes.
`The genera Trichophyton, Epidermophyton, and Microsporum are typically involved, [1] specifically
`T rubrum, T mentagrophytes var interdigitale, and E floccosum. Other fungi, moulds, or yeasts may
`be isolated, such as Scopulariopsis brevicaulis, Aspergillus, Fusarium, and Candida albicans. [3]
`T rubrum is now regarded as the most common cause of onychomycosis worldwide. [10] Several
`factors that increase the risk of developing a fungal nail infection have been identified. One survey
`found that 26% of people with diabetes had onychomycosis, and that diabetes increased the risk
`of infection, but the type and severity of diabetes was not correlated with infection (OR 2.77, 95%
`CI 2.15 to 3.57). [11] Another survey found that peripheral vascular disease (OR 1.78, 95% CI 1.68
`to 1.88) and immunosuppression (OR 1.19, 95% CI 1.01 to 1.40) increased the risk of infection.
`These factors may explain the general increase in prevalence of onychomycosis in the elderly
`population. [12] Environmental exposures such as occlusive footwear or warm, damp conditions
`[12] Fungal skin infection has been proposed
`have been cited as risk factors, as has trauma. [2]
`[10]
`[12] However, one large observational study, which included 5413 people
`as a risk factor. [3]
`with positive mycology, found that only a small proportion (21.3%) had both skin and toenail infec-
`tions. [12]
`
`Onychomycosis does not have serious consequences in otherwise healthy people. However, the
`Achilles project (846 people with fungal toenail infection) found that many people complain of dis-
`comfort in walking (51%), pain (33%), or limitation of their work or other activities (13%). [5] Gross
`distortion and dystrophy of the nail may cause trauma to the adjacent skin, and may lead to sec-
`ondary bacterial infection. In immunocompromised people, there is a risk that this infection will
`disseminate. Quality-of-life measures specific to onychomycosis have recently been developed.
`Studies using these indicators suggest that onychomycosis has negative physical and psychosocial
`[14]
`[15]
`effects. [13]
`
`AIMS OF
`INTERVENTION
`
`To eradicate fungal spores from the nail unit (nail bed, matrix, or plate); to allow a normal nail to
`regrow if permanent damage to the nail matrix has not occurred.
`
`OUTCOMES
`
`Negative microscopy and culture; satisfaction with treatment; adverse effects of treatment, espe-
`cially liver failure.
`
`METHODS
`
`Clinical Evidence search and appraisal May 2008. The following databases were used to identify
`studies for this review: Medline 1966 to May 2008, Embase 1980 to May 2008, and The Cochrane
`Library, Issue 2, 2008. Additional searches were carried out using these websites: NHS Centre for
`Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health
`Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE clinical guidelines.
`Abstracts of the studies retrieved were assessed independently by two information specialists using
`© BMJ Publishing Group Ltd 2008. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
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`predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review
`were: published systematic reviews and RCTs in any language, at least single blinded, and con-
`taining more than 20 people of whom more than 80% were followed up. The minimum length of
`follow-up required was 3 months to include studies. We excluded all studies described as “open”,
`“open label”, or not blinded unless the interventions could not be blinded. RCTs of treatment in
`fingernails and of infections related to candidal and yeast infections were also excluded. We con-
`sidered systematic reviews, RCTs, and observational studies for the harms because of the poten-
`tially serious nature of the harms (liver failure). In addition, we use a regular surveillance protocol
`to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare
`products Regulatory Agency (MHRA), which are continually added to the review as required. We
`have performed a GRADE evaluation of the quality of evidence for interventions included in this
`review (see table, p 14 ). To aid readability of the numerical data in our reviews, we round many
`percentages to the nearest whole number. Readers should be aware of this when relating percent-
`ages to summary statistics such as RRs and ORs.
`
`QUESTION What are the effects of oral treatments for fungal toenail infections?
`
`OPTION
`
`ITRACONAZOLE (ORAL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Cure rate
`Compared with placebo Oral itraconazole may be more effective at curing fungal toenail infection (very low-quality
`evidence).
`
`Compared with oral griseofulvin Oral itraconazole and oral griseofulvin may be equally effective at curing fungal
`toenail infection after 24–72 weeks (very low-quality evidence).
`
`Compared with oral terbinafine Oral itraconazole may be less effective at curing fungal toenail infection after 12–16
`weeks' treatment (very low-quality evidence).
`
`Pulsed oral itraconazole compared with continuous oral itraconazole Pulsed oral itraconazole for 3–4 months and
`continuous oral itraconazole may be equally effective at curing fungal toenail infection (low-quality evidence).
`
`Compared with topical treatments Oral antifungal treatment may lead to greater patient satisfaction after 9 months
`(very low-quality evidence).
`
`Note
`We found no clinically important results about the effects of oral itraconazole compared with oral ketoconazole or
`oral fluconazole.
`
`For GRADE evaluation of interventions for fungal toenail infections, see table, p 14 .
`
`Benefits:
`
`Oral itraconazole versus placebo:
`We found one systematic review (search date 2000). [16] It found that 12 weeks of itraconazole
`200 mg daily significantly increased cure rates at the end of treatment compared with placebo (3
`RCTs, 433 people with fungal toenail infection; AR: 63% with itraconazole v 4% with placebo; ARI
`60%, 95% CI 54% to 67%).
`
`Oral itraconazole versus oral griseofulvin:
`See benefits of oral griseofulvin, p 7 .
`
`Oral itraconazole versus oral terbinafine:
`We found one systematic review (search date 2000, 4 RCTs) [16] and one subsequenl RCT. [17]
`The first and second RCTs identified by the review found that 12 weeks of itraconazole 200 mg
`daily produced significantly lower cure rates compared with 12 weeks of terbinafine 250 mg daily
`at about 1 year (501 people with fungal toenail infection; AR: 69% with terbinafine v 48% with itra-
`conazole; ARR 21%, 95% CI 13% to 29%). The third RCT identified by the review compared three
`treatments given for 16 weeks: pulsed itraconazole (400 mg/day for 1 week in every 4 weeks);
`pulsed terbinafine (500 mg/day for 1 week in every 4 weeks); and continuous terbinafine 250 mg
`daily. It found no significant difference in cure rates between pulsed itraconazole and continuous
`terbinafine at 43 weeks (60 people with fungal toenail infection; AR: 75% with itraconazole v 84%
`with continuous terbinafine; ARR +9%, 95% CI –34% to +16%). The fourth RCT identified by the
`review compared four treatments: pulsed itraconazole for 12 weeks (400 mg/day for 1 week in
`every 4 weeks); pulsed itraconazole for 16 weeks (regimen as for 12-week treatment); continuous
`terbinafine for 12 weeks 250 mg daily; and continuous terbinafine 250 mg daily for 16 weeks. It
`found that pulsed itraconazole produced significantly lower cure rates compared with continuous
`terbinafine, regardless of duration, at 72 weeks (250 people with fungal toenail infection; AR after
`
`© BMJ Publishing Group Ltd 2008. All rights reserved. ...........................................................
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`12 weeks' treatment: 33% with itraconazole v 65% with terbinafine; ARR 33%, 95% CI 21% to
`44%; 246 people with fungal toenail infection; AR after 16 weeks' treatment: 42% with itraconazole
`v 67% with terbinafine; ARR 25%, 95% CI 13% to 37%).
`
`The subsequent RCT (70 people with diabetes and dermatophyte toenail distal and lateral subungual
`onychomycosis) compared oral pulsed itraconazole (200 mg twice daily, 1 week on/3 weeks off
`for 12 weeks) versus oral terbinafine (250 mg/day for 12 weeks). [17] The RCT found no significant
`difference in cure rates between groups at 48 weeks (30/35 [88%] with pulsed itraconazole v 23/29
`[77%] with continuous terbinafine; ARR 11.5%, 95% CI –5.2% to 28.2%). [17]
`
`Oral itraconazole versus oral ketoconazole:
`We found one systematic review (search date 2000), which found no RCTs.
`
`Oral itraconazole versus oral fluconazole:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Pulsed versus continuous oral itraconazole:
`We found one systematic review (search date 2000, 3 RCTs). [16] The first RCT identified by the
`review found no significant difference in cure rates between 12 weeks of continuous itraconazole
`(200 mg/day) and 12 weeks of pulsed itraconazole (400 mg/day for 1 week in every 4 weeks) at
`52 weeks (121 people with fungal toenail infection; AR: 66% with continuous itraconazole v 69%
`with pulsed itraconazole; ARR +3%, 95% CI –10% to +20%). The second RCT identified by the
`review found no significant difference in cure rates between 3 and 4 months of pulsed itraconazole
`(400 mg/day for 1 week in every 4 weeks) at 24 weeks (50 people with fungal toenail infection; AR:
`64% with 3 months and 72% with 4 months; ARR +8%, 95% CI –20% to +30%). The third RCT
`identified by the review found no significant difference in cure rates between 12 or 16 weeks of
`continuous itraconazole (200 mg/day) and 12 or 16 weeks of pulsed itraconazole (200 mg/day for
`1 week in every 4 weeks) at 48 weeks (64 people with fungal toenail infection; AR after 12 weeks'
`treatment: 68% with continuous itraconazole v 50% with pulsed itraconazole; ARI +18%, 95% CI
`–50% to +40%; AR after 16 weeks' treatment: 64% with continuous itraconazole v 64% with pulsed
`itraconazole; ARR 0%, 95% CI –34% to +34%).
`
`Oral itraconazole versus topical treatments:
`We found no systematic review or RCTs.We found one longitudinal study comparing oral antifungals
`versus topical treatments (see comment on oral griseofulvin, p 7 ).
`
`Harms:
`
`Oral itraconazole versus oral griseofulvin:
`See harms of oral griseofulvin, p 7 .
`
`Oral itraconazole versus oral terbinafine:
`The RCT of pulsed itraconazole versus continuous terbinafine in people with diabetes mellitus re-
`ported that only one person in the itraconazole group withdrew due to gastic pain. [17] There were
`no other serious adverse events or interactions with normal medications. [17]
`
`Re-infection rates:
`One open-label RCT comparing oral itraconazole (400 mg/day for 1 week in every 4 for 12 weeks)
`versus oral terbinfine (250 mg/day for 12 weeks) recorded the number of people initially considered
`cured (mycological cure) and who then became re-infected with either the same or a different fungal
`species during the course of the study (relapsed). [18] At the final follow-up (96 weeks), 21% of
`people in the itroconazole group versus 14% of the terbinafine group were found to have a further
`infection. This was reported to be non-significant (P greater than 0.05). [18]
`
`Comment:
`
`See comment on oral griseofulvin, p 7 .
`
`Oral itraconazole versus placebo:
`Outcomes were measured at 12 weeks. It is more clinically relevant to measure outcomes after at
`least 9 months, because it takes at least 6 months for the toenail to regrow completely.
`
`OPTION
`
`ORAL TERBINAFINE (ORAL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Cure rate
`Compared with placebo Oral terbinafine for 12–24 weeks may be more effective at curing fungal toenail infection
`(very low-quality evidence).
`
`Compared with oral itraconazole Oral terbinafine may be more effective at curing fungal toenail infection after 12–16
`weeks' treatment (very low-quality evidence).
`
`© BMJ Publishing Group Ltd 2008. All rights reserved. ...........................................................
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`Compared with oral griseofulvin Oral terbinafine may be more effective at curing fungal toenail infection after 24–52
`weeks' treatment (low-quality evidence).
`
`Compared with oral terbinafine plus topical ciclopirox Continuous terbinafine alone for 12 weeks and pulsed or con-
`tinuous terbinafine for 12 weeks plus topical ciclopirox for 48 weeks may be equally effective at curing fungal toenail
`infection (moderate-quality evidence).
`
`Adverse effects
`Terbinafine has been associated with hepatotoxicity, but serious adverse effects are rare.
`
`Note
`We found no clinically important results about the effects of oral terbinafine compared with ketoconazole or fluconazole.
`
`For GRADE evaluation of interventions for fungal toenail infections, see table, p 14 .
`
`Benefits:
`
`Oral terbinafine versus placebo:
`We found one systematic review (search date 2000, 5 RCTs). [16] The review found that 12 weeks
`of terbinafine 250 mg daily significantly increased cure rates at the end of treatment compared with
`placebo (3 RCTs, 337 people with fungal toenail infection; AR: 63% with terbinafine v 20% with
`placebo; ARI 43%, 95% CI 34% to 53%). The review identified two further RCTs, which could not
`be included in the meta-analysis because they examined different terbinafine regimens. The first
`of these RCTs found that 12 and 24 weeks of terbinafine 250 mg daily significantly increased cure
`rates at 48 weeks compared with placebo (353 people with fungal toenail infection; AR after 12
`weeks' treatment: 70% with terbinafine v 8% with placebo; ARI 62%, 95% CI 52% to 72%; AR after
`24 weeks' treatment: 87% with terbinafine v 8% with placebo; ARI 79%, 95% CI 70% to 87%). The
`second of these RCTs found that 12, 16, and 24 weeks of terbinafine 250 mg daily significantly
`increased cure rates at 72 weeks compared with placebo (109 people with fungal toenail infection;
`AR after 12 weeks' treatment: 38% with terbinafine v 0% with placebo; ARI 38%, 95% CI 20% to
`50%; AR after 16 weeks' treatment: 37% with terbinafine v 0% with placebo; ARI 37%, 95% CI
`21% to 56%; AR after 24 weeks' treatment: 65% with terbinafine v 0% with placebo; ARR 65%,
`95% CI 46% to 81%).
`
`Oral terbinafine versus oral griseofulvin:
`See benefits of oral griseofulvin, p 7 .
`
`Oral terbinafine versus oral itraconazole:
`See benefits of oral itraconazole, p 3 .
`
`Oral terbinafine versus oral ketoconazole:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral terbinafine versus oral fluconazole:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral terbinafine versus topical treatments:
`We found one RCT comparing three treatments: topical ciclopirox daily for 48 weeks plus pulsed
`terbinafine for the initial 12 weeks (250 mg daily for 4 weeks daily/4 weeks rest/4 weeks daily);
`topical ciclopirox plus continuous terbinafine for 12 weeks followed by topical ciclopirox alone for
`36 weeks; and continuous terbinafine alone for 12 weeks. [19] The RCT found no significant differ-
`ence between the three treatments in mycological cure rates at 48 weeks (73 people; 14/21 [67%]
`with ciclopirox plus pulsed terbinafine v 19/27 [70%] with ciclopirox plus continuous terbinafine v
`14/25 [56%] with continuous terbinafine alone; P value for overall comparison reported as not sig-
`nificant).We found also one longitudinal study comparing oral antifungals versus topical treatments
`(see comment on oral griseofulvin, p 7 ).
`
`Harms:
`
`Adverse events unique to terbinafine include sensory loss such as taste, smell, or hearing distur-
`bance (see harms of oral griseofulvin, p 7 andharms of oral itraconazole, p 3 ).
`
`Oral terbinafine versus topical treatments:
`The RCT found that the incidence of adverse events (including gastrointestinal effects, and subcu-
`taneous tissue and skin disorders) was similar between the three treatment groups (20.5% with
`ciclopirox plus pulsed terbinafine v 21.4% with ciclopirox plus continuous terbinafine v 22.0% with
`continuous terbinafine alone; significance not reported). No participants withdrew because of adverse
`events. One open-label RCT (249 people) compared amorolfine hydrochloride (5% nail lacquer
`for 12 months) plus oral terbinafine (250 mg/day for 3 months) versus terbinafine alone (250 mg/day
`for 3 months). [20] The study reported adverse effects in 15/103 (12%) people with terbinafine alone
`versus 19/105 (16%) people with combination treatment (no significance assessment between
`
`© BMJ Publishing Group Ltd 2008. All rights reserved. ...........................................................
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`groups performed). Only two adverse events were considered due to the amorolfine nail lacquer
`(ingrowing toenail and constipation). [20]
`
`Hepatotoxicity:
`One case report described fulminant hepatic failure in a 48-year-old woman with onychomycosis.
`She had taken terbinafine 250 mg daily for 5 days and developed fulminant hepatic failure over a
`period of 4 weeks, which required liver transplantation. Histological examination reported tissue
`status compatible with a drug-related cause of disease. The woman additionally took dosulepin
`75 mg daily and propranolol 40 mg twice daily. [21] The RCTs involving terbinafine frequently
`measured levels of liver enzymes and found that increases were asymptomatic, and reversed once
`the drug was stopped.
`
`High-risk populations:
`Several prospective cohort studies have considered the safety of terbinafine to treat fungal nail
`infections in high-risk populations. One review paper reported the results of three studies involving
`people with diabetes mellitus, two studies in people with HIV infection, and two studies involving
`organ transplant recipients. [22] The review found that no significant adverse effects were reported
`in the diabetes studies. No drug interactions were reported in people receiving terbinafine, and
`glucose levels were unchanged during the treatment period (207 people receiving 250 mg/day of
`terbinafine for 12 weeks).The review found that the HIV studies reported no serious adverse effects
`(10 people receiving 250 mg/day terbinafine for 12 weeks, 21 people receiving 250 mg/day
`terbinafine for 16 weeks). It found that blood ciclosporin levels significantly decreased in organ
`transplant patients taking terbinafine, but this did not cause significant clinical change in the people
`or lead to organ rejection. Renal function remained normal (11 people receiving 250 mg/day
`terbinafine for 12 weeks, 4 receiving 250 mg/day terbinafine for 4–24 weeks). One open-label
`prospective study examined the safety of terbinafine use in people aged over 60 years with ony-
`chomycosis of the feet confirmed by positive mycological culture. [23] It found that a total of 18 ad-
`verse events occurred, all considered mild to moderate in severity, and transient in nature. No
`participants withdrew from the study because of adverse events (30 people receiving 250 mg/day
`for 12 weeks).The study also considered the 16 people taking drugs metabolised by the cytochrome
`P-450 isoenzyme, 2D6, because of specific in vitro data suggesting a potential interaction between
`terbinafine and drugs metabolised by this isoenzyme. No drug interactions between these cases
`and terbinafine were observed.
`
`Comment:
`
`See comment on oral griseofulvin, p 7 .
`
`Oral terbinafine versus placebo:
`Outcomes were measured at 12 weeks. It is more clinically relevant to measure outcomes after 9
`months, because it takes at least 6 months for the toenail to regrow completely.
`
`Oral terbinafine versus topical treatments:
`The RCT comparing combinations of terbinafine plus ciclopirox versus terbinafine alone may have
`been underpowered to detect a significant difference between treatments. [19]
`
`OPTION
`
`FLUCONAZOLE (ORAL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Cure rate
`Compared with placebo Oral fluconazole may be more effective at curing fungal toenail infection after 16–52 weeks'
`treatment (low-quality evidence).
`
`Compared with topical treatments Oral antifungal treatment may lead to greater patient satisfaction after 9 months
`(very low-quality evidence).
`
`Note
`We found no clinically important results about the effects of fluconazole compared with griseofulvin, terbinafine,
`itraconazole, or ketoconazole.
`
`For GRADE evaluation of interventions for fungal toenail infections, see table, p 14 .
`
`Benefits:
`
`Oral fluconazole versus placebo:
`We found one systematic review (search date 2000, 2 RCTs). [16] The first RCT identified by the
`review found that 16, 26, and 39 weeks of fluconazole 150 mg weekly significantly increased cure
`rates at the end of treatment compared with placebo (331 people with fungal toenail infection; AR
`after 16 weeks' treatment: 31% with fluconazole v 7% with placebo; ARI 24%, 95% CI 12% to 35%;
`AR after 26 weeks' treatment: 48% with fluconazole v 7% with placebo; ARI 40%, 95% CI 28% to
`52%; AR after 39 weeks' treatment: 53% with fluconazole v 7% with placebo; ARI 46%, 95% CI
`34% to 58%). The second RCT identified by the review found that fluconazole (150, 300, and
`© BMJ Publishing Group Ltd 2008. All rights reserved. ...........................................................
`
`6
`
`

`

`Fungal toenail infections S
`
`kin disorders
`
`450 mg/week for a maximum of 12 months) significantly increased cure rates at the end of treatment
`compared with placebo (361 people with fungal toenail infection; AR: 43% with fluconazole 150 mg
`v 13% with placebo; ARI 30%, 95% CI 17% to 42%; AR: 47% with fluconazole 300 mg v 13% with
`placebo; ARI 35%, 95% CI 22% to 47%; AR: 51% with fluconazole 450 mg v 13% with placebo;
`ARI 38%, 95% CI 25% to 50%).
`
`Oral fluconazole versus oral griseofulvin:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral fluconazole versus oral itraconazole:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral fluconazole versus oral terbinafine:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral fluconazole versus oral ketoconazole:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral fluconazole versus topical treatments:
`We found no systematic review or RCTs.We found one longitudinal study comparing oral antifungals
`versus topical treatments (see comment on oral griseofulvin, p 7 ).
`
`Harms:
`
`See harms of oral griseofulvin, p 7 .
`
`Comment:
`
`See comment on oral griseofulvin, p 7 .
`
`OPTION
`
`GRISEOFULVIN (ORAL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Cure rate
`Compared with oral itraconazole Oral griseofulvin and oral itraconazole may be equally effective at curing fungal
`toenail infection after 24–72 weeks (very low-quality evidence).
`
`Compared with oral terbinafine Oral griseofulvin for 24–52 weeks may be less effective at curing fungal toenail infection
`(low-quality evidence).
`
`Compared with oral ketoconazole Oral griseofulvin and oral ketoconazole may be equally effective at curing fungal
`toenail infection after 24–49 weeks' treatment (very low-quality evidence).
`
`Compared with topical treatments Oral antifungal treatment may lead to greater patient satisfaction after 9 months
`(very low-quality evidence).
`
`Note
`We found no direct information about whether oral griseofulvin is better than no active treatment. We found no clini-
`cally important results about the effects of griseofulvin compared with fluconazole.
`
`For GRADE evaluation of interventions for fungal toenail infections, see table, p 14 .
`
`Benefits:
`
`Oral griseofulvin versus placebo:
`We found one systematic review (search date 2000), which found no RCTs. [16]
`
`Oral griseofulvin versus oral itraconazole:
`We found one systematic review (search date 2000, 3 RCTs). [16] None of the RCTs found a sig-
`nificant difference in cure rates between griseofulvin and itraconazole. The first RCT identified by
`the review found no significant difference in cure rates at the end of treatment between 24 weeks
`of griseofulvin 500 mg daily and 24 weeks of itraconazole 100 mg daily (19 people with fungal
`toenail infection; AR: 0% with griseofulvin v 0% with itraconazole; ARR 0%, –17% to +18%). The
`second RCT identified by the review found no significant difference in cure rates at 40 weeks be-
`tween 24–36 weeks of griseofulvin 500 mg daily and 24–36 weeks of itraconazole 100 mg daily
`(61 people with fungal toenail infection; AR: 30% with griseofulvin v 37% with itraconazole; ARR
`+5%, 95% CI –18% to +28%).The third RCT identified by the review found no significant difference
`in cure rates at 77 weeks between 72 weeks of griseofulvin 660 mg daily, 72 weeks of griseofulvin
`990 mg daily, and 72 weeks of itraconazole 100 mg daily (108 people with fungal toenail infection;
`AR: 6% with griseofulvin 660 mg/day v 8% with itraconazole 100 mg/day; ARR +2%, 95% CI –8%
`to +10%; AR: 6% with griseofulvin 990 mg/day v 8% with itraconazole 100 mg/day; ARR +2%, 95%
`CI –8% to +10%).
`
`© BMJ Publishing Group Ltd 2008. All ri