Dermatol Clin 21 (2003) 481 – 489
`
`The use of topical therapies to treat onychomycosis
`
`Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Jennifer E. Ryder, HBScb,
`Robert Baran, MDc
`
`aDivision of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site),
`University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
`bMediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada
`cNail Diseases Center, 42 Rue des Serbes 06400, Cannes, France
`
`Onychomycosis is a fungal infection of the nail
`unit, which has become increasingly prevalent. Fac-
`tors that may be attributed to the rise in the preva-
`lence of onychomycosis include an increase in the
`use of immunosuppressive therapies; aging of the
`population;
`tight-fitting footwear; and the use of
`communal areas (eg, public baths, gymnasiums,
`health spas, hotel rooms, and so forth). Onychomy-
`cosis has been reported to be more prevalent in men
`than women, among the elderly, diabetics, and other
`immunocompromised individuals [1 – 3].
`Therapeutic options for the treatment of onycho-
`mycosis include no therapy, palliative care, mechan-
`ical or chemical debridement, topical and systemic
`antifungal agents, or a combination of two or more of
`these modalities. Factors that influence the choice of
`therapy include the presentation and severity of the
`disease, the current medications the patient is taking,
`previous therapies for onychomycosis and their re-
`sponse, physician and patient preference, and the cost
`of therapy.
`The clinical presentations of onychomycosis in-
`clude distal-lateral subungual onychomycosis, proxi-
`mal subungual onychomycosis, white superficial
`onychomycosis, endonyx onychomycosis, and total
`dystrophic onychomycosis. White superficial ony-
`chomycosis should respond best to topical therapy
`because of the superficial nature of this infection. In
`
`* Corresponding author. Suite 6, 490 Wonderland Road,
`London, Ontario, N6K 1L6, Canada.
`E-mail address: agupta@execulink.com (A.K. Gupta).
`
`many instances, it may be possible to mechanically
`remove the diseased portion of nail using a curette or
`a similar device; in fact, the day-to-day activities of
`some patients may produce enough trauma to the nail
`to dislodge or remove the diseased portion of the
`superficial nail from the normal-appearing nail.
`To determine the extent of the literature relating to
`the use of topical agents for the management of
`onychomycosis, a Medline search was conducted
`from the years 1966 to June 2002. The key words
`that were used included ‘‘topical’’ and ‘‘onychomy-
`cosis.’’ Studies were excluded [4 – 12] for reasons
`including retrospective nature; preliminary data; non-
`English language format; unable to extract relevant
`data; only special populations (eg, transplant patients,
`diabetic patients, and so forth) enrolled; clinical
`presentations other than distal lateral subungual ony-
`chomycosis evaluated; and trials where only finger-
`nail onychomycosis was considered for treatment.
`This article is confined to the treatment of distal
`and lateral subungual onychomycosis.
`
`Efficacy parameters
`
`Twenty-six studies were included in the evalua-
`tion of topical therapies [13 – 38]. Most studies did
`not define the efficacy parameters used to determine
`whether a treatment was successful. When efficacy
`parameters were defined, they were often variable.
`For instance, mycologic cure was defined as ‘‘nega-
`tive culture and KOH’’ [13,15,19,24,27,34], ‘‘nega-
`tive culture’’ only [31], or ‘‘negative culture and a
`negative or missing microscopy result’’ [22]. Clinical
`
`0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.
`doi:10.1016/S0733-8635(03)00025-1
`
`

`

`482
`
`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`response was defined as less than or equal to 10%
`nail involvement and negative mycology [13], cure or
`markedly improved [22], percent of involvement
`[28,29], or 100% remission or 90% to 99% improve-
`ment [34]. Complete cure was defined as clear nail
`and negative mycology [13,15,19,27,34], clinical
`cure and negative culture [31,32], clinical cure and
`negative microscopy [38], neither clinical nor micro-
`scopic evidence of reinfection [35], or complete
`clinical recovery and negative microscopy [23].
`
`Ciclopirox and amorolfine nail lacquers
`
`The active component in the nail lacquer polymer
`film is maintained on the nail surface, from which it
`evenly diffuses through the nail plate keratin thereby
`reaching the nail bed [39]. After the evaporation of
`the solvent, the concentration of the active ingredient,
`ciclopirox or amorolfine,
`increases to 34.8% and
`25%, respectively [39,40]; this enhances transungual
`diffusion [39].
`
`Ciclopirox nail lacquer
`
`Ciclopirox solution 8% is the only approved nail
`lacquer in the United States for the treatment of
`onychomycosis. This hydroxypyridone derivative has
`been marketed worldwide for approximately 25 years
`and is approved in more than 40 countries world-
`wide [41]. In December 1999, the nail lacquer was
`approved in the United States for the treatment of
`mild to moderate onychomycosis of the fingernails
`and toenails without lunula involvement, caused by
`Trichophyton rubrum [13,41].
`
`Mode of action
`Ciclopirox has a diverse mode of action that
`targets different metabolic processes in the microbial
`cell [42]. The main mode of action is its high affinity
`for trivalent cations, such as Fe3 + and Al3 + [43].
`The inhibition of these essential cofactors affects
`mitochondrial electron transport processes in the
`course of energy production, thereby impairing mi-
`crobial metabolism [42].
`Ciclopirox also strongly reduces the activity of
`catalase and peroxidase, which are responsible for the
`intracellular degradation of toxic peroxides. In addi-
`tion, nutrient uptake into the internal pool of growing
`cells may be adversely affected; this can result in
`intracellular depletion of essential amino acids and
`nucleotides, which reduces the synthesis of proteins
`or nucleic acids [42].
`
`Activity of ciclopirox
`Ciclopirox is a broad-spectrum antifungal agent
`that exhibits fungicidal activity in vitro against der-
`matophytes, Candida species, and some nonder-
`matophyte molds. In addition, ciclopirox exhibits
`antibacterial activity against a number of gram-posi-
`tive and gram-negative aerobic and anaerobic bacteria
`[42]. Ciclopirox exhibits anti-inflammatory activity
`by preventing the formation of 5-lipoxygenase in-
`flammatory mediators, such as 5-hydroxyeicosa-
`tetraenoic acid and leukotriene B4; cyclooxygenase
`inflammatory mediator release (prostaglandin E2);
`and the cyclooxygenase-mediated synthesis of pros-
`taglandins [42].
`
`Pharmacokinetics
`In five patients with dermatophyte onychomyco-
`sis, a once daily application of ciclopirox nail lacquer
`for 6 months resulted in serum levels of the drug
`ranging between 12 and 80 ng/mL and a mean
`absorption of less than 5% of the applied dose; 1 month
`after the end of therapy serum and urine levels were
`below the level of detection [13]. Ciclopirox may be
`detectable in the nail for up to 2 weeks after discontin-
`uing the application of the nail lacquer [42].
`In two vehicle-controlled trials, patients applied
`ciclopirox topical solution 8% to all
`toenails and
`affected fingernails. Twenty-four of 66 randomly
`chosen patients had detectable serum ciclopirox con-
`centrations in the range of 10 to 24.6 ng/mL at some
`point during treatment [13]. In an in vitro investiga-
`tion, radiolabeled ciclopirox applied once to avulsed
`onychomycotic toenails demonstrated penetration up
`to a depth of approximately 0.4 mm [13]. In addition,
`the more diseased the nail (eg, rougher and more
`fissured nail surfaces) the greater the degree of
`penetration [44].
`
`Efficacy
`Table 1 is a summary of the randomized con-
`trolled trials (RCTs) where ciclopirox nail lacquer 8%
`was used to treat onychomycosis caused by dermato-
`phytes, nondermatophytes, and yeasts. In this litera-
`ture search, two RCTs [13], one open study [36], and
`two case reports [20] were found.
`In the two randomized, double-blind, vehicle-
`controlled studies, 30 (29%) of 105 and 41 (36%)
`of 115 patients who applied ciclopirox for 48 weeks
`were mycologically cured [13]. In an open multi-
`center study, 60 patients with onychomycosis
`caused by nondermatophyte molds (Scopulariopsis
`brevicaulis, Aspergillus niger, Aspergillus fumiga-
`tus, and Hendersonula toruloidea) were treated with
`ciclopirox at least once weekly for up to 6 months
`
`

`

`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`483
`
`Table 1
`Summary of RCTs where ciclopirox nail lacquer 8% solution has been used to treat onychomycosis
`
`Study location Study type
`
`Nail matrix
`involvement Treatment
`
`MCa (%) CRb (%)
`
`Complete
`curec (%) Species identified
`
`United States Double-blind,
`randomized,
`vehicle-controlled,
`parallel-group,
`multicenter [13,46]
`
`United States Double-blind,
`randomized,
`vehicle-controlled,
`parallel-group,
`multicenter [13,46]
`
`No
`
`No
`
`Ciclopirox applied
`once daily for
`48 weeks
`Vehicle applied
`once daily for
`48 weeks
`Ciclopirox applied
`once daily for
`48 weeks
`Vehicle applied
`once daily for
`48 weeks
`a MC (mycologic cure): negative KOH and negative culture.
`b CR (clinical response): V10% nail involvement and negative mycology (culture and KOH).
`c Complete cure: clear nail and negative mycology (culture and KOH).
`
`30/105
`(29)
`
`12/106
`(11)
`
`7/107
`(6.5)
`
`1/108
`(0.9)
`
`6/110
`(5.5)
`
`1/109
`(0.9)
`
`41/115
`(36)
`
`14/116
`(12)
`
`10/118
`(8.5)
`
`10/114
`(9)
`
`1/115
`(0.9)
`
`0/117
`(0)
`
`T rubrum,
`T mentagrophytes
`
`T rubrum,
`T mentagrophytes
`
`[36]. The mycologic cure rates reported were 85%
`(KOH preparation) and 90% (culture); however, the
`combined mycology result was not stated [36]. In a
`case report, a 75-year-old man applied ciclopirox
`nail lacquer 8% daily to the toenails for 6 months;
`this led to the progressive disappearance of
`symptoms associated with moderate to severe ony-
`chomycosis [20].
`Tosti et al [7] treated patients with toenail ony-
`chomycosis caused by nondermatophyte molds. The
`clinical presentations included proximal subungual
`onychomycosis, white superficial onychomycosis,
`and distal subungual onychomycosis. Twenty-one
`patients had distal subungual onychomycosis caused
`by S brevicaulis, Fusarium species, and Acremonium
`species. The authors concluded that topical therapy
`was effective in the treatment of onychomycosis
`caused by some nondermatophyte molds [7].
`
`Combination therapy with ciclopirox nail lacquer
`A multinational, multicenter, randomized, and
`evaluator-blinded study is currently evaluating the
`combination of ciclopirox nail lacquer with terbina-
`fine for the treatment of toenail onychomycosis with
`involvement of 60% or greater nail plate or matrix
`disease [45]. Patients receive one of three treatments:
`(1) terbinafine, 250 mg/d for 12 weeks with 48-week
`once daily application of ciclopirox nail lacquer; (2)
`terbinafine, 250 mg/d for 12 weeks; and (3) terbina-
`fine, 250 mg/d for 8 weeks using an intermittent
`regimen with ciclopirox nail lacquer once daily for
`48 weeks [45].
`
`Safety
`The most common adverse events are the appear-
`ance of a rash (eg, periungual erythema and erythema
`of the proximal nail fold), with some patients report-
`ing a burning or tingling sensation at the application
`site [13]. Nail disorders were infrequently reported
`for both the ciclopirox and vehicle group, and con-
`sisted of shape change, irritation, ingrown toenail,
`and discoloration [13]. The adverse reactions were
`generally mild and often resolved with continued
`application of ciclopirox nail lacquer [46].
`
`Amorolfine nail lacquer
`
`Amorolfine is a topical antifungal agent of the
`morpholine class. It has a broad-spectrum of activity
`against yeasts, dermatophytes, and molds responsible
`for superficial fungal infections. Amorolfine is avail-
`able in many countries for the treatment of onycho-
`mycosis, but is not approved in the United States for
`this indication.
`
`Mode of action
`Amorolfine acts at two points in the ergosterol
`biosynthetic pathway, inhibiting D14-reductase and
`D7-8-isomerase enzymes [47]. Inhibition of these
`enzymes leads to a lack of cell growth and cell
`death, and the accumulation of sterol molecules and
`ignosterol, a sterol containing a D14-double bond
`[48]. The accumulation of ignosterol and other sterol
`molecules no longer fulfills the steric requirements
`of the fungal membrane [48]. Also, ignosterol accu-
`
`

`

`484
`
`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`mulation in Candida albicans indicates inhibition of
`D14-reductase [48,49].
`
`Amorolfine activity
`Amorolfine demonstrates fungicidal activity
`toward dermatophytes, dimorphic fungi, C albicans,
`Cryptococcus neoformans, and dematiaceous fungi;
`activity is both time and concentration dependent
`[47,49]. This morpholine derivative has also demon-
`strated fungistatic activity toward a number of fungal
`species [47,49].
`
`Pharmacokinetics
`An in-vitro penetration study examined the pene-
`tration of amorolfine (1%, 2%, and 5%) through
`porcine hoof horn material [50]. The highest accu-
`mulation of the drug was seen with the 5% amorol-
`fine lacquer [50]. The penetration profile of the 5%
`amorolfine lacquer was examined over a 7-day peri-
`od, where the concentration of amorolfine 5% in the
`nails increased linearly with a slight curve-shaped
`line, indicating saturation kinetics [50]. The kinetics
`of amorolfine in human nails follows an exponential
`law and the concentration of amorolfine in the upper
`layer of the nail plate is approximately 100 times
`higher than in the lowest layer [51]. The total amount
`of amorolfine in the nail depends on the thickness and
`consistency of the nail plate [51].
`
`There are data in the literature on two galenic
`forms of amorolfine, one containing methylene
`chloride and the other ethanol. Franz [52] examined
`these two formulations to determine their affect on
`5% amorolfine absorption. The rate of amorolfine
`absorption through a human thumbnail, following a
`single application, peaked between 5 and 25 hours
`and declined slowly thereafter in both the methylene
`chloride and ethanol lacquer. Rates of permeation
`through the nail ranged between 20 and 100 ng/
`cm2/h [52].
`In addition, Franz [52]
`found that
`amorolfine absorption was somewhat greater from
`the methylene chloride lacquer than the ethanol
`lacquer; however, Mensing et al [53]
`found no
`statistically significant difference between the two
`lacquer formulations.
`
`Efficacy
`Table 2 is a summary of the RCTs where amorol-
`fine nail lacquer 5% has been used to treat onycho-
`mycosis caused by dermatophytes, nondermatophytes,
`and yeasts. In this literature search three RCTs
`[26,31,32] were found.
`In a comparison study, Lauharanta [26] found 5%
`nail lacquer was significantly more effective than 2%
`nail lacquer when applied once weekly for up to
`6 months for the treatment of mild to moderate
`onychomycosis. Two open, randomized studies com-
`
`Table 2
`Summary of RCTs where amorolfine nail lacquer 5% solution has been used to treat onychomycosis
`
`Study type
`
`Matrix
`involvement Treatment
`
`Follow-up
`
`MCd (%) CRd (%)
`
`Complete
`cure+ (%) Species identified
`
`Open, randomized,
`parallel,
`comparative [31]
`
`No
`
`Open, randomized,
`multicenter,
`comparative [32]
`
`No
`
`No
`
`Amorolfine 5%
`once weekly
`for 6 mo
`Amorolfine 5%
`twice weekly
`for 6 mo
`Amorolfine 5%
`once weekly for
`6 mo or more
`Amorolfine 5%
`twice weekly for
`6 mo or more
`Amorolfine 5%
`once weekly for
`up to 6 mo
`
`Double-blind,
`randomized,
`parallel-design,
`multicenter [26]
`a MC (mycologic cure): negative culture.
`b CR (clinical response): cure or V10% of nail still affected.
`c Complete cure: clinical cure and negative mycologic culture.
`d Efficacy parameter not defined unless otherwise stated.
`
`3 mo after
`treatment end
`
`114/160
`(71.2)a
`
`120/160
`(75)b
`
`73/160
`(45.6)c
`
`125/166
`(75.3)a
`
`128/166
`(77.1)b
`
`86/166
`(51.8)c
`
`3 mo after
`treatment end
`
`89/126
`(70.6)
`
`108/142
`(76.1)
`
`31/51
`(60)
`
`3 mo after
`treatment end
`
`T rubrum,
`T mentagrophytes,
`yeasts, others
`
`T rubrum,
`T mentagrophytes,
`yeasts, others
`
`T rubrum,
`T mentagrophytes,
`yeasts, others
`
`58/126
`(46)c
`
`77/142
`(54.2)c
`
`(38)
`
`

`

`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`485
`
`pared the efficacy and safety of once-weekly versus
`twice-weekly application of amorolfine [31,32]. Both
`studies found that cure rates were slightly higher in
`the twice-weekly groups; however,
`there was no
`statistically significant difference between the dosage
`regimens [31,32].
`
`Combination therapy with amorolfine nail lacquer
`In an open, multicenter study 147 patients were
`randomized to receive amorolfine 5% applied once
`weekly for 15 months in combination with terbina-
`fine (250 mg/d) administered for 6 weeks (AT6) or
`12 weeks (AT12), or terbinafine, 250 mg/d for
`12 weeks (T12) [15]. At the end of the 18-month
`study, greater than 70% of the AT6 patients, approx-
`imately 90% of the AT12 patients, and greater than
`60% of the T12 patients were mycologically cured
`(both negative microscopy and culture). The cor-
`responding values for global cure (combined clini-
`cal-mycologic response) were 44% (N = 50), 72.3%
`(N = 47), and 37.5% (N = 48), respectively. The
`authors concluded that the combination of amorol-
`fine and terbinafine might be an effective treatment
`for severe onychomycosis with nail matrix involve-
`ment [15].
`In a similar study, Lecha et al [27] compared the
`efficacy of combined topical amorolfine and itraco-
`nazole with itraconazole alone in the treatment of
`severe toenail onychomycosis, defined as greater than
`or equal to 80% involvement of the surface or the
`matrix region of at least one toenail. Patients were
`treated with amorolfine 5% nail lacquer once weekly
`for 6 months in combination with itraconazole
`(200 mg/d) for 6 weeks (AI-6) or 12 weeks (AI-12),
`or itraconazole, 200 mg/d for 12 weeks (I-12) [27]. At
`week 24, statistically more patients in the combined
`treatment group ( 90%) were mycologically cured
`(negative microscopy and culture) compared with
`those treated with itraconazole (< 69%) alone
`(P < .001). Clinical cure (reduction of  95% in the
`original diseased nail surface area) was observed
`at week 24 in 88.1%, 100%, and 90.3% in the AI-6,
`AI-12, and I-12 groups, respectively. The corre-
`sponding values for global cure (combined myco-
`logic-clinical outcome) were 83.7%, 93.9%, and
`68.8%, respectively [27].
`
`Safety
`Amorolfine nail lacquer seems to be a safe treat-
`ment of onychomycosis. Adverse events reported by
`patients included burning, itching, redness, and local
`pain; these symptoms were tolerable and confined to
`the application site [31,32]. Few complained of local
`
`irritation [31,32]. There have been no reports of
`nonlocal adverse events experienced by the patient.
`
`Other topical therapies
`
`Efficacy
`
`Several topical antifungal agents have been used
`to treat onychomycosis including tioconazole [35,38],
`miconazole [16,22,33,35], fungoid tincture [28,29],
`bifonazole urea [17,24], tea tree oil [18,34], topical
`ketoconazole [25], ciclopirox olamine cream [30,37],
`and vitamin E [21]. Most of these studies evaluated
`the effectiveness of topical agents in the treatment of
`onychomycosis caused by dermatophytes.
`Table 3 is a summary of the RCTs where topical
`agents other than ciclopirox and amorolfine nail lac-
`quers have been used to treat onychomycosis caused
`by dermatophytes, nondermatophytes, and yeasts. In
`this literature search, five RCTs [18,22,29,34,35], nine
`open studies [16,17,24,25,28,30,33,37,38], and one
`case report [21] were found.
`In the RCTs, few studies mentioned the causative
`organism. Tea tree oil 5% combined with 2% butena-
`fine was significantly more effective than tea tree
`oil alone (P < .0001) [34]. Miconazole cream was
`significantly less effective compared with oral itraco-
`nazole [22].
`In an open study, Hay et al [38] evaluated the
`effectiveness of tioconazole 28% nail solution in the
`treatment of 27 patients with onychomycosis. Six pa-
`tients, five of whom had fingernail infections, were
`clinically and mycologically free from infection 2 to
`7 months after treatment [38]. Eleven patients showed
`marked improvement [38].
`In an open, multicenter trial, 57% of the onycho-
`mycosis patients treated with a combination of 1%
`ciclopirox solution and cream for a mean duration of
`12.7 F 5.6 weeks were free from signs of infection
`[30]. In an open study, ciclopirox olamine 1% cream
`was applied two to three times daily for 3 to 24
`months in 42 patients with onychomycosis [37].
`Fourteen percent of the patients were cured and
`36% improved with treatment [37].
`Avulsion of the onychomycotic nail before the
`application of topical agents may be beneficial. The
`topical treatment of onychomycosis with 1% bifona-
`zole and 40% urea paste produced mycologic cure
`(negative direct microscopy and culture) rate of
`62.5% at week 12 [24]. A similar study, evaluating
`the effectiveness of 1% bifonazole and 40% urea
`paste, demonstrated that at month 4, 45 (90%) of
`50 patients were culture negative [17].
`
`

`

`486
`
`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`Complete
`curef (%)
`
`Species identified
`
`17/19 (89)d
`
`Not given
`
`14/17 (82)d
`
`143/238 (60)a
`
`79/238 (32)b
`
`Not given
`
`negative culture:
`5/10 (50);
`negative KOH:
`5/10 (50)
`negative culture:
`1/10 (10);
`negative KOH:
`1/10 (10)
`
`Negative culture:
`7/64 (11)
`Negative culture:
`4/53 (8)
`
`3/10 (30)c
`
`Not given
`
`1/10 (10)c
`
`32/40 (80)e
`
`0/20 (0)e
`
`T rubrum,
`T mentagrophytes,
`T tonsurans
`
`T rubrum,
`T mentagrophytes,
`other
`
`Table 3
`Summary of RCTs where topical agents have been used to treat onychomycosis
`
`Matrix
`involvement
`
`Treatment
`
`Follow-up
`
`MCf
`
`CRf (%)
`
`Study type
`
`Open, randomized,
`comparative [35]
`
`Double-blind, randomized,
`multicenter, parallel-group,
`comparative [22]
`Double-blind, randomized,
`vehicle-controlled study [29]
`
`Double-blind, randomized,
`placebo-controlled [34]
`
`Double-blind, randomized,
`multicenter [18]
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`28% tioconazole applied
`twice daily for at least 3 mo
`2% miconazole tincture
`applied twice daily for at
`least 3 mo
`Miconazole cream twice
`daily for 6 mo, oral placebo
`for 6 mo
`Fungoid tincture applied
`twice daily for 12 mo
`
`1 month after
`treatment end
`
`6 mo after
`treatment end
`
`2 mo after
`treatment end
`
`36 wk after
`treatment end
`
`Vehicle for 12 mo
`
`2% butenafine hydrochloride
`and 5% tea tree oil in cream
`applied three times daily
`for 8 wk
`Placebo containing tea tree
`oil applied three times daily
`for 8 wk
`100% tea tree oil applied
`twice daily for 6 mo
`1% clotrimazole solution
`applied twice daily for 6 mo
`
`Abbreviations: MC, mycologic cure; CR, clinical response; NS, not stated.
`a negative culture and a negative or missing microscopy result.
`b cured or markedly improved.
`c percentage of involvement.
`d Complete cure; neither clinical nor microscopic evidence of reinfection.
`e clinical cure and negative mycology.
`f Efficacy parameter not defined unless otherwise stated.
`
`

`

`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`487
`
`After surgical avulsion of the nail plate, ketoco-
`nazole cream 2% was applied to the nail bed until the
`nail grew back to its normal length in 13 patients
`(aged 16 to 63 years old). Overall success was
`achieved in 95.7% of patients [25].
`Rollman [33] evaluated the effectiveness of
`chemomechanical partial nail avulsion, followed by
`topical miconazole 2% solution applied twice daily
`for 8 weeks in the treatment of distal subungual
`onychomycosis. Clinical and mycologic examina-
`tions were based on the number of affected nails.
`Sixty percent of the nails were clinically cured,
`63% had negative microscopy, and 58% had negative
`culture [33].
`
`Summary
`
`The management of onychomycosis using topical
`agents has improved with the introduction of ciclo-
`pirox and amorolfine nail
`lacquers; other topical
`agents may be less effective. The combination of a
`nail lacquer with an oral antifungal agent may further
`improve efficacy rates in certain clinical presentations
`(eg, among those individuals with severe onychomy-
`cosis). Topical agents have a favorable adverse events
`profile. Further studies are required on the treatment
`of onychomycosis with nail lacquers.
`
`Combination therapy
`
`References
`
`A parallel-group double-blind, randomized study,
`compared the efficacy of topical bifonazole-urea
`ointment alone and in combination with short-dura-
`tion oral griseofulvin in the treatment of onychomy-
`cosis caused by dermatophytes [19]. Initially all
`patients were treated with urea 40% and bifonazole
`1% ointment until the infected nail became complete-
`ly detached. Bifonazole 1% cream was applied to the
`nail bed every 24 hours and patients were randomized
`to receive either griseofulvin (500 mg) or placebo for
`4 weeks. Four months after therapy, mycologic cure
`(negative culture and KOH) was achieved in
`45 patients (93%) in the combination group and
`31 patients (66%) in the placebo group. Complete
`cure was achieved in 21 patients (43.7%) in the
`combination group and 10 (20%) in the placebo
`group [19].
`randomized study,
`In an open, comparative,
`Arenas et al [14] evaluated the treatment of onycho-
`mycosis with itraconazole or griseofulvin alone or in
`combination with isoconazole 1% or urea 40%. When
`the systemic agent was combined with isoconazole
`1%, 73% of patients treated with itraconazole were
`90% to 100% cured compared with 46% of griseo-
`fulvin patients (P = .05) [14]. The combination of the
`systemic agent and urea 40% resulted in 90% to
`100% cure rate in 78.5% of itraconazole patients
`and 42.8% of griseofulvin patients; the results were
`not significantly different (P = .10) [14].
`Hay et al [23] evaluated the effectiveness of com-
`bined oral griseofulvin (500 mg administered twice
`daily) with 28% tioconazole (applied twice daily)
`compared with griseofulvin only in the treatment of
`toenail onychomycosis. In the combined treatment
`group, 69% achieved complete clinical and mycologic
`remission within 1 year, compared with 41% of those
`nails treated only with griseofulvin [23].
`
`[1] Gupta AK, Taborda P, Taborda V, Gilmour J, Rachlis
`A, Salit I, et al. Epidemiology and prevalence of ony-
`chomycosis in HIV-positive individuals. Int J Dermatol
`2000;39:746 – 53.
`[2] Gupta AK. Onychomycosis in the elderly. Drugs
`Aging 2000;16:397 – 407.
`[3] Gupta AK, Konnikov N, MacDonald P, Rich P,
`Rodger NW, Edmonds MW, et al. Prevalence and epi-
`demiology of toenail onychomycosis in diabetic sub-
`jects: a multicentre survey. Br J Dermatol 1998;139:
`665 – 71.
`[4] Botter AA. Topical treatment of nail and skin infec-
`tions with miconazole, a new broad-spectrum antimy-
`cotic. Mykosen 1971;14:187 – 91.
`[5] Downs AM, Lear JT, Archer CB. Scytalidium hyalinum
`onychomycosis successfully treated with 5% amorol-
`fine nail lacquer. Br J Dermatol 1999;140:555.
`[6] Seebacher C, Nietsch KH, Ulbricht HM. A multicenter,
`open-label study of the efficacy and safety of ciclo-
`pirox nail lacquer solution 8% for the treatment of
`onychomycosis in patients with diabetes. Cutis 2001;
`68(suppl 2):17 – 22.
`[7] Tosti A, Piraccini BM, Lorenzi S. Onychomycosis
`caused by nondermatophytic molds: clinical features
`and response to treatment of 59 cases. J Am Acad
`Dermatol 2000;42(2 pt 1):217 – 24.
`[8] Yu B, Zhou G, Wang B, Ben Y, Yan H, Shao Y, et al. A
`clinical and laboratory study of ciclopirox olamine
`(8% Batrafen) in the treatment of onychomycosis. Chin
`Med Sci J 1991;6:166 – 8.
`[9] Goodfield MJ, Evans EG. Treatment of superficial
`white onychomycosis with topical terbinafine cream.
`Br J Dermatol 1999;141:604 – 5.
`[10] Meyerson MS, Scher RK, Hochman LG, Cohen JL,
`Pappert AS, Holwell JE. Open-label study of the safety
`and efficacy of naftifine hydrochloride 1 percent gel in
`patients with distal subungual onychomycosis of the
`fingers. Cutis 1993;51:205 – 7.
`[11] Mahgoub ES. Clinical trial with clotrimazole cream
`(Bay b 5097) in dermatophytosis and onychomycosis.
`Mycopathologia 1975;56:149 – 52.
`
`

`

`488
`
`A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489
`
`[12] Lauharanta J, Zaug G, Polak A, Reinel D. Combina-
`tion of amorolfine with griseofulvin: in vitro activity
`and clinical results in onychomycosis. JAMA 1993;
`9(suppl. 4):23 – 7.
`[13] Penlac nail lacquer (ciclopirox) topical solution, 8% pre-
`scribing information. Dermik laboratories, Inc; 2000.
`Available at: http://www.dermik.com/prod/penlac/
`pi.html.
`[14] Arenas R, Fernandez G, Dominguez L. Onychomyco-
`sis treated with itraconazole or griseofulvin alone with
`and without a topical antimycotic or keratolytic agent.
`Int J Dermatol 1991;30:586 – 9.
`[15] Baran R, Feuilhade M, Combernale P, Datry A,
`Goettmann S, Pietrini P, et al. A randomized trial
`of amorolfine 5% solution nail
`lacquer combined
`with oral terbinafine compared with terbinafine alone
`in the treatment of dermatophytic toenail onycho-
`mycoses affecting the matrix region. Br J Dermatol
`2000;142:1177 – 83.
`[16] Bentley-Phillips B. The treatment of onychomycosis
`with miconazole tincture. S Afr Med J 1982;62:57 – 8.
`[17] Bonifaz A, Guzman A, Garcia C, Sosa J, Saul A. Effi-
`cacy and safety of bifonazole urea in the two-phase
`treatment of onychomycosis. Int J Dermatol 1995;34:
`500 – 3.
`[18] Buck DS, Nidorf DM, Addino JG. Comparison of two
`topical preparations for the treatment of onychomyco-
`sis: Melaleuca alternifolia (tea tree) oil and clotrima-
`zole. J Fam Pract 1994;38:601 – 5.
`[19] Friedman-Birnbaum R, Cohen A, Shemer A, Bitterman
`O, Bergman R, Stettendorf S. Treatment of onycho-
`mycosis: a randomized, double-blind comparison study
`with topical bifonazole-urea ointment alone and in
`combination with short-duration oral griseofulvin. Int
`J Dermatol 1997;36:67 – 9.
`[20] Galitz J. Successful
`treatment of onychomycosis
`with ciclopirox nail lacquer: a case report. Cutis 2001;
`68(suppl 2):23 – 4.
`[21] Goldsmith S. Vitamin E and onychomycosis. J Am
`Acad Dermatol 1983;8:910 – 1.
`[22] Haneke E, Tajerbashi M, De Doncker P, Heremans A.
`Itraconazole in the treatment of onychomycosis: a dou-
`ble-blind comparison with miconazole. Dermatology
`1998;196:323 – 9.
`[23] Hay RJ, Clayton YM, Moore MK. A comparison of
`tioconazole 28% nail solution versus base as an adjunct
`to oral griseofulvin in patients with onychomycosis.
`Clin Exp Dermatol 1987;12:175 – 7.
`[24] Hay RJ, Roberts DT, Doherty VR, Richardson MD,
`Midgley G. The topical treatment of onychomycosis
`using a new combined urea/imidazole preparation. Clin
`Exp Dermatol 1988;13:164 – 7.
`[25] Hettinger DF, Valinsky MS. Treatment of onychomy-
`cosis with nail avulsion and topical ketoconazole. J Am
`Podiatr Med Assoc 1991;81:28 – 32.
`[26] Lauharanta J. Comparative efficacy and safety of
`amorolfine nail lacquer 2% versus 5% once weekly.
`Clin Exp Dermatol 1992;17(suppl 1):41 – 3.
`[27] Lecha M. Amorolfine and itraconazole combina-
`
`tion for severe toenail onychomycosis; results of an
`open randomized trial in Spain. Br J Dermatol 2001;
`145(suppl 60):21 – 6.
`[28] Meyerson MS, Scher RK, Hochman LG, Cohen JL,
`Pappert AS, Holwell JE. Open-label study of the safety
`and efficacy of fungoid tincture in patients with distal
`subungual onychomycosis of the toes. Cutis 1992;49:
`359 – 62.
`[29] Montana JB, Scher RK. A double-blind, vehicle-con-
`trolled study of the safety and efficacy of fungoid tinc-
`ture in patients with distal subungual onychomycosis
`of the toes. Cutis 1994;53:313 – 6.
`[30] Qadripur SA, Horn G, Hohler T. [On the local efficacy
`of ciclopirox olamine in onychomycoses]. Arzneimit-
`telforschung 1981;31:1369 – 72.
`[31] Reinel D, Clarke C. Comparative efficacy and safety of
`amorolfine nail lacquer 5% in onychomycosis, once-
`weekly versus twice-weekly. Clin Exp Dermatol 1992;
`17(suppl 1):44 – 9.
`[32] Reinel D. Topical treatment of onychomycosis with
`amorolfine 5% nail lacquer: comparative efficacy and
`tolerability of once and twice weekly use. Dermatol-
`ogy 1992;184(suppl 1):21 – 4.
`[33] Rollman O. Treatment of onychomycosis by partial
`nail avulsion and topical miconazole. Dermatologica
`1982;165:54 – 61.
`[34] Syed TA, Qureshi ZA, Ali SM, Ahmad S, Ahmad SA.
`Treatment of toenail onychomycosis with 2% butena-
`fine and 5% Melaleuca alternifolia (tea tree) oil in
`cream. Trop Med Int Health 1999;4:284 – 7.
`[35] Tulli A, Ruffilli MP, De Simone C. The treatment of
`onychomycosis with a new form of tioconazole.
`Chemioterapia 1988;7:160 – 3.
`[36] Ulbricht H, Worz K. [Therapy with ciclopirox lacquer
`of onychomycoses caused by molds]. Mycoses 1994;
`37(suppl 1):97 – 100.
`[37] Wu YC, Chuan MT, Lu YC. Efficacy of ciclopirox
`olamine 1% cream in onychomycosis and tinea pedis.
`Mycoses 1991;34:93 – 5.
`[38] Hay RJ, Mackie RM, Clayton YM. Tioconazole nail
`solution: an open study of its efficacy in onychomyco-
`sis. Clin Exp Dermatol 1985;10:111 – 5.
`[39] Marty J-PL. Amorolfine nail lacquer: a novel formula-
`tion. J Eur Acad Dermatol Venereol 1995;4(suppl. 1):
`S17 – 21.
`[40] Gupta AK, Baran R. Ciclopirox nail lac