1. Introduction

2. Topical treatments for PV

3. Systemic (oral) treatments

for PV

4. Systematic reviews of drug

efficacy and dosing regimens

5. Conclusion

6. Expert opinion

Review

Pityriasis versicolor: an update onpharmacological treatmentoptionsAditya K Gupta† & Danika CA Lyons†Mediprobe Research, Inc., Ontario, Canada

Introduction: Pityriasis versicolor (PV) is a superficial fungal infection caused

by Malassezia species; a yeast that naturally colonizes on the skins surface.

High efficacy rates are generally obtained with both topical and systemic

treatments. However, recurrence rates following successful treatment remain

high and there are no dosage guidelines available for administration of

systemic antifungal agents that carry risks of adverse events.

Areas covered: This review focused on providing an overview of existing

treatments for PV and an introduction to new treatments. A literature search

was conducted using the search strategy, pityriasis versicolor OR tinea

versicolor. Over the past decade, few new treatments have been introduced,

but the efficacy and the dosing regimens of existing treatments have been

systematically reviewed. The results of these reviews are discussed.

Expert opinion: Existing topical and systemic agents are both effective

treatments against PV. Previous dosage recommendations for systemic agents

have been modified based on recent evidence elucidated in systematic

reviews. However, the absence of standardized collection and reporting

practices in clinical trials precludes any conclusions to be drawn regarding

the efficacy and safety of topical and systemic agents in comparison or in

concert with each other.

Keywords: pityriasis versicolor, systemic antifungal, tinea versicolor, topical antifungal, treatment

Expert Opin. Pharmacother. (2014) 15(12):1707-1713

1. Introduction

Pityriasis versicolor (PV), otherwise known as tinea versicolor, is an innocuoussuperficial fungal infection of the skin that primarily affects the face, neck, upperarms and trunk [1]. It is caused by Malassezia species (M. spp), a genus of lipophilicfungi naturally colonized on the skin’s surface [2]. However, M. spp is only etiolog-ical when converted from yeast into its’ rounded, mycelial form [1,2]. The mycelialform of M. spp is expressed in the edges of lesions characteristic of PV. Lesionstypically present as hypo- or hyper-pigmented, round, flaky patches that maycoalesce in severe cases into larger, irregularly shaped patches [1,3].

Predisposing factors for PV include: genetic predisposition, immunodeficiency,oily skin, malnutrition, hyperhidrosis, sun exposure, exposure to high temperaturesand humidity, increased plasma cortisol levels, and use of oral contraceptives [3-5].Indeed, PV is more common in tropical climates than in temperate climates andprimarily affects adults and adolescents [5,6]. Furthermore, lesions typically presenton bodily regions rife with sebaceous glands known to increase oils on the skin’ssurface [3].

Clinical presentation and bright yellow or gold-colored fluorescence under aWood’s light (WL) are indicative of PV. However, diagnosis of PV can only beconfirmed through positive mycological examination and/or a positive potassiumhydroxide (KOH) test [1]. Where PV has been identified, topical antifungals are

10.1517/14656566.2014.931373 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 1707All rights reserved: reproduction in whole or in part not permitted

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.

the first line of treatment followed by systemic antifungals inrecalcitrant and/or severe cases. While a number of topicaland systemic agents have demonstrated efficacy and safety intreating PV [7], 60 -- 80% of patients experience recurrenceof symptoms within 2 years of treatment [6].In 2005, Gupta et al. presented an extensive review of all

topical and systemic treatments available for the managementof PV [3]. The authors concluded that the large majority oftreatments are effective when used appropriately, someproducing greater long-term remission than others, but noneremedying the chronicity of the disease [3]. The aim of thecurrent review is to provide an update on emerging pharma-cological treatments for PV and on new research indicatingthe optimal dosing regimens for well-established treatments.

2. Topical treatments for PV

The efficacy and safety of topical agents, including lotions,shampoos, creams, gels and solutions, are well established aseffective treatments against PV. Existing topical treatmentsinclude nonspecific antifungal agents that primarily removedead tissue and prevent further invasion, and specific antifun-gal agents that have direct fungistatic or fungicidal effects (seeGupta 2005 for thorough overview of topical treatments) [1,3].Occasional skin irritation and laborious courses of treatment(multiple applications over days, weeks or months) associatedwith topical agents may result in poor patient compliance.Patient compliance may be further hindered by recurrenceof signs and symptoms following successful treatment.Ketoconazole foam appears to be the only new topical

treatment that has undergone evaluation in clinical trials since2005. Ketoconazole foam is a new formulation of a specifictopical antifungal agent that penetrates transcutaneous tissuewith 6 times greater penetration than lotion formulations [8].

The product is temperature-activated; it melts and evaporatespromptly allowing the active compound to penetrate into thetissue quickly [8].

In 2008, Di Fonzo et al. compared 1% ketoconazole foamwith 2% ketoconazole cream, the standard treatment againstPV [8]. Forty-six participants with PV diagnosed throughpositive WL and mycological examination, were treated with1% ketoconazole foam or 2% ketoconazole cream once dailyfor 14 days. The patients were evaluated at weeks 1, 2 and 5,and at 3 months. Complete resolution was defined as, absenceof all clinical symptoms based on global clinical scale, a nega-tive WL evaluation and negative mycological evaluation. Thetwo groups demonstrated similar efficacy and safety with nostatistically significant differences evident between the groups.Specifically, at week 5, 29% of the participants in the ketoco-nazole foam group and 47% in the ketoconazole cream groupachieved complete resolution. At 3 months, 82% of the keto-conazole foam and 92% of the ketoconazole cream groupachieved complete resolution. Urticaria was reported by onepatient in the ketoconazole cream group; no adverse eventsreported in the ketoconazole foam group [8].

Shi et al. recently compared ketoconazole cream as a mono-therapy with ketoconazole cream in combination with 1%adapalene gel [9]. Adapalene gel is a naphthoic acid derivativetypically used in the treatment of acne vulgaris [10]. It bindsto retinoic acid receptors (RAR) primarily located in the skinand epidermis (RARb and RARg , respectively) inhibiting celldifferentiation [10]. One-hundred participants with PVconfirmed by direct microscopy were randomly assigned toreceive 2% ketoconazole cream and 1% adapalene gel once aday for 2 weeks (Group 1) or 2% ketoconazole cream twicedaily for 2 weeks (Group 2). Total improvement rate wasdefined as negative direct microscopy alongside ‡ 50% clinicalimprovement 4 weeks after treatment initiation [9]. Group1 demonstrated a significantly greater total improvement ratethan Group 2 when evaluated at one (38 vs 6%; p = 0.000),two (88 vs 56%; p = 0.000) and 4 weeks (92 vs 72%;p = 0.0009) [9]. There were no serious adverse events reported;minor adverse events included erythema, skin dryness andburning with combination therapy and mild irritation withmonotherapy.

Thus, 1% ketoconazole foam may represent an alternativeto ketoconazole cream. It appears to be equally effective withminimal side effects, less residue and improved cutaneouspenetration. Additionally, combination therapy with ketoco-nazole cream and adapalene gel may offer a faster acting andmore effective treatment option than monotherapy withketoconazole cream. This may facilitate patient complianceas combination therapy.

3. Systemic (oral) treatments for PV

The efficacy of systemic (oral) agents such as ketoconazole, itra-conazole and fluconazole has been well established. Althoughoral terbinafine is an effective treatment for a number of

Article highlights.

. Both topical and oral treatments for pityriasis versicolorare effective although relapse rates remain high.

. 1% ketoconazole foam (only new topical agentintroduced since 2005) appears as effective as 2%ketoconazole cream; combination therapy with 2%ketoconazole cream and 0.1% adapalene gel may besuperior to monotherapy with 2% ketoconazole cream.

. Oral ketoconazole (once first line of systemic treatment)no longer approved for superficial fungal infections inCanada, US and UK.

. Itraconazole appears equally effective whenadministered at 200 mg/day over 5 or 7 days.

. Fluconazole appears most effective when administeredin 300 mg dosages over 2 or 4 weeks.

. Pramiconazole (only new oral agent introduced since2005) appears most effective at 200 mg/day over2 -- 3 days but may be associated with many adverseside effects.

This box summarizes key points contained in the article.

A. K. Gupta & D. C. A. Lyons

1708 Expert Opin. Pharmacother. (2014) 15(12)

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.

superficial fungal infections, it is not effective as a treatmentagainst PV [11]. Orals are on rare occasions, associated withsevere adverse events; thus, they are typically viewed as a secondline of treatment for PV in the event of severe or recalcitrantcases.

3.1 KetoconazoleKetoconazole is an imidazole antifungal used to treat PV; itacts as a broad-spectrum antifungal by inhibiting 14-a-demethylation of lanosterol, thereby interfering with ergos-terol biosynthesis in the cell wall [12]. Once the oral treatmentof choice against PV, oral ketoconazole is no longer approvedfor use on superficial fungal infections in Canada [13,14], theUS [12] or Europe [15] due to the risk of hepatotoxic side effectsassociated with it. Newer oral agents such as itraconazole andfluconazole are now preferred over ketoconazole. However,ketoconazole is inexpensive relative to the other oral agentsand it has demonstrated efficacy as a prophylactic agentagainst PV [16,17].

3.2 ItraconazoleItraconazole is a lipophilic triazole antifungal whose transmis-sion is facilitated by sebum secretion to reach the stratum cor-neum [18]. It works by inhibiting cytochrome P450-dependantbiosynthesis of ergosterol, an essential component of the cellwall [19]. Cauwenbergh et al. reported in 1987 that a minimumof 1000 mg of itraconazole should be administered over 7 daysrather than 5 days to effectively treat PV [20]. Further, theynoted that clinical and mycological evidence of effective treat-ment following itraconazole may not be apparent until 3 or4 weeks after treatment [20]. However, in two direct clinicalcomparisons of 200 mg of itraconazole administered dailyover 5 days or 7 days, it would appear that the two coursesof treatment yield comparable outcomes [21,22].

The 5 and 7-day courses of treatment have also beencompared with a single 400 mg dose of itraconazole [18,23,24]

and 400 mg daily over 3 days course of treatment [24]. Koseet al. and Wahab et al. reported equivalent efficacy betweena daily 200 mg dose of itraconazole over 7 days and a single400 mg dose [18,23]. In contrast, Kokturk et al. reported greaterefficacy of 400 mg of itraconazole a day over 3 days and200 mg a day over 5 days than 400 mg in 1 day [24]. Thus,it is unclear whether itraconazole administered in one400 mg dose is as effective in the treatment of PV as repeateddoses over a number of days. In 2002, Faergemann et al.conducted a study evaluating the use of itraconazole as pro-phylaxis against relapse in patients with PV [25]. In phase 1of the study, participants (n = 238) with mycologicallyconfirmed PV received 200 mg of itraconazole once dailyfor 7 days. In phase 2 of the study, those that achieved myco-logical cure (negative KOH) were randomized into one of twoarms: i) 200 mg of itraconazole twice daily, 1 day a month for6 months; or ii) placebo twice daily, 1 day a month for6 months. At 6 months of follow-up, a significantly greaterproportion of those in the itraconazole group maintained

mycological cure than those in the placebo group (88.2 and56.6%, p < 0.001). Fewer clinical signs and symptoms wereevident in the itraconazole group than the placebo group(p < 0.001). Respiratory tract infection and influenza-likesymptoms were reported during phase 2 of the study. Therewere no serious adverse events reported during phase 2 ofthe study [25].

3.3 FluconazoleFluconazole is triazole antifungal that inhibits P450-dependant biosynthesis of ergosterol [26]. Fluconazole hasalso demonstrated greater efficacy in the treatment of PVthan ketoconazole [27]; it is able to reach a greater plasma con-centration in the stratum corneum where it can persistfor ~ 2 weeks following treatment [28]. Fluconazole is effectiveat multiple doses and courses of treatment, including:i) 150 mg/week for 4 weeks; ii) 300 mg/week for 2 or 4 weeks;iii) 300 mg every 2 weeks for 4 weeks; and iv) a single 400 mgdose [3,29,30].

In 2010, Dehghan et al. compared oral fluconazole withtopical clotrimazole in a double-blind, randomized clinicaltrial [31]. One hundred five participants with PV verified basedon clinical presentation and KOH examination were assignedto receive a single dose of fluconazole (400 mg) and a placebocream (twice daily for 2 weeks) or a single dose of an oralplacebo and 1% clotrimazole cream (twice daily for 2 weeks).Follow-up assessments evaluating clinical signs and symptomswere performed 2, 4 and 12 weeks following treatment. Com-plete response was defined as 95% and more lesion clearage.At 2 weeks, there were no significant differences between thefluconazole and clotrimazole groups on the rate of complete(30 vs 49.1%), incomplete (66 vs 47.3%) or no clinicalresponses (4 vs 3.6%) observed (c2 = 4.03, p = 0.16). At4 weeks, a significant difference between the two groups didemerge (c2 = 4.07, p = 0.04); however, it is unclear if the dif-ference between the groups lay between their rate of completeresponse (81.2 vs 94.9%) or incomplete response (18.8 vs5.1%). The rates of complete (92 vs 81.8%), incomplete(2 vs 0%) and no clinical response or recurrence (6 vs18.2%) between the groups at week 12 were not significant(c2 = 4.55, p = 0.77). No treatment-emergent adverse eventswere reported in either group [31].

To summarize, while fluconazole is an effective treatmentagainst PV, it is unclear whether it performs better thantopical clotrimazole cream. It can be inferred from Dehghan’sstudy that clotrimazole cream may act faster than oral flucon-azole but, in the long term, clotrimazole cream and oralfluconazole treat PV with similar efficacy. Additional researchis required to elucidate any true differences between oralfluconazole and topical clotrimazole cream in the treatmentof PV.

3.4 Pramiconazole: a new oral treatment against PVPramiconazole is a relatively new triazole antifungal, whichtargets 14-a-demethylase-dependent biosynthesis of ergosterol

Pityriasis versicolor

Expert Opin. Pharmacother. (2014) 15(12) 1709

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.

[32]. In vitro, pramiconazole has demonstrated activity againstM. spp isolates similar to itraconazole and 10 times greaterthan ketoconazole at concentrations < 1 µg/ml [32]. Pramicona-zole has only been evaluated twice in clinical trials as a treatmentfor PV.In 2007, Faergemann et al. evaluated the efficacy and safety

of once-daily 200 mg pramiconazole over 3 days [33]. Nine-teen participants with PV confirmed by KOH examinationwere evaluated at baseline and days 4, 10 and 30 for clinicaland mycological signs of PV. Clinical signs and symptoms(erythema, itching and desquamation) were rated on afive-point scale using a global clinical evaluation (GCE).Mycological cure was defined as a negative KOH evaluation.At day 10, 42% of participants achieved mycological cureand at day 30, 100% of participants achieved mycologicalcure. The sum of scores from the GCE decreased significantlyfrom baseline (median = 8) to day 4 (median = 5), 10(median = 3) and 30 (median = 2; p < 0.001). However,47.4% of participants reported adverse events, including gas-trointestinal disorders, general disorders (asthenia, feelinghot), blood present in urine, neck pain, headache, respiratorythoracic and mediastinal disorders, and folliculitis [33].In 2009, Faergemann et al. undertook an extensive investi-

gation of five dosages and courses of treatment for pramicona-zole [34]. Participants (n = 147) with KOH-positive PV, milddesquamation, multiple lesions and ‡ 15% skin involvementwere included. They were assigned to receive: i) a single doseof 100 mg; ii) a single dose of 200 mg; iii) one 200 mg dosedaily for 2 days; iv) one 200mg dose daily for 3 days; v) a single400 mg dose of pramiconazole; or vi) one placebo a day for3 days. Complete cure was defined as a negative KOH evalua-tion and a score of 0 on an investigator global assessment (IGA)of erythema, desquamation or pruritus. Mycological cure wasdefined as a negative KOH evaluation. Upon follow-up onday 28, a significantly greater proportion of participantstreated with a single 200 mg dose (59.1%), 200 mg/day for2 days (72%), 200 mg/day for 3 days (84.6%) and a single400 mg dose (52.2%) achieved complete cure than those inthe placebo group (16%) (p = 0.003, p < 0.001, p < 0.001,p = 0.013, respectively). Similarly, a significantly greater pro-portion of participants treated with a single 200 mg dose(68.2%), 200 mg/day for 2 days (92%), 200 mg/day for3 days (96.2%) and a single 400 mg dose (78.3%) achievedmycological cure than those in the placebo group (16%)(p < 0.001; all groups). Diarrhea and nausea were the mostfrequently reported adverse events. The group treated with asingle 100 mg dose exhibited the highest proportion of adverseevents (46%) and the group receiving 200 mg/day for 3 daysthe lowest (31%) [34].Thus, pramiconazole appears to be effective at the follow-

ing doses: i) single 200 mg; ii) 200 mg/day for 2 days; iii)200 mg/day for 3 days; and iv) single 400 mg. A number ofadverse events were reported in both studies evaluating prami-conazole in the treatment of PV. Further research with regardto elucidating the dose and course of treatment yielding the

greatest efficacy with the lowest incidence of adverse eventsare warranted. Direct comparisons of pramiconazole withitraconazole and/or fluconazole are also warranted to establishits efficacy and safety profile in relation to existing oraltreatments are required.

4. Systematic reviews of drug efficacy anddosing regimens

Systematic reviews are useful tools for synthesizing availableevidence from clinical trials to get a clearer picture of a drugefficacy. At this time, three systematic reviews have beenpublished. Two such reviews confirmed the efficacy of topicaltreatments for PV [7,35]. One review also confirmed theefficacy of systemic treatments as compared to placebo but,was unable to answer whether any one dosage or course oftreatment for systemic agents was superior to another [35].The third review sought to answer those questions [36].

Hu and Bigby synthesized data from clinical trials evaluat-ing topical and oral treatments against PV [35]. The authorscollected, examined and compared 93 controlled trials inchildren and adults with PV. The data indicated that all top-ical azole, non-azole agents and terbinafine performed betterthan placebo [35]. The performances of topical antifungalsmay be enhanced given higher drug concentrations and longertreatment durations; however, the authors reported a lack ofsufficient power to detect significant differences [35]. Mildpruritus, burning, erythema, and skin dryness and irritationwere associated with topical antifungal agents [35].

In their evaluation of systemic treatments against PV, Huand Bigby reported greater efficacy of ketoconazole anditraconazole compared to placebo [35]. Systemic antifungalsalso demonstrated a tendency toward improved efficacy givenhigher dosages and longer courses of treatment but, againtheir analysis lacked sufficient power to detect significant dif-ferences [35]. In addition, systemic treatments were associatedwith numerous side effects, including, but not limited to,gastrointestinal symptoms (nausea, vomiting, and diarrhea),headache, fatigue and skin-related symptoms [35].

In Gupta et al. systematic review, they compared theefficacy of systemic antifungals with the aim of providing dos-age and course of treatment recommendations [36]. A total of57 clinical trials were included in the study. Based on theiranalysis, there was no association between mycological curerates (MCR) achieved using itraconazole and the duration oftreatment (5 or 7 days) or the daily concentrations (100,200 or 400 mg/day) [34]. Similarly, in regard to fluconazolethere was no correlation between MCRs and the cumulativedose, duration of treatment or weekly concentration [36].However, multiple dosing regimens of fluconazole consis-tently demonstrated MCRs ‡ 75%, whereas single dosesdid not [36]. Ketoconazole was associated with greater MCRsgiven higher cumulative doses (400 -- 5600 mg) and longertreatment duration (1 -- 28 days) [36]. Pramiconazole wasalso associated with improved MCRs given larger cumulative

A. K. Gupta & D. C. A. Lyons

1710 Expert Opin. Pharmacother. (2014) 15(12)

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.

doses (100 -- 600 mg) and longer treatment durations(1 -- 3 days) [36].

Thus, it can be inferred from these systematic reviewsthat both topical and systemic antifungals are effective treat-ments against PV. However, there would appear to be fewerside effects associated with topical agents than systemic agents.Itraconazole appears to be equally effective whether adminis-tered as a 200-mg dose over 5 or 7 days, fluconazole mayprovide greater efficacy when administered in multiple ratherthan single doses, and ketoconazole and pramiconazole aremore effective at higher cumulative dosages and longertreatment durations.

5. Conclusion

There are a number of effective treatments available for relieffrom PV; therefore, few new pharmacological treatmentshave been developed over the past decade with the exceptionof 1% ketoconazole foam and oral pramiconazole. Ketocona-zole foam, a topical agent with enhanced penetration,demonstrated comparable efficacy and safety to 2% topicalketoconazole cream in the treatment of PV [8]. Similarly, oralpramiconazole, a new oral triazole antifungal, demonstratedefficacy at multiple doses (a single 200 mg dose, 200 mg/dayfor 2 days, 200 mg/day for 3 days and a single 400 mg dose)as a treatment against PV [33,34]. However, pramiconazolewas associated with a number of adverse side effects. Thus,1% ketoconazole foam and pramiconazole may represent twonew alternative pharmacological treatment options for PV.

Systematic reviews have attempted to amalgamate andcompare existing clinical trials. While these reviews were ableto confirm the efficacy of topical or oral agents as comparedto placebo, they are unable to perform indirect statistical com-parisons between existing topical and oral antifungal agents.Nonetheless, one review was able to elucidate evidence-baseddosing recommendations for oral antifungals were once therewere none [36]. Establishing evidence-based dosing regimensfor oral treatments is of utmost importance for optimizingefficacy while minimizing side effects.

6. Expert opinion

It is unclear what causes the conversion of M. spp yeast to itsmycelial form but, oily skin is a known risk factor [1,4]. Indeed,PV primarily affects post-pubescent adolescents and adults,occurs more often in tropical climates, and PV lesions tend tocoincide with bodily regions rife with sebaceous glands [6].The persistent presence of M. spp on the skin results in a highlifetime risk of recurrence following successful treatment [3,6].

Topical antifungals are effective and inexpensive treatments

against PV. However, topical agents are only effective whenapplied properly and patient compliance may be subopti-

mal [3]. Systemic antifungals may be warranted where topicalagents are ineffective or in severe cases where lesions have coa-lesced across a significant portion of the body. To date, there

are no standard dosing regimens available for administrationof systemic antifungals in the treatment of PV [36].

Oral ketoconazole is an older systemic antifungal. It is no

longer approved for superficial fungal infections in the United

States, Canada or Europe due to its hepatotoxic side effects

[12-15]. Thus, the authors only recommend ketoconazole where

topical agents and newer antifungals are ineffective. In such

cases, we recommend 200 mg/day for 10 days. This recom-

mendation is in contrast to our 2005 recommendation

(Table 1) [3]; however, there is evidence to suggest that ketoco-

nazole is more effective at higher cumulative dosages and

longer treatment durations [36].Itraconazole is a well-established treatment against PV.

Some debate regarding whether itraconazole ought to beadministered over 5 or 7 days has persisted for many years.Recent evidence suggests that itraconazole is equally effective

when administered at 200 mg/day for 5 or 7 days [36]. Thus,in contrast to our previous recommendation of 7 days [3],

the authors recommend 200 mg once daily for 5 days ratherthan 7, thereby facilitating patient compliance (Table 1).

Fluconazole is also an effective treatment against PV. Itappears most effective at 150 and 300 mg/week dosageswhether administered over 2 or 4 weeks [35,36]. Fluconazole

administered in multiple 300 mg doses appears to achievegreater MCRs than multiple 150 mg doses [36]. As such, the

authors recommend 300 mg of fluconazole per week for2 weeks (Table 1).

Pramiconazole is an emerging antifungal treatment for PV.Pramiconazole appears to be most effective when administered

as 200 mg/day for 2 or 3 days [34]. This inference may be furthersupported by recent evidence suggesting improvedMCRs givenlarger cumulative doses and longer treatment duration [36].

Thus, the authors recommend 200 mg once daily for 2 daysof pramiconazole (Table 1). Nevertheless, further research

evaluating pramiconazole at various concentrations, dosingregimens, and in comparison to existing systemic agents arenecessary.

Posaconazole and voriconazole, two alternative azoles, mayhold promise as systemic treatments against PV. In vitro,

Table 1. Change in dosing recommendation

2005 -- 2014.

2005

recommendation

2014

recommendation

Ketoconazole* 200 mg3� 12 h apart

200 mg/day for 10 days

Itraconazole 200 mg/dayfor 7 days

200 mg/day for 5 days

Fluconazole 300 mg2� 2 days apart

300 mg/wk for 2 weeks

Pramiconazole No recommendation 200 mg/day for 2 days

*Ketoconazole is no longer recommended for the treatment of superficial

fungal infection in the US, Canada and Europe.

Note: 3� = 3 times; 2� = 2 times; wk = Week.

Pityriasis versicolor

Expert Opin. Pharmacother. (2014) 15(12) 1711

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.

posaconazole and voriconazole have demonstrated similarminimal inhibitory concentrations against M. spp isolates asketoconazole, itraconazole and fluconazole [37-39]. However,in vitro data often do not translate well into clinical efficacy.Therefore, clinical trials evaluating these two potential treat-ments are warranted in order to establish their efficacy intreating human PV.Recently published systematic reviews indicate a lack of

direct comparisons between topical and systemic agents inthe literature and substandard reporting habits associatedwith published clinical trials. In the future, topical andsystemic agents ought to be evaluated in combination withone another and compared against one another. Furthermore,heedful regard for proper reporting techniques when

conducting clinical trials is recommended in the future tofacilitate the synthesis of clinical trials for evaluation inmeta-analyses.

Declaration of interest

AK Gupta and DCA Lyons are associated with MediprobeResearch, a private company, which did not receive any finan-cial contributions from any sponsor and no sponsor wasinvolved in the writing of this manuscript. The authors haveno other relevant affiliations or financial involvement withany organization or entity with a financial interest in or finan-cial conflict with the subject matter or materials discussed inthe manuscript apart from those disclosed.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Gupta AK, Bluhm R, Summerbell R.

Pityriasis versicolor. J Eur Acad

Dermatol Venereol 2002;16:19-33

2. Gaitanis G, Velegraki A, Mayser P, et al.

Skin diseases associated with Malassezia

yeasts: facts and controversies.

Clin Dermatol 2013;31:455-63

3. Gupta AK, Kogan N, Batra R. Pityriasis

versicolor: a review of pharmacological

treatment options. Expert Opin

Pharmacother 2005;6:165-78

.. Thorough review of topical and

systemic treatments for pityriasis

versicolor (PV). The current review

continued forward from this review.

4. Mendez-Tovar LJ. Pathogenesis of

dermatophytosis and tinea versicolor.

Clin Dermatol 2010;28:185-9

5. Borelli D, Jacobs PH, Nall L. Tinea

versicolor: epidemiologic, clinical, and

therapeutic aspects. J Am Acad Dermatol

1991;25(2 Pt 1):300-5

6. Faergemann J. Pityrosporum species as a

cause of allergy and infection. Allergy

1999;54:413-19

7. Rotta I, Sanchez A, Goncalves P, et al.

Efficacy and safety of topical antifungals

in the treatment of dermatomycosis:

a systematic review. Br J Dermatol

2012;166:927-33

. Systematic review of topical antifungals

covering topical antifungals in the

treatment of PV.

8. Di Fonzo EM, Martini P, Mazzatenta C,

et al. Comparative efficacy and

tolerability of Ketomousse (ketoconazole

foam 1%) and ketoconazole cream 2% in

the treatment of pityriasis versicolor:

results of a prospective, multicentre,

randomised study. Mycoses

2008;51:532-5

. Only new topical agent for PV

uncovered in literature search.

9. Shi TW, Zhang JA, Tang YB, et al.

A randomized controlled trial of

combination treatment with ketoconazole

2% cream and adapalene 0.1% gel in

pityriasis versicolor. J Dermatolog Treat

2014. [Epub ahead of print]

10. Brogden RN, Goa KE. Adapalene.

A review of its pharmacological

properties and clinical potential in the

management of mild to moderate acne.

Drugs 1997;53:511-19

11. Vermeer BJ, Staats CC. The efficacy of a

topical application of terbinafine 1%

solution in subjects with pityriasis

versicolor: a placebo-controlled study.

Dermatology 1997;194(Suppl 1):22-4

12. Janssen Pharmaceuticals. Nizoral�

(Ketoconazole) Tablets. Drugs@FDA:

FDA Approved Drug Products.

2014. Available from: http://www.

accessdata.fda.gov/drugsatfda_docs/label/

2014/018533s041lbl.pdf

.. FDA label for ketoconazole indicating

warning of hepatotoxicity.

13. Ketoconazole - Risk of Potentially Fatal

Liver Toxicity - For Health Professionals.

2013. Available from: http://

healthycanadians.gc.ca/recall-alert-rappel-

avis/hc-sc/2013/34173a-eng.php

.. Health Canada label warning of

hepatotoxicity associated

with Ketoconazole.

14. PrApo-Ketoconazole. Ketoconazole

tablets USP 200 mg. Government of

Canada HC. Drug product database

online query. 2012. Available from:

http://webprod5.hc-sc.gc.ca/dpd-bdpp/

info.do?code=60554&lang=eng

15. European Medicines Agency recommends

suspension of marketing authorisations

for oral ketoconazole. European

Medicines Agency. 2013. Available from:

http://www.ema.europa.eu/ema/index.jsp?

curl=pages/news_and_events/news/2013/

07/news_detail_001855.

jsp&mid=WC0b01ac058004d5c1

.. European Medicines Agency warning

of hepatotoxicity associated with

Ketoconazole.

16. Faergemann J, Djarv L. Tinea versicolor:

treatment and prophylaxis with

ketoconazole. Cutis 1982;30:542-5, 550

17. Rausch LJ, Jacobs PH. Tinea versicolor:

treatment and prophylaxis with monthly

administration of ketoconazole. Cutis

1984;34:470-1

18. Kose O, Bulent Tastan H, Riza Gur A,

et al. Comparison of a single 400 mg

dose versus a 7-day 200 mg daily dose of

itraconazole in the treatment of tinea

versicolor. J Dermatolog Treat

2002;13:77-9

19. Sporanox� (itraconazole) Capsules.

Drugs@FDA: FDA Approved Drug

Products. 2014. Available from:

http://www.accessdata.fda.gov/

drugsatfda_docs/label/2014/

020083s053lbl.pdf

20. Cauwenbergh G, De Doncker P,

Stoops K, et al. Itraconazole in the

treatment of human mycoses: review of

three years of clinical experience.

Clin Infect Dis 1987;9(Suppl 1):S146-52

21. Galimberti RL, Villalba I, Galarza S,

et al. Itraconazole in pityriasis versicolor:

A. K. Gupta & D. C. A. Lyons

1712 Expert Opin. Pharmacother. (2014) 15(12)

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.

ultrastructural changes in malassezia

furfur produced during treatment.

Rev Infect Dis 1987;9:S134-8

22. Mohanty J, Sethi J, Sharma MK.

Efficacy of itraconazole in the treatment

of tinea versicolor. Indian J Dermatol

Venereol Leprol 2001;67:240-1

23. Wahab MA, Ali ME, Rahman MH,

et al. Single dose (400 mg) versus 7 day

(200 mg) daily dose itraconazole in the

treatment of tinea versicolor:

a randomized clinical trial.

Mymensingh Med J 2010;19:72-6

24. Kokturk A, Kaya TI, Ikizoglu G, et al.

Efficacy of three short-term regimens of

itraconazole in the treatment of pityriasis

versicolor. J Dermatolog Treat

2002;13:185-7

25. Faergemann J, Gupta AK, Al Mofadi A,

et al. Efficacy of itraconazole in the

prophylactic treatment of pityriasis

(tinea) versicolor. Arch Dermatol

2002;138:69-73

26. Diflucan� (Fluconazole Tablets)

(Fluconazole Injection -- for intravenous

infusion only) (Fluconazole for Oral

Suspension). Drugs@FDA: FDA Approved

Drug Products. 2014. Available from:

http://www.accessdata.fda.gov/

drugsatfda_docs/label/2014/019949

s058,019950s062,020090s042lbl.pdf

27. Bhogal CS, Singal A, Baruah MC.

Comparative efficacy of ketoconazole and

fluconazole in the treatment of pityriasis

versicolor: a one year follow-up study.

J Dermatol 2001;28:535-9

28. Partap R, Kaur I, Chakrabarti A, et al.

Single-dose fluconazole versus

itraconazole in pityriasis versicolor.

Dermatology 2004;208:55-9

29. Yazdanpanah MJ, Azizi H, Suizi B.

Comparison between fluconazole and

ketoconazole effectivity in the treatment

of pityriasis versicolor. Mycoses

2007;50:311-13

30. Karakas M, Durdu M, Memisoglu HR.

Oral fluconazole in the treatment of

tinea versicolor. J Dermatol

2005;32:19-21

31. Dehghan M, Akbari N, Alborzi N, et al.

Single-dose oral fluconazole versus topical

clotrimazole in patients with pityriasis

versicolor: a double-blind randomized

controlled trial. J Dermatol

2010;37:699-702

32. Odds F, Ausma J, Gerven FV, et al. In

vitro and in vivo activities of the Novel

azole antifungal agent R126638.

Antimicrob Agents Chemother

2004;48:388-91

. Excellent description of the efficacy of

Pramiconazole in vitro and in vivo

against fungi. Pramiconazole was the

only new systemic agent uncovered in

our literature search for the treatment

of PV.

33. Faergemann J, Ausma J,

Vandeplassche L, et al. The efficacy of

oral treatment with pramiconazole in

pityriasis versicolor: a phase II a trial.

Br J Dermatol 2007;156:1385-8

34. Faergemann J, Todd G, Pather S, et al.

A double-blind, randomized, placebo-

controlled, dose-finding study of oral

pramiconazole in the treatment of

pityriasis versicolor. J Am Acad Dermatol

2009;61:971-6

35. Hu SW, Bigby M. Pityriasis versicolor:

a systematic review of interventions.

Arch Dermatol 2010;146:1132

. Systematic review evaluating topical

and systemic antifungal agents in the

treatment of PV.

36. Gupta AK, Lane D, Paquet M.

Systematic review of systemic treatments

for tinea versicolor and evidence-based

dosing regimen recommendations.

J Cutan Med Surg 2014;18:79-90

.. Excellent systematic review elucidating

dosage recommendations for systemic

agents in the treatment of PV.

37. Budimulja U, Paul C. One-week

terbinafine 1% solution in pityriasis

versicolor: twice-daily application is more

effective than once-daily.

J Dermatolog Treat 2002;13:39-40

38. Gupta AK, Kohli Y, Li A, et al. In vitro

susceptibility of the seven Malassezia

species to ketoconazole, voriconazole,

itraconazole and terbinafine.

Br J Dermatol 2000;142:758-65

39. Miranda KC, de Araujo CR, Costa CR,

et al. Antifungal activities of azole agents

against the Malassezia species. Int J

Antimicrob Agents 2007;29:281-4

AffiliationAditya K Gupta†1,2 MD PhD FAAD FRCP(C)

& Danika CA Lyons2 MSc†Author for correspondence1University of Toronto, Department of Medicine,

Toronto, Canada2Mediprobe Research, Inc., 645 Windermere

Road, London, Ontario, N5X 2P1, Canada

Tel: +1 519 851 9715;

Fax: +1 519 657 4233;

E-mail: agupta@execulink.com

Pityriasis versicolor

Expert Opin. Pharmacother. (2014) 15(12) 1713

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

08/1

1/14

For

pers

onal

use

onl

y.