Systematic review of systemic treatments for tinea versicolor and evidence-based dosing regimen recommendations.

REVIEW

Systematic Review of Systemic Treatments for Tinea Versicolor and Evidence-Based Dosing Regimen Recommendations Aditya K. Gupta, Danielle Lane, and Maryse Paquet Background: Extensive or recurrent tinea versicolor (TV) can be treated with systemic antifungal therapies, but no dosing regimens have been approved for this indication. Objective: To provide evidence-based recommendations for dosing regimens. Methods: A systematic literature search was performed to identify trials reporting mycologic cure. All trials were included and assessed for quality. Correlation and statistical analyses were used to evaluate the effects of different dosing regimen parameters on efficacy. Results: Fifty-seven trials investigating itraconazole, ketoconazole, fluconazole, and pramiconazole were included. Cumulative dose, treatment duration, and daily/weekly concentrations were shown to significantly influence mycologic cure rates for ketoconazole and pramiconazole but not for itraconazole and fluconazole. Conclusion: Based on the efficacy evidence and potential safety concerns, this review supports the following dosing regimens: 200 mg/d for 5 or 7 days of itraconazole, 300 mg/wk for 2 weeks of fluconazole, and 200 mg/d for 2 days of pramiconazole. Contexte: Le pityriasis versicolor e´tendu ou rećidivant peut se traiter par des antifongiques a` action geńe´rale, mais aucun re´gime posologique n’a e´te´ approuve´ pour cette indication. Objectif: L’e´tude visait a` formuler des recommandations sur la posologie, fondeés sur des donneés probantes. Me´thode: Nous avons proce´de´ a` un examen me´thodique de la documentation a` la recherche d’essais faisant e´tat de la gue´rison mycologique. Tous les essais ainsi releve´s ont e´te´ inclus dans l’e´tude et soumis a` une e´valuation de la qualite´. L’effet, sur l’efficacite´, de diffe´rents parame`tres relatifs au re´gime posologique a e´te´ calcule´ a` l’aide d’analyses de corre´lation et d’analyses statistiques. Re´sultats: Ont e´te´ inclus dans l’e´tude, 57 essais de diffe´rents me´dicaments, soit d’itraconazole, de ke´toconazole, de fluconazole, et de pramiconazole. La dose cumuleé, la dureé de traitement, ainsi que les doses quotidiennes ou hebdomadaires se sont re´ve´leés des facteurs ayant une forte incidence sur le taux de gue´rison des affections mycologiques pour le ke´toconazole et le pramiconazole mais pas pour l’itraconazole et le fluconazole. Conclusions: D’apre`s les donneés probantes sur l’efficacite´ et compte tenu de possibles proble`mes d’innocuite´, l’examen de la documentation e´taye les re´gimes posologiques suivants: 200 mg/j, pendant 5 ou 7 jours pour l’itraconazole; 300 mg/semaine, pendant 2 semaines pour le fluconazole; et 200 mg/j, pendant 2 jours pour le pramiconazole.

INEA (PITYRIASIS) VERSICOLOR (TV) is a common fungal infection of the skin. This disease is caused by lipophilic yeast (Malassezia spp.), which is typically found in normal skin1,2 and can be triggered by both exogenous and endogenous factors. These can

T

From the Department of Medicine, University of Toronto, Toronto, ON, and Mediprobe Research Inc., London, ON. Address reprint requests to: Aditya K. Gupta, MD, PhD, FRCPC, FAAD, 645 Windermere Road, London, ON N5X 2P1; e-mail: agupta@ execulink.com.

DOI 10.2310/7750.2013.13062 # 2014 Canadian Dermatology Association

include application of oils, humid climates, hyperhidrosis, and immunosuppression.3 The high incidence of TV within families suggests that there may be some genetic predisposing factors as well.4,5 This disease affects individuals worldwide but at much smaller percentages in temperate climates.6,7 Indeed, the yeast most often becomes pathogenic in tropical climates, infecting up to 30 to 40% of the population in those areas.8 The sites of infection in most individuals are areas often covered by clothing and exposed to high levels of lipid saturation.1,9 Patients with TV are typically seen to have scaly lesions in the form of macules on areas of the body where sebaceous glands are present.1,4 The lesions can be

Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 18, No 2 (March/April), 2014: pp 79–90

79

Gupta et al

hyperpigmented or hypopigmented and often do not cause the patient much more than cosmetic distress.4 If left untreated, TV is chronic and can potentially affect an individual for years.10 A variety of treatment options are available, including both topical and systemic therapies. Although many of the oral antifungal treatments have been clinically tested for more than 30 years, Food and Drug Administration–approved standard doses have yet to be established for the treatment of TV. However, off-label doses typically involve 200 mg/d for 7 days for itraconazole, and 150 mg or 300 mg/wk for 2 to 4 weeks for fluconazole based on our clinical experience. However, a systematic review using a meta-analysis by Hu and Bigby suggested that longer treatment times and higher doses might increase cure rates.11 The purpose of this systematic review is to provide an evidence-based recommendation for systemic treatment regimens in the treatment of TV.

Methods Search Strategy Three databases were searched for relevant publications between November 6 and November 23, 2012: PubMed, Embase, and the Cochrane Library. The search strategy was the same on all three databases; however, PubMed and Embase were limited to ‘‘humans,’’ and the Cochrane Library was limited to ‘‘trials.’’ To collect all relevant publications, the search criteria were built in the following manner: (‘‘Tinea’’ or ‘‘Pityriasis’’) and ‘‘Versicolor’’ and ‘‘Oral,’’ not ‘‘Topical.’’ An additional search using the term ‘‘Malassezia infection,’’ limited to clinical trials and humans, was performed on June 21, 2013. The bibliography of reviews was also scanned to collect any studies not found in the main database search. Finally, clinicaltrials.gov was searched with the same terms listed above to include any ongoing, nonpublished trials. Inclusion Criteria Publications not excluded based on their title were assessed for inclusion based on their abstract and/or their full text. To collect all of the relevant trials involving the oral treatment of participants with TV, the inclusion criteria included randomized controlled trials (RCTs), open comparative trials, and single-arm trials. Due to the subjectivity of clinical and complete cure outcomes, we only analyzed mycologic cure rates. 80

Thus, all trials were required to report mycologic cure rates. To reduce variation in the outcome measured, only mycologic cure defined as a negative potassium hydroxide (KOH) preparation was included. Excluded trials were those that were not human trials, were not available in English, did not investigate at least one oral treatment, and did not explicitly report mycologic cure. The studies that did not report the efficacy for TV separately were also excluded. Data Extraction and Synthesis The program ADDIS12 was used to extract all of the relevant information from each publication. Information on the trial design (randomization, blinding, controls, sample size, interventions, dosing regimens), outcomes (mycologic cure), and population characteristics (gender, mean age, and severity at baseline) was gathered. To reduce bias, the cure rates were converted into an intention-to-treat rate when possible. The mycologic cure rate for each arm in a trial was used to evaluate the parameters of cumulative dose, duration of treatment, and daily concentration for each respective drug. The relationships between these parameters and cure rates were explored using correlation analysis with Spearman correlation coefficients and independent t-tests. Due to the high variability in the time of outcome assessment between studies that can compromise the comparability of the studies, post hoc correlation analysis was performed between the mycologic cure rates and the time of assessment from the start of therapy (expressed in days) for the individual treatment. Differences in mycologic cure rates between studies recruiting participants with extensive and/or recurring TV and studies not specifying the baseline severity were also analyzed using independent t-tests or one-way analysis of variance (ANOVA). Statistical tests were performed with IBM SPSS Statistics version 20 (IBM, Armonk, NY) and GraphPad Prism version 6 (GraphPad Software, La Jolla, CA). Quality Assessment Each study was assessed for its quality using a modified version of methods developed by Downs and Black.13 The 28-point checklist is designed to evaluate the quality of the evidence for randomized and nonrandomized clinical trials. A mean quality score (MQS) and standard deviation (SD) were calculated for each article from two


Systemic Treatments for Tinea Versicolor and Dosing Recommendations

independent raters, and the interrater reliability was assessed using the kappa statistic test.

Results Search Results PubMed, Embase, and the Cochrane Library searches resulted in 1,513 papers (Figure 1). No additional study was identified by the literature search performed on ‘‘Malassezia infection.’’ The search of the clinicaltrials.gov website did not return any ongoing trials. After screening articles based on title and removing duplications, 304 remained to have their full text searched. From these, the abstract and/or full text were not available for assessment for 27 publications and 254 trials were rejected with reasons as detailed in Figure 1. Consequently, 32 studies reporting mycologic cure rates were included in the analysis. Of these 32 studies, 20 were RCTs, including 6 double-blind studies,14–19 and 14 open studies.20–33 Three studies were open comparative trials34–36 and nine were open single-arm studies.37–45 Eighteen studies investigated itraconazole (Table 1),15,16,20-24,27-29,31,32,35,36,41,43,45 10 studies investigated ketoconazole (Table 2),14,18,26,27,29,30,34,37,38,40 and 10 involved fluconazole (Table 3).17,18,25,27,28,30,32,35,39,42 Two studies examined the use of pramiconazole for TV (Table 4).19,44 In all studies, mycologic cure was achieved by a negative KOH preparation and often supported by a negative Wood’s light examination. Quality of Trials All included studies were evaluated using the 27-question assessment, with a possible maximum score of 28. A kappa statistic of 0.490 was calculated, indicating that there was moderate agreement between the two raters. The MQSs for the individual studies can be found in Table 1, Table 2, Table 3, and Table 4. Nearly all studies lacked information on source population. Most of the evidence came from open trials, which are at higher risk for detection bias; however, the MQSs for double-blind RCTs (MQS 16.0– 21.0) were not superior to those for the open RCTs (MQS 14.0–20.0). The MQSs for RCTs varied from 12.5 to 21.0, whereas the values for nonrandomized trials were between 8.0 and 15.5. Most of the data analyzed came from arms of RCTs. The time of outcome assessment from the start of therapy varied between 15 and 112 days; however, there was no significant correlation between the mycologic cure

rates obtained and the time of assessment for itraconazole (r 5 2.127, p 5 .528, n 5 27), ketoconazole (r 5 .057, p 5 .854, n 5 13), fluconazole (r 5 2.049, p 5 .867, n 5 14), and pramiconazole (r 5 .655, p 5 .158, n 5 6). Consequently, the mycologic cure rates from these studies can be compared for parameters related to antifungal dosing regimens, such as cumulative dose administered, duration of treatment, and daily/weekly concentration.

Itraconazole Of 18 studies, 2 were double-blind RCTs,15,16 and 16 were open trials (11 RCTs,20–24,27–29,31–33 2 comparative trials,35,36 and 3 single-arm trials41,43,45) (see Table 1). The MQS for these trials was between 11.0 6 1.4 and 20.0 6 1.4 on the 28-point scale. The sample size of the itraconazole arms ranged from 10 to 85, for a total of 738 participants. The sex ratio of males to females across all studies was 1.29. The average age ranged between 23 and 33 years in the only eight studies reporting the mean age of the participants. Fifty-six percent of the studies (10 of 18) required or enrolled patients with extensive or recurrent TV. The mean mycologic cure rate obtained for the itraconazole arms requiring extensive or recurrent TV (69% 6 20%, SD, n 5 13) was not significantly lower (p 5 .143) than the mean mycologic cure rate for the arms from studies not specifying the requirement for baseline severity (82% 6 21%, n 5 14). To define the most effective regimen for itraconazole, mycologic cure rates were plotted against cumulative dose, duration of treatment, and daily concentration (Figure 2). The cumulative dose of itraconazole used in trials ranges from 400 to 6,000 mg. Participants were treated with itraconazole for 1 to 15 days, with daily concentration varying from 100 to 400 mg. The most frequently used dosing regimen was 200 mg daily. There was a lot of variation in the cure rates obtained with itraconazole treatment. The relationships between mycologic cure rates and cumulative dose, duration of treatment, or daily concentration were analyzed for (1) all itraconazole arms (see Figure 2), (2) only arms with participants with extensive or recurrent TV at baseline (data not shown), and (3) only arms from studies not specifying the severity of the disease at baseline (data not shown). No significant correlations were observed. Taken together, these analyses showed that one dosing regimen, one dose of 400 mg, clearly resulted in inferior efficacy (, 40%) (see Figure 2).


81

Gupta et al

Figure 1. Flow chart of the literature search. TV 5 tinea versicolor.

Ketoconazole Ten studies used ketoconazole: two were double-blind RCTs14,18 and eight were open trials (four RCTs,26,27,29,30 one comparative trial,34 and three single-arm trials37,38,40) (see Table 2). The MQSs ranged from 8.0 6 1.4 to 19.0 6 1.4. The sample size of the ketoconazole arms ranged from 20 to 179, for a total of 778 participants. The male to 82

female sex ratio was 1.53 across the studies, and the average age ranged between 25 and 34 years in the five studies reporting it. Participants with extensive and/or recurrent disease, moderate to extensive disease, and moderate disease only were included in five, two, and one study, respectively. Two studies did not specify the severity of the disease at baseline. There was no significant difference in the mycologic cure rates related to baseline severity.



Table 1. Oral Itraconazole Treatments for Tinea Versicolor

Source

Regimen

Follow-up Period

Double-blind randomized controlled trials Roseeuw et al, 199015 2 3 50 mg/d 15 d Hickman, 199616

200 mg/d 7 d

Open randomized controlled trials 200 mg/d 5 d del Palacio Hernanz 100 mg/d 10 d et al, 198620 200 mg/d 5 d del Palacio Hernanz et al, 198721 Shemer et al, 199929 200 mg/d 1 wk 100 mg/d 2 wk 400 mg 1 d Ko¨se et al, 200233 200 mg/d 1 wk 400 mg 1 d Partap et al, 200432 Estrada, 198722 Fiorioni et al, 199224 Kokturk et al, 200231

Morales-Doria, 198723 Montero-Gei et al, 199928 Silva et al, 199827 Open comparative trials Ko¨se, 199535 Anwer et al, 200136 Open single-arm trial Difonzo, 199241 Georgiou et al, 199745 Mohanty et al, 200143

2 3 50 mg/12 h 50 mg/12 h 5 d 2 3 100 mg/d 5 200 mg/d 5 d 2 3 200 mg/d 1 2 3 200 mg/d 3 200 mg/d 5 d 2 3 100 mg/d 5 100 mg/d 5 d 200 mg/d 7 d

5d d d d d

200 mg/d 7 d

2 3 200 mg/d 15 d 2 3 100 mg/d 7 d 200 mg/d 7 d 200 mg/d 7 d 200 mg/d 7 d (repeated if needed){ 2 3 100 mg/d 5 d to 7 d1

Severity at Baseline

15 days after the Widespread disease start of treatment 4 wk after the N/A end of treatment 3 wk after the end of treatment 3 wk after the end of treatment 16 wk after the start of treatment 6 wk after the start of treatment 8 wk after start of treatment 4 wk after the end of treatment 4 wk after the end of treatment 4 wk after the end of treatment

Extensive

4 wk after the start of treatment 60 d after the start of treatment 60 d after the start of treatment

N/A

Extensive; trunk, neck, upper arms Extensive and recurrent; $ 25% trunk involvement Extensive and/or recurrent $ 15% body involvement; 2 patients with . 40% N/A

ITT Mycologic Cure Rate (%)

MQS 6 SD

7/10 (70)

17.5 6 0.7

16/18 (89)

17.0 6 1.4

11/15 (73) 10/15 (67) 10/20 (50)

18.0 6 2.8

25/35 (71) 24/34 (71) 20/24 (83){ 23/26 (88){ 4/20 (20)

17.5 6 0.7 15.5 6 0.7 15.5 6 0.7 20.0 6 1.4

N/A

21/22 (95) 15/20 (75) 15/15 (100) 13/15 (87) 4/20 (20) 15/20 (75) 14/20 (70) 23/24 (96) 23/23 (100) 21/30 (70)

15.0 6 0.0

N/A

65/85 (76)

16.0 6 0.0

15 d after the start of treatment 4 wk after start of trial

Extensive/recurrent

20/32 (63)

12.5 6 0.7

N/A

15/15 (100) 15/15 (100)

15.5 6 0.7

1 mo after end of treatment 4 wk after the start of trial 4 wk after the start of treatment

Recurrent (relapse in past 6 mo) 18–20% of total body area Extensive; 5 with severe itching

31/33 (94)

13.5 6 0.7

50/50 (100)

14.5 6 0.7

12/20 (60)

11.0 6 1.4

N/A N/A

14.5 6 0.7 17.5 6 0.7 18.5 6 0.7

16.0 6 0.0

ITT 5 intention to treat; MQS 5 mean quality score; N/A 5 not available; SD 5 standard deviation. *Treatment was stopped once the patient was cured. { Cure rates were only reported graphically, and mycologic cure data were taken from Hu and Bigby.11 { The maximum duration of 14 days was used for analyses. 1 Data not presented separately for 5 and 7 days. A duration of 7 days was used for analyses.


83

Gupta et al

Table 2. Oral Ketoconazole Treatments for Tinea Versicolor Source

Regimen

Double-blind randomized controlled trials Farschian et al, 200218 2 3 200 mg/wk 14 d

Savin, 198414

200 mg/d 28 d

Open randomized controlled trials 400 mg/wk 1 wk apart Shemer et al, 199929

Bhogal et al, 200130

Follow-up Period 12 wk after the start of treatment 4 wk after the start of treatment 16 wk after the start of treatment


ITT Cure Rate (%) MQS 6 SD

Extensive and recurrent; $ 25% trunk involvement Moderate to extensive

39/68 (57)

16.0 6 0.0

33/36 (92)

18.5 6 0.7

Extensive and recurrent; $ 25% trunk involvement Moderate to extensive

27/36 (75)

15.5 6 0.7

19.0 6 1.4

Moderate; 25–50% body involvement N/A

24/45 33/45 25/60 31/60 61/73

400 mg 1 d 200 mg/d 10 d 2 3 200 mg 1 d 200 mg/d 10 d 200 mg/d 10 d or 14 d*

4 wk after the start of treatment 1 mo after the end of treatment 60 d after the start of treatment

200 mg/d 28 d 200 mg/d 10 d

4 wk after the start of treatment

10-50%: 16/20; 60-80%: 4/20; 10-50%: 20/20

16/21 (76) 17/20 (85)

12.5 6 0.7

200 mg/d 24 d

3 mo after the end of treatment

55/60 (92)

13.5 6 2.1

Kaur et al, 199140

200 mg/d 10 d

29/32 (91)

12.5 6 0.7

Jolliffe,198537

200 mg/d 10 d

4 d after the end of treatment 20 d after the end of treatment

Large areas of body affected/almost whole body involvement{ Extensive/long duration

Fernandez-Nava et al, 199726 Silva et al, 199827 Open comparative trial Giam and Tham, 198734 Open single-arm trials Alteras et al, 198738

N/A

(53) (73) (42) (52) (84)

146/179 (82)

16.5 6 2.1 16.0 6 0.0

8.0 6 1.4{

ITT 5 intention to treat; MQS 5 mean quality score; N/A 5 not available. * Data not presented separately for 10 and 14 days. A duration of 14 days was used for analyses. { Allowed patients with other fungal infections. { Based on information included in the abstract from a conference.

The cumulative dose of ketoconazole used in trials ranges from 400 to 5,600 mg, with most trials administering 2,000 mg by the end of treatment (Figure 3A). A significant positive correlation was detected between the cumulative dose of ketoconazole and the mycologic cure rate (r 5 .723, p 5 .005, n 5 13). The treatment duration used in trials was between 1 and 28 days, with the most frequent duration being 10 days (Figure 3B). The mycologic cure rates were also significantly correlated with the duration of treatment (r 5 .613, p 5 .026, n 5 13). Only two daily doses of ketoconazole were used to treat patients with TV: 200 and 400 mg/d (Figure 3C). The reported mycologic cure rates were, in general, lower for 400 mg/d than for 200 mg/d, and this difference was statistically significant (p 5 .0099). However, 200 mg/d was given continuously for different periods of time in eight studies, whereas 400 mg/d was given 84

as a single dose of ketoconazole in two studies or as a single dose repeated after 1 week in the other two studies. This difference in dosing regimens might explain the discrepant efficacy outcomes. Fluconazole Ten studies reported mycologic cure rates for fluconazole treatment of TV. Two studies were double-blind RCTs17,18 and eight studies were open (five RCTs,25,27,28,30,32 one comparative trial,35 and two single-arm trials39,42) (see Table 3). The MQS was between 12.50 6 0.71 and 20.0 6 1.4. The sample size of the fluconazole arms varied from 20 to 207, for a total of 1,139 participants. The sex ratio was 2.13 males to females, and the average age was between 24 and 28 years in the four studies reporting it.



Table 3. Oral Fluconazole Treatments for Tinea Versicolor Source

Regimen

Double-blind randomized controlled trials 400 mg/wk 1 wk Balachandran et al, 199917 Farschian et al, 200218 2 3 150 mg/wk 2 wk Open randomized controlled trials 400 mg/wk 1 wk Partap et al, 200432 Bhogal et al, 200130 Amer, 199725

Montero-Gei et al, 199928 Silva et al, 199827

Open comparative trial Ko¨se, 199535 Open single-arm trials Sankara and Rajashekhar, 199739 Shahid et al, 200042

150 mg/wk 4 wk 400 mg/wk 1 wk 150 mg/wk 4 wk 2 3 150 mg/wk 4 wk 2 3 150 mg repeated after 2 wk* 450 mg/wk 1 wk 300 mg/wk 2 wk 300 mg/wk 2 wk if no cure, 3rd dose 1 wk after{

ITT Cure Rate (%)

Follow-up Period


2 wk after start of treatment 12 wk after the start of treatment

Extensive; 18%+ body involvement Extensive and recurrent; $ 25% trunk involvement

8 wk after start of treatment 4 wk after the start of treatment 4 wk after the end of treatment

$ 15% body involvement; 2 patients with . 40% Moderate to extensive

60 d after the start of treatment 60 d after the start of treatment

N/A

N/A

N/A

MQS

8/18 (44)

17.5 6 0.7

41/60 (68)

16.0 6 0.0

13/20 (65)

20.0 6 1.4

29/45 37/45 161/207 176/190 179/206

(64) (82) (78) (93) (87)

19.0 6 1.4

16/30 (53) 23/30 (77) 156/194 (80)

15.0 6 0.0

15.0 6 2.8

16.0 6 0.0

2 3 300 mg/d 15 d*

15 d after the start of treatment

Extensive/recurrent

24/32 (75)

12.5 6 0.7

400 mg/wk 1 wk

3 wk after the end of treatment 4 wk after the start of treatment

Extensive/recurrent/long duration N/A

25/25 (100)

12.5 6 0.7

50/52 (96)

14.0 6 0.0

300 mg/wk 2 wk

ITT 5 intention to treat; MQS 5 mean quality score; N/A 5 not available. *Data not included in the analysis for weekly concentration of fluconazole. { Corresponding to a treatment duration of 3 weeks.

Participants with extensive and/or recurrent disease and moderate to extensive disease were included in five and one study, respectively. Four studies did not specify the

severity of the disease at baseline. There was no significant difference in the mycologic cure rates related to baseline severity.

Table 4. Oral Pramiconazole Treatments for Tinea Versicolor Source

Regimen

Double-blind randomized controlled trial Faergemann et al, 200919 100 mg 1 d 200 mg 1 d 200 mg/d 2 d 200 mg/d 3 d 400 mg 1 d Open single-arm trial Faergemann et al, 200744 200 mg/d 3 d

Follow-up Period


ITT Cure Rate (%)

4 wk after the start of treatment

Moderate body involvement; $ 15% body surface area

11/26 15/22 23/25 25/26 18/23

(42) (68) (92) (96) (78)

30 d after the start of treatment

N/A

19/19 (100)

MQS 21.0 6 0.0

13.5 6 0.7

ITT 5 intention to treat; MQS 5 mean quality score; N/A 5 not available.


85

Gupta et al

Figure 2. Intention-to-treat mycologic cure rates of itraconazole plotted against (A) cumulative dose, (B) treatment duration, and (C) daily concentration. No significant correlations were observed between the mycologic cure rates and the cumulative dose (r 5 .141, p 5 .482, n 5 27), the duration of treatment (r 5 .003, p 5 .987, n 5 27), or the daily concentration (r 5 2.180, p 5 .368, n 5 27). filled circle 5 open trial; open triangle 5 double-blind trial.

86

Figure 3. Intention-to-treat mycologic cure rates of ketoconazole plotted against (A) cumulative dose, (B) treatment duration, and (C) daily concentration. Mycologic cure rates were significantly correlated with the cumulative dose (r 5 .723, p 5 .005, n 5 13) and the duration of treatment (r 5 .613, p 5 .026, n 5 13). The mean mycologic cure rate for 200 mg daily concentration of ketoconazole (81 6 4%, n 5 9) was significantly higher (p 5 .0099) than the mean for 400 mg daily (57 6 7%, n 5 4). filled circle 5 open trial; open triangle 5 double-blind trial.



The cumulative dose of fluconazole used ranged from 400 to 9,000 mg. A cumulative dose of 600 mg was most frequently used (Figure 4A). The treatment duration for fluconazole ranged from 1 to 4 weeks (Figure 4B). Finally, fluconazole was provided in single or weekly doses in all trials except for one, which provided it in daily doses.35 The doses provided were 150 mg/wk, 300 mg/wk, 400 mg/ wk, and 450 mg/wk (Figure 4C). No significant correlation was detected between the mycologic cure rates and these three dosing regimen parameters. In contrast to singledose treatments, which were analyzed as 1-week treatments, mycologic cure rates of 75% and higher were consistently obtained with repeated doses of fluconazole (see Figure 4B). Pramiconazole Two studies, one double-blind RCT19 and one open singlearm trial,44 examined pramiconazole as a treatment for TV (see Table 4). Their MQSs were 21.0 6 0.0 and 13.5 6 0.7, respectively. The sample size of the pramiconazole arms varied from 19 to 26, for a total of 141 participants. Sixtytwo percent of the participants (n 5 147, male to female ratio 5 1.6) in the RCT were males, and the mean age was 34.9 years. The RCT recruited participants with moderate severity. No baseline information was reported in the single-arm study. Three different doses of pramiconazole (100, 200, or 300 mg/d) were administered for 1 to 3 days. The cumulative dose ranged from 100 to 600 mg. The mycologic cure rates obtained positively correlated with the cumulative dose (r 5 .971, p 5 .001, n 5 6) and the number of days (r 5 .926, p 5 .008, n 5 6) but not with the daily concentration of pramiconazole (Figure 5). A single dose of 100 mg was clearly inferior to the other dosing regimens.

Discussion Several systemic treatment options are available for patients affected by TV. The issue remains that many dosages prescribed to patients are primarily based on expert opinions.46–48 This systematic review of the oral treatments for TV aimed to summarize all of the available information on the subject and to provide evidence-based recommendations. Evidence from open and blinded trials, as well as randomized and nonrandomized trials, was combined to evaluate the effect of dosing regimens on mycologic cure rates for TV, but most of the data came from open RCTs.

Figure 4. Intention-to-treat mycological cure rates of fluconazole plotted against (A) cumulative dose, (B) treatment duration, and (C) weekly concentration. No significant correlations were observed between the mycologic cure rates and the cumulative dose (r 5 2.133, p 5 .649, n 5 14), the duration of treatment (r 5 .0.251, p 5 .386, n 5 14), or the daily concentration (r 5 2.156, p 5 .629, n 5 12). filled circle 5 open trial; open circle 5 single-blind trial; open triangle 5 double-blind trial.


87

Gupta et al

Figure 5. Intention-to-treat mycologic cure rates of pramiconazole plotted against (A) cumulative dose, (B) treatment duration, and (C) daily concentration. Significant correlations were observed between the mycologic cure rates and the cumulative dose (r 5 .971, p 5 .001, n 5 6) and the duration of treatment (r 5 .926, p 5 .008, n 5 6) but not for the daily concentration (r 5 .338, p 5 .512, n 5 6). filled circle 5 open trial; open triangle 5 double-blind trial.

The mycologic cure rates were generally similar for open, single-blind, and double-blind studies (see Figure 1, Figure 2, Figure 3, and Figure 4) and for randomized and nonrandomized trials (see Table 1, Table 2, Table 3, and Table 4), with the exception of the single-arm studies for fluconazole, which were associated with higher cure rates. In general, the evidence was of poor to moderate quality, and there was no major difference between the different types of clinical trials. Unfortunately, very few studies list the source population from which their sample was taken, and only one included the type of climate the study was conducted in.26 This type of information is critical to determine the effects of local populations and climate on the efficacies of systemic drugs. Any future studies involving TV should provide a description of the local climate as it may be likely that local climate can skew results.47 As optimized dosing regimens are further developed, particular attention should be paid to which drug is most effective in different populations and in different climates. High recurrence rates of 60 to 67.65% within only 1 year have been reported for TV,49,50 but monthly prophylaxis treatments with itraconazole (200 mg twice daily for 1 d/mo51) have proven useful for the prevention of TV recurrence. Although systemic treatments for TV have a high success rate and do not often produce severe adverse effects, it has been suggested that unless the disease is extensive, oral treatments should be saved for prophylaxis. This is because current topical treatments for TV are effective, safe, and cheap1,46,48; however, the patient compliance can be compromised by the inconvenience of topical formulations such as ointments or shampoo. Although there is agreement that systemic therapy should typically be used for recurrent or extensive disease, not all trials listed the severity or recurrence of the disease at baseline. Consequently, further studies in TV should indicate the extent of body or trunk coverage in their population. For all four antifungals, high mycologic cure rates up to 100% could be achieved. The antifungals can be divided into two groups based on the influence of the dosing regimen on the mycologic cure rate achieved. In one group, which includes ketoconazole and pramiconazole, the mycologic cure rates achieved were dependent on the dosing regimens used, whereas the dosing regimens of itraconazole and fluconazole, which constitute the other group, did not influence the mycologic cure rates.

Dosing Regimen Recommendations In addition to high efficacy rate, several factors should be taken in consideration when recommending a dosing

88



regimen. With equal efficacy, the smallest concentration of a drug would be preferred to prevent adverse events and short treatment times are preferred to improve patient compliance. For TV, mycologic cure rates of 80% and above were achievable with all oral antifungals, over a range of different dosing regimens; with the exception of single-dose regimens. Thus, the traditional dosing regimens might be optimized by reducing the amount of drug administered and shortening their duration. In the identified clinical trials for TV, the treatment duration was generally short and adverse events were infrequent for the four antifungals investigated. Consequently, safety was not taken into consideration for the dosing regimen recommendations except for ketoconazole. Indeed, due to the previous known liver toxicity associated with ketoconazole Health Canada recently released a letter stating that ketoconazole should be only used for serious or life-threatening systemic fungal infection.52 Consequently, ketoconazole could not be recommended for TV treatment. Currently, 200 mg/d of itraconazole for 7 days is typically prescribed.53 In Figure 2, the highest cure rates were generally obtained with the 200 mg/d dose, 5 or 7 days of treatment, and the resulting cumulative doses of 1,000 and 1,400 mg. Consequently, itraconazole provided as 200 mg/d for 5 days can be recommended. However, in more severe cases, we continue to recommend a 7-day regimen. Fluconazole is shown to be effective at 150 or 300 mg/wk doses for 2 or 4 weeks.9,11 Single doses of 400 to 450 mg resulted in highly variable efficacy, whereas weekly doses for 2 and 4 weeks showed similar outcomes (see Figure 4B). When comparing 150 mg to 300 mg, the higher dose achieved better mycologic cure rates (see Figure 4C). Thus, we recommend 300 mg/wk for 2 weeks. Pramiconazole is currently not on the market for the treatment of TV, but preliminary studies have shown it to be effective (see Table 4). The highest mycologic cure rates were obtained for 200 mg/d for 2 or 3 days. Because similar rates were obtained for the two dosing regimens, we recommend the shorter duration of 2 days.

Conclusion In concert with the concluding remarks of Hu and Bigby,11 it is advised that the quality of clinical studies for TV needs to be improved. Mycologic cure rates obtained with ketoconazole and pramiconazole therapies were influenced by the dosing regimens, whereas itraconazole and fluconazole dosing regimens had no influence on this

efficacy outcome. Nevertheless, this systematic review supports the following regimens: 200 mg/d for 5 or 7 days of itraconazole, 300 mg/wk for 2 weeks of fluconazole, and 200 mg/d for 2 days of pramiconazole.

Acknowledgment Financial disclosure of authors and reviewers: None reported.

References 1. Faergemann J, Fredriksson T. Tinea versicolor: some new aspects on etiology, pathogenesis, and treatment. Int J Dermatol 1982;21: 8–11, doi:10.1111/j.1365-4362.1982.tb00476.x. 2. Gordon M. The lipophilic mycoflora of the skin. Mycologia 1951; 43:524–35, doi:10.2307/3755426. 3. Borelli D, Jacobs PH, Nall L. Tinea versicolor: epidemiologic, clinical, and therapeutic aspects. J Am Acad Dermatol 1991;25: 300–5, doi:10.1016/0190-9622(91)70198-B. 4. Gupta AK, Bluhm R, Summerbell R. Pityriasis versicolor. J Eur Acad Dermatol Venereol 2002;16:19–33, doi:10.1046/j.1468-3083. 2002.00378.x. 5. Hafez M, El-Shamy S. Genetic susceptibility in pityriasis versicolor. Dermatologica 1985;171:86–8, doi:10.1159/000249397. 6. Faergemann J. Pityriasis versicolor. Semin Dermatol 1993;12:276–9. 7. Caprilli F, Nazzaro Porro M, Passi S. Pityraisis versicolor. Stud Clin Bull Inst Dermatol 1971;7:71–89. 8. Faergemann J. Tinea versicolor (Pityriasis versicolor). In: Demis DJ, editor. Clinical dermatology. Philadelphia: Lippincott-Raven; 1995. p. 1–9. 9. Faergemann J. Management of seborrheic dermatitis and pityriasis versicolor. J Clin Dermatol 2000;1:75–80, doi:10.2165/00128071200001020-00001. 10. Tate B. Pityriasis versicolor. Med Today 2008;9:60–2. 11. Hu SW, Bigby M. Pityriasis versicolor: a systematic review of interventions. Arch Dermatol 2010;146:1132–40, doi:10.1001/archdermatol.2010.259. 12. van Valkenhoef G, Tervonen T, Zwinkels T, et al. ADDIS: a decision support system for evidence-based medicine. 2012. Available at: http://drugis.org/files/addis-dss.pdf (accessed August 29, 2012). 13. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998;52:377–84, doi:10.1136/jech.52.6.377. 14. Savin RC. Systemic ketoconazole in tinea versicolor: a doubleblind evaluation and 1-year follow-up. J Am Acad Dermatol 1984; 10:824–30, doi:10.1016/S0190-9622(84)70098-3. 15. Roseeuw D, Willemsen M, Kint RT, et al. Itraconazole in the treatment of superficial mycoses—a double-blind study vs. placebo. Clin Exp Dermatol 1990;15:101–4, doi:10.1111/j.13652230.1990.tb02041.x. 16. Hickman JG. A double-blind, randomized, placebo-controlled evaluation of short-term treatment with oral itraconazole in patients with tinea versicolor. J Am Acad Dermatol 1996;34:785–7, doi:10.1016/S0190-9622(96)90014-6.


89

Gupta et al

17. Balachandran C, Thajuddin, Ravikumar BC. Comparative evaluation of single dose regimen with two dose regimen of fluconazole in the treatment of tinea versicolor: a double blind placebo controlled study. Indian J Dermatol Venereol Leprol 1999;65:20–2. 18. Farschian M, Yaghoobi R, Samadi K. Fluconazole versus ketoconazole in the treatment of tinea versicolor. J Dermatolog Treat 2002;13:73–6, doi:10.1080/095466302317584421. 19. 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, doi:10.1016/j.jaad.2008.08.033. 20. del Palacio Hernanz A, Frias-Iniesta J, Gonzalez-Valle O, et al. Itraconazole therapy in pityriasis versicolor. Br J Dermatol 1986; 115:217–25, doi:10.1111/j.1365-2133.1986.tb05721.x. 21. del Palacio Hernanz A, Delgado Vicente S, Meneńdez Ramos F, et al. Randomized comparative clinical trial of itraconazole and selenium sulfide shampoo for the treatment of pityriasis versicolor. Rev Infect Dis 1987;9 Suppl 1:S121–7, doi:10.1093/clinids/9. Supplement_1.S121. 22. Estrada RA. Itraconazole in pityriasis versicolor. Rev Infect Dis 1987;9 Suppl 1:S128–30, doi:10.1093/clinids/9.Supplement_1.S128. 23. Morales-Doria M. Pityriasis versicolor: efficacy of two five-day regimens of itraconazole. Rev Infect Dis 1987;9 Suppl 1:S131–3, doi:10.1093/clinids/9.Supplement_1.S131. 24. Fiorioni A, Cilli P, Altomare G, et al. Itraconazole: a new orally active antimyotic in the treatment of pityriasis versicolor. Comparative clinical study of two treatment regimens. Micol Dermatol 1992;6:43–6. 25. Amer M. Fluconazole in the treatment of tinea versicolor. Int J Dermatol 1997;36:940–2, doi:10.1046/j.1365-4362.1997.00213.x. 26. Fernandez-Nava HD, Laya-Cuadra B, Tianco EAV. Comparison of single dose 400 mg versus 10-day 200 mg daily dose ketoconazole in the treatment of tinea versicolor. Int J Dermatol 1997;36:64–6, doi:10.1046/j.1365-4362.1997.00023.x. 27. Silva H, Gibbs D, Arguedas J. A comparison of fluconazole with ketoconazole, itraconazole, and clotrimazole in the treatment of patients with pityriasis versicolor. Curr Ther Res 1998;59:203–14, doi:10.1016/S0011-393X(98)85073-X. 28. Montero-Gei F, Robles ME, Suchil P. Fluconazole vs. itraconazole in the treatment of tinea versicolor. Int J Dermatol 1999;38:601–3, doi:10.1046/j.1365-4362.1999.00733.x. 29. Shemer A, Nathansohn N, Kaplan B, et al. Itraconazole versus ketoconazole in the treatment of tinea versicolor. J Dermatolog Treat 1999;10:19–23, doi:10.3109/09546639909055906. 30. 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. 31. 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, doi:10.1080/09546630212345676. 32. Partap R, Kaur I, Chakrabarti A, et al. Single-dose fluconazole versus itraconazole in pityriasis versicolor. Dermatology (Basel) 2004;208:55–9, doi:10.1159/000075047. 33. Ko¨se O, Bu¨lent Tas¸tan H, Riza Gu¨r 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, doi:10.1080/095466302317584430.

90

34. Giam YC, Tham SN. Ketoconazole in tinea versicolor: is ten day therapy adequate? Singapore Med J 1987;28:13–7. 35. Ko¨se O. Fluconazole versus itraconazole in the treatment of tinea versicolor. Int J Dermatol 1995;34:498–9, doi:10.1111/j.1365-4362. 1995.tb00623.x. 36. Anwer J, Iqbal P, Aghai R, et al. The treatment of dermatophytoses and pityriasis versicolor with one week orally administered itraconazole. J Pak Assoc Derma 2001;11:60–3. 37. Jolliffe D. Preliminary results of a multicentre open trial showing the effect of ketoconazole treatment on pityriasis versicolor. In: Meinhof W, editor. Oral therapy in dermatomycoses: a step forward. Proceedings of a Symposium Held in Frankfurt Feb 1984. Medical Publishing Foundation; 1985. 107–10. 38. Alteras I, Sandbank M, Segal R. Two years of follow-up of oral ketoconazole therapy in 60 cases of pityriasis versicolor. Dermatologica 1987;175:142–4, doi:10.1159/000248812. 39. Sankara R, Rajashekhar N. Oral fluconazole in tinea versicolor. Indian R Dermatol Venereol Leprol 1997;63:166–7. 40. Kaur I, Kumar B, Sharma VK. Oral ketoconazole in tinea versicolor. Indian J Dermatol Venereol Leprol 1991;57:157–8. 41. Difonzo EM. Italian multicentre study with oral itraconazole in recurrent pityriasis versicolor. Preliminary report. J Eur Acad Dermatol Venereol 1992;Suppl 1:S19–20, doi:10.1111/j.1468-3083. 1992.tb00679.x. 42. Shahid J, Ihsan Z, Khan S. Oral fluconazole in the treatment of pityriasis versicolor. J Dermatolog Treat 2000;11:101–3, doi:10. 1080/09546630050517496. 43. Mohanty J, Sethi J, Sharma MK. Efficacy of itraconazole in the treatment of tinea versicolor. Indian J Dermatol Venereol Leprol 2001;67:240–1. 44. Faergemann J, Ausma J, Vandeplassche L, et al. The efficacy of oral treatment with pramiconazole in pityriasis versicolor: a phase II trial. J Dermatol 2007;156:1385–8, doi:10.1111/j.1365-2133.2007.07888.x. 45. Georgiou S, Monastirli A, Pasmatzi E, et al. Oral itraconazole therapy for pityriasis versicolor. J Eur Acad Dermatol Venereol 1997;8:203–7, doi:10.1111/j.1468-3083.1997.tb00479.x. 46. Caterall MD. Ketoconazole therapy for pityriasis versicolor. Clin Exp Dermatol 1982;7:679–81, doi:10.1111/j.1365-2230.1982.tb02494.x. 47. Goodless DR. Ketoconazole for the treatment of tinea versicolor. J Dermatol 1998;37:76–9. 48. Gupta AK, Kogan N, Batra R. Pityriasis versicolor: a review of pharmacological treatment options. Expert Opin Pharmacother 2005;6:165–78, doi:10.1517/14656566.6.2.165. 49. Faergemann J. Pityrosporum infections. J Am Acad Dermatol 1994;31:S18–20, doi:10.1016/S0190-9622(08)81261-3. 50. Framil VM de S, Melhem MSC, Szeszs MW, et al. New aspects in the clinical course of pityriasis versicolor. An Bras Dermatol 2011; 86:1135–40, doi:10.1590/S0365-05962011000600011. 51. 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, doi:10.1001/archderm.138.1.69. 52. Health Canada, Ketoconazole-Risk of potential fatal liver toxicityFor health professionals. June 19, 2013. Available at: http:// healthcanadians.gc.ca/recall-alert-rappe-avis/hc-sc/2013/34173a-eng. php (accessed September 27 2013). 53. Cauwenbergh G, De Doncker P, Stoops K, et al. Itraconazole in the treatment of human mycoses: review of three years of clinical experience. Rev Infect Dis 1987;9:S146–52, doi:10.1093/clinids/ 9.Supplement_1.S146.


Itraconazole in tinea versicolor: a review.

Uncommon presentations of tinea versicolor.

Tinea versicolor: epidemiologic, clinical, and therapeutic aspects.

Topical antifungal treatments for tinea cruris and tinea corporis.

Tinea versicolor in dark-skinned individuals.

Tinea versicolor treated with fluconazole shampoo.

Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup.

Dosing regimen of the 23-valent pneumococcal vaccination: a systematic review.

Tinea versicolor: histologic and ultrastructural investigation of pigmentary changes.

Systematic review and recommendations for nonodontogenic toothache.

Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation.

Topical griseofulvin in tinea versicolor: a double-blind study.

Cell-mediated immunity to Pityrosporum orbiculare in tinea versicolor.

Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement.

Preparative regimen dosing for hematopoietic stem cell transplantation in patients with chronic kidney disease: analysis of the literature and recommendations.

Procidentia in pregnancy: a systematic review and recommendations for practice.

Efficacy and Safety of Systemic Long-Term Treatments for Moderate-to-Severe Psoriasis: A Systematic Review and Meta-Analysis.

Systematic review of cost-effectiveness analyses of treatments for psoriasis.

Prednisolone Dosing Regimen for Treatment of Subacute Thyroiditis.

A critical review of culturally sensitive treatments for depression: recommendations for intervention and research.

Treatments for avascular necrosis of the talus: a systematic review.

Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review.

Dosing of sublingual immunotherapy for allergic rhinitis: evidence-based review with recommendations.

Tinea cruris and tinea corporis masquerading as tinea indecisiva: case report and review of the literature.