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Three Part Question

In [a child/adolescent with tinea versicolor] is [oral itraconazole more effective than oral fluconazole] as [regards cure]?

Clinical Scenario

A 14-year-old girl is seen in the paediatric outpatient department. She was referred by her general practitioner (GP) with persistent tinea versicolor. The GP had previously treated her with topical clotrimazole over the last few years with varying degree of success. The girl has recently returned from a trip to South America during which she experienced an exacerbation of her symptoms.
On examination you find multiple oval to round shaped lesions which are hypopigmented with superficial scaling, that appear particularly prominent in the axillary region and around the neck. The girl tells you that these areas had previously been darker than the surrounding skin, which was more obvious during the winter months. Under Wood's light examination the lesions appear fluorescent yellow. You obtain samples for microbiological confirmation but concur with the GP that this is tinea versicolor.
The girl expresses her distress about her external appearance and is very keen to finally get rid of this problem. You wonder whether oral antifungal agents may provide a more effective alternative to topical treatment and consult the British National Formulary for Children (BNFC 2006). The formulary states that oral itraconazole should be considered if topical treatment has failed. It also mentions that fluconazole may be used as an alternative. You wonder which of these treatment options is more effective in tinea versicolor.

Search Strategy

Cochrane Library using the terms "pityriasis versicolor" and "tinea versicolor": no relevant reviews.
PubMed (1950–to date/no limits set)
EMBASE database (1974–to date)
Search of multiple trials registers: UK National Research Register (NRR and MRC), ISRCTN, NIH: no relevant studies identified
Pubmed:using the terms "Pityrosporum versicolor", "Pityrosporum orbiculare", "Malassezia furfur", "pityriasis versicolor" and "tinea versicolor" in combination with [AND] itraconazole [AND] fluconazole. Search date 19 November 2006.

Search Outcome

Only three articles were relevant. From embase this same search identified two further relevant publications. One report of an RCT comparing both drugs was published in Turkish only (abstract available in English) and had to be excluded since the details available to us were insufficient, while the second article is summarised (Silva)

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Partap et al, 2004	40 consecutive patients with >15% skin surface area involvement Case definition: culture positive for Malassezia furfur+skin changes All patients >16 years (mean age 26.7 years, range 17–55 years) Patients randomly assigned to treatment with fluconazole (400 mg single dose) or itraconazole (400 mg single dose)	Individual RCT (level 1b)	Resolution of hypo-/hyperpigmentation at 8 weeks	Fluconazole group: 20% pigmentation changes resolved, 80% mild residual hypochromia Itraconazole group: 5% pigmentation changes resolved, 95% mild residual hypochromia - NS	Exclusion criteria: patient used antifungal treatment less than 3 weeks prior to the study No blinding of patients or investigators Full blood count, liver and renal function tests were monitored: no abnormalities detected Clinical side effects: only one patient developed headache and loose stools (likely unrelated to medication)
			Mycological cure: defined as culture negative at 2 and 8 weeks	Cultures at 2 and 8 weeks: fluconazole group 10% and 65% negative, respectively, itraconazole group 30% and 20% negative
			Relapse: defined as reappearance or worsening of clinical signs and symptoms or positive culture after initial improvement	Relapse rate: fluconazole 35%, itraconazole 60% (statistically significant, p<0.05)
Kose, 1995,	64 consecutive patients with recurrent and/or extensive tinea versicolor (age range: 19–42 years). Patients received either fluconazole (300 mg bd) or itraconazole (200 mg bd) for 2 weeks)	Individual RCT (level 1b)	Clinical cure: defined as resolution of scaling, pigmentation changes and pruritis	Clinical cure: 80% of patients treated with fluconazole, 74% with itraconazole (not statistically significant)	Process of randomisation not described. No blinding of patients or investigators 12 patients excluded from analysis (reasons not given): 5 in fluconazole and 7 in itraconazole group Full blood count, liver and renal function tests were monitored: no abnormalities detected Reported side effects: only mildgastrointestinal upset (2 cases in the fluconazole and 3 in the itraconazole group)
			Mycological cure: defined as negative microscopy and Wood's light examination	Mycological cure: 88% in fluconazole group, 80% in itraconazole group (not statistically significant)
			Relapse rate: not explicity defined, assessed at 12 weeks	Relapse rate: 14% in fluconazole group, 20% in itraconazole group
Montero-Gei et al, 1999	90 patients with tinea versicolor (ages not given). Patients received fluconazole 450 mg single dose (SD), or fluconazole 300 mg two doses 1 week apart (TD), or itraconazole 200 mg daily for 7 days	Multicentre open label RCT (level 1b)	Assessments carried out at day 14, 30 and 60 Clinical signs: erythema, scaling, pigmentation changes scored by investigators on a scale of 0–3 (not present–severe)	Clinical cure at day 60: 52% with fluconazole SD, 70% with fluconazole TD, 74% with itraconazole (no statistically significant difference between the latter 2 groups)	Process of randomisation not described. No blinding of patients or investigators. No clinical side effects were reported by the participants
			Mycological efficacy assessed by microscopy of skin scrapings and classified as eradication, persistence or eradication with re-infection	Mycological eradication at day 60: 55% with fluconazole SD, 77% with fluconazole TD, 78% with itraconazole
Silva et al, 1998	388 patients with mycologically proven tinea versicolor (age 16–86 years) Case definition: presence of M furfur on microscopic examination and positive Wood's light test. Patients were randomised to receive either fluconazole (104 patients, 300 mg od, 2 doses 1 week apart; 90 patients, 3 doses total), or itraconazole (200 mg for 7 days) or ketoconazole (200 mg for 10 days) or 1% clotrimazole cream (bd for 21 days) Each part of the study evaluated the response to fluconazole vs one of the "comparators" (itraconazole, ketoconazole, clotrimazole)	Three open label RCTs, multicentre (level 1b)	Assessments carried out at day 14, 30 and 60. Clinical cure: defined as resolution of scaling and pruritus	Clinical cure+improvement at day 60: fluconazole 86%, itraconazole 83.5% (not statistically significant)	No blinding of patients or investigators. Criteria for decision to give third dose of fluconazole not sufficiently described. Fluconazole group was composed of patients who have received either 2 or 3 doses. Five patients reported side-effects consisting of mild gastrointestinal upset. Full blood count, liver and renal function tests were monitored: no abnormalities detected.
			Clinical relapse: cure followed by reappearance or worsening of signs and symptoms	Clinical relapse at day 60: fluconazole 2.3%, itraconazole 5.9% (not statistically significant)
			Mycological cure: disappearance (eradication) of M furfur on microscopy	Mycological cure at day 60: fluconazole 77.6%, itraconazole 76.5%
			Reinfection: complete eradication with subsequent reappearance of the organism	Reinfection at day 60: fluconazole 5.9%, itraconazole 15.3% (? no significance calculated)

Comment(s)

Tinea versicolor, also called pityriasis versicolor, is a common skin condition which is caused by a superficial cutaneous infection with the fungal agent Malassezia furfur (previously Pityrosporum versicolor or Pityrosporum orbiculare). The infection occurs worldwide, with prevalences from 0.5% in temperate climates up to 18% in humid tropical climates reported in the literature (Hellgren, Ponnighaus). Tinea versicolor predominately affects adolescents and adults, but infection as early as in infancy has been described. The typical clinical finding consists of multiple, oval lesions with fine scaling, which are predominately distributed over the upper areas of the trunk, the upper arms and the neck. Facial involvement is particularly common in children. The lesions may be hypopigmented or hyperpigmented and are frequently associated with pruritus. The areas typically fail to tan during the summer and appear darker than the surrounding unaffected skin in the winter months when they appear yellow to brown in colour. The diagnosis can be confirmed by demonstrating fluorescence under Wood's light (ultraviolet light), microscopic examination of a potassium hydroxide (KOH) preparation or with fungal cultures of skin scrapings. Although the infection does not pose a significant health risk to the affected individual, the psychological and social implications can be profound. Spontaneous remission is generally rare. Topical treatment as a first line intervention can be curative, for which purpose clotrimazole, econazole, ketoconazole, miconazole or terbinafine can be used. However, some patients do not respond satisfactorily or experience multiple relapses and may require systemic treatment, particularly when large areas are affected. In these circumstances "azole" antifungal drugs, which include fluconazole, itraconazole and ketoconazole, are considered to be the treatment of choice. None of the studies we identified in our search was conducted in paediatric patients. However, previous studies in children using itraconazole and fluconazole for other purposes have demonstrated that both drugs are generally safe and well tolerated in this age group (Novelli, Gupta). Side effects mainly consist of transient, mild elevation of liver function tests and gastrointestinal symptoms. There is little consensus regarding the optimal dosing regimen and duration of treatment with systemic antifungal agents. The BNFC suggests a 7-day course with itraconazole or a 2–4-week course with fluconazole for the treatment of tinea versicolor. Interestingly, a randomised controlled trial in adults has demonstrated that single high dose (400 mg) fluconazole treatment can be as effective as a prolonged 4-week course with lower doses with regard to clinical cure (Bhogal). All of the studies, with the exception of the report by Silva et al, were rather small and therefore may have been insufficiently powered to demonstrate a significant difference between treatment groups. Regarding clinical cure and improvement, all of the studies included have reported marginally better results with fluconazole, with the exception of the article by Montero-Gei et al. However, in all four studies the difference between both treatment groups was small and statistically not significant. The most striking difference between the two treatment options seems to occur in relation to clinical and mycological relapses. Three of the studies assessed the clinical relapse rate. Although it appears likely that the data from these adult studies can be directly extrapolated to children, a sufficiently powered study comparing fluconazole with itraconazole in paediatric patients suffering from tinea versicolor, with a long follow-up period that would allow the evaluation of relapse rates, would be desirable. Since there is evidence from adult studies that a single high-dose antifungal treatment can be as successful as a prolonged course, such a study should ideally re-evaluate the dosing and duration of treatment for both agents. Ultimately, a shorter treatment course would reduce costs and potentially minimise the risk of adverse events.

Clinical Bottom Line

There are no published paediatric studies which have compared the efficacy of itraconazole versus fluconazole for the treatment of tinea versicolor. Evidence from adult studies suggests that the initial cure rates with both drugs are comparable. (Grade A) There is some evidence from adult studies that relapses are less frequent with fluconazole treatment. (Grade A)

References

1. Partap R, Kaur I, Chakrabarti A, et al. Single-dose fluconazole versus itraconazole in pityriasis versicolor. Dermatology 2004; 2081: 55–9.
2. Kose O. Fluconazole versus itraconazole in the treatment of tinea versicolor. Int J Dermatol 1995; 347: 498–9.
3. Montero-Gei F, Robles ME, Suchil P. Fluconazole vs. itraconazole in the treatment of tinea versicolor. Int J Dermatol 1999; 388: 601–3.
4. 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 Clin Exp 1998; 594: 203–14.
5. Hellgren L, Vincent J. The incidence of tinea versicolor in central Sweden. J Med Microbiol 1983; 164: 501–2.
6. Ponnighaus JM, Fine PE, Saul J. The epidemiology of pityriasis versicolor in Malawi, Africa. Mycoses 1996; 3911–12: 467–70.
7. Novelli V, Holzel H. Safety and tolerability of fluconazole in children. Antimicrob Agents Chemother 1999; 438: 1955–60.
8. Gupta AK, Cooper EA, Ginter G. Efficacy and safety of itraconazole use in children. Dermatol Clin 2003; 213: 521–35.
9. 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; 2810: 535–9.