Recurrent tinea versicolor: treatment with itraconazole or fluconazole?

Report by

Anastasia Pantazidou, Senior House Officer, Department of Paediatrics, North Middlesex Hospital, London, UK; natpant@yahoo.com

Checked by

Marc Tebruegge, Specialist Registrar, Department of Paediatric Infectious Diseases, St Mary's Hospital, London, UK

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.

Structured clinical question

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

Search strategy and outcome

Cochrane Library using the terms “pityriasis versicolor” and “tinea versicolor”: no relevant reviews.

PubMed (1950–to date/no limits set) 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. Results in the same order: 8, 11, 14, 18 and 16 articles. There was considerable overlap between the results produced by the different search terms. Only three articles were relevant which are summarised in table 3.^1–3

Table 3 Itraconazole versus fluconazole in the treatment of tinea versicolor.

Citation	Study group	Study type (level of evidence)	Outcome	Key results	Comments
Partap	40 consecutive patients	Individual	Resolution of hypo‐	Fluconazole group: 20%	Exclusion criteria: patient used
et al	with >15% skin surface	RCT	/hyperpigmentation	pigmentation changes resolved,	antifungal treatment less than
(2004)1	area involvement	(level 1b)	at 8 weeks	80% mild residual hypochromia	3 weeks prior to the study
	Case definition: culture		Mycological cure: defined	Itraconazole group: 5%	No blinding of patients or
	positive for Malassezia		as culture negative at	pigmentation changes resolved,	investigators
	furfur+skin changes		2 and 8 weeks	95% mild residual hypochromia	Full blood count, liver and renal
	All patients >16 years		Relapse: defined as	(not statistically significant)	function tests were monitored:
	(mean age 26.7 years,		reappearance or worsening	Cultures at 2 and 8 weeks:	no abnormalities detected
	range 17–55 years)		of clinical signs and	fluconazole group 10% and 65%	Clinical side effects: only one
	Patients randomly		symptoms or positive culture	negative, respectively, itraconazole	patient developed headache
	assigned to treatment		after initial improvement	group 30% and 20% negative	and loose stools (likely
	with fluconazole			Relapse rate: fluconazole 35%,	unrelated to medication)
	(400 mg single dose)			itraconazole 60% (statistically
	or itraconazole			significant, p<0.05)
	(400 mg single dose)
Kose	64 consecutive patients	Individual RCT	Clinical cure: defined	Clinical cure: 80% of patients	Process of randomisation not
(1995)2	with recurrent and/or	(level 1b)	as resolution of	treated with fluconazole, 74%	described
	extensive tinea versi‐		scaling, pigmentation	with itraconazole (not	No blinding of patients or
	color (age range: 19–		changes and pruritus	statistically significant)	investigators
	42 years). Patients		Mycological cure: defined	Mycological cure: 88% in	12 patients excluded from
	received either		as negative microscopy and	fluconazole group, 80% in	analysis (reasons not given):
	fluconazole (300 mg		Wood's light examination	itraconazole group (not	5 in fluconazole and 7 in
	bd) or itraconazole		Relapse: not explicitly	statistically significant)	itraconazole group
	(200 mg bd) for		defined, assessed at	Relapse rate: 14% in fluconazole	Full blood count, liver and renal
	2 weeks		12 weeks	group, 20% in itraconazole group	function tests were monitored:
					no abnormalities detected
					Reported side effects: only mild
					gastrointestinal upset (2 cases in
					the fluconazole and 3 in the
					itraconazole group)
Montero‐	90 patients with tinea	Multicentre	Assessments carried out at	Clinical cure at day 60: 52%	Process of randomisation not
Gei et al	versicolor (ages not	open label	day 14, 30 and 60	with fluconazole SD, 70% with	described
(1999)3	given). Patients received	RCT (level 1b)	Clinical signs: erythema,	fluconazole TD, 74% with	No blinding of patients or
	fluconazole 450 mg		scaling, pigmentation	itraconazole (no statistically	investigators
	single dose (SD), or		changes scored by	significant difference between	No clinical side effects were
	fluconazole 300 mg		investigators on a scale of	the latter 2 groups)	reported by the participants
	two doses 1 week		0–3 (not present–severe)	Mycological eradication at day 60:
	apart (TD), or		Mycological efficacy	55% with fluconazole SD,
	itraconazole 200 mg		assessed by microscopy of	77% with fluconazole TD,
	daily for 7 days		skin scrapings and classified	78% with itraconazole
			as eradication, persistence or
			eradication with re‐infection
Silva	388 patients with	Three open label	Assessments carried out at	Clinical cure+improvement	No blinding of patients or
et al	mycologically proven	RCTs, multicentre	day 14, 30 and 60	at day 60: fluconazole 86%,	investigators
(1998)4	tinea versicolor (age	(level 1b)	Clinical cure: defined as	itraconazole 83.5% (not	Criteria for decision to give
	16–86 years)	Each part of the	resolution of scaling and	statistically significant)	third dose of fluconazole not
	Case definition:	study evaluated	pruritus	Clinical relapse at day 60:	sufficiently described
	presence of M furfur on	the response to	Clinical relapse: cure	fluconazole 2.3%, itraconazole	Fluconazole group was
	microscopic examination	fluconazole vs	followed by reappearance	5.9% (not statistically significant)	composed of patients who have
	and positive Wood's	one of the	or worsening of signs	Mycological cure at day 60:	received either 2 or 3 doses
	light test. Patients were	“comparators”	and symptoms	fluconazole 77.6%,	Five patients reported side
	randomised to receive	(itraconazole,	Mycological cure:	itraconazole 76.5%	effects consisting of mild
	either fluconazole (104	ketoconazole,	disappearance (eradication)	Reinfection at day 60:	gastrointestinal upset
	patients, 300 mg od, 2	clotrimazole)	of M furfur on microscopy	fluconazole 5.9%, itraconazole	Full blood count, liver and
	doses 1 week apart; 90		Reinfection: complete	15.3% (? no significance	renal function tests
	patients, 3 doses total),		eradication with subsequent	calculated)	were monitored: no
	or itraconazole		reappearance of the		abnormalities detected
	(200 mg for 7 days) or		organism
	ketoconazole (200 mg
	for 10 days) or 1%
	clotrimazole cream (bd
	for 21 days)

EMBASE database (1974–to date) using the same set of search terms employed in the PubMed search – results in the same order as above: 0, 4, 34, 28 and 20 articles. This 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 in table 3.⁴

Search of multiple trials registers: UK National Research Register (NRR and MRC), ISRCTN, NIH: no relevant studies identified.

Search date: 9 December 2006.

Commentary

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.^{5 6} 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.^{7 8} 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.⁹

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)