Clinical and Experimental Dermatology 1987; 12: 178-180.

Itraconazoie in the treatment of widespread tinea

versicolor
L.I.ROBERTSON 300 Sparks Road, Sydenham 4091, Durban, Republic of South Africa

Accepted for publication ^ July 1986

Pityriasis versicolor affects 35% of patients between the tive, was effective when taken orally"* was an encouraging
ages of 15 and 50 in our family practice in the subtropical step forward. Unfortunately, however, recurrences after
seaport city of Durban. Whilst most cases are mild with systemic ketoconazole have also been demonstrated.^
involvement of only a small surface area, usually of the This has led to the suggestion that monthly follow-up
trunk, there is a sizeable reservoir of patients with severe doses should be employed.^-' The fact that transient
and widely disseminated lesions who have had numerous elevations of hepatic enzymes may occur on ketoconazole,
relapses despite a variety of topical treatments, and many and, more important, that occasional cases of hepatitis
of them have all but given up hope of ever having a have been reported^ has caused dermatologists to ques-
normal skin. In a climate which allows year-round tion the use of the drug in a disorder with essentially
swimming this can be an intolerable burden, especially cosmetic effects.
for the younger patients. We have recently had encouraging results with the use
The assessment of the results of treatment of pityriasis of itraconazoie (R51 211 Janssen Pharmaceutica), a
versicolor has been bedevilled by the fact that the triazole derivative for systemic use, in 40 patients with
organism, Pityrosporum orbiculare, in its spore form, is a extensive pityriasis versicolor. These patients in the pilot
normal skin commensal in over 90% of adults' and only study had all suffered numerous relapses after a variety of
becomes invasive and causes the recognizable disorder in topical and/or systemic antimycotic therapy.
certain susceptible individuals, at which stage the orga- The objective of the study was to establish a suitable
nism is referred to by its original name, Malassezia furfur. dosage range for the drug in pityriasis versicolor, and the
As the conditions which predispose to mycelial conver- 40 patients were alternatively assigned to one of four
sion and invasiveness are not entirely clear, it is not regimes and in each group 10 patients received between
unusual to find that relapses after apparent 'cures' follow 500 mg and 1000 mg of itraconazoie in the following
on a variety of treatment methods. Furthermore, it has dosage schedules:
been our experience that spontaneous conversion to the (A) 100 mg daily for 5 days (500 mg),
spore phase, with negative microscopy and Wood's light (B) 200 mg daily for 3 days (600 mg),
examination, is not uncommon even in extensive disease. (C) 200 mg daily for 5 days (1000 mg),
Many topical medications have been effective in the (D) 100 mg daily for 10 days (1000 mg).
short-term, such as selenium sulphide ('selsun'), zinc After two weeks 90% of the patients in Groups C and D
pyrithione, propylene glycol, and also topical forms of and 80% of those in Group B were clinically and
various imidazole derivatives, such as econazole, micona- mycologically cured. Only 40% of those who had
zole, clotrimazole, ketoconazole and, recently, bifona- received 500 mg of itraconazoie were cured at 2 weeks.
zole.^ In widespread pityriasis versicolor their use is not a After 10 weeks the percentages with clinical and mycolo-
practical proposition, however, although shampoo-type gical cure were 70% in Group D, 60% in Group C but
preparations have an advantage in being easier to apply. only 30% and 10% in Groups B and A respectively.
Our experience with selenium sulphide shampoo, which Encouraged by these results with low total doses of the
has been described as 'simple, safe, cheap and effective'^, drug, as well as by the fact that no side-effects were noted
has not been nearly as encouraging. Many of our patients and no alterations in serum gamma glutamyl transferase
balk at its use due to the burning irritation which results or serum alanine transaminase resulted from therapy, we
where there are extensive active lesions. Further inconve- decided to use itraconazoie in a slightly larger total dose in
nience follows from the fact that applications have to be our most severely affected cases of pityriasis versicolor.
made daily for at least a week so that compliance is
difficult to achieve.
Patients and methods
The discovery that ketoconazole, an imidazole deriva-
Correspondence: Dr L.I.Robertson, 300 Sparks Road, Sydenham Twenty of our patients with the most extensive involve-
4091, Durban, Republic of South Africa. ment received 100 mg of itraconazoie daily for 15 days.
178
 TINEA VERSICOLOR 179

All of them had more than 90% of the surface area of their Table 1. Clinical and demo-
graphic data
arms and trunks affected by active lesions and all had
suffered numerous relapses after a variety of topical
treatments. Eighteen of them had had relapses following Number of patients 20
one or more courses of ketoconazole. The diagnosis of Female 11
activity was confirmed by microscopy of scrapings from Male 9
all discoloured areas stained with Parker Quink/KOH, Age (years)
and by Wood's light examination for fluorescence. Each Mean 28-5
patient was examined at the end of the treatment course Range 17-49
(day 15), again after 30 days, and therafter every 4 weeks Mass (kg)
Mean 58-2
for a total of 40 weeks. On each of these follow-up visits 43-88
Range
Wood's light examination was performed and all disco-
Duration of rash (weeks)
loured areas examined for the highly characteristic and Mean 182
profuse scales which denote activity as opposed to Range 80-396
achromasia. Any scales obtained were checked microsco- Previous treatment
pically for mycelia and the finding of any mycelial forms Selenium sulphide 17
of P. orbiculare., however scanty, was taken as evidence of Topical imidazoles 15
a relapse. Oral ketoconazole 18
GGT (U/1)
Pregnant women and women of childbearing age who Before treatment 1312
were not on any form of contraception were excluded After treatment 13-05
from the study, as were any patients with serious (Reference range) 8-37
concomitant disease or patients who had been on any SGPT (U/1)
anti-fungal therapy in the month preceding entry into the Before treatment 12-54
trial. Serum gamma glutamyl transferase (GGT) and After treatment 12-24
(Reference range) 0-29
serum alanine transaminase (SGPT) estimations were
performed before and immediately after the treatment
period. problems with any similar systemically active broad-
spectrum antimycotic. It is useful, therefore, to consider
Results all 60 of our patients who received itraconazoie, both the
40 in the pilot-study who had received a total dose of
The clinical data on the patients is shown in Table 1. Two between 500 mg and 1000 mg, and also the 20 patients in
of the patients had acne vulgaris but were not on any this study who had had a total dose of 1500 mg. In the
topical treatment or antibiotics, and another had hyper- pilot-study the only results outside the reference range
uricaemia for which he took allopurinol throughout the were, with one exception, found before commencing
trial. All patients completed the treatment course on time treatment. The exception was a male with a palpably
and no patients were lost to follow-up right to the end of enlarged liver and a history of alcohol abuse who had a
the 40-week period. Thirteen of the 20 complained of pre-treatment GGT of 92 U/1 and though this had
pruritus in addition to the cosmetic problem. dropped to 81 U/1 after treatment, this was still outside
After 15 days all patients were symptom-free and the reference range of 8-37 U/1. In no case did the enzyme
mycologically clear. At the end of the 40-week period all levels exceed the reference range as a result of treatment,
but one were still clinically and mycologically cured. The whilst the vast majority of patients had figures which were
one patient who relapsed had, at the 36-week check-up, a slightly lower at the end of itraconazoie treatment. The
single 1-cm diameter lesion over the right deltoid which, mean GGT was 14 28 U/1 before and 13-55 U/1 after
while not itchy, did produce sparse scales and a few treatment, and the figures for the SGPT were 13-52 U/1
mycelial forms of P. orbiculare on microscopy. He before and 12-32 U/1 after treatment. In the main study
received no further treatment and continued to the 40- the results were similar and no abnormal hepatic enzyme
week check-up, at which stage the small area was neither levels were recorded either before or after treatment, the
visible nor scaly, but he was still considered a relapse. mean levels are indicated in Table 1. No side-effects were
reported in any of the 60 patients and the drug was
uniformly well-tolerated.
Liver function tests
Discussion
The fact that ketoconazole has been found to produce
transient elevations of hepatic enzymes, and, on rare The fact that so many preparations have been advocated
occasions, hepatitis, warrants a careful search for similar for use in this essentially cosmetic disorder is an
180 L.I.ROBERTSON
indication of the long-term inefficiency of most if not all ing the outcome of the pilot study to determine an
treatment methods. The ideal preparation would be one optimum dose for itraconazoie, their scaliness disap-
which is easily administered, uniformly effective and safe. peared without treatment and when the offer of entry into
Itraconazoie is a triazole derivative (C35H38CI2N8O4) the present study was made they were found to be
which has shown pronounced antifungal activity in vitro mycologically negative. The incidence of this sponta-
and in animal models against a wide range of fungi neous reversal to the spore form of P. orbiculare, with
including Candida., dermatophytes, Pityrosporum, Asper- clinical improvement without specific treatment,
gillus., Cryptococcus, Sporothrix and Cladosporum.^ In- warrants further study, as it could be a factor which
vitro studies in Candida suggest that itraconazoie inhibits would make the assessment of the results of any treatment
the morphogenetic transformation from yeast cells into method open to question, particularly in a study with a
mycelium, resulting in abnormalities of the yeast cell wall small number of patients, unless there has been placebo
with an increase in cell volume and defective cell division. control.
This action appears, at least in part, to be due to the If our results can be repeated in such a larger and
accumulation of C-14 methylated sterols which are controlled study, it may well be that in itraconazoie we
known to disturb membrane properties and cell growth. may be approaching the 'ideal' treatment for the severer
Itraconazoie has been free from side-effects and and widely disseminated forms of tinea versicolor.
hepatotoxicity in the 60 patients treated in this and our
previous study. At the dose employed in the present study
it also appears effective in clearing the mycelial forms of References
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