Ozgur Bakar, MD, Zeynep Demirgay, MD, and Oya Gurbuz, MD

Abstract

Background Systemic antibiotics currently used in the treatment of rosacea are sometimes associated with uncomfortable side-effects. Therefore, a need for an effective agent with few side-effects and good patient compliance exists. Azithromycin, a macrolide antibiotic with prolonged mode of action, has recently been found to be an effective alternative in the treatment of inflammatory acne. We planned a study to evaluate the efficacy and safety of azithromycin in rosacea.

Methods An open-labeled study was performed in a population of 18 patients, with Plewig-Kligman stage 2 rosacea. Patients were given oral azithromycin for 12 weeks in decreasing doses.

Results Fourteen subjects completed the trial. The treatment produced therapeutic benefits with regard to total scores as well as inflammatory lesion scores. At the end of 12 weeks, there was a 75% decrease in total scores (P< 0.001) and an 89% decrease in inflammatory lesion scores compared with basal values. Improvement continued during the 4 weeks after treatment. Adverse effects were minimal and well tolerated in most patients. Conclusion Azithromycin is a promising agent in the treatment of rosacea with its few side-effects and good patient compliance.

Introduction

Rosacea is a chronic cutaneous disorder primarily of the convexities of the central face (cheeks, chin, nose, and central forehead), often characterized by remissions and exacerbations. It is considered a syndrome or typology, with various combinations of cutaneous signs such as flushing, erythema, telengiectasia, edema, papules, pustules, ocular lesions, and rhinophyma.1

Symptoms and signs of rosacea can usually be controlled with a combination of systemic and topical antibiotics. Tet-racyclines and erythromycin are the most commonly used oral antimicrobials.2’3 In many cases, long-term treatment is needed to maintain remission. However, long-term use of antibiotics is not well tolerated because of side-effects, including gastrointestinal intolerance, photosenstivity and candidal vaginitis.3

Azithromycin is a newer macrolide that was developed to overcome the shortcomings of erythromycin, such as gastrointestinal intolerance and short half-life.4 It has a unique pharmacokinetics that give rise to prolonged tissue levels and allow less frequent dosage.4 Recently, azithromycin was found to be effective in the treatment of inflammatory acne.5 Considering the successful results of that study, we planned an open-labeled study to evaluate the efficacy and safety of azithromycin in rosacea patients.

Methods

Study design

An, open-labeled study was performed in a population of 18 patients with rosacea. All patients gave written informed consent before entering the trial. The study was approved by the institutional Ethics Committee.

Patients

Patients with a diagnosis of Plewig-Kligman stage 2 rosacea (persistant erythema, numerous papules, pustules and telangiectasias) were eligible for the study. Patients had to be in good health. Subjects were excluded if they required other systemic or topical preparations that might interfere with evaluations. Patients with a known hypersensitivity to macrolides or azithromycin were also excluded. All topical and systemic treatments were withdrawn 2 weeks and 4 weeks before the study, respectively.

Treatment schedule

Patients were assigned to receive oral azithromycin (Zithromax®, 500 mg tablets, Pfizer, New York, NY, USA) for 12 weeks. Azithromycin 500 mg/day was given for three consecutive days (days 1, 2 and 3) weekly for the first 4 weeks, 250 mg/day for three consecutive days (days 1, 2 and 3) weekly for the next 4 weeks and 500 mg/week (day 1) for the last 4 weeks. All patients were strictly advised not to use any topical formulation other than sunscreen (Coppertone®, 30 SPF oil-free lotion, Schering Plough, Memphis, TN, USA). Patients were also advised to avoid excessive sun exposure.

Efficacy assessments

In order to assess the efficacy of the treatment, the Walsgrave Hospital rosacea scoring system was used.6 According to this method, facial involvement was assessed in seven different areas (forehead, nose, right cheek, left cheek, chin, right paranasal, left paranasal) and for six different parameters (erythema, telengiectasia, papules, pustules, edema and scaling). A score of 1 was given if less than half of each area was involved and a score of 2 if half or more was involved. Extra-facial involvement was noted. Total and inflammatory lesion scores were calculated separately. Total scores were the sum of the scores given to each parameter for each area. For inflammatory lesion scores, only the score of two parameters (papules and pustules) was used for evaluation.

Patients were evaluated at baseline and on the 4th, 8th, 12th and 16th weeks (4 weeks after cessation of treatment). The same investigator conducted all evaluations at each visit. The primary efficacy end-point was mean percentage change in total scores from baseline to the end point (week 12). Repeated measures anova (P < 0.05) and Newman-Keuls multiple comparison tests were used for statistical analysis.

Safety assessments

Gastrointestinal intolerance and other side-effects were assessed and recorded on each visit. Standard laboratory analyses (hematology, biochemistry) were performed on baseline and at the 8th week of treatment.

Results

Patients

From a total of 18 patients (11 women and seven men) enrolled into the study, 14 patients (nine women, five men) completed the 12 weeks of treatment. Three patients were lost to follow up after the first visit and there was one withdrawal because of diarrhea after the first 4 weeks of therapy. There were no dropouts because of treatment failure. The ages ranged from 30 to 71 years (mean: 44.78 ± 2.79. The subjects had had symptoms of rosacea for a considerable period of time (mean: 83.4 ± 17.74 months, range: 2-240).

Efficacy

The change in the total and inflammatory scores during the study is shown in Fig. i(a-d). The mean number of total scores decreased from 19.21 ± 8.04 at baseline to 4.857 ± 4.016 at week 12 (P < 0.001). From a total of 14 patients, nine had a greater than 70% decrease in their total scores (Fig. 2a,b). The mean percentage of decrease in total scores at the end-point was 75%. The mean percentage of decline from the baseline total scores was 53% at week 4, 67% at week 8, 75% at week 12 and 78% at week 16 (4 weeks after cessation of therapy) (P < 0.001). The mean number of inflammatory lesion scores decreased from 7.786 ± 3.068 at baseline to 0.7857 ± 1.122 at week 12 (P < 0.001). The mean percentage of decrease in inflammatory scores at the end-point was 89%. The mean percentage of decline from the baseline inflammatory scores was 83% at week 4, and 89% at weeks 8, 12 and 16 (P-values < 0.001). The mean percentage of decrease in the erythema scores was 62% and 75% at weeks 12 and 16 (P < 0.001), respectively. The mean percentage of decline in the telengiectasia scores were noted as 55% and 53% (P < 0.001) at weeks 12 and 16, respectively. The patient who was withdrawn from therapy after the first 4 weeks because of developing diarrhea also showed a 64% decline in total scores. Edema and scaling was not noted in any of the patients.

Safety and tolerability

Overall the treatment was well tolerated. There were no treatment related serious adverse events. There were no dropouts as a result of side-effects, except one patient who developed diarrhea. Constipation, mild dyspepsia and abdominal pain were the other side-effects observed in three patients. No significant laboratory abnormalities were noted. One patient had transient elevation of the ALT level following 8 weeks of treatment.

Discussion

The cause of rosacea remains unknown. Many etiological factors such as racial, phsycogenic, thermal, alimentary, infectious and immunologic have been considered.1 Therapeutic activity of the most commonly used antibiotics such as tetracyclines and metronidazole has been attributed to their anti-inflammatory effects.7’8 Similarly, the anti-inflammatory action of macrolides has been shown in various studies.9-12 The results of these studies indicate that macrolides affect several inflammatory processes such as migration of neu-trophils, the oxidative burst in phagocytes and production of pro-inflammatory cytokines.9-12 However, the precise mechanisms underlying these actions are not clear. Recently, Torresani found clarithromycin; a new generation macrolide effective in the treatment of rosacea.13 Azithromycin is another new macrolide, which has a superior pharmacokinetic profile when compared with other macrolides.4 It penetrates tissues rapidly, where it remains for prolonged periods. Steady-state tissue levels are substantially increased in relationship to serum levels. The steady-state skin level of azithromycin was found to be 0.4 |g/ml at 72-96 h with a tissue/serum ratio of 35. It remains in human polymorphnuclear leukocytes with a mean tissue half-life of 2-4 days.4 This enables less frequent dosing and shorter duration of therapy.4 Moreover it shows affinity for inflammatory tissues.4 The results of our study suggests that azithromycin is an effective and safe alternative in the treatment of rosacea. It decreased total scores by 75%. The decrease in inflammatory lesions was even higher at 89% (P < 0.001). As for erythema and telengiectasia, lower response rates were noted: 62% and 55%, respectively (P < 0.001). Like other antibiotics used in rosacea, this remarkable response may be because of its anti-inflammatory effects. The maximum decline in both scores was achieved at the end of 4 weeks. The patients were followed up for 1 month and the decrease in the scores continued during this period. These factors increased patient satisfaction. However, as the follow-up period in this study is inadequate, long-term efficacy of the treatment should be evaluated in further studies.

In contrast to other antibiotics used in rosacea, azithromy-cin has a long tissue half-life that allows a three times a week dosing schedule.4 As remission of rosacea is achieved, dosage may be tapered to a single dose of 500 mg per week. This dosage successfully maintained remission in our patients. Single-dose regimen improves patient compliance and is of particular interest for those who require long-term oral antibiotics. Azithromycin may also be the preferable agent for those taking other medications, because it has no major drug interactions.4 Incidence of gastrointestinal side-effects compared with erythromycin was reported to be lower (9.5% vs. 20.6%).14 It was well tolerated by our patients, except in one patient in whom treatment was withheld because of diarrhea. In three patients mild gastric distress was observed.

In summary, the results of our preliminary study indicate that azithromycin is a promising agent in the treatment of rosacea, with few side-effects and good patient compliance.

Further controlled studies comparing the effectiveness, toler-ability and cost effectiveness of azithromycin with conventional antibiotics are needed.

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