Dermatology Online Journal

Azithromycin: A new therapeutical strategy for acne in adolescents
Federico Bardazzi MD, Francesco Savoia MD, Gianluca Parente MD, Michela Tabanelli MD, Riccardo Balestri MD, Giuseppe Spadola MD, Emi Dika MD
Dermatology Online Journal 13 (4): 4

Department of Specialistic and Experimental Clinical Medicine, Division of Dermatology,University of Bologna, Italy.

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Abstract

AIM: To study the efficacy, safety, and compliance of 500 mg azithromycin thrice weekly for 8 weeks to treat acne vulgaris in adolescents. METHODS: An open-label, non-comparative study was carried out for 8 weeks. Fifty-two teenagers with moderate to severe papulo-pustular acne vulgaris were enrolled. Azithromycin, 500 mg orally thrice weekly for 8 weeks, was prescribed. No topical treatment was permitted. At the baseline visit, patients were scheduled to return at two-weekly intervals for 8 weeks. Efficacy was gauged by the percentage clearance of papulo-pustular acne lesions. All patients were also evaluated at four months post-treatment. RESULTS: A majority of patients (47/52) showed remarkable improvement in the first 4 weeks with a more than 20 percent reduction of their inflammatory papulo-pustular lesions. Maximum clearance was observed in 32 patients at 8 weeks. Slow improvement with eruptions of new lesions was seen in 6 patients. Adverse events, such as heartburn and nausea, were reported by 3 patients. All patients completed the 8-week study period. The beneficial effect was maintained at 4 months after the conclusion of treatment. CONCLUSIONS: Azithromycin, 500 mg thrice weekly for 8 weeks, appears to be a safe and effective treatment for acne vulgaris in adolescents, with excellent patient compliance.

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Introduction

Acne vulgaris is a common inflammatory disorder of the pilo-sebaceous follicles. It is a multifactorial disease and its pathophysiology centers on the interplay of follicular hyperkeratinization, colonization with Propionibacterium acnes (PA), increased sebum production, and inflammation. This disease has a high prevalence, occurring mainly in adolescence. Although the peak of prevalence is around the 17th year of life, acne lesions can appear earlier and are not uncommonly observed in the age group ranging from 12 to 14 years, in which the condition is underreported [1]. In a recent study the prevalence of acne among teenagers in various European countries was calculated to range from 70-87 percent, according to different methods of classification [2]. Early and adequate treatment helps to reduce psychological stress caused by acne lesions and the long-term risk of scarring. Diverse therapeutical options are available in the treatment of acne [3, 4, 5].

Antibiotic therapy has long been found useful in the management of moderate-to-severe acne vulgaris. Mechanisms of action include suppressing growth of PA, reducing the production of inflammatory mediators, and acting in immunomodulation [6]. Commonly prescribed antibiotics include tetracyclines, doxycycline, minocycline, limecycline and erythromycin [5].

Recent research has been carried out to demonstrate the role of azithromycin in acne treatment and its efficacy [7, 8, 9]. There are no reports in the literature of PA resistance to azithromycin [10].

We performed open-label, non-comparative study that was not sponsored by any pharmaceutical company, using an 8-week pulse-therapy regimen in adolescents who were not currently using any other topical or systemic treatment.

Methods

The primary focus of this study was to assess the efficacy, safety, tolerability and compliance of 500 mg of azithromycin thrice weekly for 8 weeks in the treatment of acne in a cohort of adolescent patients.

Azithromycin is an orally administered macrolide that has a wide spectrum of activity. It is characterized by rapid and extensive uptake from the circulation into intracellular compartments following oral administration and by a long half-life (68 h). The drug remains in the tissues for prolonged periods, from 2 to 4 days, at levels higher than the minimum inhibitory concentration for many common pathogens [11, 12], making azithromycin a promising alternative to conventional antibiotics.

Fifty-two patients underwent a clinical session with a dermatologist during which a global assessment was made, including a full face count of papular and pustular lesions [13] (Table 1). The number of lesions was calculated at the beginning of the treatment (baseline, day 1) and at 2-weekly intervals for 8 weeks (day 14-28-42-56). The difference between the number of lesions observed at baseline and the number seen in subsequent examinations was used to evaluate the efficacy of the therapy (Table 2). A difference equal to or greater than 50 percent was considered "good-excellent", between 20 and 50 percent "moderate," and less than 20 percent "poor".

Furthermore, all patients completed the dermatology life quality index (DLQI), a questionnaire that is simple to administer, reproducible, validated, and designed to be practical and of clinical value when used in a busy clinical setting [14]. At every check-up we assessed the clinical response to the acne treatment, any adverse events, and patient compliance.

Patients with relapsing acne previously treated with antimicrobials such as doxycycline, minocycline, lymecycline and erythromycin were eligible to be enrolled in the study after a six-month wash-out period. No patients had previously been treated with oral isotretinoin. The main exclusion criterium was a history of macrolide sensitization.

Azithromycin (500 mg thrice weekly for 8 weeks) was prescribed to the patients. No topical therapy was associated. Patients were advised not to undergo any beauty procedures, such as chemical peels, bleaches, or facials, during the study period.

All patients were also evaluated at a 4 month, post-treatment follow-up visit. Only topical rinse-off cleaners were allowed during follow-up.

Results

Fifty-two adolescent patients were enrolled, 37 males and 15 females, ranging in age from 13 to 17 years and all suffering from moderate to severe papulo-pustular acne vulgaris. Forty-seven patients (90.4%) showed remarkable improvement within the first 4 weeks, with a significant reduction in their inflammatory papulo-pustular lesions (23 showed "moderate" reduction and 24 "good-excellent"). Maximum clearance was observed at 8 weeks (Table 3)

Figure 1a	Figure 1b

Figure 2a	Figure 2b

Figure 3a	Figure 3b
a Figures: before treatment b Figures: after treatment

Pustular lesions showed a major degree of clearance, but comedones persisted as would be expected. All sites showed an equal degree of clearance. Residual post-inflammatory pigmentation and pitted and linear scarring represented the aftermath of the relapsing pattern of acne. Six patients (11.5%) showed "poor" results characterized by slow clearance with eruptions of new lesions whilst on treatment; they nevertheless completed the 8-week treatment. Adverse events, such as heartburn and nausea, as a result of gastrointestinal intolerance, were reported by three patients (5.8%). These patients were advised to use the antacid, magnesium trisilicate, before meals. This successfully alleviated the symptoms.

All patients completed the 8-week study period. In 25 (78.1%) patients out of the 32 patients labeled as "good-excellent responders," the beneficial effect persisted during a follow-up of 4 months without any therapy.

DLQI at the end of treatment confirmed the improvement in the quality of life after 8 weeks of treatment in all the patients who obtained a reduction rated as "good-excellent". In the remaining patients the results of DLQI were variable and not related to the percentage of reduction in mean lesion count.

Discussion

Acne vulgaris is a common skin disorder among children and young adults that carries enormous financial and psychosocial impact. Approximately 40 percent of adolescents below the age of 15 years develop physiological acne and in 15 percent of these patients the acne is sufficiently troublesome to merit a visit to a dermatologist [2]. There is no doubt that early and adequate treatment will reduce the severity of the problem and the long-term risk of scarring.

The choice of treatment depends on the clinical severity. A patient with mild acne should receive topical therapy. In moderate-to-severe acne, systemic treatment is required in most cases, using antibiotics, hormonal therapy, and oral retinoids [10, 15, 16]. As a first line systemic treatment in adolescence most authors recommend the use of systemic antibiotics, including tetracyclines, doxycycline, minocycline, limecycline and erythromycin [5, 6]. Recently, azithromycin has been added to this list [9, 17]. Comparative clinical trials have shown that the tolerability profile of azithromycin is superior to that of erythromycin and doxycycline [8]. Moreover, tetracyclines can cause both mucocutaneoeus and systemic adverse effects [10].

The unique pharmacokinetics of azithromycin, together with its effectiveness, make it a highly suitable agent for the treatment of acne. The drug shows an affinity for inflammatory tissue and demonstrates activity against many anaerobic species, including PA. Clinical isolates of PA are known to be highly susceptible to azithromycin [19].

In selecting the appropriate antibiotic for patients, the clinician should take into account the severity of the acne, the safety profile of the drug, the potential for development of resistance, and the cost-effectiveness.

Azithromycin has many advantages compared to other antibiotics. It is more stable than erythromycin in low gastric pH; it produces fewer gastrointestinal side-effects and presents no major drug interactions [20]. It also appears to be safer than the new tetracyclines such as lymecycline, in pediatric patients. Finally, the possible efficacy of a less frequent dosage improves compliance, cost-effectiveness and tolerability.

The widespread and long-term use of antibiotics over the years has unfortunately led to the emergence of resistant bacteria. Resistance to tetracycline and cross-resistance to doxycycline are also common. The incidence of PA resistance in the UK is estimated to be approximately 65 percent for erythromycin and clindamycin and 40 percent for tetracycline and doxycycline [5], whereas there are no reports on resistance to azithromycin [10, 21, 22]. The global increase in the antibiotic resistance of PA may be a significant contributing factor in treatment failures.

Recently some studies have been published on the effective use of azithromycin in treating acne in adults, but until now there is scant published information on azithromycin use for acne in the adolescent population [7, 8, 9, 10, 17]. Our study confirms that azithromycin is a safe, effective, and tolerable antimicrobial agent with minimal side effects and good compliance, even in adolescent patients. Moreover, it is not photosensitizing; fifteen patients in this study were treated during the summer months with no photosensitivity problems. Azithromycin proved to be successful within 8 weeks of treatment in 88.5 percent of patients. Patient compliance was excellent and only three patients had gastrointestinal disturbances in the form of heartburn and nausea.

Differences between the patients' personal assessment (DLQI) and the mean lesion counts are explainable by the fact that healed lesions often leave hyperpigmented macules, which patients evaluate as active lesions; an additional factor may be their excessive expectations.

All patients found azithromycin easy to take, and the majority found it effective in controlling and clearing their acne. Perhaps, the ease of this pulse regimen contributed to patient and parental compliance.

No comment about absolute and relative cost of azithromycin treatment for acne can be made because the cost of this medication is variable in every country. In Italy, National Health Service (NHS) distributes antibiotics to citizens free of charge. However, considering the price imposed by this institution for these drugs, the cost of 8 weeks of therapy with azithromycin (3-250 mg tabs/week) would be 137,68 €. This is higher than the cost of therapy with doxycycline (100 mg BID), which would be 23,46 €. In the US, the typical retail cost for 8 weeks of generic azithromycin therapy under the suggested regimen would be approximately $440, although different pharmacy prices may vary widely. Because there are patients who do not respond to or tolerate the tetracyclines, we think that azithromycin is a valid alternative.

Finally, a few studies have compared azithromycin with other antibiotics [10, 22, 23], but there are no data about the optimum dose of azithromycin for treating acne in adolescents or in adults. Further randomized, controlled comparative trials are needed to assess this point, and to establish the duration of the treatment in patients with acne.

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