ASSESSMENT OF ORAL AZITHROMYCIN MONOTHERPY IN THE TREATMENT OF SEVERE NODULOCYSTIC ACNE: A PROSPECTIVE CLINICAL STUDY

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1 IJMPS Sci. Journal Impact Factor Research Article ASSESSMENT OF ORAL AZITHROMYCIN MONOTHERPY IN THE TREATMENT OF SEVERE NODULOCYSTIC ACNE: A PROSPECTIVE CLINICAL STUDY Samer A. Dhaher 1, Najih M. Mahdi 2 1 Assistant Professor in Dermatology and Venereology, Basra College of Medicine, Basra, Iraq; 2 Dermatologist in Department of Dermatology, Basra General Hospital, Basra, Iraq. ABSTRACT Background: Although systemic treatment with oral azithromycin was considered as first line of therapy for inflammatory papulopustular acne. Its beneficial effects on severe nodulocystic type was not well studied before Objectives: To evaluate the efficacy, safety and tolerability of azithromycin as monotherapy for treatment of severe nodulocystic acne. Patients and Methods: The study was a prospective clinical trial recruiting 49 patients with severe nodulocystic acne. Azithromycin 500mg was given orally thrice weekly for 12 weeks. Four weekly follow up were performed for 3 months to assess clinical response and report any adverse effects. Results: Compared to baseline, there was marked and significant reduction in the number of the inflammatory lesions at 12 weeks of treatment with the clearance of 87.05% of the papules, 90.5% of the pustules and 78.82% of the nodulocysts. At the end of the treatment there was a remarkable clearance of the inflammatory lesions in the majority of the patients ( 63% of the patients showed excellent response to the treatment, 19.5% good response, 8.6% moderate and only 8.4% reported poor response). Adverse effects were mild and mainly gastrointestinal. Conclusion: Azithromycin is an effective, safe and well tolerated alternative in treatment of severe nodulocystic acnewith minimal adverse effects. Key Words: Azithromycin, Nodulocystic, Acne, Vulgaris INTRODUCTION Acne is a chronic inflammatory disease of the pilosebaceous unit, with pleomorphic variety of lesions, consisting of comedons, papules, pustules, and nodules. The course of acne may be self-limiting but the sequelae can be lifelong, with pitted or hypertrophic scar formation(1). Although all age groups may be affected by its many variants, it is primarily a disorder of adolescence(2).the pathogenesis of acne is multifactorial but four basic steps have been reported : excess sebum production (seborrhea), comedon formation (comedogensis) due to follicular epidermal per proliferation, the presence and activity of propionibacterium acnes and Inflammation (3,4). Systemic treatment with oral antibiotic such as tetracycline, doxycyclin or erythromycin is considered as first line of therapeutic strategy for moderate to severe acne. However the mucocutaneous and systemic adverse effects of these drugs as well as the emergence of resistance strain of Propionibacteria acne was greatly impend the treatment and frequently associated with treatment failure(5). Therefore the search will continue for an ideal antimicrobial agents with long half-life, minimal side-effects, Propionibacteria acne sensitivity with increased patient compliance and adherence to the treatment. Azithromycin is a nitrogen-containing macrolide (azalide) with actions and uses similar to those of erythromycin. It is given in the treatment of respiratory-tract infections including otitis media, in skin and soft-tissue infections, and in uncomplicated genital infections (6).With a half-life of 68 hours, it may be inter- Corresponding Author: Corresponding Author: Anil Samer Pawar, A. Dhaher, Assistant Assistant Professor, Professor Department in Dermatology of Zoology, and D.A.V. Venereology, College Basra for Girls, College Yamunanagar of Medicine, (Haryana); Basra, Iraq. Mobile: ; sumanil27@yahoo.co.in sameralamir2@yahoo.com Received: Revised: Accepted: Int J Med Phar Sci Vol 6 Issue 4 December

2 mittently dosed three times a week with high adherence to this regime (7).In addition to high susceptibility of propionibacterium acne (8) azithromycin may be suitable alternative antibiotics for the treatment of acne. Recent studies demonstrated that oral azithromycin 500mg in 3 divided doses per week was efficacious and well tolerated therapy for inflammatory papulopustular acne (9,10). However, data confirming its efficacy in the treatment of severe nodulocystic acne were lacking. The objective of the study was to assess the efficacy, safety and tolerability of azithromycin as monotherapy for treatment of severe nodulocystic acne among Iraqi patients. Patients and methods The study was a prospective clinical trial designed to assess the efficacy, safety and tolerability of 500mg azithromycin given orally thrice weekly for 12 weeks in the treatment of severe nodulocystic acne in adolescent and young adult patients in our population. This study was conducted in Basra Teaching Hospital in the south of Iraq at the period between 1st of September 2012 to 31th of November2013. A total of 49 young adult and adolescent patients with severe nodulocystic acne were enrolled in this study, their ages ranged from years (mean =18 years), each patient includes in this study was informed that he or she is part of scientific study and written consent was obtained from them. Azithromycin 500mg orally thrice weekly for 12 weeks was prescribed to the patients. Four weekly follow up were performed for 3 months to assess clinical response of acne and report any adverse effects. The main exclusion criteria were: previous treatment with isotretinoin or oral contraceptive pills, uses of topical acne treatment in the last month and history of macrolides sensitization. Also patients were advised not to do any beauty procedure such as facial bleach, chemical peel and only topical rinse-off cleaners were allowed during follow up period. The efficacy of azithromycin treatment was evaluated by counting the number of inflammatory lesions (papules, pustule and nodulocysts) at acne sites (face, upper chest and back) initially at the baseline visit and at 4 weekly intervals for 12 weeks. The response to treatment was assessed by the following parameters: 1. Calculation and comparison of the percentage of reduction in the number of inflammatory lesions before and at the end of the trial (12 weeks). 2. Grading the response according to the percentage of total reduction in inflammatory lesions as follows: 80% = excellent, 60% - 79% = good response, 40% - 59% = moderate,< 40% = poor 3. Patient assess their satisfaction to the treatment at the end of the trial : 0 = no response,1 = mild response, 2 = moderate,3 = good response, 4 = excellent. Adverse effects of the treatment were recorded at each visit. t test was used for statistical analysis of data RESULTS Forty nine young adult and adolescent patients with severe nodulocystic acne were enrolled in this study, their ages ranged from 12 to 31 years (mean = 18 years), only 3 patients were withdrawn from the trial because of the gastrointestinal intolerance. In the reminder 46 patients, there was marked and significant reduction in the number of the inflammatory lesions during the first 4 weeks of the treatment in which the mean number of papular lesions was reduced from at the baseline to 12.06, similarly pustular and nodular lesions were also reduced significantly from baseline and 4.72 to 4.08 and 2.45 respectively (table 1) (p <0.05), with the clearance of 64.1% of the papular, 75.78% of the pustular and 48.1% of the nodular lesions at the end of first month (table 2). At the end of the study (12 weeks) there was marked and statistically significant reduction in the number of inflammatory lesions, with the clearance of 87.05% of the papules, 90.5% of the pustules and 78.82% of the nodules (table 2) (figure 1 and 2). Furthermore the pustular lesions were responded earlier as compared to other inflammatory lesions, where pustular lesions reach clearance of 75.78% at 4 weeks, compared to 64.1% of papular and 48.1% of the nodular lesions in the same interval (table 2). At the end of the treatment there was a remarkable improvement of the inflammatory lesions in the majority of the patients and 63% of the patients showed excellent response to the treatment, 19.5% good response, 8.6% moderate response and only 4 patients (8.4%) reported poor response(table 3). All the acne sites including face, upper chest and back were responded equally to the treatment leaving behind either spots of pigmentation, minimal erythema or pitted scaring. Adverse effects were reported only in 11 patients (24%) and these include; mild abdominal pain in 9 patients (19%), diarrhea in 5 (11%) vomiting in 2 (4%), palpitation in 2 (4%) and only one patient with headache(1%), therefore most of these side effects were gastrointestinal intolerance and were mild and did not necessitate cessation of treatment and tended to be self limited (table 4). Patients assessment at the end of the treatment course (12 weeks), demonstrated that most of the patients reported good response to the treatment(67.39%), and 9 patients (19.57%) scored their response to treatment as excellent, however moderate response was reported by 4 patients (8.79%) and only 2 patients(4.35%) was reported mild response (table 5). Int J Med Phar Sci Vol 6 Issue 4 December

3 DISCUSSION In recent published studies the effectiveness of azithromycin in the treatment of acne has been confirmed(21). The first case series of 3 patients using azithromycin to treat acne was published in 1997 when Fernandez-Obregon et al reported that azithromycin 250 mg 3 times per week improved acne significantly at 4 weeks and maintained the improvement at 12 weeks(6). The author later followed up his small case series with a retrospective analysis of 79 patients, 21 of whom were treated with azithromycin 250 mg three times each week for an average 12 weeks. He compared these patients with those he had treated in the past with tetracycline, doxycycline, minocycline, and erythromycin. Although not statistically significantly different from patients treated with the other antibiotics, the azithromycin group had the greatest percentage of patients (85.7%) with a significant amount of lesion reduction (7). In another study, Elewski et al treated 20 patients with both oral azithromycin and topical tretinoin 0.01 % gel. A 75% improvement in acne was reported (12) Furthermore, a comparative trial studying azithromycin for the treatment of acne have been shown that azithromycin in pulse therapy was as effective as daily doxycycline and with less frequent dose administration and the patients demonstrated better compliance and adherence to treatment (13,14,15).The results of our study were in consistent with the above findings and we demonstrated that azithromycin taken orally was highly suitable agent for the treatment of inflammatory lesions in severe nodulocystic acne and 63% of our patients were reported excellent response to treatment with good compliance and adherence to treatment regime with minimal side effects. In our study there was significant reduction of the inflammatory lesions count especially at the end of the 12 weeks of azithromycin treatment, these finding are in consistent with other studies (10,11,16) Interestingly the pustular lesions responded earlier as compared to other inflammatory lesions, and the lesions reach clearance of 75.78% at initial 4 weeks. The effectiveness of azithromycin in eradication of acne lesions are attributed to the high affinity of azithromycin for inflammatory acne lesions (16,17) including nodules and cysts and the demonstrated highest antibacterial activity against many anaerobic species including Propionibacteria acne with lack of bacterial resistance (9,10). In addition,many authors proposed that azithromycin is also had comedolytic effect and significantly reduced comedons counts by decreasing Propionibacteria acne colonization(11) however in the present study we did not observe any remarkable alteration in the count of comedons during azithromycin treatment i.e. we did not include comedon counting as a parameter for assessment of the response to treatment and comedolytic effect of azithromycin remain speculative. We observed low incidence of adverse effects in our patients and most of these were mild gastrointestinal and did not necessitate withdrawal from the trial. This finding was similarly reported by other studies(,18,19,20) CONCLUSIONS Azithromycin was efficacious and safe orally administered antibiotics in treatment of inflammatory lesions of acne including cystic nodules and a dose of 500 mg three times per week is well tolerated regimen with minimal adverse effects. ACKNOWLEDGEMENT The authors acknowledge the immense help received from the scholars whose articles are cited and included in the references of this manuscript. The authors are also grateful to authors, editors and publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed. We would like also to thank all the medical staff in the Department of Dermatology, Basra General Hospital for their help and support and we are grateful for Public Health Department staff, Basra medical college for their help and assistant in statistical analysis of data. Table 1: Mean No. of the inflammatory lesions before, during and at the end of treatment course. Duration of treatment Type of the inflammatory lesions Papules Pustules Nodules Baseline weeks 12.06* 4.08* 2.45* 8 weeks 6.93* 2.95* 1.2* 12 weeks 4.34* 1.6* 1* *p < 0.05 significant when compared with the baseline Table 2: Percentage of the reduction of the inflammatory lesions from the baseline to the end of the treatment. Duration of treatment Type of the inflammatory lesions Papules Pustules Nodules Baseline 100% 100% 100% 4 weeks 64.1% 75.78% 48.1% 8 weeks 79.37% 85.49% 74.58% 12 weeks 87.05% 90.5% 78.82% 3 Int J Med Phar Sci Vol 6 Issue 4 December 2015

4 Table 3 : Scoring the response according to percentage of total reduction of the inflammatory lesions Percentage of reduction Number of patients 80% reduction (excellent) 29 63% Percentage of patients 60%-79% reduction (good) % 40%-59% reduction (moderate) 4 8.6% < 40% reduction (poor) 4 8.6% Table 4: Adverse reactions of azithromycin therapy Adverse reaction Number of patient Percentage Mild abdominal pain 9 19% Diarrhea 5 11% Vomiting 2 4% Palpitation 2 4% Headache 1 2% Table 5 Patients assessment of the treatment response Type of response Number of patients No response 0 0 0% Percentage of patients Mild response % Moderate response % Good response % Excellent response % Total % Figure 1: Shows female patient with sever nodulocystic acne before and 12weeks after azithromycin therapy Figure 2: Shows male patient with sever nodulocystic acne before and 12 weeks after azithromycin therapy. REFERENCES 1. Zaenglein A L, Graber E M, Thiboutot D M, Strauss J S. Acne Vulgaris and AcneiformEruptions. In: Wolff K, Goldsmith L A, Katz S I, Gilchrest B A, Paller A S, Leffell D J, eds. Fitzpatrick s Dermatology in General Medicine. 7th edition, New York: McGraw-Hill companies; 2008: Zaenglein A L,Thiboutot D M. Acne vulgaris. In: BolongiaJ L, Jorrizo J L, Schaffer J V, eds. Dermatology. 3rd edition, China, Elsevier limited; P Harper J C. An update on the pathogenesis and management of acne vulgaris. J Am Acad Dermatol. 2004, 51 (1): Gollnick H. Current Concepts of the Pathogenesis of Acne: implications for drug treatment.drugs. 2003;63(15): Ghali F, Kang S, Leyden J, Shalita AR, Thiboutot DM. Changing the face of acne therapy.cutis. 2009;83(2): Fernandez-Obregon AC. Azithromycin for the treatment of acne. Int J Dermatol.1997;36: Adolfo C, Fernandez-Obregon AC. Azithromycin for the treatment of acne. Int J Dermatol. 2000;39: Mycek MJ, Harvey RH, Pamela C. Howland CRD. eds. Lippincott s illustrated reviews pharmacology. 3 rd edition. Philadelphia: Lippincott Williams and Wilkings; Abdel Fattah NS, Darwish YW. In vitro antibiotic susceptibility patterns of Propionibacterium acnes isolated from acne patients: an Egyptian university hospital-based study. J Eur Acad Dermatol Venereol. 2013;27(12): Kapadia N Talib A Acne treated successfully with azithromycin. Int J Dermatol. 2004, 43(10): Bardazzi F, Savoia F, ParenteG,Tabanelli M, Balestri R, Spadola G, et al.azithromycin: A new therapeutical strategy for acne in adolescents. Dermatol Online J. 2007;13(4):4. Int J Med Phar Sci Vol 6 Issue 4 December

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