Guidelines of Care for Acne Vulgaris Management Technical Report
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Guidelines of Care for Acne Vulgaris Management Technical Report
2 Acne Vulgaris Table of Contents Page No. Introduction ................................................................................................ 3 Clinical questions ....................................................................................... 3 Method of evaluation of evidence .............................................................. 4 Grading and classification systems............................................................ 7 Microbiological and endocrine testing ...................................................... 12 Topical agents.......................................................................................... 18 Systemic agents....................................................................................... 30 Hormonal agents...................................................................................... 36 Isotretinoin ............................................................................................... 42 Miscellaneous therapies .......................................................................... 49 Complementary/alternative therapies ...................................................... 53 Dietary restriction ..................................................................................... 58 Graded References.................................................................................. 60
3 Introduction Approximately 40-50 million people in the United States have acne vulgaris. It is the most common skin disease, especially in adolescents and young adults. Acne affects more than 85% of teenagers. There is no mortality associated with acne disease, but there is often significant physical and psychological morbidity such as permanent scarring, poor self-image, depression and anxiety. The direct cost of acne is estimated to exceed $1 billion per year, with $100 million spent on over-the-counter acne products in the United States. Acne is a multifactorial disease affecting the pilosebaceous follicles of the skin. Some factors that play an important role in the pathogenesis of acne are follicular hyperkeratinization, microbial colonization, sebum production inflammation following chemotaxis and the release of various pro-inflammatory mediators. Appropriate evaluation and management of acne vulgaris are important. At present there are many topical and systemic therapeutic options available for the treatment of acne because of the multifactorial etiology of acne vulgaris. Various therapies are discussed in the “Guidelines of care for acne vulgaris management” (J Am Acad Dermatol. 2007 Apr;56(4):651-63). Clinical Questions This is a comprehensive search of the peer-reviewed biomedical literature and analysis of the evidence regarding therapies for acne as a basis for the development of the American Academy of Dermatology (AAD) clinical guidelines of care for the treatment of acne. Specific Clinical Questions addressed in the acne guidelines are the following: I. What systems are most commonly used for the grading and classification of adult acne and acne vulgaris in adolescents (11 to 21 years) to adults? II. What is the role of microbiological and endocrine testing in evaluating patients with adult acne and acne vulgaris in adolescents to adults? III. What is the effectiveness and what are the potential side effects of the following topical agents in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) retinoids and retinoid-like drugs b) benzoyl peroxide c) topical antibiotics d) salicylic/azelaic acids e) sulfur and resorcinol f) aluminum chloride g) zinc h) combinations of topical agents IV. What is the effectiveness and what are the potential side effects of the following systemic antibacterial agents in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) tetracyclines: doxycycline, minocycline b) macrolides: erythromycin
4 c) clindamycin d) trimethoprim e) ampicillin/amoxicillin V. What is the effectiveness and what are the potential side effects of hormonal agents in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) contraceptive agents, especially oral preparations b) spironolactone c) antiandrogens d) oral corticosteroids VI. What is the effectiveness and what are the potential side effects of isotretinoin in the treatment of adult acne and acne vulgaris in adolescents to adults? VII. What is the effectiveness and what are the potential side effects of miscellaneous therapies in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) chemical peels b) comedo removal c) intralesional steroids VIII. What is the effectiveness and what are the potential side effects of complementary/alternative therapies in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) herbal agents b) homeopathy c) psychological approaches d) massage therapy e) hypnosis/biofeedback IX. What is the effectiveness of dietary restriction in the treatment of adult acne and acne vulgaris in adolescents to adults? Method Evidence evaluated for this report was obtained primarily from a search of MEDLINE and EMBASE databases spanning the years 1966 to 2006. The available evidence was evaluated using a unified system called the Strength of Recommendation Taxonomy (SORT) developed by editors of the US family medicine and primary care journals (i.e., American Family Physician, Family Medicine, Journal of Family Practice and BMJ-USA). This strategy was supported by a decision of the Clinical Guidelines Task Force in 2005 with some minor modifications for a consistent approach to rating the strength of the evidence of scientific studies.1 Evidence was graded using a three-point scale based on the quality of methodology as follows: I Good quality patient-oriented evidence II Limited quality patient-oriented evidence
5 III Other evidence including consensus guidelines, extrapolations from bench research, opinion or case studies
6 Clinical recommendations were developed based on evidence tabled in the guideline and explained further in the technical report. These are ranked as follows: A. Recommendation based on consistent and good-quality patient-oriented evidence B. Recommendation based on inconsistent or limited quality patient-oriented evidence C. Recommendation based on consensus, opinion or case studies For each intervention within the Clinical Questions, an effort was made to identify and present the best evidence regarding its use in the treatment of acne. Studies of clinical measurements of outcome were considered for analysis whether or not the clinical outcome was the primary outcome measured. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations The Academy must ensure balance, independence, objectivity and scientific rigor in its evidence-based guidelines of care. The Board of Directors requires that all participating members of the guidelines of care associated work groups must comply with regulations governing disclosure. All participants are expected to disclose in the document “Authors’ Conflict of Interest Disclosure Statement” any significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed by them. The intent of this disclosure is not to prevent anyone with a significant financial or other relationship from participating, but rather to provide readers of the guidelines with information on which to make their own judgments. It remains for the reader to determine whether any work member’s interests or relationships may influence the discussion. Following are the Work Group members that developed the acne guidelines along with their affiliation and disclosure of potential conflict of interest:” John Strauss, MD, Chair Acne Work Group – the Department of Dermatology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa Dr. Strauss was a consultant and investigator for Roche Laboratories receiving honoraria and grants, and a consultant for Medicis receiving honoraria. Karl R. Beutner, MD, PhD, Chair Clinical Guidelines Task Force – Anacor Pharmaceuticals, Inc., Palo Alto, California Dr. Beutner was an employee of Anacor receiving salary and stock options and a stockholder of Dow Pharmaceutical Sciences receiving stock. Daniel Krowchuk, MD – the Departments of Pediatrics and Dermatology, Wake Forest University School of Medicine, Brenner Children’s Hospital, Winston-Salem, North Carolina Dr. Krowchuk had no relevant conflicts of interest to disclose. James J. Leyden, MD – the Department of Dermatology, University of Pennsylvania Hospital, Philadelphia, Pennsylvania Dr. Leyden was a consultant for Stiefel and SkinMedica, receiving honoraria; served on the Advisory Board and was a consultant for Galderma and Obaj, receiving honoraria; was on the Advisory Board and was a consultant and investigator for Connetics, Collagenex, Allergan, and Medicis, receiving honoraria.
7 Anne W. Lucky, MD – the Division of Pediatric Dermatology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati School of Medicine, Cincinnati, Ohio Dr. Lucky was an investigator for Connetics, Dow, Galderma, Healthpoint, Johnson & Johnson, QLT, and Stiefel, receiving grants, and an investigator and consultant for Berlex receiving grants and honoraria. Alan R. Shalita, MD – the Department of Dermatology, State University of New York Downstate Medical Center, Brooklyn, New York Dr. Shalita was a consultant, investigator, stockholder, and speaker for Allergan, receiving grants and honoraria; a consultant for Bradley/Doak receiving honoraria; served on the Advisory Board and was a consultant for Collagenex, receiving honoraria; was a consultant and investigator for Connetics receiving grants and honoraria; an Advisory Board member, consultant, investigator, and speaker for Galderma receiving grants and honoraria; a consultant, speaker, and stockholder for Medicis receiving honoraria; an Advisory Board member for Ranbaxy receiving honoraria; and a consultant, investigator, and speaker for Stiefel, receiving grants and honoraria. Elaine C. Siegfried, MD – the Department of Dermatology, St. Louis University School of Medicine, St. Louis, Missouri Dr. Siegfried was an investigator for Atrix receiving salary. Diane M. Thiboutot, MD – the Department of Dermatology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania Dr. Thiboutot served on the Advisory Board and was an investigator and speaker for Allergan and Galderma, receiving honoraria; was on the Advisory Board and was a consultant and investigator for Collagenex receiving honoraria; was on the Advisory Board and was an investigator for Connetics, Dermik, and QLT, receiving honoraria; and was a consultant, investigator, and speaker for Intendis, receiving honoraria. Abby S. Van Voorhees, MD – the Department of Dermatology, University of Pennsylvania Hospital, Philadelphia, Pennsylvania Dr. Van Voorhees served on the Advisory Board and was an investigator and speaker for Amgen, receiving grants and honoraria; was an investigator for Astellas, Bristol Myers Squibb, and GlaxoSmithKline, receiving grants; was an Advisory Board member and investigator for Genentech and Warner Chilcott, receiving grants and honoraria; was on the Advisory Board for Centocor receiving honoraria; was a speaker for Connetics receiving honoraria; and was a stockholder of Merck, owning stock and stock options. Carol Sieck, RN, MSN – the American Academy of Dermatology, Schaumburg, Illinois C. Sieck had no relevant conflicts of interest to disclose. Reva Bhushan, PhD - the American Academy of Dermatology, Schaumburg, Illinois Dr. Bhushan had no relevant conflicts of interest to disclose.
8 I. Grading and classification systems of adult acne and acne vulgaris in adolescents (11 to 21 years) to adults Many acne grading and classification systems have been proposed but at present there is not any one system universally accepted for assessing and grading acne severity. The grading and classification of acne is essential for the initial evaluation as a base of comparison during treatment and as a method to assess clinical trials. Acne severity is generally considered the most important patient characteristic used in determining individual treatment profiles. There are several grading/classification systems; most include lesion counting combined with some type of global severity assessment. Global evaluation takes into account the total impact of the disease. Grading systems are mainly used in clinical studies for the evaluation of acne treatment. Comparing therapeutic efficacy in different studies because of the lack of a validated classification system becomes difficult. It is important to standardize a specific and reproducible method to grade the severity of acne.
9 Table 1. Acne Grading/Classification Systems Level Author/Date/ of Evi- Type of scale Method of Assessment Conclusions study design dence Lehmann et al., J Am Acad Review of acne The target population for the review 250 papers were reviewed. There were more than II Dermatol 2002; 47: 231-40.2 clinical trials to was all patients with acne who did not 25 different methods of assessment of acne provide clinicians the have complicating co-morbidities such severity and 19 methods of counting lesions. There Methodological review of background needed as endocrinopathies. were many different ways the outcomes were literature and to interpret current expressed. There was no standard approach to recommendations. and future clinical The search was an expert-advised describing side effects, and no standard follow-up trials, and scientists a structured literature synthesis. times. basis for further The authors made recommendations for the studies. scientists for future clinical trials. Pochi et al., Global evaluation of Includes a total evaluation of lesions Panel recommendations: II J Am Acad Dermatol 1991; lesions. and complications; categorizes Dividing acne into 4 grades of severity was overly 24: 495-500.3 inflammatory lesions as mild, moderate simplistic. or severe. AAD Consensus conference It is the opinion of the consensus panel that acne on acne classification. grading can be accomplished by the use of a pattern-diagnosis system, which includes a global (total) evaluation of lesions and their complications. A strictly quantitative definition of acne severity cannot be established because of the variable expression of the disease. The clinical diagnosis of acne severity should be based on persistent or recurrent inflammatory nodules, papulopustular disease, ongoing scarring, drainage from lesions or the presence of sinus tracks and psychological factors. The consensus panel recommendations did not include non-inflammatory lesions.
10 Level Author/Date/ of Evi- Type of scale Method of Assessment Conclusions study design dence Doshi et al., Int J Dermatol Global Acne Grading The GAGS considers 6 locations on the This system is accurate and reproducible. Grading 1997; 36: 416-8.4 System (GAGS) face and chest/upper back, with factor with the GAGS system takes under 1 minute in an II for each location based on surface office setting. This paper proposed a new area, distribution and density of grading system called Global The authors suggest that time saved in grading can pilosebaceous units. Each of the six Acne Grading System be spent on counseling patients. locations is graded separately on a 0-4 (GAGS). scale. The global score is a summation Includes both inflammatory and non-inflammatory of each factor. lesions. Patients with numerous lesions confined to only 1 or 2 locations may end up with a lower total score and less severe classification than observed clinically.
11 Level Author/Date/ of Evi- Type of scale Method of Assessment Conclusions study design dence Allen and Smith, Arch Acne severity and Study 1. Physicians and research The authors concluded that acne grading scales Dermatol 1982; 118: 23-5.5 comedo grading scale technician evaluated 190 subjects - and papule counts are equally reproducible II including lesion male college students with acne at methods of grading inflammatory acne. The Randomized, double-blinded, counts. baseline and every two weeks comedo grading scale and comedo count are placebo-controlled trial to independently for 12 weeks. All equally reproducible. evaluate grading of acne subjects at each visit received a severity. This study does not include the back and chest. It severity grade, papule count, pustule uses half of the face for comedo and papule count and comedo grade. Comedo counts; both sides of the face for pustule counts counts were not performed in this and severity grades. study. Study 2. Physicians and research technician evaluated 141 male college students with acne at baseline and every two weeks independently for 10 weeks. All subjects at each visit received a severity grade, papule count, pustule count and comedo grade. Comedo count was also done. Severity scale ranges from 0 (no or few comedones) to 8 (all of facial area involved with large, prominent nodules). This study used the acne grading scale devised by Cook et al.7 Photographs of all the subjects were also used for evaluations. Cook et al., Arch Dermatol Acne severity grading Double-blinded, controlled clinical trial. The overall severity grade based on the 0 to 8 II 1979; 115: 571-5.7 scale. Ranges from 0 (no or few comedones) scale with the photographic reference standards to 8 (all of facial area involved with showed to be useful, reliable and sensitive. Double-blinded, placebo- large, prominent nodules). controlled trial to determine a The photograph creates a permanent record. method of grading of acne Uses photographic reference This method includes both inflammatory and non- severity. standards; photographs taken at each inflammatory lesions. visit become part of patient’s clinical record.
12 Level Author/Date/ of Evi- Type of scale Method of Assessment Conclusions study design dence Lewis-Jones and Finlay, Children’s This study was conducted on 169 The CDLQI is based on the Dermatology Life II Br J Dermatol 1995; 132: Dermatology Life children aged 3-16 years in a pediatric Quality Index (DLQI). 942-9.11 Quality Index dermatology clinic for 1 year. CDLQI provides a new technique for comparative (CDLQI). The aim of the study was to A 10-item questionnaire was used in purposes. create and validate a simple this study, similar to the adult DLQI This is a simple scoring method. This method can questionnaire to measure the questions. The questionnaire was be used for clinical trials and clinical practice. quality of life in children with designed for a child. It may sometimes skin disease. require parent’s help. Each question was scored individually. The CDLQI score was calculated by adding the scores of the 10 questions. Scores range from 0-30, 0 being the best score.
13 II. The role of microbiological and endocrine testing in evaluating patients with adult acne and acne vulgaris in adolescents to adults The most prevalent bacterium implicated in the clinical course of acne is Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium that normally inhabits the skin. Studies have found that in patients affected with acne, the population of P. acnes is higher than in the unaffected general population. Routine microbiologic testing is unnecessary in the evaluation and management of patients with acne. In patients who exhibit acne-like lesions, microbiologic testing may be helpful. Gram- negative folliculitis is an uncommon complication often observed following long-term systemic treatment of acne. Adrenal and gonadal androgens play an integral role in the pathogenesis of acne. Laboratory evaluation is indicated for those with acne and additional signs of androgen excess. Most people with acne have normal levels of androgenic hormones, despite the importance of androgens in this disorder. However, in females, acne severity and other virilizing signs are associated with subtle differences in circulating androgens. These include elevated free testosterone and DHEA-S, and reduced sex hormone-binding globulin (SHBG). Presently, routine endocrinologic testing is not indicated for the majority of patients with acne. Laboratory tests like free testosterone DHEA-S, LH and FSH may be helpful.
14 Table 2a. Microbiological Testing Level of Author(s)/Date/ Method of Study Population Results Conclusions Evi- Study Design Assessment dence Cove et al., Br J Dermatol Ages 18-20 years. Degree of acne This study showed no difference in There is no co-relationship II 1980; 102: 277-80.16 (1) 35 patients with was graded on a the number of microorganisms between the severity of acne 2 separate studies to determine mild acne and 35 simple scoring between mild and moderate study and the number of bacteria. levels of P. acnes and patients with system: groups. There is no direct relationship Micrococcaceae. moderate acne bacteria sampled There was no significant decrease in between the size of the were compared for using scrub bacterial populations after 3 months bacterial population and the (1) This study compared level of P. acnes method. of tetracycline. extent of acne severity. bacterial populations on and Micro- CFU (colony- There was not a significant decrease Greater numbers of bacteria foreheads of patients with mild coccaceae. forming units) were in the number of P. acnes or are not associated with to moderate acne. (2) 12 patients on determined by Micrococcaceae after the 3 months of increasing severity of acne. The (2) This study compared 250 mg of plating out ten-fold treatment of either bacterium. effectiveness of oral bacterial populations and acne tetracycline twice serial dilutions. There was a significant decrease in tetracycline in treating acne grade pre-treatment and post- daily for 3 months Colonies were the acne grade in patients after 4 cannot be explained by the treatment with tetracycline were compared for counted after 7 weeks of therapy. reduction in the number of 250 mg twice daily for 3 months. bacterial days or 48 hours viable bacteria. populations of P. anaerobically for P. acnes and acnes and Micrococcaceae. Micrococcaceae.
15 Level of Author(s)/Date/ Method of Study Population Results Conclusions Evi- Study Design Assessment dence Bojar et al., Drugs 1995; 49 86 volunteers with Used the scrub Significant reduction in the number of It was demonstrated that topical II Suppl 2: 164-7.17 mild/moderate technique. propionibacteria with both 1% 1% nadifloxacin is clinically as Double-blinded, randomized acne: nadifloxacin and 2% erythromycin effective as and clinical study to assess 1% 1% nadifloxacin after 12 weeks. microbiologically superior to 2% nadifloxacin compared to 2% (n=43); The carriage of Micrococcaceae was erythromycin. erythromycin to determine the 2% erythromycin reduced in the nadifloxacin treated Widespread incidence of susceptibility of all cutaneous (n=43). group only. erythromycin-resistant microorganisms isolated before propionibacteria may limit future and after treatment of patients Minimum inhibitory concentration (MIC)values were determined. usefulness of erythromycin as a with mild/moderate facial acne. therapeutic agent. After 12 weeks of treatment with nadifloxacin, no resistant bacteria were isolated. Erythromycin-resistant P. acnes and erythromycin-resistant Micrococcaceae were isolated from 27.9% and 97.7% erythromycin- treated subjects respectively.
16 Level of Author(s)/Date/ Method of Study Population Results Conclusions Evi- Study Design Assessment dence Eady et al., Br J Dermatol 51 patients on oral Bacterial samples 42-51 bacteria were isolated from the This study showed that the use II 1989; 121: 51-7.18 erythromycin and were obtained by skin surface of both erythromycin- of oral erythromycin has Controlled study to determine 53 patients on detergent scrub and clindamycin-treated patients developed more resistant the incidence of erythromycin- topical clindamycin technique. compared to 3% of controls. bacteria than the use of topical resistant propionibacteria in were included in the MIC of each Patients responding to erythromycin clindamycin. various groups treated with study; 100 control antibiotic was carried less erythromycin-resistant This study suggests that use of antibiotics for acne. subjects. recorded as the bacteria compared to patients who oral erythromycin should be lowest did not respond or those who had limited to patients with no concentration relapsed. previous exposure to the drug yielding no growth. There was an increased incidence of and therapy should be erythromycin-resistant bacteria in discontinued after 6 months to clindamycin patients who had used allow any resistant bacteria to erythromycin previously compared to be overgrown by sensitive those who received no erythromycin. bacteria. The use of benzoyl peroxide alone for a short period may eradicate resistant bacteria.
17 Level of Author(s)/Date/ Method of Study Population Results Conclusions Evi- Study Design Assessment dence Harkaway et al., Br J Dermatol 60 subjects (30 Cultures obtained After 12 weeks of treatment with the These results showed that II 1992; 126: 586-90.19 male, 30 female) from the forehead erythromycin group, the aerobic flora topical erythromycin excretes a ages 18-30 years. at 0, 4, 8, 12 and dominated by S. epidermis (2/3) selective pressure. Controlled trial to examine the 2% erythromycin 16 weeks of which was completely erythromycin- Erythromycin-resistant strains development of antibiotic (n=20) treatment. resistant. were suppressed the same as resistance in coagulase- 5% benzoyl There was also an increased sensitive strains. negative staphylococci during peroxide (n=20) resistance to tetracycline and The use of benzoyl peroxide treatment with of erythromycin, 5% benzoyl clindamycin. interferes with the selection or benzoyl peroxide or combination peroxide + 3% the induction of erythromycin- of the two for 16 weeks. erythromycin (n=20) Treatment with benzoyl peroxide and resistant bacteria. the combination of benzoyl peroxide + erythromycin resulted in significant decrease in the number of aerobic bacteria without any change in resistance pattern to erythromycin or other antibiotics.
18 Table 2b. Endocrine testing Level of Author(s)/Date/ Study Population/ Method of Assessment Results Conclusion Evi- Study Design Intervention dence Lawrence et al., Moderate to severe acne Testosterone concentration 29% of women with acne had elevated This study shows Clin Endocrinol (simple acne) (n=24); was measured by testosterone levels and 41% had free testosterone that a deficiency in I (Oxf) 1981; 15: 87- chromatography and RIA. elevated values. SHBG and an Moderate to severe acne 91.20 elevation in derived and with hirsutism and/or Testosterone concentrations were higher in both free testosterone is Controlled cohort trial irregular menstrual cycles acne groups compared with controls. a frequent finding in to determine levels of (complicated acne) There was no correlation between the women with severe SHBG, testosterone (n=23); concentration of testosterone and SHBG. acne. and free testosterone Unaffected women as in women with controls (n=15); moderate to severe acne and hirsutes. No patients or controls were receiving oral contraceptives. Lucky et al., J 871 fourth and fifth grade The degree of facial acne No racial differences in acne or hormonal levels The results suggest Pediatr 1997; 130: girls were in this study was classified annually as were found. that the early I 30-9.22 Black (n=439) mild, moderate or severe. development of There were more comedones at early age in girls White (n=432) comedonal acne 5-year longitudinal Blood samples were obtained who later developed severe acne. may be the best cohort study to Subjects were placed in 3 at first, third and fifth years of Those who developed severe inflammatory acne predictor of later determine which groups based on severity study. had more inflammatory and comedonal lesions more severe factors in early of acne at year 5. Facial comedonal and from -36 months to +36 months from menarche disease. pubertal girls might Mean acne scores, level nodular inflammatory lesions compared with girls who developed mild acne. be predictive of later The DHEAS of sex steroid hormones were recorded in the following severe facial acne. Girls who developed mild acne had significantly concentration is and testosterone-estrogen way: later menarche than girls who developed severe higher in those girls binding globulin (TEBG) Mild – up to 10 lesions; given acne. destined to have were compared among a numerical value of 5. severe acne. the 3 groups. Girls who developed severe comedonal acne had Moderate – 11-25 lesions; significantly increased DHEAS and somewhat given a numerical value of 17. increased testosterone and free testosterone. Severe – more than 25 There were no differences in estradiol, lesions; given a numerical progesterone and TEBG. value of 25.
19 III. Topical agents in the treatment of adult acne and acne vulgaris in adolescents and adults The effectiveness of topical therapy for acne is well-known. Topical retinoids are the most effective comedolytic agents and since the microcomedo is thought to be the precursor of all other acne lesions, they are appropriate for comedonal and inflammatory acne. The effectiveness of topical retinoids (adapalene, tazarotene, tretinoin and isotretinoin) is well documented. Topical retinoids such as tretinoin and adapalene correct abnormalities in follicular keratinocytes. Topical isotretinoin is not available in the United States. Salicylic acid and azelaic acid are weaker comedolytic agents, but may be useful when retinoids are not tolerated. Topical antimicrobials include benzoyl peroxide and topical antibiotics. Topical antibiotics such as clindamycin, tetracycline, and erythromycin are bacteriostatic for P. acnes and are effective for mild to moderate inflammatory acne. Benzoyl peroxide is bactericidal and improves both inflammatory and non-inflammatory lesions. It is an oxidizing agent that works by introducing oxygen into follicles, which then kills P. acnes. This is why P. acnes does not develop resistance to benzoyl peroxide. In addition, there is increasing resistance to antibiotics by P. acnes. Combining benzoyl peroxide with antibiotics reduces or eliminate this resistance. Sulfur, resorcinol, aluminum chloride and sodium sulfacetamide are weaker antimicrobial agents which can be useful in selected circumstances. Topical zinc alone is ineffective but may enhance the activity of antimicrobial agents. Combination therapy, involving benzoyl peroxide or retinoids and oral antibiotics, is effective treatment for acne.
20 Table 3a. Use of Topical Retinoids Level of Author(s)/Date/ Study Population/ Method of Evidence Study Design Intervention Assessment Results Conclusions Christiansen et al., 256 patients with acne were The effect of There was a statistically significant Tretinoin is very Dermatologica 1974; 148: randomized to receive 1 of the treatment was reduction in comedones and papules successful in reducing I 82-9.25 following daily for 12 weeks: determined by compared to placebo. comedones and counting the papules. Double-blinded, Tretinoin 0.02% cream, 0.05% cream had a quicker onset of comedones, randomized clinical trial to Tretinoin 0.05% cream, action and had quantitatively greater A very high rate of papules, pustules evaluate the effect of Placebo vehicle control. effect than 0.02% cream. adverse effects was and cysts and topical tretinoin in patients seen. Patients were evaluated at scoring each type of Pustule and cyst counts were not with of acne. baseline, 2, 4, and 8 weeks of acne lesion at significantly different for all the 3 treatment. baseline and at 2, 4, groups. and 8 weeks. 231 patients completed the Local adverse reactions such as study. erythema and peeling were noted by 40% of placebo group, and 81% and 86% in the 0.05% and 0.02% groups respectively. Chalker et al., J Am Acad 313 subjects (age range 13-30 Facial inflammatory At 8 weeks, the non-inflammatory 0.05% isotretinoin gel Dermatol 1987; 17: 251- years) with at least 12 and non- lesion count was significantly is effective in the I 4.28 inflammatory lesions, 12 non- inflammatory reduced in the isotretinoin-treated treatment of acne. inflammatory lesions, and no lesions were group compared to the placebo Multicenter, randomized, More adverse effects more than 3 facial nodulocystic counted and overall group. double-blinded, controlled were observed in the lesions. acne grade clinical trial to determine Inflammatory and non-inflammatory treated group than in assigned using the efficacy of 0.05% 268 subjects completed the lesion counts were reduced by 55% the placebo group. Cook’s et al. topical isotretinoin gel in the study. and 46% respectively in the treated method (0-8). 7 treatment of acne group compared to 25% and 14% Subjects were randomized to compared its vehicle. reduction in the placebo group. receive 0.05% isotretinoin or vehicle gel twice daily for 12-14 Mean acne severity grade was weeks. reduced by 40% after 12 weeks Subjects were evaluated at 0, 2, isotretinoin treated vs. placebo 5, 8, 10-11, and 12-14 weeks of peeling: 71% 51% treatment. erythema: 76% 62%
21 Level of Author(s)/Date/ Study Population/ Method of Evidence Study Design Intervention Assessment Results Conclusions Shalita et al., Cutis 1999; 446 subjects (14-44 years) with Percentage of There was significant reduction in Tazarotene 0.1% and 63: 349-54.38 mild to moderate facial acne change was non-inflammatory and total lesion 0.05% aqueous gels I were randomized to receive determined by count at week 12. were safe and effective Multicenter, double-blinded, tazarotene 0.1% gel, tazarotene lesion count and in reducing acne lesion randomized, parallel-group, 0.1% gel tazarotene had of 68%, 0.05% gel, or vehicle-only global evaluation count. controlled trial to evaluate 0.05% gel tazarotene had 51% and placebo daily for 12 weeks. response to the safety and efficacy of placebo had 40% reduction of non- Both concentrations Patients were evaluated at 0, 4, treatment methods. tazarotene in the treatment inflammatory and total lesion counts. had acceptable 8, and 12 weeks of treatment. of acne. Pharmacokinetics tolerability. 333 subjects completed the and safety analyses There were few study. were conducted. adverse events. Lucky et al., J Am Acad 215 patient study; patients were Efficacy The efficacy of both treatments was Both treatments Dermatol 1998; 38: S17- randomized to receive any one assessments were comparable and more effective than demonstrated I 23.41 of the treatments. measured by lesion the control vehicle. comparable efficacy. counts and Physical Multicenter, double-blinded, The formulation tested ethanol The gel containing polyolprepolymer- Global Evaluation randomized, parallel-group, gel containing 0.025% tretinoin 2 caused significantly less peeling (PGE). vehicle-controlled trial to gel and polyolprepolymer-2, (n- and drying than the commercially- evaluate the safety and 71) vehicle control (n-70) and available gel by day 84 of the study. efficacy of tretinoin with commercially available 0.025% polyolprepolymer-2 tretinoin gel (n-72). compared with Evaluations were performed at commercially available day 0, 7, 14, 28, 56 and 84. 0.025% tretinoin gel in the treatment of acne.
22 Table 3b. Use of Benzoyl Peroxide Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Belknap, Cutis 1979; 23: 69 patients ages 15-30 with Patients were A significantly higher percentage of The benzoyl peroxide 856-9.42 acne. evaluated by total patients in the benzoyl peroxide group showed I lesion counts. group exhibited excellent overall improvement earlier Randomized, controlled Patients were randomly response compared to the retinoic than the retinoic acid clinical trial to compare the assigned to receive 0.05% Overall evaluation acid group. group. effectiveness of topical vitamin A acid cream or benzoyl of clinical response benzoyl peroxide and peroxide 5% gel treatments for 8 was done for each Both treatment groups were effective Statistically, there was tretinoin in the treatment of weeks. patient. in reducing lesions. no significant acne. difference between the Subjects were evaluated at There was significantly less peeling two drugs after 8 baseline and after 2, 4, and 8 in the benzoyl peroxide compared to weeks. weeks for the response to the the vitamin A acid group after 4 treatments. This study should weeks. have used proper controls especially because the trial is comparing gel versus cream. Each treatment should have had its respective vehicle as a control. Schutte et al., Br J 65 patients ages 17-23 years Patients were The control preparation had no effect This study indicates Dermatol 1982; 106: 91- with acne. evaluated by lesion on the number of papules or that 5% benzoyl I 4.48 count before the pustules. peroxide lotion does Patients were randomly start of therapy and have a rapid effect in A multicenter, randomized, assigned 5% benzoyl peroxide There was a significant reduction of after 5 days after resolving inflamed double-blinded, placebo- lotion or placebo/base. lesions seen in the treatment group treatment. lesions. controlled study to and there was significantly reduced determine the effect of a Facial fluorescence facial prophyrin fluorescence. The mechanism of 5% benzoyl peroxide lotion by ultraviolet action of benzoyl in the treatment of acne photography was peroxide lotion should compared to its base. done. be studied. The degree of Larger populations of redness and scaling patients are required was recorded. in studies to prove safety and efficacy.
23 Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Smith et al., Cutis 1980; 59 patients (mean age 20 years, Patients were Benzoyl peroxide treated group had This study showed 25:90-2.50 range 18-30) with at least 10 evaluated for an excellent response compared to that 20% benzoyl I inflammatory lesions and 3 or efficacy by counting the placebo group. peroxide is effective in A multicenter, randomized, fewer nodulocystic lesions were all lesions on the reducing the lesions of double-blinded, controlled Redness and peeling were observed selected for the study. face. acne. study to evaluate the effect in both groups but more in the active of 20% benzoyl peroxide The patients were randomized to Erythema and treated group. There was some lotion in the treatment of receive 20% benzoyl peroxide peeling were also improvement in the acne. lotion or placebo lotion base assessed. placebo group also. twice daily for 12 weeks: Study with a larger Benzoyl peroxide 20% lotion number of population (n=29); is required to prove safety and efficacy. Placebo control lotion (n=30). Subjects were evaluated at baseline and every 2 weeks.
24 Table 3c. Use of Topical Antibiotics Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Bernstein and Shalita, J 348 patients (age range 13-30 Efficacy was There was a significant reduction in Topical erythromycin is Am Acad Dermatol 1980; years) with inflammatory acne assessed by total papulopustule count in the treatment effective in the I 2: 318-21.52 were randomized to receive 2% lesion count and group compared to the placebo treatment of erythromycin solution (n=178) or papulopustule group. papulopustular acne. Randomized, placebo- placebo control (n=170) twice count. controlled trial to evaluate Comedones and cysts and total Vehicle base daily for 8 weeks. the effectiveness of topical Physician global lesions were not significantly different preparation contained 2% erythromycin compared Patients were evaluated at severity rating was after 8 weeks in both groups. alcohol and to its vehicle in the baseline and after 2, 4, 8 and 12 assessed at polyethylene which are Fewer adverse effects were noted in treatment of acne. weeks. baseline and after local irritants. the active preparation compared to 2, 4, and 8 weeks of the placebo group. treatment. Jones and Crumley, Arch 175 subjects (ages 12 years and Efficacy was The total count of inflammatory Topical 2% Dermatol 1981; 117: 551- over) with inflammatory acne assessed by total pustules was significantly reduced erythromycin I 3.53 were randomized to receive 2% lesion count and after therapy in the 2% erythromycin demonstrated erythromycin (n-90) solution or inflammatory group. significantly better Randomized, double- placebo control (n-85) twice daily papulopustule results than the blank blinded, placebo-controlled After 12 weeks, there was a 56% for 12 weeks. count. vehicle. trial to evaluate the papule reduction in the treated group effectiveness of topical 2% compared to 33% in the blank Study confirms the erythromycin compared to vehicle group. effectiveness of topical its vehicle in the treatment erythromycin in the 62% of subjects in the topical 2% of acne. treatment of acne. erythromycin group had good to excellent response compared to 27% Adverse effects were in the blank vehicle. similar in both groups.
25 Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Lesher et al., J Am Acad 225 subjects (range 14-30 years) Facial inflammatory Erythromycin group had 46% mean This study showed that Dermatol 1985; 12: 526- with at least 10 inflammatory lesions were lesion count reductions compared to 2% erythromycin I 31.55 lesions, 10 non-inflammatory counted and overall 19% in the placebo group after 12 ointment was lesions, and no more than 3 severity grade was weeks of treatment. significantly more Multicenter, double-blinded, nodulocystic lesions were assessed using effective than its controlled clinical trial to Topical 2% erythromycin group had a randomized to receive topical Cook’s et al. 7 placebo control in assess the effectiveness of 40% reduction in mean acne severity 2% erythromycin ointment grading scale for decreasing topical 2% erythromycin in grade compared to 23% reduction for (n=112) or placebo vehicle acne severity 0-8 inflammatory acne the treatment of acne. the vehicle group. control (n=113) twice daily for 12 scale. lesions. weeks. No significant differences were noted between groups for side effects. Subjects were evaluated at baseline and after 2, 4, 8, 10, and 12 weeks of treatment. Pochi et al., Cutis 1988; 187 patients (range 13-48 years) Facial lesions were 2% erythromycin gel proved to be 2% erythromycin gel 41: 132-6.56 with mild to moderate acne were counted at each significantly more effective than the was effective and well I randomized to receive topical visit and a grade placebo in the reduction of the tolerated in the Multicenter, double-blinded, 2% erythromycin gel (n=93) was based on number of inflammatory and non- treatment of acne. controlled clinical trial to compared to placebo vehicle percentage of inflammatory lesions. assess the effectiveness of A strong placebo effect control (n=94) twice daily for 8 overall topical 2% erythromycin gel After 8 weeks, 60% of the treated was noted. weeks. improvement. compared to its vehicle in group had a good to excellent the treatment of acne. Patients were evaluated at Adverse effects response compared to 36% of the baseline, 4 and 8 weeks after were evaluated on vehicle group. treatment. mild-to-severe Side effects were generally mild and scale. transient, with no significant differences noted between the groups. Dobson and Bellknap, J 253 patients were randomized to Total lesion count The reduction in the number of This study Am Acad Dermatol 1980; receive either topical 1.5% was used for inflammatory lesions, papules, and demonstrated a I 3: 478-82.57 erythromycin solution (n=127) or evaluation of the pustules was significantly greater in statistically significant placebo vehicle control (n=126) treatment. the erythromycin treated group. benefit in the patients Multicenter, double-blinded, twice daily for 12 weeks. with acne receiving controlled clinical trial to Global physician The global evaluation of the clinical 1.5% erythromycin assess the effectiveness of Patients were evaluated at evaluation was also response correlated well with the solution compared to topical 1.5% erythromycin baseline and at 2, 4, 8, 10 and performed after 2, reduction in the lesion counts. its vehicle. solution compared to its 12 weeks of treatment. 4, 8, 10 and 12 vehicle in the treatment of weeks of treatment. No serious or acne. irreversible adverse effects were seen.
26 Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Mills et al., Acta Derm 208 patients were randomized to Acne severity was The prevalence of erythromycin Resistance Venereol 2002; 82: 260- receive either topical 2% evaluated by total coagulase-negative staph on the development was I 58 5. erythromycin gel or placebo lesion count and the face was high at 87% at baseline. At confined to the vehicle control twice daily for 12 use of photographs. the end of 12 weeks of erythromycin, macrolide class of Randomized, single- weeks. coagulase-negative staph increased antibiotics. blinded, controlled clinical Bacteriologic to 98% in the erythromycin-treated trial to assess the Patients were evaluated at samples were also No anti-acne efficacy group. effectiveness of topical baseline and after 2, 4, 8, 10 and assessed at was observed. 2% erythromycin gel 12 weeks of treatment. baseline and at 4, Nearly all bacteria were highly This suggests that 12, 16 and 24 resistant (MIC > 128ug/ml). compared to its vehicle in To study the regression of any topical treatment with weeks of treatment. the treatment of acne and bacteriologic changes at 12 erythromycin may to determine the bacterial weeks, the patients on active result in higher resistance associated with treatment were switched over to carriage rates and its use. placebo. The patients on dissemination of placebo continued their placebo erythromycin-resistant treatments. S. aureus from nares. Leyden et al., J Am Acad 102 patients (14 to 34 years) Acne severity was Both medications significantly Topical antibiotics Dermatol 1987; 16: 822- were randomized to receive evaluated by total reduced the number of papules and have advantages over I 7.62 either topical 2% erythromycin facial lesion count. open and closed comedones. systemic therapy gel or 1% clindamycin phosphate because of direct local Multicenter, randomized Global physician There was no significant difference of solution twice daily for 12 weeks. application on the parallel-group clinical trial evaluation was also lesion count detected between the affected areas of the to assess the effectiveness Patients were evaluated at performed. treatment groups after 8 and 12 skin and a resultant of topical 2% erythromycin baseline and at 4, 8, and 12 weeks of treatment. decrease in systemic in the treatment of acne. weeks of treatment. At the end of 12 weeks, about 50% side effects. of patients had a good to excellent response. Side effects included peeling, erythema, burning, and itching.
27 Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Becker et al., Arch 413 patients (14-29 years) with Acne severity was 86% of patients in the clindamycin Both clindamycin Dermatol 1981; 117: 482- acne were randomized to evaluated by hydrochloride group, 77% of the phosphate and I 5.65 receive either 1% clindamycin counting pustules, clindamycin phosphate group, and clindamycin phosphate solution (n=123), 1% papules, and 56% of the placebo group reported hydrochloride Multicenter, double-blinded, clindamycin hydrochloride nodules over the improvement. treatment had controlled clinical trial to solution (n=120) or placebo entire face. significant reduction in evaluate the effectiveness Side effects included peeling, vehicle control (n=112) twice lesion count when of topical clindamycin Mean change in erythema, burning, and itching. daily for 8 weeks. compared to baseline hydrochloride and lesion count in each and placebo group. clindamycin phosphate Patients were evaluated at group was reported. compared to placebo in the baseline and after 2, 4, 6, and 8 treatment of acne. weeks of treatment.
28 Table 3d. Use of Other Topical Agents Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Zouboulis et al., Br J 209 patients (aged 14-26 years) Acne severity was At week 12 there was significantly A single daily topical Dermatol 2000; 143: 498- were randomized to receive evaluated by greater reduction of inflamed lesions application of 1% I 505.70 either CTG once (n=104) or CLN counting open and from baseline to week 12 in the CTG clindamycin/0.025% (n=105) twice daily for 12 weeks.closed comedones, group compared to the CLN group. tretinoin gel formulation Multicenter, randomized, pustules, papules, was superior to 1% single-blinded, controlled Patients were evaluated at 50% reduction in total lesion count and nodules. Acne clindamycin lotion clinical trial to compare the baseline and after 2, 4, and 8 was observed by day 60 in 77% of severity grade by applied twice daily for efficacy and safety of 1% weeks of treatment to assess the patients on CTG compared with 56% Cook et al. 7 was the reduction of acne. clindamycin/0.025% efficacy of both treatments. receiving CLN. also used. tretinoin gel formulation CTG had a rapid effect Both treatments were well tolerated. (CTG) to 1% clindamycin on the onset of lotion (CLN) for the improvement treatment of acne. compared to CLN. Chalker et al., J Am Acad 165 subjects (age 15-30 years) Patients were There was no statistically significant The combination of 3% Dermatol 1983; 9: 933-6.72 with grade 3 acne on the Cook et evaluated at each difference between the groups for the erythromycin/ I al. scale7 were randomized to visit by lesion count. first 8 weeks. 5% benzoyl peroxide Randomized, double- receive one of the following gel was more effective blinded, placebo-controlled Grading method of At week 10, the active groups were topicals twice daily for 10 wks. than the individual clinical trial to determine if Cook et al.7 was statistically different. constituents or topical erythromycin and 3% erythromycin/5% benzoyl also used. Mean comedonal and pustule counts placebo. benzoyl peroxide were peroxide gel (n=44); were reduced in all active treatment effective in the treatment of 5% benzoyl peroxide gel (n=44); The most dramatic groups. acne. This study also 3% erythromycin gel (n=45); effect was on compared the combination placebo gel base, vehicle control Combination therapy consistently combined inflammatory to its vehicle base. (n=44). improved papule and inflammatory lesions (papules and lesion counts. pustules). All patients were evaluated at baseline and every 2 weeks for Adverse effects were not reported. 10 weeks.
29 Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Tschen et al., Cutis 2001; 287 patients (ages13-30 years) Total improvement All study groups demonstrated There was greater 67: 165-9.73 with moderately severe acne in lesion counts significant improvement from efficacy obtained with I were randomly selected to from baseline was baseline. the combination Randomized, double- receive one of the following monitored. therapy and it was as blinded, parallel-group The number of lesions was reduced topicals twice daily for 10 weeks: safe as the other clinical trial to evaluate the Patients’ global to a greater extent in patients treated treatments. effectiveness of benzoyl (1) 5% benzoyl peroxide/1% evaluations were with the combination of 5% benzoyl peroxide and clindamycin clindamycin phosphate gel measured at week peroxide/1% clindamycin phosphate separately and in (n=95); 10. gel compared to the other combination. (2) 5% benzoyl peroxide gel treatments. (n=95); Some patients reported adverse (3) 1% clindamycin phosphate effects. gel (n=49); (4) placebo control (n=48). Safety and efficacy was evaluated at baseline and at 2, 4, 6, 8, and 10 weeks of treatment. Lookingbill et al., J Am 334 subjects (ages 13-30 years) The study evaluated All three active treatments were Topical clindamycin/ Acad Dermatol 1997; 37: were randomly assigned to lesion counts, significantly superior to the placebo benzoyl peroxide I 590-5.75 receive one of the following assessed global in global improvement and in combination gel is well- topicals once daily: responses and reducing both inflammatory and non- tolerated and superior Multicenter, randomized, irritant effects. inflammatory lesions. to the other treatments. double-blinded, placebo 1% clindamycin phosphate/5% controlled clinical trial to benzoyl peroxide gel; The combination gel was significantly This has an advantage determine the safety and 1% clindamycin phosphate gel; superior to the two individual agents. over the combination of efficacy of combination 5% benzoyl peroxide gel; erythromycin/benzoyl clindamycin/benzoyl placebo vehicle gel control. peroxide gel because it peroxide when compared is not required to be Safety and efficacy evaluations with clindamycin, benzoyl refrigerated. were performed at baseline and peroxide or placebo at 2, 5, 8 and 11 weeks. separately.
30 Level of Author(s)/Date/ Study Population/ Method of Results Conclusions Evidence Study Design Intervention Assessment Hjorth and Graupe, Acta First study had subjects with Total lesion count Both studies demonstrated significant 20% azelaic acid Derm Venereol Suppl moderate to severe acne. was monitored at clinically relevant reduction in the cream is an effective I (Stockh) 1989; 143: 45- monthly intervals. initial number of lesions during treatment for Patients were randomized to 8.79 therapy. inflammatory acne and receive one of the following is well tolerated. Multicenter, randomized, topicals twice daily: No significant difference in either double-blinded, placebo- treatment was observed after 5 20% azelaic acid cream (n-164); controlled clinical trial to months. placebo capsules (n-126). compare the 20% azelaic acid cream with its base Second study had patients and compare it to oral receiving oral tetracycline tetracycline treatment. 1-g/day for the first month, 0.75-g/day for the second month and 0.5-g/day for the third month (n-169); and cream base (n- 135). Patients with moderate acne were treated for 5 months and patients with severe acne were treated for 6 months.
31 IV. The efficacy and safety of systemic antibacterial agents in the treatment of adult acne and acne vulgaris in adolescents to adults Oral antibiotic therapy has been used for the treatment of moderate and severe acne for many years. Systemic antibiotics have been shown to be effective as monotherapy and also in combination with other therapies. Many clinical trials have shown the effectiveness of antibiotics like tetracyclines, erythromycin, doxycycline, minocycline, trimethoprim with or without sulfamethoxazole and azithromycin. These systemic antibiotics suppress P. acnes growth, and because of this, there is a decrease in the production of inflammatory factors. The prevalent and long-term use of antibiotics has led to the emergence of resistance to P. acnes. To minimize the development of bacterial resistance, antibiotics should be used for a short period of time and combination therapy should be used.
32 Table 4a. Use of Tetracyclines Level of Author(s)/Date/ Study Population/ Method of Evidence Study Design Intervention Assessment Results Conclusion Smith et al., South Med 135 subjects (age 18-35 years) All subjects were Oral and systemic groups both had This study confirms J 1976; 69: 695-7.90 with acne grade 2 and over, evaluated with achieved statistically significant that tetracycline in I according to Cooke et al., 7 visual grading and improvement after 4, 7, 10, and 12 oral dose of Randomized, double- were randomized to receive photographs to weeks of treatment compared to 0.5-gm/day is blinded study to evaluate one of the following: assure critical placebo. effective treatment for (1) patients treated with evaluation. acne after 4 weeks of topical and oral placebo; (1) topical placebo and The topical treatment was effective, therapy. (2) patients receiving systemic placebo treatment; but somewhat less than the oral topical placebo and tetracycline, but significantly better systemic tetracycline (2) topical placebo/systemic than the placebo after seven weeks 0.5-gm/day; tetracycline 0.5-gm/day; of treatment. (3) patients treated with a (3) new topical tetracycline and Slight yellowish discoloration was new topical tetracycline oral placebo. observed in 25% of subjects. preparation and an oral placebo. New topical tetracycline consists of tetracycline hydrochloride 0.22% with 4- epi-tetracycline 0.28% and n- decylmethyl sulfoxide in ethanol/water; this was applied twice daily. Gratton et al., J Am 305 patients (age range 18-35 Severity was Both oral tetracycline and topical Both oral tetracycline Acad Dermatol 1982; 7: years) with moderate to severe defined by papule, clindamycin significantly reduced and topical I 50-3.91 acne were randomized to pustule and the papule and pustule counts clindamycin are receive one of the following nodulocystic lesion compared to placebo. effective in the A multicenter, three groups twice daily for 8 count. treatment of moderate randomized, double- The most frequent side effect weeks: to severe acne. blinded, placebo- Efficacy was reported in the patients was controlled study to (1) 250 mg oral tetracycline evaluated with diarrhea. compare oral tetracycline, hydrochloride (n=103); lesion count and topical clindamycin and physicians’ overall (2) 1% topical clindamycin placebo for treatment of evaluation of phosphate solution (n=97); acne. therapy. (3) placebo (n=97). Subjects were evaluated at baseline and after 2, 4, 6, and 8 weeks.
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