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Clin Evid (Online). 2011; 2011: 1714.
Published online Jan 5, 2011.
PMCID: PMC3275168
Acne vulgaris
Sarah Purdy, MD MPH MRCGP, Consultant Senior Lecturer in Primary Health Care# and David de Berker, Consultant Dermatologist#
Sarah Purdy, University of Bristol, Bristol, UK;
#Contributed equally.
SP is the co-author of one cohort study referenced in this review. DdB declares that he has no competing interests.
Introduction
Acne vulgaris affects over 80% of teenagers, and persists beyond the age of 25 years in 3% of men and 12% of women. Typical lesions of acne include comedones, inflammatory papules, and pustules. Nodules and cysts occur in more severe acne and can cause scarring and psychological distress.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of topical and oral treatments in people with acne vulgaris? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: topical treatments (adapalene, azelaic acid, benzoyl peroxide, clindamycin, erythromycin [alone or plus zinc]; isotretinoin, tetracycline, tretinoin); and oral treatments (doxycycline, isotretinoin, lymecycline, minocycline, oxytetracycline, tetracycline).
Acne vulgaris affects over 80% of teenagers, and persists beyond the age of 25 years in 3% of men and 12% of women.
  • Typical lesions of acne include comedones, inflammatory papules, and pustules. Nodules and cysts occur in more severe acne, and can cause scarring and psychological distress.
Topical benzoyl peroxide should be considered as first-line treatment in mild acne.
  • Topical benzoyl peroxide and topical azelaic acid reduce inflammatory and non-inflammatory lesions compared with placebo, but can cause itching, burning, stinging, and redness of the skin.
Topical antibiotics such as clindamycin and erythromycin (alone or with zinc) reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions. Tetracycline may reduce overall acne severity.
  • Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.
  • Tetracyclines may cause skin discoloration, and should be avoided in pregnant or breastfeeding women.
  • Topical preparations of tretinoin, adapalene, and isotretinoin may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.
Oral antibiotics (doxycycline, erythromycin, lymecycline, minocycline, oxytetracycline, and tetracycline) are considered useful for people with more severe acne, although we don't know for sure whether they are effective.
  • Oral antibiotics can cause adverse effects such as contraceptive failure.
  • Minocycline has been associated with an increased risk of systemic lupus erythematosus and liver disorders.
  • Oral isotretinoin has been associated with skin problems, change in liver function, teratogenesis, and psychiatric disorders.
Definition
Acne vulgaris is a common inflammatory pilosebaceous disease characterised by comedones; papules; pustules; inflamed nodules; superficial pus-filled cysts; and (in extreme cases) canalising and deep, inflamed, sometimes purulent sacs.[1] Lesions are most common on the face, but the neck, chest, upper back, and shoulders may also be affected. Acne can cause scarring and considerable psychological distress.[2] It is classified as mild, moderate, or severe.[1] Mild acne is defined as non-inflammatory lesions (comedones), a few inflammatory (papulopustular) lesions, or both. Moderate acne is defined as more inflammatory lesions, occasional nodules, or both, and mild scarring. Severe acne is defined as widespread inflammatory lesions, nodules, or both, and scarring, moderate acne that has not settled with 6 months of treatment, or acne of any "severity" with serious psychological upset. This review does not cover acne rosacea, acne secondary to industrial occupations, and treatment of acne in people under 13 years of age.
Incidence/ Prevalence
Acne is the most common skin disease of adolescence, affecting over 80% of teenagers (aged 13–18 years) at some point.[3] Estimates of prevalence vary depending on study populations and the method of assessment used. Prevalence of acne in a community sample of 14- to 16-year-olds in the UK has been recorded as 50%.[4] In a sample of adolescents from schools in New Zealand, acne was present in 91% of males and 79% of females, and in a similar population in Portugal the prevalence was 82%.[5] [6] It has been estimated that up to 30% of teenagers have acne of sufficient severity to require medical treatment.[7] Acne was the presenting complaint in 3.1% of people aged 13 to 25 years attending primary care in a UK population.[8] Overall incidence is similar in both men and women, and peaks at 17 years of age.[7] The number of adults with acne, including people over 25 years, is increasing; the reasons for this increase are uncertain.[9]
Aetiology/ Risk factors
The exact cause of acne is unknown. Four factors contribute to the development of acne: increased sebum secretion rate, abnormal follicular differentiation causing obstruction of the pilosebaceous duct, bacteriology of the pilosebaceous duct, and inflammation.[10] The anaerobic bacterium Propionibacterium acnes plays an important role in the pathogenesis of acne. Androgen secretion is the major trigger for adolescent acne.[11]
Prognosis
In 3% of men (95% CI 1.2% to 4.8%) and 12% of women (95% CI 9% to 15%), facial acne persists after the age of 25 years,[12] and in a few people (1% of men and 5% of women) acne persists into their 40s.[9]
Aims of intervention
To reduce the number of non-inflammatory and inflammatory lesions and scarring, with minimal adverse effects of treatment.
Outcomes
Acne severity: as measured by number of non-inflammatory lesions (comedones), number of inflammatory lesions (papules, pustules, and nodules), severity scores and scales; patient perception of improvement; psychological distress; quality of life; and adverse effects of treatment. Commonly used severity scores and scales include: Leeds Acne Grading Technique, which involves counting and categorising lesions into inflammatory and non-inflammatory;[13] Cook's acne grading scale method, which uses photographs to document severity of acne and grades severity from 0 (least severe) to 8 (most severe);[14] and the Pillsbury Scale, which classifies acne from 1 (mildest) to 4 (severe).[15]
Methods
Clinical Evidence search and appraisal February 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2010, Embase 1980 to February 2010, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. The review by Lehmann et al[16] included both randomised and non-randomised controlled trials, and did not state in all cases whether trials were randomised. We have focused on reporting results for RCTs only and, where necessary, have analysed original papers to ascertain whether trials were randomised. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table
Table
GRADE Evaluation of interventions for Acne vulgaris.
Glossary
Low-quality evidenceFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidenceFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidenceAny estimate of effect is very uncertain.

Notes
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Sarah Purdy, University of Bristol, Bristol, UK.
David de Berker, Bristol Dermatology Centre, Bristol, UK.
1. Healy E, Simpson N. Acne vulgaris. BMJ1994;308:831–833. [PMC free article] [PubMed]
2. Mallon E, Newton JN, Klassen A, et al. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol1999;140:672–676. [PubMed]
3. Chu TC. Acne and other facial eruptions. Medicine 1997;25:30–33.
4. Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol2001;145:274–279. [PubMed]
5. Pearl A, Arroll B, Lello J, et al. The impact of acne: a study of adolescents' attitudes, perception and knowledge. N Z Med J1998;111:269–271. [PubMed]
6. Amado JM, Matos ME, Abreu AM, et al. The prevalence of acne in the north of Portugal. J Eur Acad Dermatol Venereol2006;20:1287–1295. [PubMed]
7. Garner S. Acne vulgaris. In: Williams H. Evidence-based dermatology. London: BMJ, 2003.
8. Purdy S, Langston J, Tait L. Presentation and management of acne in primary care: a retrospective cohort study. Br J Gen Pract2003;53:525–529. [PMC free article] [PubMed]
9. Cunliffe WJ. Management of adult acne and acne variants. J Cutan Med Surg 1998;2(suppl 3):7–13. [PubMed]
10. Brown SK, Shalita AR. Acne vulgaris. Lancet1998;351:1871–1876. [PubMed]
11. Webster GF. Acne vulgaris: state of the science. Arch Dermatol1999;135:1101–1102. [PubMed]
12. Goulden V, Stables G, Cunliffe W. Prevalence of facial acne in adults. J Am Acad Dermatol1999;578:577–580. [PubMed]
13. Burke BM, Cunliffe WJ. The assessment of acne vulgaris - the Leeds technique. Br J Dermatol 1984;111:83–92. [PubMed]
14. Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol1979;115:571–575. [PubMed]
15. Pillsbury DM, Shelley WB, Kligman AM. A manual of cutaneous medicine. Philadelphia: Saunders, 1961.
16. Lehmann HP, Andrews JS, Robinson KA, et al. Management of acne (Evidence Report/Technology Assessment No 17). Agency for Healthcare Research and Quality Publication No 01-E019. Rockville, MD. Agency for Healthcare Research and Quality, 2001. Search date 1999.
17. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA2004;292:726–735. Search date 2004. [PubMed]
18. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol1997;37:590–595. [PubMed]
19. Ede M. A double-blind comparative study of benzoyl peroxide, benzoyl peroxide–chlorhydroxyquinolone, benzoyl peroxide–chlorhydroxyquinolone–hydrocortisone, and placebo lotions in acne. Curr Ther Res Clin Exp1973;15:624–629. [PubMed]
20. Hughes BR, Norris JF, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%, benzoyl peroxide gel 5% and placebo in patients with acne. Clin Exp Dermatol1992;17:165–168. [PubMed]
21. Smith EB, Padilla RS, McCabe JM, et al. Benzoyl peroxide lotion (20 percent) in acne. Cutis1980;25:90–92. [PubMed]
22. Hunt MJ, Barnetson RS. A comparative study of gluconolactone versus benzoyl peroxide in the treatment of acne. Australas J Dermatol1992;33:131–134. [PubMed]
23. Braathen LR. Topical clindamycin versus oral tetracycline and placebo in acne vulgaris. Scand J Infect Dis Suppl1984;43:71–75. [PubMed]
24. Ellis CN, Gammon WR, Stone DZ, et al. A comparison of Cleocin T Solution, Cleocin T Gel, and placebo in the treatment of acne vulgaris. Cutis1988;42:245–247. [PubMed]
25. Lucchina LC, Kollias N, Gillies R, et al. Fluorescence photography in the evaluation of acne. J Am Acad Dermatol1996;35:58–63. [PubMed]
26. Gratton D, Raymond GP, Guertin-Larochelle S, et al. Topical clindamycin versus systemic tetracycline in the treatment of acne. Results of a multiclinic trial. J Am Acad Dermatol1982;7:50–53. [PubMed]
27. Becker LE, Bergstresser PR, Whiting DA, et al. Topical clindamycin therapy for acne vulgaris. A cooperative clinical study. Arch Dermatol1981;117:482–485. [PubMed]
28. Kuhlman DS, Callen JP. A comparison of clindamycin phosphate 1 percent topical lotion and placebo in the treatment of acne vulgaris. Cutis1986;38:203–206. [PubMed]
29. Noble WC, Naidoo J. Evolution of antibiotic resistance in Staphylococcus aureus: the role of the skin. Br J Dermatol 1978;98:481–489. [PubMed]
30. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol2005;153:395–403. [PubMed]
31. Kellett N, West F, Finlay AY. Conjoint analysis: a novel, rigorous tool for determining patient preferences for topical antibiotic treatment for acne. A randomised controlled trial. Br J Dermatol2006;154:524–532. [PubMed]
32. Glass D, Boorman GC, Stables GI, et al. A placebo-controlled clinical trial to compare a gel containing a combination of isotretinoin (0.05%) and erythromycin (2%) with gels containing isotretinoin (0.05%) or erythromycin (2%) alone in the topical treatment of acne vulgaris. Dermatology1999;199:242–247. [PubMed]
33. Lesher JL Jr, Chalker DK, Smith JG Jr, et al. An evaluation of a 2% erythromycin ointment in the topical therapy of acne vulgaris. J Am Acad Dermatol1985;12:526–531. [PubMed]
34. Pochi PE, Bagatell FK, Ellis CN, et al. Erythromycin 2% gel in the treatment of acne vulgaris. Cutis1988;41:132–136. [PubMed]
35. Jones EL, Crumley AF. Topical erythromycin vs blank vehicle in a multiclinic acne study. Arch Dermatol1981;117:551–553. [PubMed]
36. Dobson RL, Belknap BS. Topical erythromycin solution in acne. Results of a multiclinic trial. J Am Acad Dermatol1980;3:478–482. [PubMed]
37. Rivkin L, Rapaport M. Clinical evaluation of a new erythromycin solution for acne vulgaris. Cutis1980;25:552–555. [PubMed]
38. Hellgren L, Vincent J. Topical erythromycin for acne vulgaris. Dermatologica1980;161:409–414. [PubMed]
39. Prince RA, Busch DA, Hepler CD, et al. Clinical trial of topical erythromycin in inflammatory acne. Drug Intell Clin Pharm1981;15:372–376. [PubMed]
40. Christiansen JV, Gadborg E, Ludvigsen K, et al. Topical tretinoin, vitamin A acid (Airol) in acne vulgaris: a controlled clinical trial. Dermatologica1974;148:82–89. [PubMed]
41. Christiansen J, Holm P, Reymann F. The retinoic acid derivative Ro 11-1430 in acne vulgaris: a controlled multicenter trial against retinoic acid. Dermatologica1977;154:219–227. [PubMed]
42. Krishnan G. Comparison of two concentrations of tretinoin solution in the topical treatment of acne vulgaris. Practitioner1976;216:106–109. [PubMed]
43. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study. J Am Acad Dermatol1998;38:S17–S23. [PubMed]
44. Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol1998;38:S24–S30. [PubMed]
45. Pinnock CB, Alderman CP. The potential for teratogenicity of vitamin A and its congeners. Med J Aust 1992;157:805–809. [PubMed]
46. Thiboutot DM, Shalita AR, Yamauchi PS, et al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study. Arch Dermatol2006;142:597–602. [PubMed]
47. Thiboutot D, Pariser DM, Egan N, et al. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad Dermatol2006;54:242–250. [PubMed]
48. Kawashima M, Harada S, Loesche C, et al. Adapalene gel 0.1% is effective and safe for Japanese patients with acne vulgaris: a randomized, multicenter, investigator-blinded, controlled study. J Dermatol Sci2008;49:241–248. [PubMed]
49. Lucky A, Jorizzo JL, Rodriguez D, et al. Efficacy and tolerance of adapalene cream 0.1% compared with its cream vehicle for the treatment of acne vulgaris. Cutis2001;68:34–40. [PubMed]
50. Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm Venereol Suppl (Stockh)1989;143:31–34. [PubMed]
51. Katsambus A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin. Acta Derm Venereol Suppl (Stockh)1989;143:35–39. [PubMed]
52. Graupe K, Cunliffe WJ, Gollnick HP, et al. Efficacy and safety of topical azelaic acid (20% cream): an overview of results from European clinical trials and experimental reports. Cutis 1996;57(suppl 1):20–35. [PubMed]
53. Feucht CL, Allen BS, Chalker DK, et al. Topical erythromycin with zinc in acne. A double-blind controlled study. J Am Acad Dermatol1980;3:483–491. [PubMed]
54. Schachner L, Eaglestein W, Kittles C, et al. Topical erythromycin and zinc therapy for acne. J Am Acad Dermatol1990;22:253–260. [PubMed]
55. Chalker DK, Lesher JL Jr, Smith JG Jr, et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol1987;17:251–254. [PubMed]
56. Langner A, Boorman GC, Stapor V, et al. Isotretinoin cream 0.05% and 0.1% in the treatment of acne vulgaris. J Dermatol Treat 1994;5:177–180.
57. Blaney DJ, Cook CH. Topical use of tetracycline in the treatment of acne: a double-blind study comparing topical and oral tetracycline therapy and placebo. Arch Dermatol1976;112:971–973. [PubMed]
58. Anderson RL, Cook CH, Smith DE. The effect of oral and topical tetracycline on acne severity and on surface lipid composition. J Invest Dermatol1976;66:172–177. [PubMed]
59. Smith JG Jr, Chalker DK, Wehr RF. The effectiveness of topical and oral tetracycline for acne. South Med J1976;69:695–697. [PubMed]
60. Burton J. A placebo-controlled study to evaluate the efficacy of topical tetracycline and oral tetracycline in the treatment of mild to moderate acne. Dermatology Research Group. J Int Med Res1990;18:94–103. [PubMed]
61. Ochsendorf F. Systemic antibiotic therapy of acne vulgaris. J Deutschen Dermatologischen Gesellschaft2006;4:828–841. [PubMed]
62. Bleeker J, Hellgren L, Vincent J. Effect of systemic erythromycin stearate on the inflammatory lesions and skin surface fatty acids in acne vulgaris. Dermatologica1981;162:342–349. [PubMed]
63. Brandt H, Attila P, Ahokas T, et al. Erythromycin acistrate – an alternative treatment for acne. J Dermatol Treat 1994;5:3–5.
64. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol1986;14:183–186. [PubMed]
65. Al-Mishari MA. Clinical and bacteriological evaluation of tetracycline and erythromycin in acne vulgaris. Clin Ther1987;9:273–280. [PubMed]
66. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust1998;169:259–261. Search date 1998. [PubMed]
67. Plewig G, Petrozzi JW, Berendes U. A double-blind study of doxycycline in acne vulgaris. Arch Dermatol1970;101:435–438. [PubMed]
68. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol2003;139:459–464. [PubMed]
69. Juhlin L, Liden S. A quantitative evaluation of the effect of oxytetracycline and doxycycline in acne vulgaris. Br J Dermatol1969;81:154–158. [PubMed]
70. The National Prescribing Centre. The treatment of acne vulgaris: an update. MeReC Bulletin 1999;10:29–32.
71. Sanchez AR, Rogers RS, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol2004;43:709–715. [PubMed]
72. Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acne vulgaris: a review. Br J Dermatol2008;158:208–216. [PubMed]
73. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne vulgaris: efficacy and safety. In: The Cochrane Library: Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002. [PubMed]
74. Fleischer AB, Dinehart S, Stough D, et al. Safety and efficacy of a new extended-release formulation of minocycline. Cutis2006;78:21–31. [PubMed]
75. Hersle K, Gisslen H. Minocycline in acne vulgaris: a double-blind study. Curr Ther Res Clin Exp1976;19:339–342. [PubMed]
76. Ólafsson JH, Gudgeirsson J, Eggertsdóttir GE, et al. Doxycycline versus minocycline in the treatment of acne vulgaris: a double-blind study. J Dermatol Treat 1989;1:15–17.
77. Grosshans E, Belaich S, Meynadier J, et al. A comparison of the efficacy and safety of lymecycline and minocycline in patients with moderately severe acne vulgaris. Eur J Dermatol2010;8:161–166. [PubMed]
78. Bossuyt L, Bosschaert J, Richert B, et al. Lymecycline in the treatment of acne: an efficacious, safe and cost-effective alternative to minocycline. Eur J Dermatol2010;13:130–135. [PubMed]
79. Piérard-Franchimont C, Goffin V, Arrese JE, et al. Lymecycline and minocycline in inflammatory acne: a randomized, double-blind intent-to-treat study on clinical and in vivo antibacterial efficacy. Skin Pharmacol Appl Skin Physiol2002;15:112–119. [PubMed]
80. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet2004;364:2188–2197. [PubMed]
81. Samuelson JS. An accurate photographic method for grading acne: initial use in a double-blind clinical comparison of minocycline and tetracycline. J Am Acad Dermatol1985;12:461–467. [PubMed]
82. Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systematic review. Dermatology2000;200:223–231. Search date 1999. [PubMed]
83. Lawrenson RA, Seaman HE, Sundstrom A, et al. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf2000;23:333–349. Search date 1998. [PubMed]
84. Goulden V, Glass D, Cunliffe WJ. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol1996;134:693–695. [PubMed]
85. Sturkenboom MC, Meier CR, Jick H, et al. Minocycline and lupuslike syndrome in acne patients. Arch Intern Med1999;159:493–497. [PubMed]
86. Heslett C, Chilvers ER, Boon NA, et al. Davidson's principals and practices of medicine. London: Churchill Livingstone, 2002.
87. British National Formulary. http://www.bnf.org/bnf/ (last accessed 26 November 2010).
88. Lane P, Williamson DM. Treatment of acne vulgaris with tetracycline hydrochloride: a double-blind trial with 51 patients. BMJ1969;2:76–79. [PMC free article] [PubMed]
89. Wong RC, Kang S, Heezen JL, et al. Oral ibuprofen and tetracycline for the treatment of acne vulgaris. J Am Acad Dermatol1984;11:1076–1081. [PubMed]
90. Peck GL, Olsen TG, Butkus D. Isotretinoin versus placebo in the treatment of cystic acne. J Am Acad Dermatol1982;6:735–745. [PubMed]
91. Lester RS, Schachter GD, Light MJ. Isotretinoin and tetracycline in the management of severe nodulocystic acne. Int J Dermatol1985;24:252–257. [PubMed]
92. Goulden V, Clark SM, McGeown C, et al. Treatment of acne with intermittent isotretinoin. Br J Dermatol1997137:106–108. [PubMed]
93. Barth JH, Macdonald-Hull SP, Mark J, et al. Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol1993;129:704–707. [PubMed]
94. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med1995;333:101–106. [PubMed]
95. Berard A, Azoulay L, Koren G, et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. B J Clin Pharmacol2007;63:196–205. [PubMed]
96. Strahan JE, Raimer S. Isotretinoin and the controversy of psychiatric adverse effects. Int J Dermatol2006;45:789–799. [PubMed]
97. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg2007;26:210–220. [PubMed]
98. Hull PR, D'Arcy C. Isotretinoin use and subsequent depression and suicide: presenting the evidence. Am J Clin Dermatol2003;4:493–505. [PubMed]
99. Jick SS, Kremers HM, Vasilakis-Scaramozza C, et al. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol2000;136:1231–1236. [PubMed]
100. Magin P, Pond D, Smith W, et al. Isotretinoin, depression and suicide: a review of the evidence. Br J Gen Pract2005;55:134–138. [PMC free article] [PubMed]

Benzoyl peroxide (topical)
Summary
Topical benzoyl peroxide should be considered as first-line treatment in mild acne.
Topical benzoyl peroxide and topical azelaic acid reduce inflammatory and non-inflammatory lesions compared with placebo, but can cause itching, burning, stinging, and redness of the skin.
Benefits and harms
Topical benzoyl peroxide versus placebo:
We found two systematic reviews comparing topical benzoyl peroxide acid versus placebo (vehicle).[16] [17] The first review (search date 1999, 5 RCTs) did not perform a meta-analysis owing to heterogeneity among the trials in methods of outcome assessment.[16] The second review (search date 2004),[17] which had more stringent inclusion criteria than the earlier review, included one RCT,[18] which was also identified by the earlier review.
Acne severity
Topical benzoyl peroxide compared with placebo Topical benzoyl peroxide may be more effective at reducing the total lesion count or the number of inflammatory and non-inflammatory lesions at 4 to 12 weeks in people with moderate acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total lesion count/severity
[19]
RCT
4-armed trial
196 people with moderate acne
In review [16]
Percentage reduction in total lesion count 4 weeks
37% with benzoyl peroxide 5.5% 4 times daily
6% with vehicle

P = 0.001 for benzoyl peroxide v vehicle
Effect size not calculatedBenzoyl peroxide
[22]
RCT
3-armed trial
150 people with mild to moderate acne
In review [16]
Reduction in total lesion count from baseline 12 weeks
with benzoyl peroxide 5%
with vehicle

No direct comparison between benzoyl peroxide and vehicle
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Leeds severity score (where 0 = no acne and 10 = severest acne) 12 weeks
0 with benzoyl peroxide 5%
1 with vehicle

P <0.05 for benzoyl peroxide v vehicle
Effect size not calculatedBenzoyl peroxide
[21]
RCT
59 people with mild to moderate acne
In review [16]
Proportion of people with "good" (51–75% reduction) or "excellent" (76–100% reduction) response 12 weeks
19/26 (73%) with benzoyl peroxide 20%
10/25 (40%) with vehicle

P <0.05
Effect size not calculatedBenzoyl peroxide
Non-inflammatory lesions
[18]
RCT
4-armed trial
393 people with moderate acne
In review [16] [17]
Percentage change in non-inflammatory lesions 11 weeks
–30% with benzoyl peroxide 5%
+11% with vehicle

P <0.005 for benzoyl peroxide v vehicle
Effect size not calculatedBenzoyl peroxide
[22]
RCT
3-armed trial
150 people with mild to moderate acne
In review [16]
Reduction in non-inflammatory lesions from baseline 12 weeks
with benzoyl peroxide 5%
with vehicle

No direct comparison between benzoyl peroxide and vehicle
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Mean percentage change in number of non-inflammatory lesions
–52% with benzoyl peroxide 5%
+6% with vehicle

P = 0.01 for benzoyl peroxide v vehicle
Effect size not calculatedBenzoyl peroxide
Inflammatory lesions
[18]
RCT
4-armed trial
393 people with moderate acne
In review [16] [17]
Percentage reduction in inflammatory lesions 11 weeks
39% with benzoyl peroxide 5%
5% with vehicle

P <0.002 for benzoyl peroxide v vehicle
Effect size not calculatedBenzoyl peroxide
[22]
RCT
3-armed trial
150 people with mild to moderate acne
In review [16]
Reduction in inflammatory lesions from baseline 12 weeks
with benzoyl peroxide 5%
with vehicle

No direct comparison between benzoyl peroxide and vehicle
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Mean percentage change in number of inflammatory lesions
–52% with benzoyl peroxide 5%
+9% with vehicle

P = 0.01 for benzoyl peroxide v vehicle
Effect size not calculatedBenzoyl peroxide
Patient perception of improvement
No data from the following reference on this outcome.[19] [18] [22] [20] [21]
Psychological distress
No data from the following reference on this outcome.[19] [18] [22] [20] [21]
Quality of life
No data from the following reference on this outcome.[19] [18] [22] [20] [21]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Skin irritation
[19]
RCT
4-armed trial
196 people with moderate acne
In review [16]
Adverse effects 4 weeks
with benzoyl peroxide 5.5% 4 times daily
with vehicle
[18]
RCT
4-armed trial
393 people with moderate acne
In review [16] [17]
Peeling 11 weeks
21% with benzoyl peroxide 5%
15% with vehicle

Significance not assessed
[22]
RCT
3-armed trial
150 people with mild to moderate acne
In review [16]
Adverse effects 12 weeks
22/75 (29%) with benzoyl peroxide 5%
5/75 (7%) with vehicle

P = 0.05
Effect size not calculatedVehicle
[20]
RCT
3-armed trial
77 people with mild to moderate
In review [16]
Adverse effects 12 weeks
with benzoyl peroxide 5%
with vehicle
[21]
RCT
59 people with mild to moderate acne
In review [16]
Redness and peeling 12 weeks
21/29 (72%) with benzoyl peroxide 20%
17/30 (57%) with vehicle

Significance not assessed
Further information on studies
Comment
Clinical guide:
Benzoyl peroxide is indicated as an effective first-line treatment for mild acne. It has antimicrobial and anticomedonal properties, in addition to an anti-inflammatory effect. It is recommended to start with a lower strength and increase gradually. Reducing frequency of application or temporarily discontinuing treatment helps with irritation.
Substantive changes
No new evidence

Clindamycin (topical)
Summary
Topical antibiotics such as clindamycin reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions.
Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.
Benefits and harms
Topical clindamycin versus placebo:
We found two systematic reviews.[16] [17] The first review (search date 1999, 7 RCTs,[18] [23] [24] [25] [26] [27] [28] 1502 people with mild to severe acne) compared topical clindamycin 1% (phosphate or hydrochloride) 1 to 4 times daily versus placebo or vehicle for 8 to 12 weeks.[16] The review did not perform a meta-analysis owing to heterogeneity among the trials in comparisons and outcomes assessed. The second systematic review (search date 2004), which had more stringent inclusion criteria, identified two RCTs,[18] [27] both of which were identified by the earlier review.
Acne severity
Topical clindamycin compared with placebo/vehicle Topical clindamycin may be more effective at reducing the number of inflammatory lesions at 8 to 12 weeks in people with mild to severe acne, but we don't know whether it is more effective at reducing total lesion count or non-inflammatory lesions (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total lesion count
[28]
RCT
46 people with moderate to severe acne
In review [16] [17]
Mean lesion count 12 weeks
0.2 with clindamycin phosphate 1% twice daily
0.6 with placebo

P = 0.34
Not significant
Non-inflammatory lesions
[18]
RCT
4-armed trial
393 people with moderate acne
In review [16] [17]
Mean percentage change in non-inflammatory lesions from baseline 11 weeks
–9% with clindamycin 1% 4 times daily
+11% with vehicle 4 times daily

P = 0.04 for clindamycin v vehicle
Effect size not calculatedClindamycin
[25]
RCT
40 people with mild to moderate acne
In review [16]
Percentage reduction in open comedones 12 weeks
38% with clindamycin phosphate 1% twice daily
32% with placebo

Reported as not significant
P value not reported
Not significant
[28]
RCT
46 people with moderate to severe acne
In review [16] [17]
Mean number of open comedones per person 12 weeks
3.3 with clindamycin phosphate 1% twice daily
5.2 with placebo

P = 0.49
Not significant
[28]
RCT
46 people with moderate to severe acne
In review [16] [17]
Mean number of closed comedones per person 12 weeks
3.4 with clindamycin phosphate 1% twice daily
5.1 with placebo

P = 0.47
Not significant
Inflammatory lesions
[18]
RCT
4-armed trial
393 people with moderate acne
In review [16] [17]
Mean percentage reduction in inflammatory lesions from baseline 11 weeks
35% with clindamycin 1% 4 times daily
5% with vehicle 4 times daily

P <0.001 for clindamycin v vehicle
Effect size not calculatedClindamycin
[23]
RCT
3-armed trial
108 people with mild to moderate acne
In review [16]
Mean reduction in inflammatory lesion count (change from baseline) 8 weeks
From 8.52 to 2.38 with clindamycin
From 7.10 to 6.24 with placebo

No direct comparison of topical clindamycin v placebo
RCT designed to compare topical clindamycin v oral tetracycline
[25]
RCT
40 people with mild to moderate acne
In review [16]
Percentage reduction in papules 12 weeks
22% with clindamycin phosphate 1% twice daily
19% with placebo

Reported as not significant
P value not reported
Not significant
[25]
RCT
40 people with mild to moderate acne
In review [16]
Percentage reduction in pustules 12 weeks
12% with clindamycin phosphate 1% twice daily
22% with placebo

Reported as not significant
P value not reported
Not significant
[26]
RCT
3-armed trial
367 people with moderate to severe acne
In review [16]
Mean number of papules per person 8 weeks
8.3 with clindamycin
11.7 with placebo

P <0.05 for clindamycin v placebo
Effect size not calculatedClindamycin
[26]
RCT
3-armed trial
367 people with moderate to severe acne
In review [16]
Mean number of pustules per person 8 weeks
1.1 with clindamycin
2.7 with placebo

P <0.05 for clindamycin v placebo
Effect size not calculatedClindamycin
[27]
RCT
3-armed trial
413 people with moderate acne
In review [16] [17]
Percentage reduction in papules 8 weeks
56% with clindamycin phosphate 1% twice daily
42% with vehicle

P = 0.05 or less for clindamycin phosphate v vehicle
Effect size not calculatedClindamycin
[27]
RCT
3-armed trial
413 people with moderate acne
In review [16] [17]
Percentage reduction in papules 8 weeks
64% with clindamycin hydrochloride 1% twice daily
42% with vehicle

P = 0.05 or less for clindamycin hydrochloride v vehicle
Effect size not calculatedClindamycin
[27]
RCT
3-armed trial
413 people with moderate acne
In review [16] [17]
Percentage reduction in pustules 8 weeks
72% with clindamycin phosphate 1% twice daily
43% with vehicle

P = 0.05 or less for clindamycin phosphate v vehicle
Effect size not calculatedClindamycin
[27]
RCT
3-armed trial
413 people with moderate acne
In review [16] [17]
Percentage reduction in pustules 8 weeks
62% with clindamycin hydrochloride 1% twice daily
43% with vehicle

Significance not assessed
[28]
RCT
46 people with moderate to severe acne
In review [16] [17]
Mean number of pustules per person 12 weeks
1.5 with clindamycin phosphate 1% twice daily
3.1 with placebo

P = 0.02
Effect size not calculatedClindamycin
[28]
RCT
46 people with moderate to severe acne
In review [16] [17]
Mean number of papules per person 12 weeks
6.8 with clindamycin phosphate 1% twice daily
10.6 with placebo

P = 0.16
Not significant
Patient perception of improvement
Topical clindamycin compared with placebo/vehicle Topical clindamycin may be more effective at increasing the proportion of people with mild to severe acne who rate their acne as markedly improved or improved (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[23]
RCT
3-armed trial
108 people with mild to moderate acne
In review [16]
Proportion of people whose acne had "markedly improved" or "improved" from baseline 8 weeks
72% with clindamycin
3% with placebo

No direct comparison of topical clindamycin v placebo
RCT designed to compare topical clindamycin v oral clindamycin
[26]
RCT
3-armed trial
367 people with moderate to severe acne
In review [16]
Proportion of people who thought their acne was "markedly improved" or "improved" 8 weeks
88% with clindamycin
57% with placebo

P <0.05 for clindamycin v placebo
Effect size not calculatedClindamycin
[27]
RCT
3-armed trial
413 people with moderate acne, 8 weeks
In review [16] [17]
Proportion of people who rated acne "markedly improved" or "improved" compared with vehicle 8 weeks
77% with clindamycin phosphate 1% twice daily
56% with vehicle

Difference for clindamycin phosphate versus placebo reported as significant
P value not reported
Effect size not calculatedClindamycin
[27]
RCT
3-armed trial
413 people with moderate acne, 8 weeks
In review [16] [17]
Proportion of people who rated acne "markedly improved" or "improved" compared with vehicle 8 weeks
77% with clindamycin hydrochloride 1% twice daily
56% with vehicle

Difference for clindamycin hydrochloride versus placebo reported as significant
P value not reported
Effect size not calculatedClindamycin
No data from the following reference on this outcome.[18] [25] [28]
Psychological distress
No data from the following reference on this outcome.[18] [23] [25] [26] [27] [28]
Quality of life
No data from the following reference on this outcome.[18] [23] [25] [26] [27] [28]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[18]
RCT
4-armed trial
393 people with moderate acne
In review [16] [17]
Adverse effects (erythema, dryness, peeling, burning, or pruritus) 11 weeks
with clindamycin 1% 4 times daily
with vehicle 4 times daily

Reported as not significant
P value not reported
Not significant
[23]
RCT
3-armed trial
108 people with mild to moderate acne
In review [16]
Adverse effects 8 weeks
with clindamycin
with placebo
[26]
RCT
3-armed trial
367 people with moderate to severe acne
In review [16]
Adverse effects 8 weeks
with clindamycin
with placebo
[27]
RCT
3-armed trial
413 people with moderate acne
In review [16] [17]
Adverse effects 8 weeks
with clindamycin phosphate 1% twice daily
with clindamycin hydrochloride 1% twice daily
with vehicle
[28]
RCT
46 people with moderate to severe acne
In review [16] [17]
Adverse effects 12 weeks
with clindamycin phosphate 1% twice daily
with placebo
No data from the following reference on this outcome.[25]
Further information on studies
Comment
The review[16] identified one open-label RCT, which did not meet Clinical Evidence inclusion criteria (135 people with moderate acne),[24]which found that clindamycin significantly reduced papules and pustules at 12 weeks compared with placebo. It found that clindamycin was associated with burning.
Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance to Propionibacterium acnes.[7] [29] One systematic review (search date 2003) analysed the efficacy of topical antibiotics in clinical trials (randomised and non-randomised) conducted between 1966 and 2003 using linear regression.[30] It found no significant change in the efficacy of 12 weeks' treatment with topical clindamycin 1.0% to 1.2% for inflammatory or non-inflammatory lesion count over this period (inflammatory lesions: 8 studies, change in efficacy [regression coefficient]: +0.2%/year, P = 0.7; non-inflammatory lesions: 7 studies, change in efficacy: –0.3%/year, P = 0.7).[30]
Clinical guide:
Topical antibiotics or topical retinoids are indicated as treatments for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical clindamycin or erythromycin than with erythromycin plus zinc or tetracycline. A conjoint analysis study of patient preference for different topical antibiotic characteristics found that acne patients preferred a gel formulation that could be applied with the fingers once daily and stored at room temperature for up to 18 months.[31]
Substantive changes
No new evidence

Erythromycin (topical)
Summary
Topical antibiotics, such as erythromycin, reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions.
Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.
Benefits and harms
Topical erythromycin versus placebo:
We found two systematic reviews.[16] [17] The first review (search date 1999, 8 RCTs,[32] [33] [34] [35] [36] [37] [38] [39] 347 people with mild to moderate acne, 555 people with moderate to severe acne) compared topical erythromycin 1% to 2% versus vehicle for 4 to 12 weeks.[16] The review did not perform a meta-analysis owing to heterogeneity among the trials in outcomes assessed. The second systematic review (search date 2004),[17] which had more stringent inclusion criteria, included 3 RCTs, all of which were identified by the earlier review.[33] [35] [36]
Acne severity
Topical erythromycin compared with placebo Topical erythromycin may be more effective at reducing inflammatory lesions at 8 to 12 weeks in people with mild to severe acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[32]
RCT
4-armed trial
160 people with mild to moderate acne
In review [16]
Mean percentage change in total lesion count from baseline 12 weeks
–25% (95% CI –39.04% to –11.44%) with erythromycin 2%
–11% (95% CI –24.29% to +2.65%) with placebo

No direct comparison between erythromycin alone and placebo
[33]
RCT
225 people with mild to moderate acne
In review [16] [17]
Reduction in Cook's severity score 12 weeks
–40 with erythromycin 2% twice daily
–22 with vehicle

Reported as not significant
P value not reported
Not significant
[35]
RCT
175 people with moderate to severe acne unresponsive to oral tetracycline, topical benzoyl peroxide, or topical tretinoin
In review [16] [17]
Proportion of people rated by physician as having "excellent" or "good" response 12 weeks
62% with erythromycin 2%
27% with vehicle

P <0.001
Effect size not calculatedErythromycin
[36]
RCT
253 people with moderate to severe acne
In review [16] [17]
Total lesion count 12 weeks
with erythromycin 1.5% twice daily
with vehicle
Absolute results reported graphically

P = 0.01
Effect size not calculatedErythromycin
[37]
RCT
26 people with moderate to severe acne
In review [16]
Proportion of people rated by physician as having "excellent" or "good" response 12 weeks
92% with erythromycin 1.5% twice daily
20% with vehicle

P = 0.005
Effect size not calculatedErythromycin
Non-inflammatory lesions
[32]
RCT
4-armed trial
160 people with mild to moderate acne
In review [16]
Mean percentage change in non-inflammatory lesions from baseline 12 weeks
–17% (95% CI –38.07% to +4.63%) with erythromycin 2%
–7% (95% CI –28.31% to +14.16%) with placebo

No direct comparison between erythromycin alone and placebo
[37]
RCT
26 people with moderate to severe acne
In review [16]
Comedones 12 weeks
with erythromycin
with vehicle
Absolute results not reported
[34]
RCT
187 people with mild to moderate acne
In review [16]
Mean reduction in open comedones per person 8 weeks
–7.5 with erythromycin 2% twice daily
–4.6 with vehicle

P <0.01
Effect size not calculatedErythromycin
[34]
RCT
187 people with mild to moderate acne
In review [16]
Mean reduction in closed comedones per person 8 weeks
–1.7 with erythromycin 2% twice daily
–2.3 with vehicle

Reported as not significant
P value not reported
Not significant
[36]
RCT
253 people with moderate to severe acne
In review [16] [17]
Open or closed comedones 12 weeks
with erythromycin 1.5% twice daily
with vehicle
Absolute results reported graphically

Reported as not significant
P value not reported
Not significant
Inflammatory lesions
[32]
RCT
4-armed trial
160 people with mild to moderate acne
In review [16]
Mean percentage change in inflammatory lesions from baseline 12 weeks
–28% (95% CI –41.29% to –14.14%) with erythromycin 2%
–10% (95% CI –24.51% to +5.36%) with placebo

No direct comparison between erythromycin alone and placebo
[33]
RCT
225 people with mild to moderate acne
In review [16] [17]
Percentage reduction in inflammatory lesions 12 weeks
46% with erythromycin 2% twice daily
19% with vehicle

P = 0.01
Effect size not calculatedErythromycin
[34]
RCT
187 people with mild to moderate acne
In review [16]
Mean reduction in papules per person 8 weeks
–6.2 with erythromycin 2% twice daily
–4.3 with vehicle

P <0.01
Effect size not calculatedErythromycin
[34]
RCT
187 people with mild to moderate acne
In review [16]
Mean reduction in pustules per person 8 weeks
–1.7 with erythromycin 2% twice daily
–1.2 with vehicle

Reported as not significant
P value not reported
Not significant
[35]
RCT
175 people with moderate to severe acne unresponsive to oral tetracycline, topical benzoyl peroxide, or topical tretinoin
In review [16] [17]
Total inflammatory lesion count 12 weeks
856 with erythromycin 2%
1338 with vehicle

P <0.01
Effect size not calculatedErythromycin
[36]
RCT
253 people with moderate to severe acne
In review [16] [17]
Papules and pustules 12 weeks
with erythromycin 1.5% twice daily
with vehicle
Absolute results reported graphically

P <0.025
Effect size not calculatedErythromycin
[37]
RCT
26 people with moderate to severe acne
In review [16]
Proportion of people who had more than 50% reduction in papules 12 weeks
11/12 (92%) with erythromycin
4/10 (40%) with vehicle

P = 0.01
Effect size not calculatedErythromycin
[27]
RCT
28 people with moderate to severe acne
In review [16]
Reduction in inflammatory lesions 4 to 8 weeks
with erythromycin 1% twice daily
with vehicle

Significance not assessed
[39]
RCT
73 people with moderate to severe acne
In review [16]
Proportion of people who had more than 50% reduction in inflammatory lesions 12 weeks
30% with erythromycin 2% twice daily
20% with vehicle

Reported as not significant
P value not reported
Not significant
Patient perception of improvement
Topical erythromycin compared with placebo We don’t know whether topical erythromycin is more effective at increasing the proportion of people with mild to moderate acne who perceive their acne as improved at 12 weeks (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[32]
RCT
4-armed trial
160 people with mild to moderate acne
In review [16]
Proportion of people who perceived that their acne had improved from baseline 12 weeks
58% with erythromycin 2%
53% with placebo

Significance not assessed
Psychological distress
No data from the following reference on this outcome.[32] [33] [34] [35] [36] [37] [38] [39]
Quality of life
No data from the following reference on this outcome.[32] [33] [34] [35] [36] [37] [38] [39]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[35]
RCT
175 people with moderate to severe acne unresponsive to oral tetracycline, topical benzoyl peroxide, or topical tretinoin
In review [16] [17]
Proportion of people with one or more adverse effects, including redness, scaling, dryness, and pruritus 12 weeks
17/90 (19%) with erythromycin 2% twice daily
21/85 (25%) with vehicle

Significance not assessed
[33]
RCT
225 people with mild to moderate acne
In review [16] [17]
Erythema 12 weeks
with erythromycin 2% twice daily
with vehicle
Absolute results not reported

Reported as not significant
P value not reported
Not significant
[33]
RCT
225 people with mild to moderate acne
In review [16] [17]
Peeling 12 weeks
with erythromycin 2% twice daily
with vehicle
Absolute results not reported

Reported as not significant
P value not reported
Not significant
[34]
RCT
187 people with mild to moderate acne
In review [16]
Adverse effects 8 weeks
with erythromycin 2% twice daily
with vehicle
Absolute results not reported

Reported as not significant
P value not reported
Not significant
[36]
RCT
253 people with moderate to severe acne
In review [16] [17]
Number of people with one or more adverse effect 12 weeks
26 with erythromycin 1.5% twice daily
26 with vehicle
Absolute results reported graphically
[37]
RCT
26 people with moderate to severe acne
In review [16]
Adverse effects 12 weeks
with erythromycin
with vehicle
No data from the following reference on this outcome.[32] [27] [39]
Further information on studies
Comment
Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance in Propionibacterium acnes.[7] [29] One systematic review (search date 2003) analysed the efficacy of topical antibiotics in clinical trials (randomised and non-randomised) conducted between 1966 to 2003 using linear regression.[30] It found that the efficacy of 12 weeks' treatment with topical erythromycin 1.5% to 2% for inflammatory and non-inflammatory lesion count decreased significantly over this period (inflammatory lesions, 8 studies, change in efficacy [regression coefficient]: –2.1%/year, P = 0.001; non-inflammatory lesions, 6 studies, change in efficacy: –2.0%/year, P = 0.001).
Clinical guide:
Topical antibiotics or topical retinoids are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical erythromycin or clindamycin than with erythromycin plus zinc or tetracycline. However, there is some evidence that topical erythromycin may be less effective now than in the past, owing to increasing P acnes resistance.
Substantive changes
No new evidence

Tretinoin (topical)
Summary
Topical preparations of tretinoin may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.
Topical tretinoin has been associated with erythema, peeling, burning, and pruritus.
Topical retinoids are not recommended in women of childbearing age not taking adequate contraceptive precautions, or during pregnancy.
Benefits and harms
Topical tretinoin versus placebo:
We found one systematic review[16] (search date 1999, 5 RCTs,[40] [41] [42] [43] [44] 802 people with mild to moderate acne, 257 people with moderate to severe acne) comparing topical tretinoin 0.02%, 0.025%, or 0.05% versus vehicle twice daily for 8 to 12 weeks. The review did not perform a meta-analysis because of heterogeneity among the RCTs in methods of outcome assessment.[16]
Acne severity
Topical tretinoin compared with placebo Topical tretinoin may be more effective at 8 to 12 weeks at reducing the number of inflammatory and non-inflammatory lesions in people with mild to severe acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total lesion count
[43]
RCT
3-armed trial
215 people with mild to moderate acne
In review [16]
Percentage reduction in total lesion count 12 weeks
40% with tretinoin 0.025%
24% with vehicle

P <0.05
Effect size not calculatedTretinoin
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Percentage reduction in total lesion count 12 weeks
39% with tretinoin 0.025%
28% with vehicle

P <0.05
Effect size not calculatedTretinoin
Non-inflammatory lesions
[40]
RCT
3-armed trial
256 people with mild to moderate acne
In review [16]
Comedones (measured by total score) 7 to 8 weeks
89 with tretinoin 0.05%
131 with vehicle

P <0.01 for tretinoin 0.05% v vehicle
The RCT had weak methods for assessing outcomes
Effect size not calculatedTretinoin
[40]
RCT
3-armed trial
256 people with mild to moderate acne
In review [16]
Comedones (measured by total score) 7 to 8 weeks
94 with tretinoin 0.02%
131 with vehicle

P <0.01 for tretinoin 0.02% v vehicle
The RCT had weak methods for assessing outcomes
Effect size not calculatedTretinoin
[41]
RCT
3-armed trial
257 people with moderate to severe acne
In review [16]
Number of non-inflammatory lesions 8 weeks
89 with tretinoin 0.05% twice daily
131 with vehicle twice daily

P = 0.01
Effect size not calculatedTretinoin
[43]
RCT
3-armed trial
215 people with mild to moderate acne
In review [16]
Percentage reduction in non-inflammatory lesions 12 weeks
39% with tretinoin 0.025%
19% with vehicle

P <0.05
Effect size not calculatedTretinoin
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Percentage reduction in non-inflammatory lesions 12 weeks
49% with tretinoin 0.025%
31% with vehicle

P <0.05
Effect size not calculatedTretinoin
Inflammatory lesions
[40]
RCT
3-armed trial
256 people with mild to moderate acne
In review [16]
Number of papules (measured by total score) 7 to 8 weeks
61 with tretinoin 0.05%
83 with vehicle

P <0.05 for tretinoin 0.05% v vehicle
The RCT had weak methods for assessing outcomes
Effect size not calculatedTretinoin 0.05%
[40]
RCT
3-armed trial
256 people with mild to moderate acne
In review [16]
Number of papules (measured by total score) 7 to 8 weeks
76 with tretinoin 0.02%
83 with vehicle

Reported as not significant for tretinoin 0.02% v vehicle
P value not reported
The RCT had weak methods for assessing outcomes
Not significant
[41]
RCT
3-armed trial
257 people with moderate to severe acne
In review [16]
Number of papules 8 weeks
61 with tretinoin 0.05% twice daily
83 with vehicle twice daily

P = 0.05
Effect size not calculatedTretinoin
[43]
RCT
3-armed trial
215 people with mild to moderate acne
In review [16]
Percentage reduction in papules 12 weeks
42% with tretinoin 0.025%
19% with vehicle

P <0.05
Effect size not calculatedTretinoin
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Percentage reduction in papules 12 weeks
49% with tretinoin 0.025%
28% with vehicle

P <0.05
Effect size not calculatedTretinoin
No data from the following reference on this outcome.[42]
Patient perception of improvement
Topical tretinoin compared with placebo We don't know whether topical tretinoin is more effective at increasing patient perception of improvement in people with mild to moderate acne (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[42]
RCT
3-armed trial
60 people with mild to moderate acne
In review [16]
Patient perception of severity on a visual analogue scale (VAS) 12 weeks
18 with tretinoin 0.05% or 0.025%
39 with vehicle

Significance not assessed
The RCT had weak methods for assessing outcomes
Psychological distress
No data from the following reference on this outcome.[40] [41] [42] [43] [44]
Quality of life
No data from the following reference on this outcome.[40] [41] [42] [43] [44]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Erythema
[40]
RCT
3-armed trial
256 people with mild to moderate acne
In review [16]
Erythema, peeling, or both 1 to 3 weeks
86% with tretinoin 0.05%
40% with vehicle

P <0.01 for tretinoin 0.05% v vehicle
Effect size not calculatedVehicle
[40]
RCT
3-armed trial
256 people with mild to moderate acne
In review [16]
Erythema, peeling, or both 1 to 3 weeks
81% with tretinoin 0.02%
40% with vehicle

P <0.01 for tretinoin 0.02% v vehicle
Effect size not calculatedVehicle
[41]
RCT
3-armed trial
257 people with moderate to severe acne
In review [16]
Erythema and desquamation 8 weeks
76/84 (90%) with tretinoin 0.05% twice daily
16/84 (19%) with vehicle twice daily

P <0.005
Effect size not calculatedVehicle
[43]
RCT
3-armed trial
215 people with mild to moderate acne
In review [16]
Proportion of people with erythema 12 weeks
20% with tretinoin 0.025%
9% with vehicle

P <0.005
Effect size not calculatedVehicle
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Proportion of people with erythema 12 weeks
8% with tretinoin 0.025%
3% with vehicle

P <0.005
Effect size not calculatedVehicle
Burning
[41]
RCT
3-armed trial
257 people with moderate to severe acne
In review [16]
Burning 8 weeks
69/84 (82%) with tretinoin 0.05% twice daily
23/84 (27%) with vehicle twice daily

P <0.005
Effect size not calculatedVehicle
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Proportion of people with burning 12 weeks
8% with tretinoin 0.025%
3% with vehicle

P <0.005
Effect size not calculatedVehicle
Itching
[41]
RCT
3-armed trial
257 people with moderate to severe acne
In review [16]
Pruritus 8 weeks
62/84 (74%) with tretinoin 0.05% twice daily
26/84 (31%) with vehicle twice daily

P <0.005
Effect size not calculatedVehicle
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Proportion of people with itching 12 weeks
15% with tretinoin 0.025%
6% with vehicle

P <0.005
Effect size not calculatedVehicle
Peeling
[43]
RCT
3-armed trial
215 people with mild to moderate acne
In review [16]
Proportion of people with peeling 12 weeks
21% with tretinoin 0.025%
3% with vehicle

P <0.005
Effect size not calculatedVehicle
Dryness
[43]
RCT
3-armed trial
215 people with mild to moderate acne
In review [16]
Proportion of people with dryness 12 weeks
21% with tretinoin 0.025%
8% with vehicle

P <0.005
Effect size not calculatedVehicle
Skin tightness
[44]
RCT
3-armed trial
271 people with mild to moderate acne
In review [16]
Proportion of people with skin tightness 12 weeks
22% with tretinoin 0.025%
15% with vehicle

P <0.005
Effect size not calculatedVehicle
Further information on studies
None.
Comment
Birth defects:
We found no RCTs assessing the risk of birth defects in women using topical retinoids. One non-systematic review found that oral retinoids were teratogenic in case reports and case series in humans, and in experimental studies in animals.[45] In the absence of data regarding the risk of birth defects, it is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.[7]
Clinical guide:
Topical retinoids or topical antibiotics are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the retinoid class, there is more evidence of benefit with topical tretinoin than with isotretinoin or adapalene. It is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.[7]
Substantive changes
No new evidence

Adapalene (topical)
Summary
Topical adapalene may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.
Topical retinoids are not recommended in women of childbearing age not taking adequate contraceptive precautions, or during pregnancy.
Benefits and harms
Topical adapalene versus placebo:
We found one systematic review (search date 2004; 1 RCT)[17] and 3 subsequent RCTs.[46] [47] [48]
Acne severity
Topical adapalene compared with placebo Topical adapalene seems more effective at reducing the number of total lesions and the number of non-inflammatory and inflammatory lesions at 12 weeks in people with mild to moderate acne, and at maintaining improvement of lesions at 16 weeks in people who have responded to previous treatment with oral doxycycline with or without adapalene gel (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total lesion count
[49]
RCT
237 people with moderate acne
In review [17]
Mean reduction in total lesion count 12 weeks
40% with adapalene 0.1% daily
20% with vehicle

P <0.01
Effect size not calculatedAdapalene
[46]
RCT
253 people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle) Total lesion count 16 weeks
with adapalene gel 0.1% daily
with placebo daily
Absolute results reported graphically

P = 0.005
Effect size not calculatedAdapalene
[46]
RCT
253 people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle) Maintenance of at least 50% of the improvement in total lesion count 16 weeks
75% with adapalene gel 0.1% daily
54% with placebo daily
Absolute numbers not reported

P <0.001
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Mean reduction in total lesion count 12 weeks
48% with adapalene gel 0.1% daily
36% with vehicle daily
Absolute numbers not reported

P <0.001 for adapalene 0.1% v vehicle
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Success rate 12 weeks
17% with adapalene gel 0.1% daily
10% with vehicle daily
Absolute numbers not reported

P = 0.02 for adapalene 0.1% v vehicle
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Mean reduction in total lesion count 12 weeks
56% with adapalene gel 0.3% daily
36% with vehicle daily
Absolute numbers not reported

P value not reported for adapalene 0.3% v vehicle
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Success rate 12 weeks
23% with adapalene gel 0.3% daily
10% with vehicle daily
Absolute numbers not reported

P value not reported for adapalene 0.3% v vehicle
[48]
RCT
200 Japanese people with at least 30 acne lesions Median reduction in total lesion count from baseline 12 weeks
63.2% with adapalene gel 0.1% daily
36.9% with placebo (vehicle gel) daily
Absolute numbers not reported

P <0.0001
Effect size not calculatedAdapalene
Non-inflammatory lesions
[49]
RCT
237 people with moderate acne
In review [17]
Mean reduction in non-inflammatory lesion count
38% with adapalene 0.1% daily
20% with vehicle

P <0.01
Effect size not calculatedAdapalene
[46]
RCT
253 people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle) Non-inflammatory lesion count 16 weeks
with adapalene gel 0.1% daily
with placebo daily
Absolute results reported graphically

P = 0.02
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Mean reduction in non-inflammatory lesions 12 weeks
43% with adapalene gel 0.1% daily
29% with vehicle daily
Absolute numbers not reported

P <0.001 for adapalene 0.1% v vehicle
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Mean reduction in non-inflammatory lesion count 12 weeks
52% with adapalene gel 0.3% daily
29% with vehicle daily
Absolute numbers not reported

P value not reported for adapalene 0.3% v vehicle
[48]
RCT
200 Japanese people with at least 30 acne lesions Median reduction in number of non-inflammatory lesions from baseline 12 weeks
64.6% with adapalene gel 0.1% daily
38.1% with placebo (vehicle gel) daily
Absolute numbers not reported

P <0.0001
Effect size not calculatedAdapalene
Inflammatory lesions
[49]
RCT
237 people with moderate acne
In review [17]
Mean reduction in inflammatory lesion count
35% with adapalene 0.1% daily
19% with vehicle

P <0.01
Effect size not calculatedAdapalene
[46]
RCT
253 people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle) Inflammatory lesion count 16 weeks
with adapalene gel 0.1% daily
with placebo daily
Absolute results reported graphically

P = 0.01
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Mean reduction in inflammatory lesions 12 weeks
58% with adapalene gel 0.1% daily
47% with vehicle daily
Absolute numbers not reported

P <0.001 for adapalene 0.1% v vehicle
Effect size not calculatedAdapalene
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Mean reduction in inflammatory lesions 12 weeks
63% with adapalene gel 0.3% daily
47% with vehicle daily
Absolute numbers not reported

P value not reported for adapalene 0.1% v vehicle
[48]
RCT
200 Japanese people with at least 30 acne lesions Median reduction in number of inflammatory lesions from baseline 12 weeks
63.7% with adapalene gel 0.1% daily
45.8% with placebo (vehicle gel) daily
Absolute numbers not reported

P = 0.001
Effect size not calculatedAdapalene
Patient perception of improvement
Topical adapalene compared with placebo We don't know whether topical adapalene is more effective at improving patient satisfaction in people with acne (at least 30 lesions) at 12 weeks, but topical adapalene may be more effective at increasing patient satisfaction with maintenance treatment at 12 weeks in people with severe acne who have responded to previous treatment with oral doxycycline with or without adapalene gel (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[46]
RCT
253 people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle) Proportion reporting being "satisfied" or "very satisfied" with maintenance treatment 12 weeks
76% with adapalene gel 0.1% daily
65% with placebo daily
Absolute numbers not reported

P = 0.01
Effect size not calculatedAdapalene
[48]
RCT
200 Japanese people with at least 30 acne lesions Proportion of people with greater than 75% satisfaction with treatment effect on a visual analogue scale (VAS) 12 weeks
60% with adapalene gel 0.1% daily
42% with placebo (vehicle gel) daily
Absolute numbers not reported
Quality of life
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[49]
RCT
237 people with moderate acne
In review [17]
Quality of life 12 weeks
with adapalene 0.1% daily
with vehicle
Absolute results not reported
No data from the following reference on this outcome.[46] [47]
Psychological distress
No data from the following reference on this outcome.[46] [47] [49]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Skin adverse effects
[49]
RCT
237 people with moderate acne
In review [17]
Adverse effects (erythema, dryness, scaling, stinging/burning, and pruritus) 2 weeks
with adapalene 0.1% daily
with vehicle

P <0.01
Effect size not calculatedVehicle
[49]
RCT
237 people with moderate acne
In review [17]
Adverse effects (erythema, dryness, scaling, stinging/burning) 12 weeks
with adapalene 0.1% daily
with vehicle

Reported as not significant
P value not reported
Not significant
[46]
RCT
253 people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle) Adverse effects (erythema, scaling, dryness, stinging, burning)
25% with adapalene gel 0.1% daily
23% with placebo daily
Absolute numbers not reported

Significance not assessed
[47]
RCT
3-armed trial
653 people with mild to moderate acne vulgaris Adverse effects (dry skin and skin discomfort) 12 weeks
22% with adapalene gel 0.3% daily
12% with adapalene gel 0.1% daily
5% with vehicle daily
Absolute numbers not reported

Significance not assessed
[48]
RCT
200 Japanese people with at least 30 acne lesions Adverse events related to study drugs 12 weeks
56/100 (56%) with adapalene gel 0.1% daily
8/99 (8%) with placebo (vehicle gel) daily
Further information on studies
Comment
Birth defects:
We found no RCTs assessing the risk of birth defects in women using topical retinoids. One non-systematic review found that oral retinoids were teratogenic in case reports and case series in humans, and in experimental studies in animals.[45] In the absence of data regarding the risk of birth defects, it is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.[7]
Clinical guide:
Topical retinoids or topical antibiotics are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the retinoid class, there is more evidence of benefit with topical tretinoin than with isotretinoin or adapalene. It is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.[7] Adapalene 0.3% is not available in the UK.
Substantive changes
Adapalene (topical) New evidence added.[48] Categorisation unchanged (Likely to be beneficial).

Azelaic acid (topical)
Summary
Topical azelaic acid reduces inflammatory and non-inflammatory lesions compared with placebo, but can cause itching, burning, stinging, and redness of the skin.
Topical azelaic acid has been associated with itching, stinging, burning, and erythema.
Benefits and harms
Azelaic acid versus placebo:
We found two systematic reviews, which compared topical azelaic acid 20% versus placebo.[16] [17] The first review (search date 1999)[16] identified two RCTs.[50] [51] The second review (search date 2004),[17] which had more stringent inclusion criteria than the earlier review, included one RCT[51] also identified by the earlier review.
Acne severity
Azelaic acid compared with placebo Topical azelaic acid may be more effective at 8 to 12 weeks at reducing the number of comedones and inflammatory lesions in people with moderate acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total lesion count
[51]
RCT
92 people with moderate acne
In review [16] [17]
Proportion of people who had a physician rating of response to treatment of "excellent" or "good" 12 weeks
28/43 (65%) with azelaic acid
18/49 (37%) with placebo

P = 0.05
Effect size not calculatedAzelaic acid
Non-inflammatory lesions
[51]
RCT
92 people with moderate acne
In review [16] [17]
Percentage reduction in comedones
56% with azelaic acid
0% with placebo

P = 0.05
Effect size not calculatedAzelaic acid
[50]
RCT
40 people, severity of acne unclear
In review [16]
Percentage reduction in non-inflammatory lesions 8 weeks
50% with azelaic acid
25% with placebo

P = 0.027
Effect size not calculatedAzelaic acid
Inflammatory lesions
[51]
RCT
92 people with moderate acne
In review [16] [17]
Percentage reduction in inflammatory lesions
72% with azelaic acid
47% with vehicle

P = 0.05
Effect size not calculatedAzelaic acid
[50]
RCT
40 people, severity of acne unclear
In review [16]
Percentage reduction in inflammatory lesions 8 weeks
50% with azelaic acid
12% with placebo

P = 0.001
Effect size not calculatedAzelaic acid
Patient perception of improvement
No data from the following reference on this outcome.[50] [51]
Psychological distress
No data from the following reference on this outcome.[50] [51]
Quality of life
No data from the following reference on this outcome.[50] [51]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[51]
RCT
92 people with moderate acne
In review [16] [17]
Proportion of people with burning
4/43 (9%) with azelaic acid
1/49 (2%) with vehicle

Significance not assessed
[51]
RCT
92 people with moderate acne
In review [16] [17]
Proportion of people with itching
2/43 (5%) with azelaic acid
0/49 (0%) with vehicle

Significance not assessed
[51]
RCT
92 people with moderate acne
In review [16] [17]
Proportion of people with erythema
2/43 (5%) with azelaic acid
1/49 (2%) with vehicle

Significance not assessed
[50]
RCT
40 people, severity of acne unclear
In review [16]
Itching and stinging 8 weeks
2/20 (10%) with azelaic acid
1/20 (5%) with placebo

Significance not assessed
Further information on studies
Comment
One non-systematic review of RCTs and uncontrolled studies found that 0% to 5% of people taking azelaic acid had scaling, 5% to 23% had burning, and 13% to 29% had itching.[52]
Clinical guide:
Azelaic acid is a similar type of treatment to benzoyl peroxide, but there is less evidence of benefit for azelaic acid than for benzoyl peroxide. It can also cause irritation, which is helped by reducing the frequency of application or temporarily discontinuing treatment.
Substantive changes
No new evidence

Erythromycin plus zinc (topical)
Summary
Topical antibiotics, such as erythromycin with zinc, reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions.
Benefits and harms
Topical erythromycin plus zinc versus placebo:
We found one systematic review (search date 1999, 2 RCTs, 222 people with mild to severe acne), which compared topical erythromycin 4% plus zinc acetate 1.2% versus placebo.[16] The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed.
Acne severity
Topical erythromycin plus zinc compared with placebo Topical erythromycin plus zinc may be more effective at reducing inflammatory and non-inflammatory lesions and at reducing overall acne severity at 10 to 12 weeks (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Reduction in severity measured by Cook's acne grading scale 10 weeks
46% with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
7% with topical vehicle plus oral placebo

P <0.001 for topical erythromycin plus zinc liquid plus oral placebo v topical vehicle plus oral placebo
Effect size not calculatedErythromycin plus zinc
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Reduction in severity measured by Cook's acne grading scale 10 weeks
33% with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
7% with topical vehicle plus oral placebo

P <0.01 for topical erythromycin plus zinc gel plus oral placebo v topical vehicle plus oral placebo
Effect size not calculatedErythromycin plus zinc
Non-inflammatory lesions
[54]
RCT
73 women with Cook's acne grade score 3 or more
In review [16]
Reduction in non-inflammatory lesions 12 weeks
61% with topical erythromycin plus zinc acetate
48% with vehicle

P <0.01
Effect size not calculatedErythromycin plus zinc
Inflammatory lesions
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Reduction in papules measured by Cook's acne grading scale 10 weeks
58% with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
25% with topical vehicle plus oral placebo

P <0.001 for topical erythromycin plus zinc liquid plus oral placebo v topical vehicle plus oral placebo
Effect size not calculatedErythromycin plus zinc
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Reduction in papules measured by Cook's acne grading scale 10 weeks
45% with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
25% with topical vehicle plus oral placebo

P <0.05 for topical erythromycin plus zinc gel plus oral placebo v topical vehicle plus oral placebo
Effect size not calculatedErythromycin plus zinc
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Reduction in pustules measured by Cook's acne grading scale 10 weeks
with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
with topical vehicle plus oral placebo
Absolute results not reported

Reported as not significant for topical erythromycin plus zinc liquid plus oral placebo v topical vehicle plus oral placebo
P value not reported
Not significant
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Reduction in pustules measured by Cook's acne grading scale 10 weeks
with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
with topical vehicle plus oral placebo
Absolute results not reported

Reported as not significant for topical erythromycin plus zinc gel plus oral placebo v topical vehicle plus oral placebo
P value not reported
Not significant
[54]
RCT
73 women with Cook's acne grade score 3 or more
In review [16]
Reduction in inflammatory lesions 12 weeks
73% with topical erythromycin (4%) plus zinc acetate (1.2%) twice daily
46% with vehicle

P <0.01
Effect size not calculatedErythromycin plus zinc
Patient perception of improvement
No data from the following reference on this outcome.[53] [54]
Psychological distress
No data from the following reference on this outcome.[53] [54]
Quality of life
No data from the following reference on this outcome.[53] [54]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[53]
RCT
4-armed trial
149 men, severity of acne unclear
In review [16]
Adverse effects 10 weeks
with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
with topical vehicle plus oral placebo
[54]
RCT
73 women with Cook's acne grade score 3 or more
In review [16]
Adverse effects 12 weeks
with topical erythromycin plus zinc acetate
with vehicle
Further information on studies
Comment
Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance in Propionibacterium acnes.[7] [29] One systematic review (search date 2003) has found evidence that the efficacy of topical erythromycin 1.5% to 2% has decreased over the period 1966 to 2003, which may be as a result of increasing bacterial resistance (see comment on topical erythromycin).[30]
Clinical guide:
Topical antibiotics or topical retinoids are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical clindamycin or erythromycin than with erythromycin plus zinc or tetracycline. However, there is some evidence that topical erythromycin may be less effective now than in the past, owing to increasing P acnes resistance. Erythromycin plus zinc is available as a formulated combination topical solution.
Substantive changes
No new evidence

Isotretinoin (topical)
Summary
Topical preparations of isotretinoin may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.
Topical isotretinoin has been associated with severe erythema, dryness, soreness, and burning.
Topical retinoids are not recommended in women of childbearing age who are not taking adequate contraceptive precautions, or during pregnancy.
Benefits and harms
Topical isotretinoin versus placebo:
We found one systematic review[16] (search date 1999, 3 RCTs,[20] [55] [56] 472 people with mild to moderate acne) and one subsequent RCT[32] comparing isotretinoin versus placebo (vehicle). The review did not perform a meta-analysis because of heterogeneity among the trials in methods of outcome assessment.[16]
Acne severity
Topical isotretinoin compared with placebo Topical isotretinoin may be more effective at reducing the number of inflammatory and non-inflammatory lesions at 12 weeks in people with mild to moderate acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[55]
RCT
313 people with moderate acne
In review [16]
Mean reduction in severity scores
40% with isotretinoin
20% with vehicle

Reported as significant
P value not reported
Effect size not calculatedIsotretinoin
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Mean change in severity scores 12 weeks
0 with isotretinoin
1 with vehicle

P <0.05 for isotretinoin v vehicle
Effect size not calculatedIsotretinoin
[32]
RCT
4-armed trial
160 people with mild to moderate acne Mean change in total lesion count from baseline 12 weeks
–21.52% (95% CI –32.44% to –10.60%) with isotretinoin
–10.82% (95% CI –24.29% to +2.65% with vehicle

Significance of between-group difference not assessed
Non-inflammatory lesions
[55]
RCT
313 people with moderate acne
In review [16]
Mean reduction in non-inflammatory lesions
46% with isotretinoin
14% with vehicle

Reported as significant
P value not reported
Effect size not calculatedIsotretinoin
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Mean change in number of non-inflammatory lesions 12 weeks
–47% with isotretinoin
+6% with vehicle

P = 0.01 for isotretinoin v vehicle
Effect size not calculatedIsotretinoin
[32]
RCT
4-armed trial
160 people with mild to moderate acne Mean change in non-inflammatory lesion count from baseline 12 weeks
–18.49 (95% CI –35.5 to –1.63) with isotretinoin
–7.07 (95% CI –28.31 to +14.16) with vehicle

Significance of between-group difference not assessed
Inflammatory lesions
[55]
RCT
313 people with moderate acne
In review [16]
Mean reduction in inflammatory lesions
55% with isotretinoin
25% with vehicle

Reported as significant
P value not reported
Effect size not calculatedIsotretinoin
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Mean change in number of inflammatory lesions 12 weeks
–33% with isotretinoin
+9% with vehicle

P = 0.01 for isotretinoin v vehicle
Effect size not calculatedIsotretinoin
[56]
RCT
3-armed trial
82 people with mild to moderate acne
In review [16]
Mean change in papules from baseline 12 weeks
–7.6 with isotretinoin 0.05%
–13.3 with isotretinoin 0.1%
–7.3 with placebo

Significance of differences between groups not assessed
[56]
RCT
3-armed trial
82 people with mild to moderate acne
In review [16]
Mean change in whiteheads from baseline 12 weeks
–9.6 with isotretinoin 0.05%
–9.4 with isotretinoin 0.1%
–2.6 with placebo

Significance of differences between groups not assessed
[32]
RCT
4-armed trial
160 people with mild to moderate acne Mean change in inflammatory lesion count from baseline 12 weeks
–15.66 (95% CI –27.71 to –3.62) with isotretinoin
–9.58 (95% CI –24.51 to +5.36) with vehicle

Significance of differences between groups not assessed
Patient perception of improvement
Topical isotretinoin compared with placebo We don't know whether topical isotretinoin is more effective at increasing the proportion of people who perceive their acne as improved at 12 weeks (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[32]
RCT
4-armed trial
160 people with mild to moderate acne Proportion of people who perceived that their acne had improved from baseline 12 weeks
66% with isotretinoin
53% with vehicle
Absolute numbers not reported

Significance not assessed
Psychological distress
No data from the following reference on this outcome.[20] [55] [56] [32]
Quality of life
No data from the following reference on this outcome.[20] [55] [56] [32]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Skin adverse effects
[55]
RCT
313 people with moderate acne
In review [16]
Proportion of people with peeling
71% with isotretinoin
51% with vehicle
Absolute numbers not reported

Significance not assessed
[55]
RCT
313 people with moderate acne
In review [16]
Proportion of people with erythema
76% with isotretinoin
62% with vehicle
Absolute numbers not reported

Significance not assessed
[20]
RCT
3-armed trial
77 people with mild to moderate acne
In review [16]
Adverse effects 12 weeks
with isotretinoin
with vehicle
[56]
RCT
3-armed trial
82 people with mild to moderate acne
In review [16]
Peeling 12 weeks
with isotretinoin 0.05%
with isotretinoin 0.1%
with placebo
Absolute results not reported

P <0.01
Unclear whether P value is for separate comparisons of isotretinoin v placebo or combined analysis of both isotretinoin groups versus placebo
[32]
RCT
4-armed trial
160 people with mild to moderate acne Overall tolerance 12 weeks
with isotretinoin
with vehicle

Reported as not significant
P value not reported
This RCT is likely to have been underpowered to detect a clinically important difference in adverse effects among treatments
Further information on studies
Comment
Birth defects:
In the absence of data regarding the risk of birth defects, it is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.[7]
Clinical guide:
Topical retinoids or topical antibiotics are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the retinoid class, there is more evidence of benefit with topical tretinoin than with isotretinoin or adapalene. It is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age who are not taking adequate contraceptive precautions.[7]
Substantive changes
No new evidence

Tetracycline (topical)
Summary
Tetracycline may reduce overall acne severity.
Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.
Tetracyclines may cause skin discoloration, and should be avoided in pregnant or breastfeeding women.
Benefits and harms
Topical tetracycline versus placebo:
We found one systematic review (search date 1999, 4 RCTs, 355 people with moderate to severe acne).[16] The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed.
Acne severity
Topical tetracycline compared with placebo Topical tetracycline may be more effective at reducing severity of acne at 12 to 16 weeks in people with mild to moderate acne (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[57]
RCT
3-armed trial
75 people
In review [16]
Mean reduction in severity 12 weeks
1.43 with topical tetracycline 0.5% plus oral placebo
0.62 with topical plus oral placebo

P <0.05
Effect size not calculatedTetracycline
[58]
RCT
3-armed trial
60 male adolescents
In review [16]
Proportion of people with improvement of at least 1 on a scale from 0 (least improvement) to 8 (most improvement)
14/19 (74%) with topical tetracycline plus oral placebo
6/17 (35%) with topical vehicle plus oral placebo

Significance not assessed
[59]
RCT
3-armed trial
135 people aged 18 to 25 years with mild to moderate acne
In review [16]
Acne severity 7, 10, and 12 weeks
with topical tetracycline 0.22% plus oral placebo
with topical vehicle plus oral placebo
Absolute results reported graphically

P <0.05
Effect size not calculatedTetracycline
[60]
RCT
85 people with mild to moderate acne
In review [16]
Proportion of people who had improved acne on a scale from 0 to 8 16 weeks
29/31 (94%) with topical tetracycline 2.2%
13/23 (57%) with placebo

P = 0.035
Effect size not calculatedTetracycline
Patient perception of improvement
Topical tetracycline compared with placebo Topical tetracycline may be no more effective at increasing the proportion of people who consider their condition better than before treatment (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[60]
RCT
85 people with mild to moderate acne
In review [16]
Proportion of people who considered that their condition was better than before treatment
25/31 (81%) with topical tetracycline
18/24 (75%) with placebo

Significance not assessed
No data from the following reference on this outcome.[57] [58] [59]
Psychological distress
No data from the following reference on this outcome.[57] [58] [59] [60]
Quality of life
No data from the following reference on this outcome.[57] [58] [59] [60]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Skin discoloration
[57]
RCT
3-armed trial
75 people
In review [16]
Skin discoloration
with topical tetracycline 0.5% plus oral placebo
with topical plus oral placebo
[59]
RCT
3-armed trial
135 people aged 18 to 25 years with mild to moderate acne
In review [16]
Skin discoloration
with topical tetracycline 0.22% plus oral placebo
with topical vehicle plus oral placebo
Absolute results reported graphically
[60]
RCT
85 people with mild to moderate acne
In review [16]
Proportion of people with skin discoloration
17/43 (40%) with topical tetracycline 2.2%
4/42 (10%) with placebo

P <0.005
Effect size not calculatedPlacebo
No data from the following reference on this outcome.[58]
Further information on studies
None.
Comment
Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance in Propionibacterium acnes.[7] [29]
Clinical guide:
Topical antibiotics or topical retinoids are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical clindamycin or erythromycin than with erythromycin plus zinc, or with tetracycline.
Substantive changes
No new evidence

Erythromycin (oral)
Summary
Oral erythromycin is considered useful for people with more severe acne, although we don't know for sure whether it is effective. Oral antibiotics can cause adverse effects such as contraceptive failure.
Benefits and harms
Oral erythromycin versus placebo:
We found two systematic reviews (search dates 2004;[17] not reported[61]), which identified no RCTs comparing oral erythromycin versus placebo. We found no subsequent RCTs.
Oral erythromycin versus oral doxycycline:
We found one RCT.[62]
Acne severity
Oral erythromycin compared with oral doxycycline We don’t know how oral erythromycin and oral doxycycline compare at reducing the number of papules and pustules at 6 weeks in people with moderate acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Inflammatory lesions
[62]
RCT
56 people with moderate acne Mean number of papules and pustules 6 weeks
16 with oral doxycycline (100 mg daily for 2 weeks, then on alternate days for 4 weeks)
15 with oral erythromycin (500 mg twice daily for 2 weeks, then 250 mg twice daily for 4 weeks)

P >0.1
Not significant
Patient perception of improvement
No data from the following reference on this outcome.[62]
Psychological distress
No data from the following reference on this outcome.[62]
Quality of life
No data from the following reference on this outcome.[62]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[62]
RCT
56 people with moderate acne Adverse effects 6 weeks
with doxycycline (100 mg daily for 2 weeks, then on alternate days for 4 weeks)
with erythromycin (500 mg twice daily for 2 weeks, then 250 mg twice daily for 4 weeks)
Oral erythromycin versus oral tetracycline:
We found two systematic reviews.[16] [17] The first review (search date 1999)[16] identified 3 RCTs (300 people)[63] [64] [65], which compared oral erythromycin versus oral tetracycline in people with mild, moderate, or severe acne. The second review (search date 2004),[17] which had more stringent inclusion criteria, included one RCT identified by the first review.[64]
Acne severity
Oral erythromycin compared with oral tetracycline We don’t know how oral erythromycin and oral tetracycline compare at improving inflammation scores at 6 months, or at reducing the number of pustules, papules, or open or closed comedones at 12 weeks in people with moderate to severe acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[63]
RCT
60 people with moderate to severe acne
In review [16]
Proportion of people symptom-free 6 months
9/21 (43%) with erythromycin 200 to 400 mg daily
7/21 (33%) with tetracycline 250 to 400 mg daily

Reported as not significant
P value not reported
Not significant
[65]
RCT
40 people with mild, moderate, or severe acne
In review [16]
Proportion with "good" or "very good" response as assessed by their physician 16 weeks
65% with erythromycin 250 mg twice daily
90% with tetracycline 250 mg twice daily

Significance not assessed
Non-inflammatory lesions
[64]
RCT
200 people with moderate to severe acne
In review [16] [17]
Percentage change in open comedones 12 weeks
–26% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–31% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)

Reported as not significant
P value not reported
Not significant
[64]
RCT
200 people with moderate to severe acne
In review [16] [17]
Percentage change in closed comedones 12 weeks
–17% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–36% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)

Reported as not significant
P value not reported
Not significant
Inflammatory lesions
[63]
RCT
60 people with moderate to severe acne
In review [16]
Inflammation score on face 6 months
1 with erythromycin 200 to 400 mg daily
1 with tetracycline 250 to 400 mg daily

Reported as not significant
P value not reported
Not significant
[64]
RCT
200 people with moderate to severe acne
In review [16] [17]
Percentage change in papules 12 weeks
–60% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–62% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)

Reported as not significant
P value not reported
Not significant
[64]
RCT
200 people with moderate to severe acne
In review [16] [17]
Percentage change in pustules 12 weeks
–73% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–65% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)

Reported as not significant
P value not reported
Not significant
Patient perception of improvement
Oral erythromycin compared with oral tetracycline Oral erythromycin and oral tetracycline are equally effective at increasing the proportion of people with moderate to severe acne who perceive their acne as markedly improved or improved at 12 weeks (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[64]
RCT
200 people with moderate to severe acne
In review [16] [17]
Proportion of people who reported acne as "markedly improved" or "improved" 12 weeks
77% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
89% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)

Reported as not significant
P value not reported
Not significant
No data from the following reference on this outcome.[63] [65]
Psychological distress
No data from the following reference on this outcome.[63] [64] [65]
Quality of life
No data from the following reference on this outcome.[63] [64] [65]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[63]
RCT
60 people with moderate to severe acne
In review [16]
Adverse effects
with erythromycin 200 to 400 mg daily
with tetracycline 250 to 400 mg daily
[64]
RCT
200 people with moderate to severe acne
In review [16] [17]
Number of people reporting an adverse effect
12 with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
7 with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
[65]
RCT
40 people with mild, moderate, or severe acne
In review [16]
Adverse effects
with erythromycin 250 mg twice daily
with tetracycline 250 mg twice daily
Further information on studies
None.
Comment
Propionibacterium acnes is becoming increasingly resistant to systemic antibiotics. One systematic review (search date 1998, 12 studies) found an increase in the prevalence of P acnes resistance from 20% in 1978 to 62% in 1996.[66] Resistance to systemic antibiotics varied, but was most commonly reported in people taking erythromycin, clindamycin, tetracycline, doxycycline, and trimethoprim. Resistance to minocycline was rare.
Clinical guide:
Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and can be supplemented by non-antibiotic topical treatment (e.g., benzoyl peroxide) if needed. There is evidence that erythromycin is effective, but there are some concerns about bacterial resistance. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.
Substantive changes
No new evidence

Doxycycline (oral)
Summary
Oral doxycycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.
Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.
Benefits and harms
Oral doxycycline versus placebo:
We found 3 systematic reviews (search dates 1999,[16] 2004,[17] not reported[61]), which between them identified two RCTs comparing doxycycline versus placebo.[67] [68]
Acne severity
Oral doxycycline compared with placebo Oral doxycycline may be more effective than placebo at improving clinician's global assessment and inflammatory and non-inflammatory lesions after 6 months in people with moderate acne. However, we don’t know whether oral doxycycline is more effective at reducing the number of inflammatory lesions at 4 weeks in people with mild acne (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total lesion count
[68]
RCT
51 people with moderate acne
In review [17] [61]
Clinician’s global assessment scores 6 months
4.4 with doxycycline 20 mg twice daily
5.1 with placebo

P = 0.03
Effect size not calculatedDoxycycline
Inflammatory lesions
[67]
RCT
Crossover design
62 people with mild acne
In review [16] [61]
Percentage change in the number of inflammatory lesions from baseline 4 weeks
–36% with oral doxycycline 100 mg daily
+12% with placebo

Significance of between-group difference not assessed
The RCT had large loss to follow-up (no further data reported)
[68]
RCT
51 people with moderate acne
In review [17] [61]
Reduction in inflammatory lesions 6 months
50% with doxycycline 20 mg twice daily
30% with placebo

P = 0.04
Effect size not calculatedDoxycycline
Non-inflammatory lesions
[68]
RCT
51 people with moderate acne
In review [17] [61]
Reduction in comedones 6 months
54% with doxycycline 20 mg twice daily
11% with placebo

P <0.01
Effect size not calculatedDoxycycline
Patient perception of improvement
Oral doxycycline compared with placebo We don’t know whether oral doxycycline is more effective at improving patient perception of acne at 6 months in people with moderate acne (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[68]
RCT
51 people with moderate acne
In review [17] [61]
Patient perception of improvement 6 months
4.8 with doxycycline 20 mg twice daily
5.3 with placebo

Reported as not significant
P value and CI not reported
Not significant
No data from the following reference on this outcome.[67]
Psychological distress
No data from the following reference on this outcome.[67] [68]
Quality of life
No data from the following reference on this outcome.[67] [68]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[67]
RCT
Crossover design
62 people with mild acne
In review [16] [61]
Adverse effects
with oral doxycycline 100 mg daily
with placebo

The RCT had large loss to follow-up (no further data reported)
The RCT may have been underpowered to detect a difference in adverse effects
No data from the following reference on this outcome.[68]
Oral doxycycline versus oral erythromycin:
See option on oral erythromycin.
Oral doxycycline versus oral minocycline:
See option on oral minocycline.
Oral doxycycline versus oral oxytetracycline:
We found one double-blind RCT.[69]
Acne severity
Oral doxycycline compared with oral oxytetracycline We don’t know how oral doxycycline and oral oxytetracycline compare at reducing the number of lesions at 8 weeks in people with moderate to severe acne (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[69]
RCT
Crossover design
28 people with moderate to severe acne Mean number of lesions per person 8 weeks
62 with oral doxycycline (100 mg daily for 8 weeks)
32 with oral oxytetracycline (250 mg 3 times daily for 4 weeks then once daily for 4 weeks)

Reported as not significant
P value not reported
Not significant
Patient perception of improvement
No data from the following reference on this outcome.[69]
Psychological distress
No data from the following reference on this outcome.[69]
Quality of life
No data from the following reference on this outcome.[69]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[69]
RCT
Crossover design
28 people with moderate to severe acne Adverse effects
with oral doxycycline (100 mg daily for 8 weeks)
with oral oxytetracycline (250 mg 3 times daily for 4 weeks then once daily for 4 weeks)
Further information on studies
Comment
See comment on oral erythromycin regarding antibiotic resistance.
Clinical guide:
Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and can be supplemented by non-antibiotic topical treatment (e.g., benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) offer benefits, but have differing adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.[70] [71] Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.
Substantive changes
Doxycycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

Lymecycline (oral)
Summary
Oral lymecycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.
Oral antibiotics can cause adverse effects such as contraceptive failure.
Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.
Benefits and harms
Oral lymecycline versus placebo:
We found one systematic review (search date 1999), which identified no RCTs comparing oral lymecycline versus placebo.[16] We found no subsequent RCTs.
Oral lymecycline versus oral minocycline:
See option on oral minocycline.
Further information on studies
Comment
Clinical guide:
Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g., benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.[70] [71] Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.
Substantive changes
Lymecycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

Minocycline (oral)
Summary
Oral minocycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.
Oral antibiotics can cause adverse effects such as contraceptive failure.
Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.
Minocycline has been associated with an increased risk of systemic lupus erythematosus, and of liver disorders.
Benefits and harms
Oral minocycline versus placebo:
We found one systematic review (search date 2002),[73] which identified one crossover RCT. We also found a pooled analysis of 3 RCTs comparing minocycline (extended-release formulation) versus placebo, reported in one publication.[74] One of the RCTs was a 4-armed phase 2 trial comparing minocycline at 3 different doses (1, 2, or 3 mg/kg/day) versus placebo; however, only the data on minocycline 1 mg/kg/day versus placebo (114 people) were included in the pooled analysis. The other two RCTs (924 people) were phase 3 trials comparing minocycline 1 mg/kg/day versus placebo. For additional information on harms of minocycline, in particular systemic lupus erythematosus and liver toxicity from observational studies, see comments.
Acne severity
Oral minocycline compared with placebo Oral minocycline may be more effective at reducing the number of inflammatory lesions and total number of lesions at 12 weeks (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[75]
RCT
Crossover design
50 people, 43 completed
In review [73]
Total lesion score (compared with baseline score of 100%) 5 weeks
60% with oral minocycline (200 mg daily for first 7 days, then 100 mg daily)
84% with placebo
Absolute results not reported

No direct comparison between groups
The RCT was of insufficient duration to adequately assess the effects of minocycline
[74] 1038 people with moderate or severe facial acne Reduction from baseline in total number of lesions 12 weeks
33% with extended-release minocycline (1 mg/kg daily)
22% with placebo
Absolute numbers not reported

P <0.001
Effect size not calculatedMinocycline
Inflammatory lesions
[74] 1038 people with moderate or severe facial acne Reduction in number of inflammatory lesions from baseline 12 weeks
46% with extended-release minocycline (1 mg/kg daily)
32% with placebo
Absolute numbers not reported

P <0.001
Effect size not calculatedMinocycline
Patient perception of improvement
No data from the following reference on this outcome.[75] [74]
Psychological distress
No data from the following reference on this outcome.[75] [74]
Quality of life
No data from the following reference on this outcome.[75] [74]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall adverse effects
[74] 1038 people with moderate or severe facial acne Adverse effects 12 weeks
56% with minocycline
54% with placebo

Significance not assessed
No data from the following reference on this outcome.[75]
Oral minocycline versus oral doxycycline:
We found two systematic reviews (search dates 2002, 5 RCTs;[73] 2006, 1 RCT [also identified by the first review][72]) comparing oral minocycline versus oral doxycycline. The first review did not perform a meta-analysis because of heterogeneity among the trials in methods, outcomes assessed, and drug doses. It found problems with the methods used in all of the RCTs: 3 were open label, and the two double-blind RCTs reported insufficient information to allow calculation of effect sizes.[73] Similarly, the second systematic review did not perform a meta-analysis.[72] Only one RCT (identified by both reviews) fulfilled Clinical Evidence inclusion criteria.[76]
Acne severity
Oral minocycline compared with oral doxycycline We don't know how oral minocycline and oral doxycycline compare at decreasing the total number of lesions or the number of papules or pustules, or open or closed comedones on the face, back, and chest after 12 weeks (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[76]
RCT
79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72]
Number of all lesions on the face, back, and chest 12 weeks
with oral minocycline
with oral doxycycline
Absolute results reported graphically

Reported as no significant difference
Not significant
Inflammatory lesions
[76]
RCT
79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72]
Number of papules and pustules on the face, back, and chest 12 weeks
with oral minocycline
with oral doxycycline
Absolute results reported graphically

Reported as no significant difference
Not significant
Non-inflammatory lesions
[76]
RCT
79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72]
Number of all open comedones and closed comedones on the face, back, and chest 12 weeks
with oral minocycline
with oral doxycycline (mean dosage 66 mg)
Absolute results reported graphically

Reported as no significant difference
Not significant
Patient perception of improvement
Oral minocycline compared with oral doxycycline We don't know how oral minocycline and oral doxycycline compare at increasing patient perception of improvement (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[76]
RCT
79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72]
Proportion of patients who evaluated treatment as effective or very effective 12 weeks
90% with oral minocycline
85% with oral tetracycline
Absolute results reported graphically

Statistical assessment not reported
Psychological distress
No data from the following reference on this outcome.[76]
Quality of life
No data from the following reference on this outcome.[76]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[76]
RCT
79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72]
Adverse effects 12 weeks
with oral minocycline
with oral doxycycline
Absolute results reported graphically
Oral minocycline versus oral lymecycline:
We found two systematic reviews (search dates 2002, 2 RCTs [1 RCT also identified by the second review];[73] 2006, 3 RCTs[72]) comparing oral minocycline versus oral lymecycline. Neither of the reviews pooled the data, and so we have reported those RCTs that agreed with Clinical Evidence inclusion criteria.
Acne severity
Oral minocycline compared with oral lymecycline Oral minocycline and oral lymecycline seem equally effective at 12 weeks at increasing the proportion of people with 50% or greater reduction in inflammatory or non-inflammatory lesions (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Total count
[77]
RCT
144 people with at least 20 inflammatory lesions on the face
In review [73] [72]
Overall reduction in total lesion count 12 weeks
43% with minocycline
45% with lymecycline

Reported as no significant difference between groups
Intention-to-treat analysis
Not significant
[78]
RCT
136 people randomised
In review [72]
Mean reduction in total lesion count from baseline 12 weeks
–55% with minocycline (100 mg daily)
–56% with lymecycline (300 mg daily)
Absolute numbers not reported

Difference –0.29
95% CI –10.53 to +9.95
Intention-to-treat analysis
Not significant
Non-inflammatory lesions
[77]
RCT
144 people with at least 20 inflammatory lesions on the face
In review [73] [72]
Overall reduction in non-inflammatory lesion count 12 weeks
32% with minocycline
41% with lymecycline

P = 0.093
Intention-to-treat analysis
Not significant
[78]
RCT
136 people randomised
In review [72]
Mean reduction in non-inflammatory lesion count from baseline 12 weeks
–47% with minocycline (100 mg daily)
– 54% with lymecycline (300 mg daily)
Absolute numbers not reported

95% CI –23.8 to +8.1
Intention-to-treat analysis
Not significant
[79]
RCT
3-armed trial
86 people, 68 completed
In review [72]
Total lesion count 12 weeks
with minocycline (100 mg daily for 4 weeks followed by 50 mg daily for 8 weeks)
with lymecycline (300 mg daily for 12 weeks)
Absolute results reported graphically

P (minocycline 100 mg/50 mg v lymecycline) <0.05
Effect size not calculatedMinocycline 100 mg/50 mg
[79]
RCT
3-armed trial
86 people, 68 completed (week 12)
In review [72]
Total lesion count 12 weeks
with minocycline (50 mg daily for 12 weeks)
with lymecycline (300 mg daily for 12 weeks)
Absolute results reported graphically

Reported as no clinically relevant difference between minocycline 50 mg v lymecycline
Inflammatory lesions
[77]
RCT
144 people with at least 20 inflammatory lesions on the face
In review [73] [72]
Overall reduction in inflammatory lesion count 12 weeks
52.2% with minocycline
50.6% with lymecycline

Reported as no significant difference between groups
Intention-to-treat analysis
Not significant
[78]
RCT
136 people randomised
In review [72]
Mean reduction in inflammatory count from baseline 12 weeks
–64.5% with minocycline (100 mg daily)
–58.7% with lymecycline (300 mg daily)
Absolute numbers not reported

Difference +2.32
95% CI –9.59 to +14.22
Intention-to-treat analysis
Not significant
Patient perception of improvement
Oral minocycline compared with oral lymecycline Oral minocycline and oral lymecycline seem equally effective at 12 weeks at increasing the proportion of people who perceive an overall improvement in their acne (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[77]
RCT
144 people with at least 20 inflammatory lesions on the face
In review [73] [72]
Proportion of patients who considered their condition to have improved, much improved, or cleared 12 weeks
83% with minocycline
85% with lymecycline
Absolute numbers not reported

Reported no significant difference between groups
Not significant
[78]
RCT
136 people randomised
In review [72]
Proportion of patients who considered their condition to have improved, much improved, or cleared 12 weeks
44/68 (65%) with minocycline (100 mg daily)
57/66 (86%) with lymecycline (300 mg daily)
Psychological distress
No data from the following reference on this outcome.[73]
Quality of life
No data from the following reference on this outcome.[73]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[78]
RCT
136 people randomised
In review [72]
Proportion of people with at least 1 adverse effect 12 weeks
20/68 (29%) with minocycline (100 mg daily)
18/66 (27%) with lymecycline (300 mg daily)
Oral minocycline versus oral oxytetracycline:
We found one systematic review (search date 2002), which identified one open-label RCT comparing oral minocycline versus oral oxytetracycline that did not meet Clinical Evidence inclusion criteria.[73]We found one subsequent RCT.[80]
Acne severity
No data from the following reference on this outcome.[80]
Patient perception of improvement
Oral minocycline compared with oral oxytetracycline Oral minocycline seems no more effective at increasing the proportion of people who report moderate improvement at 18 weeks (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[80]
RCT
5-armed trial
649 people with mild to moderate acne (Leeds acne grade 3 or less) Proportion of people reporting at least moderate improvement in facial acne 18 weeks
70/130 (54%) with oral minocycline 100 mg once daily plus topical placebo
72/131 (55%) with oral oxytetracycline 500 mg twice daily plus topical placebo

OR 0.95
95% CI 0.58 to 1.55
Not significant
Psychological distress
No data from the following reference on this outcome.[80]
Quality of life
No data from the following reference on this outcome.[80]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Skin adverse effects
[80]
RCT
5-armed trial
649 people with mild to moderate acne (Leeds acne grade 3 or less) Skin adverse effects 18 weeks
4% with oral minocycline 100 mg once daily plus topical placebo
4% with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported

Significance not assessed
Gastrointestinal adverse effects
[80]
RCT
5-armed trial
649 people with mild to moderate acne (Leeds acne grade 3 or less) Gastrointestinal adverse effects 18 weeks
9% with oral minocycline 100 mg once daily plus topical placebo
8% with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported

Significance not assessed
Central nervous system adverse events
[80]
RCT
5-armed trial
649 people with mild to moderate acne (Leeds acne grade 3 or less) Central nervous system adverse events 18 weeks
11% with oral minocycline 100 mg once daily plus topical placebo
17% with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported

Significance not assessed
Musculoskeletal symptoms
[80]
RCT
5-armed trial
649 people with mild to moderate acne (Leeds acne grade 3 or less) Proportion of people with musculoskeletal symptoms week 12
2% with oral minocycline 100 mg once daily plus topical placebo
with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
[80]
RCT
5-armed trial
649 people with mild to moderate acne (Leeds acne grade 3 or less) Proportion of people with musculoskeletal symptoms week 18
4% with oral minocycline 100 mg once daily plus topical placebo
with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
Oral minocycline versus oral tetracycline:
We found two systematic reviews (search dates 2002, 6 RCTs;[73] 2006, 5 RCTs [all of which were also identified by the first review][72]) comparing oral minocycline versus oral tetracycline. The reviews did not perform meta-analyses because of heterogeneity among the trials in outcomes assessed. We have reported those RCTs that satisfy Clinical Evidence inclusion criteria.
Acne severity
Oral minocycline compared with oral tetracycline Oral minocycline and oral tetracycline seem equally effective at improving overall acne severity assessed on a variety of scales (including the Samuelson Lesion Scale) (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[73]
Systematic review
100 people randomised, 82 people completed
Data from 1 RCT
Investigator assessed improvement 12 weeks
32/50 (64%) with minocycline (100 mg daily)
36/50 (72%) with tetracycline (500 mg daily)

OR 0.69
95% CI 0.30 to 1.61
(Absolute numbers and statistics from systematic review as we were unable to access the original text of this RCT)
Not significant
[81]
RCT
62 college students with moderate to severe inflammatory acne
In review [73] [72]
Investigator assessed severity scores (change from baseline) 12 weeks
from 5.50 to 2.88 with minocycline (50 mg twice daily)
from 5.04 to 2.85 with tetracycline (250 mg twice daily)

Reported as no significant difference between groups
Not significant
Patient perception of improvement
Oral minocycline compared with oral tetracycline We don't know how oral minocycline and oral tetracycline compare at increasing the proportion of people with moderate to severe acne who report an overall improvement or rate response as satisfactory (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[81]
RCT
62 college students with moderate to severe inflammatory acne
In review [73] [72]
Patient assessed severity scores (change from baseline) 12 weeks
from 5.32 to 3.27 with minocycline (50 mg twice daily)
from 4.89 to 3.48 with tetracycline (250 mg twice daily)

Reported as no significant difference between groups
Not significant
[73]
Systematic review
100 people randomised, 82 people completed
Data from 1 RCT
Patient perception of improvement 20 weeks
with minocycline (100 mg daily)
with tetracycline (500 mg daily)
Not significant
Psychological distress
No data from the following reference on this outcome.[73]
Quality of life
No data from the following reference on this outcome.[73]
Adverse effects
No data from the following reference on this outcome.[73]
Further information on studies
Comment
See comment on oral erythromycin regarding antibiotic resistance.
Adverse effects:
We found 3 systematic reviews assessing the adverse effects of minocycline.[73] [82] [83] The first review (search date 2002) pooled data on adverse effects of minocycline from 21 RCTs examining minocycline versus control (placebo or other oral or topical treatments).[73] It found that 137/1230 (11%) people had an adverse reaction attributed to minocycline, 36/1230 (3%) of whom withdrew because of adverse effects. It also found that 17/700 (2%) people taking minocycline had abnormal pigmentation.[73] One prospective cohort study identified by the review (700 people) assessed adverse effects in people taking minocycline 100 to 200 mg daily for a mean 10.5 months.[84] It found that adverse effects were reported in 13.6% of people. They included vestibular disturbance, candida infection, gastrointestinal disturbance, cutaneous symptoms (pigmentation, pruritus, photosensitive rash, and urticaria), and benign intracranial hypertension.
Systemic lupus erythematosus (SLE):
We found two systematic reviews.[73] [82] The first review[73] identified one case control study[85] (27,688 people aged 15–19 years with acne) assessing the risk of SLE in people taking tetracyclines compared with matched controls. Women had a significantly higher risk of developing SLE compared with men (RR 14, 95% CI 1.8 to 111). The case control study found that 29 people (27 women) taking tetracyclines had an SLE-like syndrome. It found that current minocycline use significantly increased the risk of developing SLE (AR 52.8 cases per 100,000 prescriptions; RR 8.5, 95% CI 2.1 to 35). It found no significant difference in the risk of developing SLE with tetracyclines other than minocycline, although use of tetracyclines was associated with an increased risk (RR 1.7, 95% CI 0.4 to 8.1). Cumulative minocycline dose and prolonged exposure (more than 100 days) to minocycline may also be risk factors, but no quantitative data were reported. The second review (search date 1999) identified 57 case reports of SLE in people taking minocycline.[82] It suggested that minocycline may induce SLE, but did not quantify its conclusions. Evidence about adverse effects should be interpreted with caution because of wide variation between studies in numbers of reported adverse events. The prevalence of SLE in the general population is 30/100,000 in white people, rising to 200/100,000 in Afro-Caribbean people.[86]
Liver damage:
We found one systematic review (search date 1998) of case reports and case series, which found 65 cases of liver damage in people taking minocycline.[83] The review did not quantify the increased risk in people taking minocycline. It suggested that minocycline was associated with severe hepatic dysfunction, including hypersensitivity, within a few weeks of taking minocycline (16 cases), autoimmune hepatitis within 1 year or more of taking minocycline (29 cases), or unspecified hepatitis (20 cases).
Clinical guide:
Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g., benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Current clinical guidance in the UK suggests that people taking minocycline for more than 6 months should be monitored for hepatotoxicity, pigmentation, and SLE.[87] Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.[70] [71] They may cause contraceptive failure during the initial weeks of treatment.
Substantive changes
Minocycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

Oxytetracycline (oral)
Summary
Oral oxytetracycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.
Oral antibiotics can cause adverse effects such as contraceptive failure.
Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.
Benefits and harms
Oral oxytetracycline versus placebo:
We found one systematic review (search date not reported),[61] which identified no RCTs comparing oral oxytetracycline versus placebo. We found no subsequent RCTs.
Oral oxytetracycline versus oral minocycline:
See option on oral minocycline.
Oral oxytetracycline versus oral doxycycline:
See option on oral doxycycline.
Further information on studies
Comment
See comment on oral erythromycin regarding antibiotic resistance.
Clinical guide:
Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g., benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.[70] [71] Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.
Substantive changes
No new evidence

Tetracycline (oral)
Summary
Oral tetracycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective. Oral antibiotics can cause adverse effects such as contraceptive failure.
Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.
Benefits and harms
Oral tetracycline versus placebo:
We found 3 systematic reviews.[16] [17] [61] The first review (search date 1999, 7 RCTs, 864 people with mild, moderate, or severe acne) compared oral tetracycline 250 mg twice daily versus placebo.[16] The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed. The second review (search date 2004),[17] which had more stringent inclusion criteria, identified one RCT included in the earlier review.[23] The third review (search date not reported) did not include any further RCTs.[61]
Acne severity
Oral tetracycline compared with placebo Oral tetracycline may be more effective at reducing severity of acne at 6 to 13 weeks in people with acne (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Overall severity
[26]
RCT
3-armed trial
367 people with moderate to severe acne
In review [16]
Proportion for whom physician assessment of treatment was "excellent" or "good"
64% with oral tetracycline
46% with placebo

P <0.05
Effect size not calculatedTetracycline
[57]
RCT
3-armed trial
75 people with moderate acne
In review [16]
Mean reduction in acne severity grade measured on a scale from 0 (least severe) to 8 (most severe) 6 weeks
1.14 with oral tetracycline 250 mg twice daily plus topical placebo
0.43 with topical plus oral placebo

P <0.05
Effect size not calculatedTetracycline
[57]
RCT
3-armed trial
75 people with moderate acne
In review [16]
Mean reduction in acne severity grade measured on a scale from 0 (least severe) to 8 (most severe) 13 weeks
1.91 with oral tetracycline 250 mg twice daily plus topical placebo
0.62 with topical plus oral placebo

P <0.05
Effect size not calculatedTetracycline
[58]
RCT
3-armed trial
60 male adolescents with mild to moderate acne
In review [16]
Improvement from baseline of 1 or more on a scale from 0 to 8 8 weeks
12/18 (67%) with oral tetracycline plus topical vehicle
6/17 (35%) with oral placebo plus topical vehicle

Significance not assessed
[59]
RCT
3-armed trial
135 people aged 18 to 25 years with mild to moderate acne, Cook's grades 0 to 8
In review [16]
Acne severity 7 weeks
with oral tetracycline plus topical vehicle
with topical vehicle plus oral placebo
Absolute results reported graphically

P <0.05
Effect size not calculatedTetracycline
[59]
RCT
3-armed trial
135 people aged 18 to 25 years with mild to moderate acne, Cook's grades 0 to 8
In review [16]
Acne severity 10 weeks
with oral tetracycline plus topical vehicle
with topical vehicle plus oral placebo
Absolute results reported graphically

P <0.05
Effect size not calculatedTetracycline
[59]
RCT
3-armed trial
135 people aged 18 to 25 years with mild to moderate acne, Cook's grades 0 to 8
In review [16]
Acne severity 12 weeks
with oral tetracycline plus topical vehicle
with topical vehicle plus oral placebo
Absolute results reported graphically

P <0.05
Effect size not calculatedTetracycline
[88]
RCT
51 people (severity of acne unclear)
In review [16]
Change in Pillsbury modified score 12 weeks
–2 with tetracycline 250 mg twice daily
0 with placebo

P = 0.001
Effect size not calculatedTetracycline
[88]
RCT
51 people (severity of acne unclear)
In review [16]
Proportion of people assessed as "improved" 12 weeks
23/24 (96%) with tetracycline 250 mg twice daily
15/27 (56%) with placebo

P = 0.01
Effect size not calculatedTetracycline
Inflammatory lesions
[23]
RCT
3-armed trial
108 people with mild to moderate acne
In review [16] [17]
Mean inflammatory lesion count (change from baseline) 8 weeks
2.66 with oral tetracycline 500 mg twice daily
6.24 with placebo

Significance of between-group difference not assessed
RCT designed to compare oral tetracycline v topical clindamycin
[89]
RCT
4-armed trial
68 people with mild to moderate acne
In review [16]
Percentage reduction in inflammatory lesions 8 weeks
26% with tetracycline plus placebo
16% with placebo

Reported as not significant
P value not reported
RCT may have lacked power to detect a clinically important difference among groups
Not significant
Patient perception of improvement
Oral tetracycline compared with placebo Oral tetracycline seems more effective at increasing the proportion of people with moderate to severe acne who perceive their acne as markedly improved or improved at 8 weeks (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patient perception of improvement
[23]
RCT
3-armed trial
108 people with mild to moderate acne
In review [16] [17]
"Markedly improved" or "improved" from baseline
72% with oral tetracycline 500 mg twice daily
3% with placebo

Significance of between-group difference not assessed
RCT designed to compare oral tetracycline v topical clindamycin
[26]
RCT
3-armed trial
367 people with moderate to severe acne
In review [16]
Proportion of people who thought their acne was "markedly improved" or "improved"
84% with oral tetracycline
57% with placebo

P <0.05
Effect size not calculatedTetracycline
No data from the following reference on this outcome.[57] [58] [59] [88] [89]
Psychological distress
No data from the following reference on this outcome.[23] [26] [57] [58] [59] [88] [89]
Quality of life
No data from the following reference on this outcome.[23] [26] [57] [58] [59] [88] [89]
Adverse effects
No data from the following reference on this outcome.[23] [26] [57] [58] [59] [88] [89]
Oral tetracycline versus oral erythromycin:
See option on oral erythromycin.
Oral tetracycline versus oral minocycline:
See option on oral minocycline.
Oral tetracycline versus oral isotretinoin:
See option on oral retinoids
Further information on studies
The RCT reported in the discussion section of the article that patient perception of improvement was "close" to clinical assessment; no further data provided.
Comment
See comment on oral erythromycin regarding antibiotic resistance.
Clinical guide:
Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g., benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.
Substantive changes
Tetracycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

Isotretinoin (oral)
Summary
Oral isotretinoin is teratogenic and is associated with a wide range of adverse effects, such as skin problems, changes in liver function, and development of psychiatric disorders.
Benefits and harms
Oral isotretinoin versus placebo:
We found one RCT.[90] For additional information from observational studies on harms of isotretinoin, see comment.
Acne severity
Oral isotretinoin compared with placebo Oral isotretinoin is more effective at reducing nodules at 1 month in people with treatment-resistant cystic and conglobate acne (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Nodules
[90]
RCT
33 people with treatment-resistant cystic and conglobate acne Mean change in nodules 1 month
–32% with oral isotretinoin (0.5 mg/kg/day)
+33% with placebo group
Absolute numbers not reported

P <0.008
Effect size not calculatedIsotretinoin
Patient perception of improvement
No data from the following reference on this outcome.[90]
Psychological distress
No data from the following reference on this outcome.[90]
Quality of life
No data from the following reference on this outcome.[90]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[90]
RCT
33 people with treatment-resistant cystic and conglobate acne Adverse effects
with oral isotretinoin (0.5 mg/kg/day)
with placebo group
Absolute results not reported
Oral isotretinoin versus oral tetracycline:
We found one small RCT.[91] For additional information from observational studies on harms of isotretinoin, see comment.
Acne severity
Oral isotretinoin compared with oral tetracycline Oral isotretinoin is more effective at reducing acne cysts, pustules, and comedones at 24 weeks in people with severe nodulocystic acne (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Inflammatory lesions
[91]
RCT
29 people with severe nodulocystic acne Reduction in acne cysts 24 weeks
82% with oral isotretinoin (1–2 mg/kg/day)
52% with oral tetracycline (0.5–1 mg/day)
Absolute numbers not reported

P <0.01
Effect size not calculatedIsotretinoin
[91]
RCT
29 people with severe nodulocystic acne Reduction in pustules and comedones 24 weeks
85% with oral isotretinoin (1–2 mg/kg/day)
58% with oral tetracycline (0.5–1 mg/day)
Absolute numbers not reported

P <0.01
Effect size not calculatedIsotretinoin
Patient perception of improvement
No data from the following reference on this outcome.[91]
Psychological distress
No data from the following reference on this outcome.[91]
Quality of life
No data from the following reference on this outcome.[91]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[91]
RCT
29 people with severe nodulocystic acne Xerosis
15/15 (100%) with isotretinoin
2/15 (13%) with oral tetracycline

Significance not assessed
[91]
RCT
29 people with severe nodulocystic acne Cheilitis/dry lips
15/15 (100%) with isotretinoin
3/15 (20%) with oral tetracycline

Significance not assessed
[91]
RCT
29 people with severe nodulocystic acne Dry nose
10/15 (67%) with isotretinoin
1/15 (7%) with oral tetracycline

Significance not assessed
[91]
RCT
29 people with severe nodulocystic acne Dry mouth
3/15 (20%) with isotretinoin
1/15 (7%) with oral tetracycline

Significance not assessed
[91]
RCT
29 people with severe nodulocystic acne Adverse effects (other)
with isotretinoin
with oral tetracycline
Absolute results not reported

Significance not assessed
Further information on studies
An open phase extension to this RCT for a further 2 to 4 months showed further improvement in the treatment group as dose increased to a mean of 0.9 mg/kg/day.
Comment
Skin:
Dry skin and mucosal surfaces are a well-known adverse effect of isotretinoin treatment. We found one open study (80 people with a range of acne types failing to respond to oral antibiotics) of intermittent dosing with isotretinoin 0.5 mg/kg/daily (1 week in 4 for 6 months), to determine the relative efficacy versus adverse effects.[92] Although there was no control group, the authors reported modest cheilitis at the lower end of the spectrum for isotretinoin adverse effects.[92]
Liver function:
Isotretinoin treatment affects the metabolic system, and is reflected in altered liver function tests and elevated blood lipids. We found one retrospective analysis of people receiving isotretinoin for acne to determine the necessity for routine testing of lipid profiles and liver function during treatment. The 209 people in the study included 113 people treated with 1 mg/kg/day, and 96 people treated with 0.5 mg/kg/day, who had serial fasting blood samples taken at 0, 8, and 16 weeks. The study found no significant changes in any of the tests of liver function. It concluded that, if the baseline tests are normal, in the absence of clinical indicators or doses greater than 1 mg/kg, it is safe to measure just once at about 4 weeks. For prolonged doses, or where there are pre-existing abnormalities or higher doses, more frequent testing may be warranted.[93]
Pregnancy (teratogenesis):
Isotretinoin is teratogenic. We found two studies evaluating the effect of isotretinoin treatment on pregnancy and unborn infants. The first study (24,503 women self-registered for a pregnancy prevention programme) found that, in 402 pregnancies, 32 went to term; 13 of the infants were examined for teratogenic effects, revealing changes in 5/32.[94] In the second study (8609 women), 90 women became pregnant, with 9 women progressing to live birth. One of the 9 infants had a congenital anomaly of the neck and face.[95] It is not clear how many of the 76/90 terminated pregnancies had already identified anomalies by ultrasound that might have biased the results.
Psychiatric adverse effects:
There is controversy and conflicting evidence on the association of isotretinoin with a variety of adverse psychiatric effects. We found two systematic reviews (search dates 2004;[96] not reported[97]). The first review included one prospective survey[98] and one case control study[99] that was also included in the second review, on psychiatric adverse effects with isotretinoin. The prospective survey reported that the manufacturers had supplied 12 million treatments of isotretinoin by 2001. The data on adverse effects documented 1247 people with mood disorders. The authors also had records of 168 people with suicidal behaviour, 104 with suicide attempts, and 64 with completed suicides, at 10 years' follow-up after the completion of medication. Thirty suicides were confirmed in people while taking the medication. However, this figure should be considered in the context of a very large denominator. In addition, behavioural disorders and suicides are relatively common in the age group typically taking isotretinoin. US healthcare data reviewed in the same publication noted that 5 million people in the US are taking isotretinoin. The number of suicides expected in that group from national standardised rates would be 190, whereas the number actually reported was 37.[98] The second systematic review included 6 prospective studies (of which 2 were RCTs [158 people], 3 were cohort studies [272 people], and 1 was a descriptive study [189 people]) and 3 retrospective studies (of which 2 were cohort studies [32,092 people], and 1 was a descriptive study [877 people]). A total of 9 studies examined the association between isotretinoin and depression, whereas only two studies examined the association between isotretinoin and suicidal behaviour. The review concluded that overall no association could be demonstrated between risk of depression or suicidal behaviour and use of isotretinoin. However, it was acknowledged that all included studies fell short of providing a definitive answer, mainly through small size and difficulties in randomisation and blinding. The review authors commented that more than 100,000 people and long-term follow-up would be needed in an RCT to provide conclusive evidence about an association between isotretinoin and suicide.[97] We found one subsequent cohort study indicating a lack of association between isotretinoin and suicidal thoughts or action. In spite of this, there remain clinical concerns that isotretinoin might be associated with idiosyncratic adverse mood and behavioural effects in a small number of people. This means that guidelines for use and the drug licence include an outline psychiatric history and assessment undertaken by the dermatologist, with relevant monitoring questions at each consultation.
Clinical guide:
Many of the studies reported here are from the 1990s, assessing data from the 1980s. At that time, the threshold for prescribing oral isotretinoin was higher, where it was typically used on more severe acne. The norms have since shifted, such that it may well be that the milder grades of acne may be effectively managed with lower doses. In addition, adverse effects (see harms, above) may warrant a trial of different regimens in order to achieve clearance with less discomfort. Clinical experience demonstrates that oral isotretinoin is an immensely valuable drug in the management of complex and aggressive acne. It shortens the duration of suffering, and typically reduces the amount of scarring. However, adverse effects are common and sometimes severe. People in their 20s or older may relapse more frequently than adolescents with similar treatment. Those with milder acne may need smaller doses, but the data on the degree of improvement are not as clear for this group as they are in classic severe nodulocystic acne. Measures to prevent pregnancy and screen for psychological factors were revised in 2005, with changes to the drug licence, effective in the US and EU.[100] The current "pregnancy protection programme" recommends monthly pregnancy tests from 1 month before treatment to 1 month after the end of treatment, the use of two different forms of contraception, and the issue of prescriptions for only 4 weeks' medication at a time. The oral contraceptive, or co-cyprindiol, may be commenced before treatment of women of child-bearing age with isotretinoin, and continued for at least 1 month after. This provides some additional and independent therapeutic effect in some instances. As documented in harms (see above), there remains uncertainty about the relevance of isotretinoin treatment to adverse psychological events and suicide. However, it remains important that the medical history and monitoring take close note of psychiatric history and symptoms when reviewed in clinic. One systematic review from primary care suggested that, although the general practitioner (GP) was best placed to undertake this, it would introduce potential for error through communication between the GP and dermatologist, where the dermatologist would be responsible for prescribing.[100]
Substantive changes
No new evidence
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