Quick Evidence Synopsis

Date completed: July 14, 2015

Elsevier EBM Center contributors: Megan Sands-Lincoln, PhD, MPH and David R. Goldmann, MD

What is the clinical question? What are the benefits and harms of oral minocycline for moderate to severe acne vulgaris?

Intervention	Quality of Evidence	Balance Between Benefits and Harms
Minocycline vs placebo	Low	Trade-off between benefits and harms

Quality of evidence: quality of evidence scale (GRADE [Grading of Recommendations Assessment, Development, and Evaluation]): high, moderate, low, and very low. For more information on the GRADE rating system, see http://www.gradeworkinggroup.org/index.htm .

Balance between benefits and harms: The Guideline Elements Model: beneficial, likely to be beneficial, unknown effectiveness, trade-off between benefits and harms, likely harmful, and harmful. For more information, see http://gem.med.yale.edu/default.htm .

What are the parameters of the evidence search?

Population: adults and adolescents (≥12 years old) with moderate to severe acne vulgaris
Setting: outpatient
Intervention: minocycline (oral)
Comparator: placebo
Outcomes: change in lesion count, adverse events

What is the basis for the conclusions?

Population: adults and adolescents (≥12 years old) with moderate to severe acne vulgaris
Intervention: minocycline (oral)
Comparator: placebo

Setting: outpatient ( Table 1 )

Table 1

Outcomes	Assumed Risk ^a	Corresponding Risk ^a	Relative Effect (95% CI)	Number of Participants (Studies)	Confidence in the Effect Estimates (GRADE)	Comments
Outcomes	Placebo	Minocycline	Relative Effect (95% CI)	Number of Participants (Studies)	Confidence in the Effect Estimates (GRADE)	Comments
Mean % decrease in total lesion count (SD) at 12-wk follow-up	23.9 (41.9) N = 364	35.6 (41.9) N = 674	9.84 (4.84–14.84)	1038 (3 RCTs)	Low	Favors minocycline
Adverse drug reactions ^b	28 out of 76	106 out of 186	1.25 (0.95–1.65)	262 (2 RCTs)	Low	No difference

Abbreviations: CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; RCT, randomized controlled trial; SD, standard deviation.

a Illustrative comparative risks.

b Adverse drug reactions include gastrointestinal disorders, nausea, vertigo, drug-induced lupus, autoimmune hepatitis, autoimmune vasculitis, rheumatoid arthritis, hyperpigmentation, intracranial hypertension, liver damage, inflammatory bowel disease, and antineutrophil antibody and antineutrophil cytoplasmic antibody positivity.

What do clinical guidelines say?

Guidelines of Care for the Management of Acne Vulgaris. American Academy of Dermatology, 2016 (AGREE II [Appraisal of Guidelines for Research and Evaluation II] score: unavailable).

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Tetracyclines, including minocycline, doxycycline, and tetracycline, are recommended as first-line therapy in the treatment of moderate to severe acne and forms of inflammatory acne that are difficult to treat (Strength of recommendation: A. level of evidence: I, II)
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Tetracyclines should not be used when contraindicated, such as in pregnant women or children less than or equal to 8 years of age, or allergy, in which case oral erythromycin and azithromycin can be administered.
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Doxycycline and minocycline are more effective than tetracycline, but neither is superior to the other.
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Erythromycin use should be restricted, because of its increased risk of bacterial resistance. Use of systemic antibiotics, other than the tetracyclines and macrolides, is discouraged, because there are limited data for their use in acne.

Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric Acne. American Academy of Pediatrics, 2013 (AGREE II score: unavailable)

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Extended-release minocycline dosed at 1 mg/kg/d (administered as 1 tablet daily) is US Food and Drug Administration (FDA) approved for the treatment of moderate to severe inflammatory acne vulgaris that is not predominantly nodular in patients greater than or equal to 12 years of age.
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Both immediate-release doxycycline and immediate-release minocycline have the indication listed in their FDA-approved labeling of adjunctive use for severe acne, although this was not based on formal submission for FDA approval for either drug.
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For children more than 8 years old, the commonly used oral antibiotics are minocycline, tetracycline, and doxycycline.
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For children less than 8 years old or those with allergies, alternative antibiotics (azithromycin, erythromycin, trimethoprim/sulfamethoxazole) may be used judiciously.

European Evidence-based (S3) Guidelines for the Treatment of Acne. European Academy of Dermatology and Venereology, 2012 . (AGREE II score: 81.8%)

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The use of topical and systemic antibiotics should be optimized by using appropriate combinations for a predefined duration to reduce the development of antibiotic resistance.
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When choosing a treatment, different skin types, ethnic groups, and subtypes of acne must also be considered.
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The efficacies of doxycycline, lymecycline, minocycline, and tetracycline are comparable.
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Tetracycline has a lower practicability and patient preference compared with doxycycline, lymecycline, and minocycline.
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More severe drug reactions are experienced during treatment with minocycline compared with doxycycline, lymecycline, and tetracycline.

Antibiotic resistance:

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The first relevant changes in Propionibacterium acnes antibiotic sensitivity were found in the United States shortly after the introduction of the topical formulations of erythromycin and clindamycin.
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Combined resistance to clindamycin and erythromycin is much more common (the highest prevalence is 91% in Spain) than resistance to the tetracyclines, which includes minocycline (the highest prevalence is 26% in the United Kingdom).
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Use of topical antibiotics can lead to resistance largely confined to the skin of treated sites, whereas oral antibiotics can lead to resistance in commensal flora at all body sites.

Author commentary

Acne vulgaris is an inflammatory skin disease that can affect the face, back, and chest. It is characterized by open or closed comedones (blackheads and whiteheads) and inflammatory lesions, including papules, pustules, or nodules. It is generally characterized as mild, moderate, or severe, but according to the American Academy of Dermatology there is no consensus on a universal acne grading/classifying system. Although topical agents constitute the usual first-line treatment of mild to moderate acne, in cases of moderate to severe acne, oral antibiotics are often included in the regimen.

The authors searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for meta-analyses, randomized controlled trials, and guidelines for studies on the use of oral minocycline compared with placebo in the treatment of acne. Forty-three studies were retrieved, including 1 high-quality Cochrane Review on oral minocycline in the treatment of acne vulgaris from 2012, and relevant guidelines, as well as descriptive studies and narrative reviews, which were excluded from our analysis. An older review comparing the use of different oral tetracyclines in patients with acne was found by hand searching.

The data forming the basis of our analysis suggest that oral minocycline decreases lesion count in adults and adolescents with moderate to severe acne ( Table 1 ). The overall quality of the evidence is low because of limited available data from placebo-controlled trials, significant variability in outcome measures, and use of multiple different scales and approaches to lesion count measurement. Studies comparing effectiveness of minocycline with other tetracyclines also showed comparable outcomes over 12 weeks of follow-up, but there was significant heterogeneity across studies. These findings were further supported by a systematic review identified through hand searching that suggested similar efficacy across the drug class regardless of formulation or dosing regimen.

Although minocycline is associated with a lower lesion count than placebo, it has side effects, which may be more severe than those of other antibiotics in the tetracycline class of drugs. The most common side effect is gastrointestinal manifestations, and other reported but less frequent effects include skin discoloration, drug-induced lupus, hepatitis, dizziness, and vertigo. It should also be noted that oral tetracyclines are generally not indicated in children younger than 8 years of age and are contraindicated in pregnant women.

The American Academy of Dermatology recommends minocycline along with tetracycline and doxycycline for treatment of moderate to severe acne. The European Academy of Dermatology and Venereology notes the similar efficacy of minocycline compared with doxycycline, lymecycline, and tetracycline but also highlights the issue of antibiotic resistance to the systemic tetracycline class. It voices concerns regarding antimicrobial resistance, which is an important population health issue, but also concerns about resistance in commensal flora in all body sites with oral antibiotics, unlike topical antibiotics, which do not pose the same risks.

Several questions remain about the use of oral minocycline and oral antibiotics in general in the treatment of acne. These questions include optimal dose, duration of treatment, role in combination treatment, and differences in side effect profiles. Additional research on the comparative effectiveness, safety, and tolerability of these drugs in trials using standardized outcome measures for lesion count, quality of life, and long-term treatment harms is needed.

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