Acne: What's New?



Acne: What’s New


Linda F. Stein Gold, MD*
Director of Dermatology Research
Henry Ford Health System
Detroit, Michigan
Abstract
Acne vulgaris is one of the most prevalent skin conditions. Antibiotics, when considered, are most effective in combination with other therapies, and limited evidence suggests that submicrobial doses of antibiotics may improve acne without increasing the risk for antibiotic resistance. A small but significant risk for inflammatory bowel disease has also been identified in children treated with multiple courses of antibiotics. New topical agents are expanding therapeutic options for acne.
Semin Cutan Med Surg 35(supp6):S114-S116
© 2016 published by Frontline Medical Communications


Keywords
Acne vulgaris; antibiotics; inflammatory bowel disease; topical therapy

Acne vulgaris affects a majority of young people worldwide and is one of the most prevalent skin conditions in the general population.1 A common approach to the treatment of moderate to severe acne is the use of antibiotics to target both Propionibacterium acnes and inflammation. However, the potential for antibiotic resistance is a serious consideration. According to the Centers for Disease Control and Prevention (CDC), at least 2 million Americans become infected with resistant bacteria each year, and 23,000 die as a result of these infections.2 What does the potential for antibiotic resistance mean for the treatment of acne?
Factors that affect the risk for the development of antibiotic resistance include the dose and duration of antibiotic treatment. Finding the most effective dose, frequency, and duration of administration for the treatment of acne could limit the risk for ineffective dosing or approaches that may increase the risk for the development of resistance.


  • For example, a 12-week dose-ranging study of extended-release minocycline in subjects with moderate to severe acne (N=233) found no difference in efficacy between doses of 1, 2, or 3 mg once daily, although higher doses were associated with a higher incidence of adverse events.3 This study clearly suggests no advantage to higher doses of minocycline for the treatment of acne.
    A similar 12-week dose-ranging study of doxycycline (0.6, 1, 2, or 2.4 mg/kg/day) found that only the highest dose (2.4 mg/ kg/day, equivalent to approximately 160 mg/day) was statistically superior to placebo for improving acne.4 However, conflicting results were found in 2 studies looking at lower doses of doxycycline (ie, below antimicrobial doses), which both suggest potential efficacy for acne. A small randomized study of adults with moderate acne (N=51) compared low-dose doxycycline (20 mg twice daily) to placebo for 6 months.5 At study end, the doxycycline group showed significantly greater reductions in the number of comedones and inflammatory and non-inflammatory lesions compared to placebo. Treatment with low-dose doxycycline had no detectable antimicrobial effect on the cultivable skin flora and did not increase resistance to antibiotics.
    A recent, larger study of subjects with moderate to severe acne (N=662) compared subantimicrobial (40 mg, modifiedrelease) and routine (100 mg) doses of doxycycline to placebo for 16 weeks.6 The subantimicrobial dose of modified-release doxycycline was associated with statistically greater reduction in the mean number of inflammatory lesions compared to placebo (16.1 vs 12.6; P=0.006) and compared to doxycycline 100 mg (16.1 vs 12.9; P=0.024). Other outcomes were equivalent between doxycycline groups (and superior to placebo), such as percent reduction of total lesions and Investigator Global Assessment (IGA) success rate. These findings suggest that subantimicrobial doses of doxycycline are at least as effective as antimicrobial doses for the treatment of acne. Indeed, it may be that targeting P. acnes is not essential; rather, the anti-inflammatory effects of antibiotics may account for their efficacy in acne.
    Are Antibiotics Even Necessary?
    Another question is whether oral antibiotics are even necessary for the successful treatment of acne. For example, a randomized study compared oral doxycycline (100 mg once daily) with or without topical adapalene 0.1%/benzoyl peroxide 2.5%.7 Although the doxycycline monotherapy group showed improvement in IGA scores by 8-12 weeks, the combination group had significantly greater improvements at these time points. As illustrated in the Figure, only 8% of subjects taking oral doxycycline monotherapy were clear or almost clear of acne by week 12, whereas adding a potent topical agent quadrupled the proportion of subjects achieving this target. Based on such data, it appears that oral antibiotics contribute to therapeutic effect but have limited utility as monotherapy.

  • FIGURE Percentage of Patients Achieving Treatment Success (Clear or Almost Clear) on Investigator Global Assessment With Oral Doxycycline Compared With Oral Doxycycline Plus Adapalene/Benzoyl Peroxide.

    BPO=benzoyl peroxide. Source: Stein Gold L, Cruz A, Eichenfield L, et al.7
    The Risks of Tapering Antibiotics
    Tapering of antibiotics used for the treatment of acne has been routinely used in clinical practice. However, evidence indicates that there is no need to taper antibiotics. Studies of combination therapy with oral antibiotics and topical agents show that efficacy is maintained in a significant number of patients when the antibiotic is discontinued after 3 months, while the topical agent is continued.8,9
    In fact, this practice may increase risk for the development of resistance. The reason has to do with minimum antimicrobial serum drug levels and bacterial selection pressures. If antibiotic serum levels exceed this minimum antimicrobial threshold and then drop below the threshold, there is an increased risk that only the weaker bacteria will be killed, leaving more robust bacteria unaffected. This association also underlies the risks of poor adherence to antibiotic therapy, potentially leading to the selection of more resistant bacteria. For the same reason, clinicians should use caution when selecting subantimicrobial doses of antibiotics for the treatment of acne. As demonstrated in a pharmacokinetic study, doxycycline dosed at 20 mg twice daily does not exceed the minimum antimicrobial level, but a 50-mg dose exceeds the threshold for a few hours per day, theoretically increasing risk for the selection of resistance.5


  • Antibiotics and Inflammatory Bowel Disease:
    How Great Is the Risk?
    patients with acne who were treated with tetracycline-type antibiotics. 10 Patients were treated with antibiotics for at least 1 month and followed for at least 1 year. Overall, the hazard ratio (HR) for developing inflammatory bowel disease (IBD) was 1.39 (95% CI, 1.02-1.90) for patients with any exposure to a tetracycline antibiotic. Risk for IBD was greatest for developing Crohn’s disease among patients treated with doxycycline (HR, 2.25; 95% CI, 1.27- 4.00). A second study used a nested case-control design, matching 2,234 patients with IBD to 22,346 controls.11 Information on antibiotic use was extracted from a comprehensive prescription database. The use of more than 3 courses of antibiotics was associated with an odds ratio (OR) for IBD of 1.5 (95% CI, 1.3-1.8). Dose-response relationships were identified between antibiotic use and risk for both ulcerative colitis and Crohn’s disease.
    More recently, a meta-analysis of 11 observational studies (N=7208 with IBD) found a significant relationship between antibiotic exposure and Crohn’s disease (OR, 1.74; 95% CI, 1.35-1.94) but not ulcerative colitis.12 Children with antibiotic exposure had the greatest increase in risk for Crohn’s disease (OR, 2.75; 95% CI, 1.72-4.38). The risk for IBD in children was further evaluated in a retrospective cohort study from 464 ambulatory care centers in the United Kingdom, including 1,072,426 patients.13 In this study, the risk for IBD with antibiotic use decreased with older age at time of exposure. Antibiotic use before 1 year of age had the greatest risk (HR, 5.51; 95% CI, 1.66-18.28). The risk decreased with age (HR, 1.57 by age 15). Furthermore, each course of antibiotics increased the hazard of IBD by 6%. Although the absolute risk for IBD likely remains small, these data suggest caution when considering antibiotic treatment of children with acne.
    Topical Agents
    Several topical formulations of antibiotics are currently available and used in some patients with acne (eg, erythromycin, clindamycin). New topical antibiotic formulations in development have demonstrated promise, including minocycline foam and gel. A 12-week study of once-daily minocycline foam demonstrated a dose-response relationship, with 4% minocycline achieving statistical superiority to vehicle for reducing acne lesions and achieving an IGA score <2.14


    New fixed-combination topical agents have been approved for use in acne. One contains a higher dose of adapalene (0.3%), combined with benzoyl peroxide 2.5%. This combination was compared to vehicle and the regular-strength combination (adapalene 0.1%/benzoyl peroxide 2.5%) in a randomized, 12-week study.15 Approximately half the subjects enrolled in this trial had severe acne, a substantially larger proportion than any other topical acne trial. Overall, 33.5% of subjects treated with the high-dose adapalene formulation achieved IGA success (ie, clear or almost clear), compared to 11.5% of the vehicle group (P<0.001). Among patients with severe acne, IGA success was achieved by 31.2% of the high-dose adapalene group, compared to 21% of the regular-dose adapalene group and 13.3% of the vehicle group. Only the high-dose group was statistically superior to vehicle in patients with severe acne (P=0.029). Tolerability was not significantly different between the adapalene groups, and local irritation generally faded after the first 2 weeks of treatment.
    A new formulation of dapsone containing 7.5% active drug was recently approved by the US Food and Drug Administration for once-daily use (compared with 5% dapsone, which is applied twice daily). A recent study randomized 2,102 patients with moderate acne to once-daily dapsone gel 7.5% or vehicle for 12 weeks.16 At weeks 8 and 12, significantly more subjects treated with dapsone gel achieved treatment success compared to vehicle (P<0.05 and P<0.001, weeks 8 and 12, respectively).
    A recently approved combination topical gel consists of clindamycin 1.2% plus benzoyl peroxide 3.75%. In a 12-week trial (N=498), once-daily application of this agent produced significantly greater reductions in comedonal and inflammatory lesions compared to vehicle (P<0.001, all comparisons). Also, statistically more patients achieved a two-grade improvement in investigator’s global improvement compared to vehicle.17
    Topical Agents to Reduce Sebum Production?
    Until recently, no topical agent has demonstrated the ability to reduce sebum production, which contributes to the pathophysiology of acne. Currently, three topical agents in development have shown the ability to affect sebum production. The first is SB204, a topical agent that releases nitric oxide. Nitric oxide has both antimicrobial and anti-inflammatory activities and may also reduce sebum production.18,19 In a phase IIa trial, 2 doses of SB204 (1% and 4%) were compared to vehicle in 153 subjects with acne.20 At 4 weeks, the 4% dose of SB204 demonstrated a statistically significant reduction in both non-inflammatory and inflammatory lesions compared to vehicle.




  • A second drug that may decrease sebum production is DRM01. This agent targets acetyl coenzyme-A carboxylase (ACC), which is a key regulator of sebum production. A phase IIa trial randomized 108 subjects to DRM01 7.5% twice daily or to vehicle for 12 weeks.21 Statistical improvement in all efficacy parameters was demonstrated with DRM01, including significantly greater reductions in inflammatory and non-inflammatory lesions compared to placebo (P=0.0005 and 0.0025, respectively).
    The third topical agent is a potent antiandrogen called CB-03-01 (cortexolone 17α-propionate 1%).22 Initial study compared this agent to tretinoin 0.05% and vehicle in 77 men with facial acne.23 After 8 weeks, CB-03-01 produced significantly greater reductions in total and inflammatory lesion counts compared to vehicle, and at least comparable efficacy to tretinoin.
    Summary
    The treatment of acne continues to advance, with new agents and combinations of agents in development and approved for clinical use. Emerging data also suggest limiting the use of oral antibiotics in patients with acne—in particular, minimizing exposure of children to oral antibiotics. Finally, new topical agents that reduce sebum production offer possible novel therapeutic approaches for our acne patients
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