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Optimizing Topical Acne Therapy

Maha Dutil, MD, MEd, FRCPC

Division of Dermatology, University of Toronto, Toronto, ON, Canada
Women’s College Hospital, Toronto, ON, Canada

Introduction

Acne vulgaris is a disease of the pilosebaceous follicle characterized by non-inflammatory (open and closed comedones) and inflammatory lesions (papules, pustules, and nodules). Its pathogenesis is multifactorial - the interplay of hormonal, bacterial, and immunological (inflammatory) factors results in the formation of acne lesions. Although acne is not a life-threatening condition, it can have detrimental effects on the quality of life of affected individuals. Fortunately, acne is readily responsive to the wide-range of available medications, with the goals of therapy being to clear the lesions, prevent scarring, and limit any treatment-related side-effects and psychosocial sequelae. Newer fixed-dose combination products target multiple acne pathogenic factors and offer simplified dosing regimens, which may potentially enhance both efficacy and patient adherence when compared with single agent therapy.

Acne Overview

Pathogenesis

  • All forms of acne involve one or more of these pathophysiologic factors:
    • hyperkeratinization of the follicular epithelium with comedo formation
    • increased sebum production
    • bacterial proliferation of Propionibacterium acnes (P. acnes)
    • local immune activity causing inflammation
  • Hormones are known to affect sebum production, but may also play a role in follicular hyperkeratinization independent of the effect on the sebaceous gland. During adrenarche, an increase in adrenal androgens leads to:
    • enlargement of sebaceous glands that results in increased sebum production.
    • abnormal desquamation and greater adhesion of the exfoliated keratinocytes in the sebaceous follicle, leading to obstruction in the follicle, and resulting in production of the microcomedo (a plug of keratin and sebum - the precursor of all acne lesions).
  • Colonization of the pilosebaceous apparatus by P. acnes occurs in this anaerobic environment where sebum provides the nutrition for its survival. This gram-positive bacterium contributes to the inflammation by:
    • releasing enzymes
    • inducing cytokine release from other cells
    • triggering an immune response (e.g., antibody production)

Prevalence and Disease Features

  • Acne affects about 85% of individuals between the ages of 12-24 years.1 Persistent acne (beyond the teenage years) and adultonset are increasingly common.2
  • Grading to determine acne severity is inherently subjective, as the process is largely based on clinical observation. Many grading systems have been developed that take into account lesion type and extent of involvement for measuring severity. Depending on the chosen technique, the measurement spectrum can range from Grades 1 to 4 all the way up to Grades 1 to 12. Acne may be classified according to predominance of specific skin lesions and the number of each lesion determines classification from mild to severe:
    • Comedonal (non-inflammatory) - mild, moderate, or severe
    • Papular (inflammatory) - mild, moderate, or severe
    • Pustular (inflammatory) - mild, moderate, or severe
    • Nodular - mild, moderate, or severe
  • Acne can be physically and emotionally scarring, causing significant psychosocial morbidity and reduced self-esteem independent of acne severity.

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Treatment Overview

  • The majority of patients present with mild-to-moderate comedonal or papulopustular acne that can be treated with topical agents (Table 1).
  • Severe cases with nodules, cysts, or scarring will require the addition of systemic therapy.
  • Available topical anti-acne compounds have a direct or indirect influence on the above mentioned pathogenetic factors.
  • Treatment selection is guided by the predominant acne lesion type.
Drug Type Topical Acne Agents Comments
Antimicrobials
  • Benzoyl peroxide (BP)
  • Clindamycin
  • Erythromycin
  • Sodium sulfacetamide
  • Directed against P. acnes
  • Formulated as creams, ointments, lotions, gels, and foams
  • May induce irritation and dryness
  • BP has mild comedolytic activity
  • BP can bleach coloured fabrics
Combination products
  • Topical antibiotic + BP
  • Topical retinoid + antibiotic
  • Topical retinoid + BP
  • Facilitate treatment of multiple pathogenic factors
  • Combined efficacy is greater than either agent alone
  • Gel formulations
  • BP + antibiotic can inhibit bacterial resistance
  • Simplifies treatment regimen and reduces dosing frequency (i.e., oncedaily application) and drug exposure time
  • Retinoid + antibiotic may increase tolerability
  • Potentially more cost effective
Retinoids
  • Adapalene
  • Tazarotene
  • Tretinoin
  • May be used for all grades of acne and for maintenance therapy
  • Non-inflammatory (comedonal) acne is best treated with a topical retinoid; noticeable improvement may take several months
  • Common side-effects include irritation (e.g., stinging or burning sensation), redness or inflammation, and scaling or dryness
  • Formulated as gels, creams, and solutions
  • Advancements in vehicle delivery reduce irritation and enhance efficacy (e.g., emollient cream and microsponge gel)

Table 1: The spectrum of approved topical acne medications2-4

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Rationale for BP/Antibiotic Combination

Effective treatment considers all pathogenic factors and single-agent therapy does not address all four major pathophysiologic features of acne.

  • Topical antibiotics have been used to treat acne for more than 40 years and are still widely used. The efficacy of antibiotics is attributable to their inhibitory effects on both the proliferation of P. acnes and inflammatory mediators.
  • The emergence of resistant strains has, in some cases, been associated with a failure to respond to antibiotic therapy, which was first reported with the topical antibiotics clindamycin and erythromycin.3
  • The use of BP reduces the occurrence of resistance and can be effective in the treatment of both nonresistant and resistant P. acnes strains.4
  • BP does not promote antimicrobial resistance and has been shown to prevent such resistance when used concomitantly with topical erythromycin or topical clindamycin.
  • A number of clinical studies have demonstrated improved efficacy and safety of combinational BP/antibiotic approach to acne management (Table 2).
Combination Treatment Study Design/Results
5% BP/3% erythromycin (BP/E) gel vs. erythromycin alone applied for 6 weeks
  • Double-blind study of patients with mild-to-moderate acne5
  • The number of erythromycin-resistant strains of P. acnes was significantly reduced in the BP/E group compared with the group that received erythromycin alone.
5% BP/3% erythromycin gel vs. erythromycin alone applied for 6 weeks
  • Open study of patients with erythromycin-resistant strains of P. acnes5
  • Highly significant reductions were also seen in acne grade and lesion counts with the BP/E combination.
BP/clindamycin (BP/C) combination, BP, clindamycin, or vehicle gels applied once nightly for 11 weeks
  • Two double-blind, randomized, parallel, vehicle-controlled trials of acne patients6
  • The combination gel was significantly superior to the two individual agents in global improvement and reduction of inflammatory lesions.
5% BP/1% clindamycin, 5% BP/3% erythromycin, or 5% BP applied twice daily for 10 weeks
  • Randomized, multicenter, single-blind trial of moderate-to-severe acne patients7
  • Both BP/C and BP/E were comparable and demonstrated significantly greater reductions in inflammatory lesions over BP alone.

Table 2: Clinical trials demonstrating efficacy for combination treatments with BP and erythromycin or clindamycin

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Combination Treatment Considerations

  • Mild-to-moderate inflammatory acne can usually be managed with two topical drugs. Typically one is applied in the morning and the other at bedtime.
  • A retinoid is used to deal with the precursor of all acne lesions (i.e., the microcomedo) and an antibacterial agent for its effects on P. acnes. Topical antibacterial options include BP or a BP/antibiotic combination.
  • BP is extremely effective against P. acnes, but can be irritating. The irritation can be minimized by using the lowest concentration of BP in a water-based vehicle that does not reduce its efficacy. Another way to reduce the irritation induced by BP is to combine it with an antibiotic.
  • BP/antibiotic combinations also reduce the irritation that can be induced by a topical retinoid. Only if a patient is allergic to BP (estimates range from 1%-2% of the population8) should a topical retinoid be used with a topical antibiotic alone. The topical antibiotic should be discontinued as soon as possible and the retinoid can be used for maintenance alone.

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Prescribing Recommendations to Minimize Bacterial Resistance

  • Antibiotics should not be used as monotherapy, nor should they be used to treat mild acne.
  • Avoid topical antibiotics if non-antibiotic topical preparations will suffice.
  • Use alternatives to antibiotics for maintenance.
  • Stop antibiotic treatment when the skin clears or if no further improvement is noted.
  • If there is a failure to respond to oral antibiotics or a rapid relapse after discontinuation, consider other therapy (e.g., systemic retinoid, anti-androgens in women).
  • If the antibiotic is needed again, use the same antibiotic.
  • Use full doses of antibiotics and do not taper.
  • Avoid concomitant topical and systemic use of different antibiotics to reduce the risk of developing resistance to both agents.
  • Do not switch or rotate antibiotics in non-responding patients.
  • Use BP during antibiotic therapy.
  • BP bleaches clothing and hair, and thus, patients should be warned when prescribed.
  • Limit the use of BP on the chest and back to night-time due to its bleaching effect on clothing or recommend that patients wear a white T-shirt under clothing for daytime application.

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Non-Adherence

  • Patient non-adherence to treatment can influence outcomes, which is of particular concern with topical medications (e.g., proper application and accurate dosing).
  • Some clinical strategies to promote treatment adherence include:
    • advocating patient involvement in therapeutic decision-making
    • devoting time to patient education on acne and the selected treatments, instructions for use, potential side-effects, and expected rate of improvement
    • selecting treatments that facilitate ease of use (i.e., once-daily dosing)
    • modifying current treatment if patient dissatisfaction is encountered

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Conclusion

Since multiple factors are involved in acne pathogenesis, treatment that targets the majority of these elements can be expected to achieve optimal results. When considering the options for reducing the P. acnes population, it is best to choose therapeutic agents that do not encourage resistance patterns. Evidence for improved efficacy, safety, and onset of action, as well as longer remission, has been noted with combination therapies. Advances in dual agent fixed-dose compounds offer simpler dosing regimes that can promote patient adherence. Furthermore, the cumulative benefits of these advances may lead to improved therapeutic outcomes and overall improvements in quality of life for acne patients.

References

  1. Krowchuk DP, et al. Adolesc Med 12(2):vii, 355-74 (2001 Jun).
  2. Tan JK. Skin Therapy Lett Pharm 4(2):1-3 (2009 Jul-Aug).
  3. Crawford WW, et al. J Invest Dermatol 72(4):187-90 (1979 Apr).
  4. Dutil M. Skin Therapy Lett 15(10):5-7 (2010 Nov-Dec).
  5. Eady EA, et al. Br J Dermatol 134(1):107-13 (1996 Jan).
  6. Lookingbill DP, et al. J Am Acad Dermatol 37(4):590-5 (1997 Oct).
  7. Leyden JJ, et al. J Cutan Med Surg 5(1):37-42 (2001 Jan-Feb).
  8. Lindemayr H, et al. Contact Dermatitis 7(3):137-40 (1981 May).

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