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Topical Approaches in Combination Therapy for Acne

Lisa W. Fu, BHSc and Ronald B. Vender, MD, FRCPC

Department of Medicine, McMaster University, Hamilton, ON, Canada

Introduction

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Its pathophysiology is multifactorial and complex, including obstruction of the pilosebaceous unit due to increased sebum production, abnormal keratinization, proliferation of Propionibacterium acnes (P. acnes), and inflammation.

Topical agents are the most commonly used therapy for acne. First generation topicals mainly consist of single agent retinoids, benzoyl peroxide (BP), and antibacterials that target comedones, P. acnes, and inflammation. Novel topical therapies include combination products with advanced vehicle formulations that target multiple acne pathophysiologies and offer simplified treatment regimes. For example, the combination of clindamycin and tretinoin in a unique vehicle formulation of suspended crystalline tretinoin allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BP combinations target comedones, inflammation, and P. acnes synergistically. These newer combination products have the potential to increase both efficacy and patient adherence when compared with single agent treatment.

Disease Overview

Diagnostic Features and Grading (Table 1)

  • Acne vulgaris has distinguishing comedones (open and closed) and inflammatory lesions in the form of papules, pustules, or nodules and cysts.1,2
  • The presence of comedones confirms the diagnosis of acne vulgaris.3
Severity Grade
Description
Mild I Open and closed comedones and few inflammatory lesions
Mild to moderate II Comedones with occasional inflammatory papules and pustules that are confined to the face
Moderate to severe III Many comedones with small and large inflammatory papules and pustules; more extensive but confined to the face
Severe IV Many comedones and inflammatory lesions with nodules and cysts tending to coalesce and canalize; involving the face and the upper aspects of the trunk

Table 1: Severity grading of acne vulgaris2,3

Differential Diagnosis Include:

  • Rosacea
  • Perioral dermatitis
  • Bacterial folliculitis
  • Drug induced acneiform eruptions

Prevalence, Pathophysiology and Psychosocial Impacts

  • Acne is a common worldwide skin disease that affects about 85% of individuals between the ages of 12-24 years.4
  • The four main pathophysiologic features include:3
    1. androgen-mediated stimulation of sebaceous gland activity,
    2. abnormal keratinization leading to follicular plugging (comedone formation),
    3. proliferation of P. acnes within the follicle, and
    4. inflammation.
  • Genetic factors, stress, and possibly diet may influence the development of acne.3
  • Acne can cause a considerable amount of emotional distress and physical discomfort, thus, medical treatment must be accompanied by patient counseling and education, which can contribute to improved self-esteem and adherence to therapy.

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Topical Treatment Overview and Options

Topical therapy (Tables 2 and 3) is used for mild to moderate acne and also for maintenance therapy in all levels of disease severity.

Acne Severity Treatment
Mild
  • Topical retinoids for treatment and maintenance
Mild to moderate
  • Benzoyl peroxide + topical antibiotics +/– topical retinoids; 8 to 12 week course
Moderate to severe
  • Topical therapies used in mild to moderate acne + oral antibiotics for a minimum of 6 to 8 weeks
Severe
  • Oral isotretinoin; 16 to 20 week course

Table 2: Treatment indications based on acne severity3-5

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Drug Type Topical Acne Agents Overview
Retinoids
  • Adapalene
  • Tazarotene
  • Tretinoin
  • Effective against acne vulgaris through comedolysis, which acts to reduce dyskeratosis at the pilosebaceous unit
  • Inhibits the formation of microcomedones and has mild anti-inflammatory effects6
  • Gel, cream, and solution formulations may induce irritation and dryness
  • Advanced formulations include an emollient cream and microsphere gel
  • Vehicle delivery advancements reduce irritation and enhance efficacy
Antimicrobials
  • Benzoyl peroxide
  • Clindamycin
  • Erythromycin
  • Sodium sulfacetamide
  • Bactericidal or bacteriostatic action directed against P. acnes
  • Formulated in creams, lotions, and gels
  • Can induce irritation and dryness
  • Benzoyl peroxide may bleach coloured fabrics
  • Antibiotics have anti-inflammatory properties
  • Sulfonamides inhibit P. acnes with limited potential for antibiotic resistance
Combination products
  • Benzoyl peroxide + antibiotic
  • Retinoid + antibiotic
  • Facilitates treatment of multiple pathogenic factors that are complementary and synergistic in mechanisms of action
  • Combined efficacy is greater than either agent alone6
  • Gel formulations
  • Simplifies treatment regimen and reduces dosing frequency
  • Combined use of benzoyl peroxide + topical antibiotic can reduce bacterial resistance; once opened, these products have a limited shelf life (3 to 4 months)

Table 3: Topical therapies currently used for acne vulgaris treatment5

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Newer Novel Topical Agents

Clindamycin Phosphate 1.2% + Tretinoin 0.025% Gel (Biacna™)

  • This fixed-dose combination gel was approved by Health Canada in December 2010 for the topical treatment of acne vulgaris in patients ≥12 years of age.7
  • It combines the anti-inflammatory and antibacterial actions of clindamycin with the comedolytic and anticomedogenic actions of tretinoin7 to target several mechanisms in the pathogenesis of acne.
  • Multiple studies have demonstrated significantly greater reductions in comedones and inflammatory lesions by 12 weeks compared with either agent alone or vehicle.8-10
  • A more rapid reduction in acne lesions was observed by 8 weeks compared with either agent alone or vehicle.8
  • Application is recommended once-daily at bedtime (preferred) or morning (as the vehicle delivery formulation provides for the photostability of tretinoin).7
    • Patients should be instructed to use only a pea-sized amount.
  • Vehicle characteristics
    • It is available as an aqueous gel that is alcohol free with a unique formulation.11
    • It contains solubilized clindamycin phosphate and a stable combination of both solubilized and crystalline tretinoin.11
    • The crystalline suspension allows for tretinoin to be released in a rate-controlled manner, thereby resulting in slower and progressive follicular penetration and increased tolerability.11
    • Long-term efficacy and a favourable safety profile was shown in a 52 week study.12
  • Side-effects and contraindications
    • Crohn’s disease, ulcerative colitis, colitis with previous antibiotic therapy, use of concomitant erythromycincontaining products, pregnancy (category C)7
    • Side-effects from topical retinoids may include peeling, redness, dryness, itching, and photosensitivity
    • Because tretinoin increases the skin’s sensitivity to UV light, patients should be reminded to avoid excessive or unnecessary sun exposure and wear sunscreen and protective clothing daily.

Adapalene 0.1% + Benzoyl Peroxide 2.5% Gel (Tactuo™)

  • This combination treatment was Health Canada approved in May 2011.
  • Proposed mechanism of action: adapalene has comedolytic, anticomedogenic, and anti-inflammatory effects and BP is a highly lipophilic oxidizing agent with bacteriocidal and keratolytic effects.13
  • BP lowers the incidence of bacterial resistance compared with other topical antibiotics and can be used for the longterm management of acne.
  • The complementary modes of action address 3 out of the 4 pathophysiologic processes of acne:
    1. abnormal keratinization leading to follicular plugging (comedone formation),
    2. proliferation of the bacterium P. acnes within the follicle, and
    3. inflammation.
  • Large double-blinded randomized controlled trials showed that this combination gel was significantly more effective than the respective monotherapies, producing marked differences in total lesion counts.14,15
  • Studies demonstrated a comparable safety profile to adapalene.15
  • Adapalene is stable when combined with BP in the presence or absence of light.13
  • Once-daily dosing provides regime simplicity.

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Bacterial Resistance in Acne

  • Antibiotics are recommended for use with BP (available in gel, lotion, and wash).
  • BP is an efficient bactericidal agent that will minimize the development of bacterial resistance at skin sites where topical antibiotic (i.e., clindamycin and erythromycin) therapy is applied.
  • BP is effective against both nonresistant and resistant P. acnes strains.16
  • A 4-week randomized study of patients with mild to moderate acne explored the safety and tolerability of fixed combination clindamycin phosphate and tretinoin gel (CT) once-daily in conjunction with morning use of a BP wash, targeting several pathologic factors and limiting the potential for clindamycin-induced P. acnes resistant strains.17
    • Side-effects were mild and included transient dryness, scaling, erythema, burning, stinging, and itching during the first week of therapy, then improving within 1-2 weeks.
    • CT gel + BP wash was shown to be a safe and welltolerated therapeutic regimen to effectively treat acne while mitigating the potential for bacterial resistance.

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Patient Adherence

Acne is a chronic disease and poor medication adherence is a major contributor to treatment unresponsiveness.18 Factors that can impact treatment follow-through include:

  • Convenience and decreased complexity of treatment encourage patient adherence.
  • Treatment regimens that are effective and well-tolerated, as well as simple and easy to incorporate into the patient’s lifestyle, are more likely to increase adherence.
  • Patients most commonly attribute frustration with the therapeutic regimen and forgetfulness as reasons for failure to use prescribed medications.19

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Conclusion

The successful topical treatment of acne depends on appropriate agent selection based on patient-specific acne severity, tolerance, adherence, and adequate follow-up. The advent of combinational therapeutic products provide increased efficacy by targeting multiple pathophysiologic processes. Additional advantages of using combination therapy include reduced complexity of treatment regimen and convenient once-daily dosing. The future of topical acne treatment holds the promise of more novel uses of conventional anti-acne agents formulated with advanced vehicle delivery systems that offer less side-effects, increased tolerance, dosing simplicity, and improved efficacy.

References

  1. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol 56(4):651-63 (2007 Apr).
  2. Witkowski JA, Parish LC. The assessment of acne: an evaluation of grading and lesion counting in the measurement of acne. Clin Dermatol 22(5):394-7 (2004 Sep-Oct).
  3. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 292(6):726-35 (2004 Aug).
  4. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 49(3 Suppl):S200-10 (2003 Sep).
  5. Tan JK. Topical acne therapy: current and advanced options for optimizing adherence. Skin Therapy Lett Pharm 4(2):1-3 (2009 Jul-Aug).
  6. Alexis AF. Clinical considerations on the use of concomitant therapy in the treatment of acne. J Dermatolog Treat 19(4):199-209 (2008).
  7. Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/tretinoin gel formulation in the treatment of acne vulgaris. Expert Opin Pharmacother 9(16):2931-7 (2008 Nov).
  8. Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/ tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris. J Am Acad Dermatol 54(1):73-81 (2006 Jan).
  9. Eichenfield LF, Wortzman M. A novel gel formulation of 0.25% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Pediatr Dermatol 26(3):257-61 (2009 May-Jun).
  10. Schlessinger J, Menter A, Gold M, et al. Clinical safety and efficacy studies of a novel formulation combining 1.2% clindamycin phosphate and 0.025% tretinoin for the treatment of acne vulgaris. J Drugs Dermatol 6(6):607-15 (2007 Jun).
  11. Del Rosso JQ, Jitpraphai W, Bhambri S, et al. Clindamycin phosphate 1.2%-tretinoin 0.025% gel: vehicle characteristics, stability, and tolerability. Cutis 81(5):405-8 (2008 May).
  12. Kircik LH, Peredo MI, Bucko AD, et al. Safety of a novel gel formulation of clindamycin phosphate 1.2%-tretinoin 0.025%: results from a 52-week openlabel study. Cutis 82(5):358-66 (2008 Nov).
  13. Tan JK. Adapalene 0.1% and benzoyl peroxide 2.5%: a novel combination for treatment of acne vulgaris. Skin Therapy Lett 14(6):4-5 (2009 Jul-Aug).
  14. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixeddose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 57(5):791-9 (2007 Nov).
  15. Gold LS, Tan J, Cruz-Santana A, et al. A North American study of adapalenebenzoyl peroxide combination gel in the treatment of acne. Cutis 84(2):110-6 (2009 Aug).
  16. Dutil M. Benzoyl peroxide: enhancing antibiotic efficacy in acne management. Skin Therapy Lett 15(10):5-7 (2010 Nov-Dec).
  17. Draelos ZD, Potts A, Alio Saenz AB. Randomized tolerability analysis of clindamycin phosphate 1.2%-tretinoin 0.025% gel used with benzoyl peroxide wash 4% for acne vulgaris. Cutis 86(6):310-8 (2010 Dec).
  18. Yentzer BA, Ade RA, Fountain JM, et al. Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. Cutis 86(2):103-8 (2010 Aug).
  19. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol 152(5):1015-21 (2005 May).

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