Dušan Sajić, MD, PhD and Sandy Skotnicki, MD, FRCPC

Divisions of Dermatology and Occupational Health,
University of Toronto Dermatology, Toronto, ON
Bay Dermatology Centre, Toronto, ON



Acne vulgaris is a multifactorial disease characterized by different types of lesions at various stages of development. The most frequently used therapeutic agents for acne are topical. While first generation topicals are primarily composed of single agent preparations, the increased knowledge of acne pathogenesis and the numerous steps involved in comedone formation have led to increasing development and clinical use of combination products (Table 1). Numerous studies have shown that combination therapy is more efficacious and better tolerated compared to monotherapy. Consequently, current consensus guidelines recommend the use of combination treatment as first-line therapy for most patients with acne. Nevertheless, several obstacles encountered in the treatment of acne, including irritation resulting from topical medications and the emergence of bacterial resistance to both topical and oral antibiotics, remain significant barriers to patient adherence to therapy. It is estimated that 30-40% of patients using topical formulations do not comply with their prescribed regimen.1 However, recent advances in vehicle technology have improved efficacy, local tolerance and adherence.2 Additionally, delivery mechanisms, such as pumps are convenient and preferred by patients, and may improve adherence.3

  • Adapalene
  • Tretinoin
  • Tazarotene
  • Benzoyl peroxide (BPO)
  • Clindamycin
  • Erythromycin
  • Dapsone
  • Sodium sulfacetamide
Combination products
  • Topical antibiotic + BPO
    • Clindamycin +BPO
    • Erythromycin + BPO
  • Topical retinoid + antibiotic
    • Tretinoin + clindamycin
    • Tretinoin + erythromycin
  • Topical retinoid + BPO
    • Adapalene + BPO
Table 1. Topical acne medications

Combination Therapy

Because the typical clinical presentation of acne vulgaris exhibits lesions at different stages, employing combination therapy that utilizes multiple agents to produce additive or synergistic benefits is logical.

  • Studies have shown that the topical combination of retinoids and antimicrobial agents expedites a clinical response.4 This may be due to enhanced penetration of agents by the retinoids.
  • Retinoids may be prescribed as initial therapy. If inflammatory lesions are present, the addition of a BPO alone, or in combination with a topical or oral antibiotic, should be the next step.
  • Data show that the combined use of a clindamycin 1%/BPO 5% formulation with a 0.04% tretinoin microsphere gel can result in good resolution of post-inflammatory hyperpigmentation in ethnic skin, i.e., individuals of colour.5
  • A once-daily, fixed-dose gel formulation containing solubilized and crystalline clindamycin phosphate 1.2% and tretinoin 0.025% (CT gel) was recently introduced in Canada.
    • Clindamycin has anti-inflammatory and antibacterial properties and tretinoin exerts comedolytic and anticomedogenic activities to target several mechanisms in acne pathogenesis.6
    • A 4-week randomized study investigated the safety and
      tolerability of combination CT gel with morning use of a
      BPO wash for mild to moderate acne. This regimen widens
      the number of targeted pathogenic factors and suppresses
      the emergence of clindamycin-induced Propionibacterium
      acnes (P. acnes) resistant bacterial strains.7
  • Combination products offer much higher levels of patient compliance with 67% adherence observed in the combination therapy group versus 8% in patients using both agents separately.8

Topical Dapsone for Inflammatory Lesions

  • Dapsone 5% gel is a new, twice daily topical treatment that is effective against both inflammatory and noninflammatory acne, however greater improvement occurs with inflammatory lesions.9
  • In two identically designed 12-week, phase 3, double-blind, randomized, vehicle-controlled trials in acne (total N=3010), significant reduction in non-inflammatory, inflammatory, and total lesion counts were noted with dapsone gel versus vehicle groups (32% versus 24%, 39% versus 32%, 48% versus 42%, all P>0.001, respectively).10
  • An investigator-blinded, randomized, split-face study assessed female subjects aged 18-40 years, with Fitzpatrick skin types I, II, or III. The results suggest that dapsone applied prior to tretinoin 0.1% may mitigate the irritation potential of tretinoin.11

Retinoids for Initial/Maintenance Therapy

Retinoids are pivotal for treatment in the early stages of acne as well as for maintenance therapy, and have both anti-comedonal and anti-inflammatory activities.

  • Topical retinoids can be used for all types and grades of acne, either initially or early in the therapy.
  • Topical retinoids are effective as monotherapy in pure comedonal acne.
  • Topical retinoids down-regulate TLR2 and CD14 messenger RNA, which, in turn, reduces their cell surface expression, resulting in anti-inflammatory activity.12
  • Evidence shows that retinoids can enhance the effects of topical antibiotic-BPO combination creams.4 In addition to their synergistic effect, this may be because retinoids can improve the penetration of other topical agents.
  • Maintenance therapy or long-term use of retinoids may help to prevent the re-emergence of micro-comedones.
  • The tretinoin gel microsphere (TGM) 0.04% pump formulation protects tretinoin from degradation by BPO and from photoinactivation in daylight: this enables its use in the morning, and with a BPO wash, without diminishing efficacy.13
  • A phase 4 study showed that TGM resulted in a 95% compliance rate.14
  • Maintenance therapy with retinoids may diminish the need for chronic antibiotic use, especially oral antibiotics. This may lead to decreased bacterial resistance associated with long-term oral and topical antibiotic use.
  • Due to a complex pathogenesis, maintenance therapy may need to be continued for months to years after resolution.15
  • Therapy with topical antibiotics but without BPO should be avoided so as to prevent development of resistance to P. acnes.15
  • Adapalene is photostable and may be applied immediately before or after a BPO containing product.16

Tretinoin Microsphere Technology and Pump Delivery Systems

Tretinoin has been formulated with a patented microsphere delivery system and a novel metered pump bottle design, which, according to the manufacturer, allows for proper dosage and clean dispensing of the active agent. Clinical trials have shown:

  • Lower levels of irritation due to the slow release of tretinoin from the microspheres into the epidermis.12,17
    • Reduced irritation may increase tolerability and patient adherence.
    • This is a less irritating water-based gel formulation that contains no alcohol and may be applied to the face immediately after washing with no waiting period.
  • TGM delivery entraps the active ingredient, releasing it in a time-controlled manner, reducing irritation.14,18
    • The controlled dispensing with this delivery system can mitigate the overuse of tretinoin, thus reducing irritation and increasing treatment adherence.12
    • A multicenter trial of 544 acne patients who were dissatisfied with their current treatment used TGM for 12 weeks. Most patients (82.3%) rated the pump as an excellent or very good method of dispensing acne medication. The tretinoin pump system significantly increased adherence, quality of life, and treatment satisfaction for study patients.14
  • The dual chambered pump dispenser releases the correct pea-sized amount for full face application and may help to maintain the optimal dosing level.
  • Microsphere technology allows for 3-fold greater deposition of tretinoin in the deep dermis and the pilosebaceous unit and may account for its stability.19
  • The microsphere technology leads to greater photostability of the tretinoin and allows for morning use, if necessary, and is minimally degraded when combined with BPO.20,21
    • Retinoids formulated in a conventional gel or cream vehicle are unstable in the presence of ultraviolet light or BPO.12

Vehicle Technology Advancements

Patient preferences go beyond side-effects and studies have shown that several variables decrease adherence including vehicle composition, difficulty of use, lack of early improvement, messiness, odours, and staining.22

  • In a Patient Preferences in Acne: A Point-of-Care Educational Initiative, a survey of 1709 patients across Canada found that pump delivery systems are the preferred format (42% of patients).3
  • Many new topical acne formulations have aqueous-based gel vehicle delivery systems that do not contain alcohol and are suitable for use in all skin types.
  • It is known that topical acne agents cause cutaneous irritation related in part to impaired epidermal barrier function.23
    • The use of gentle cleansers and moisturizers has been shown to reduce this cutaneous irritation.24
    • Moisturizers containing ceramides can be considered to improve skin barrier function in acne.
    • Dimethicone’s occlusive properties result in less greasiness for enhanced cosmetic acceptability.
  • Vehicle advances, such as microsphere technology and solubilized crystalline formulations reduce the potential of irritation from tretinoin.
  • Microsphere tretinoin and adapalene do not increase photosensitivity, allowing for morning application.
  • Clindamycin/BPO formulations with humectants and emollients may reduce the dry skin associated with BPO use.
  • Clindamycin/BPO formulations without preservatives may reduce the irritation associated with these agents.25
  • The risk of bacterial resistance is decreased due to the addition of BPO to topical antibiotic agents, and the use of BPO with long-term oral antibiotics.


The multifactorial nature of acne vulgaris often requires a combination of topical and/or oral agents for successful management. Common challenges of this multipronged approach include the potential development of skin irritation, which results in nonadherence, as well as concern over bacterial resistance. Recent advances in topical acne agents offer simpler dosing regimes that can promote patient adherence. Furthermore, the cumulative benefits of these advances may lead to improved therapeutic outcomes and overall increase in quality of life.


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