Introduction

Topical retinoids have been used for almost half a century and remain a mainstay in the treatment of acne. They target two of the pathogenic processes in acne: The abnormal keratinization in the pilosebaceous apparatus and inflammation. They act on existing acne lesions and prevent new lesions by targeting the microcomedo and by reducing inflammation. Yet they are underutilized in the treatment acne among generalist physicians. A new topical retinoid, trifarotene, the first fourth-generation retinoid, is now available in Canada for the treatment of moderate facial and truncal acne. It selectively binds to the retinoic acid receptor (RAR)-γ making for an efficacious and safe new option and is the only topical acne therapy to have been rigorously studied in truncal acne.

Background

Acne is a chronic inflammatory skin disease that mostly affects teenagers and young adults and can lead to permanent physical and psychological scarring.

50 years after Kligman described the use of tretinoin in the treatment of acne¹, a new fourth-generation topical retinoid, trifarotene, is now available in Canada for the treatment of facial and truncal acne. It is a potent and selective RAR gamma agonist.

Though most patients present with facial acne, 50-60% of them are also afflicted with truncal acne.² Acne severity was found to have a higher correlation between chest and back acne than face/back or face/chest combinations. Recognition of truncal acne can be problematic as patients often fail to report it, making clinical evaluation of the trunk necessary in acne assessment. Despite the fact that patients may not report its presence, most of them are interested in treating it.³

The key pathogenic mechanisms involved in the production of acne include:

• Increased sebum production under androgen control
• Proliferation of Cutibacterium acnes (formerly Propionibacterium acnes)
• Abnormal keratinization in the pilosebaceous apparatus
• Inflammation mostly via innate immunity

Topical Retinoids

Topical retinoids are critical in the treatment of acne. They are recommended by acne guidelines to be used first line and in the maintenance of all forms of acne.^4,5 They are the cornerstone of acne treatment because of their comedolytic and anti-comedogenic effects which are brought about by their ability to modify cellular proliferation and differentiation, and because of their anti-inflammatory properties. Some of these anti-inflammatory activities include blocking inflammation via toll-like receptor-2, inhibiting neutrophil chemotaxis and blocking the AP-1 pathway, thus reducing the production of inflammatory cytokines.⁶ They also have other effects such as the prevention and reduction of acne scarring^7,8 and improvement of hyperpigmentation.^9,10

Retinoids are a group of compounds that resemble the Vitamin A molecule retinol. Their effects are mediated by two types of nuclear hormone receptors, the retinoid A receptors (RARs: alpha, beta and gamma) and the second receptor system, the retinoid X receptors (RXRs: alpha, beta and gamma).

The first-generation retinoids include tretinoin (retinoic acid) and isotretinoin; they bind all three retinoid A receptors: RAR-α, RAR-β and RAR-γ. The second-generation retinoids are not used in acne. The third-generation retinoids include adapalene and tazarotene; they selectively bind both RAR-β and RAR-γ. The only fourth-generation retinoid is trifarotene; it selectively binds to the retinoic acid receptor (RAR)-γ. RAR-γ is abundantly expressed in the skin¹¹ and is the most important receptor involved in epidermal differentiation.¹²

The different molecular structures of these retinoids and the different receptors they bind will affect their impact on acne. For instance, the third-generation retinoid adapalene was found to have more potent anti-inflammatory effects in vitro and in animal studies than the first-generation all-trans retinoic acid and 13-cis retinoic acid.¹³

Trifarotene

Trifarotene was designed for metabolic stability in the skin, while being rapidly metabolized in human liver microsomes with a halflife (t ½) of five minutes. It should result in low systemic levels, while retaining strong cutaneous activity. These properties are particularly important when treating large body surface areas such as the face, chest and back. In ex-vivo cultured human skin, trifarotene was three times more potent than tazarotene. In vivo, trifarotene eliminated almost all comedones from the classical retinoid-responsive rhino mouse model, with a dose ten times lower than that required for tazarotene. The rapid in vivo anti-pigmenting activity of trifarotene is another useful advantage of this molecule that may reduce the hyperpigmentation that is seen secondary to acne.¹⁴

Two multicentre, double-blind, randomized, vehicle-controlled, 12-week phase 3 trials were undertaken to study trifarotene.¹⁵ Of note, these were the first-ever large-scale randomized trials to simultaneously evaluate a topical therapy for facial and truncal acne treatment.

The study subjects, all of whom had moderate acne vulgaris on the face and trunk, ranged in age from 9 to 58 years, with a mean age of 19 years. They were randomized to once-daily application of trifarotene cream or its vehicle in the evening.

The primary efficacy end points on the face were achievement of Investigator Global Assessment (IGA) success as defined by a score of 0 or 1, meaning clear or almost clear, coupled with at least a 2-grade improvement from baseline to week 12. Another primary endpoint was the absolute reduction from baseline in facial inflammatory and non-inflammatory acne lesions. The secondary end points were similar but as applied to truncal acne from baseline to week 12. Safety was assessed through adverse events, local tolerability, vital signs, and routine laboratory testing results.

In both studies response rates were significantly better than in the vehicle-treated controls. For the 1214 patients treated with trifarotene and 1206 treated with vehicle, the week 12 facial success rates according to the IGA were 29.4% in the first trial and 42.3% in the second (vs 19.5% and 25.7% for vehicle [p < .001]). Trifarotene treatment also achieved significantly superior reductions in facial acne lesion counts in both studies, with statistical differences apparent as early as weeks one or two. With trifarotene treatment, the mean absolute inflammatory lesion counts were reduced by 19.0 and 24.2 in trial one and two respectively (vs by 15.4 and 18.7 with vehicle [p < .001]) and the mean absolute non-inflammatory lesion counts were reduced by 25.0 and 30.1 (vs by 17.9 and 21.6 with vehicle [p < .001]).

The rates of success with trifarotene at week 12 according to the truncal PGA (Physician’s Global Assessment) were 35.7% in the first trial and 42.6% in the second (vs 25.0% and 29.9%, respectively for vehicle [each p < .001]). In both trials, trifarotene was statistically significantly superior in reducing both inflammatory and non-inflammatory lesions on the trunk starting by week 4 in the first trial and by week 2 in the second. Rates of success on the trunk were statistically significant for trifarotene versus vehicle starting at week 8 in both trials.

Treatment-emergent adverse events leading to study discontinuation were low. They occurred in 1.9% of trifarotene-treated patients in one trial and 1% in the other. The typical adverse effects of retinoids include local skin irritation such as redness, peeling, dryness, stinging and burning.

Retinoid cutaneous reactions are typically dependent on concentration and formulation of the retinoid but more importantly may be related to the sensitivity of the patient’s skin.¹⁶ There are various strategies to improve retinoid tolerability. A clinical trial looking at four different regimens showed that adding a moisturizer to the treatment regime improved dryness and scaling while every other night application improved stinging and burning sensations as well as erythema.¹⁷

In the long-term safety study (52-week trial) trifarotene was found to be well tolerated and efficacious in moderate facial and truncal acne.¹⁸

Conclusions

Retinoids are essential in the treatment of acne, but they are generally under prescribed by physicians.¹⁹ There are many ways to improve the tolerability of topical retinoids, allowing the majority of acne sufferers access to this crucial therapy. The practice of altering treatment regimens has been shown to improve local tolerability, which may in turn improve overall adherence to treatment. Using these techniques to help patients tolerate the first 4-6 weeks of retinoid use will help patients stay with this most effective therapy.²⁰ Now Canadians will have a new fourth-generation topical retinoid, trifarotene, for the treatment of moderate facial and truncal acne.

Introduction

Acne knows no borders. It is estimated that up to 85% of the world population between the ages of 12 and 24 is afflicted by acne at some point.^1,2 The disease often persists beyond young adulthood, despite treatment.^3-5 Acne can adversely affect quality of life^6-13 and may lead to emotional distress and physical scarring.^14,15 The clinical presentation of acne (Figure 1) varies from primarily comedonal to mixed comedonal and inflammatory acne.¹⁶

Background

In 2000, Canadian doctors proposed guidelines for the treatment of acne. Guidelines are considered to be effective in improving clinical decisions. They can be perceived, by specialists and generalists alike, as useful in evaluating a clinical situation and in weighing various options for treatment. Physicians will be particularly reassured if the suggested guidelines are supported by scientific evidence. Guidelines that are not validated scientifically, however, can pose a risk. Similarly, guidelines that are not regularly updated in light of new findings can become misleading.¹⁷ This new Canadian clinical guideline for the treatment of acne was developed taking into account new data published up to March 2015, as well as expert opinion and clinical experience.

The recommendations in the Guideline are intended to assist Canadian health care professionals in the diagnosis of acne vulgaris; provide updates and information on the pathogenesis of acne; outline methods for evaluating acne severity; provide evidence-based guidance on treatments for acne vulgaris; and recommend treatments for acne according to severity.

Recommendations are made for three categories of acne severity:

1. Comedonal acne, which consists of small white papules (closed comedones) or grey-white papules (open comedones) resulting from complete or partial ductal occlusion, respectively, and sebum accretion (Figure 1A);
2. Mild-to-moderate papulopustular acne, which is characterized by mostly superficial inflammatory lesions (Figures 1B and 1C); and
3. Severe acne, consisting of deep pustules and/or nodules, which may be painful, may extend over large areas and can lead to tissue destruction (Figures 1D and 1E). A subtype of severe acne, conglobate acne, is rare and consists of extensive inflammatory papules, nodules and cysts and can lead to disfiguring scars.¹⁶

• A clinical algorithm for the most highly recommended treatments for comedonal, mild-to-moderate papulopustular and severe acne is presented in Figure 2.
• For a complete listing of recommendations and more detailed discussion of the evidence, please see the full guideline at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140665/-/DC1.

The Guideline Panel

Members of the guideline panel were selected by the steering committee of Drs. Charles Lynde and Jerry Tan. They were chosen according to their acknowledged expertise in acne, as indicated by peer-reviewed publications and reputation. Dermatologists from across Canada were included for geographic representation; Yuka Asai, Akerke Baibergenova, Maha Dutil, Shannon Humphrey, Peter Hull, Charles Lynde, Yves Poulin, Neil H. Shear, Jerry Tan, John Toole, and Catherine Zip. Two experts with dual credentials in epidemiology and dermatology (Y.A. and A.B.) served as methodologic experts and performed literature evaluation and grading. The guideline was developed in accordance with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument¹⁸ and the ADAPTE framework¹⁹ for guideline adaptation.

Before submitting the guideline for publication, the committee sought input from the following stakeholders: a discussion group of university students representing patients (University of Windsor, Windsor, Ontario), the Canadian Dermatology Association, the Canadian Skin Patient Alliance, the Canadian Dermatology Nurses Association, the Canadian Pharmacists Association, family physicians, pediatricians and authors of the ES3 guidelines. Pilot testing was also undertaken in the clinic of one guideline panel member. Development of this guideline was funded by Valeant, Galderma, Cipher, Bayer and Mylan. Funding sponsors had no role in the development or approval of the guideline. The identity of sponsors was not disclosed to the guideline panel members until the time of submission of the draft for publication. None of the panel members received honoraria for their contributions to this work.

Recommendations

Comedonal Acne

• Topical therapies are recommended for first-line treatment of comedonal acne, namely retinoids, benzoyl peroxide and fixed-dose combinations of retinoids with benzoyl peroxide or clindamycin.
• Those with dry or sensitive skin may prefer creams or lotions, which tend to be less drying, whereas those with oily skin may prefer a less greasy formula, such as a gel. Convenience and treatment adherence may be enhanced with combination therapy or once-daily application instead of separate therapies or routines requiring multiple applications. Many acne medications may not be covered by provincial plans; in these cases, it may be particularly important to consider cost.
• For comedonal acne the committee recommends topical retinoids or benzoyl peroxide (medium-strength recommendation; confidence in effect estimate is moderate).
• Benzoyl peroxide in 2.5% and 5% gels was superior to vehicle for comedonal acne in eight grade A studies (level 1 evidence), with reduction in comedonal lesions of 21-52%, compared with increases of 11-42% for vehicle.¹⁶
• Benzoyl peroxide products have a fast onset of action²⁰ and are available over the counter, thus, they should be considered for initial treatment.
• Topical retinoids (tretinoin, adapalene and tazarotene) are also recommended for initial treatment. Despite one grade B study showing superiority, tazarotene is likely equivalent to adapalene (four grade B studies), but may result in more irritation.¹⁶
• For comedonal acne, the committee recommends the fixed-dose combinations adapalene-benzoyl peroxide and clindamycin-benzoyl peroxide (medium-strength recommendation; confidence in effect estimate is moderate).
• Fixed-dose combinations can be used as initial treatment. For treatment of comedones, the combination of adapalene 0.1% and benzoyl peroxide 2.5% was equivalent or superior to adapalene.
• If a fixed-dose combination is inadequately effective after a two-to-three-month trial, the addition of a topical retinoid (especially tazarotene, adapalene or tretinoin) should be considered, if no retinoid is in use.
• If response to a topical retinoid or benzoyl peroxide alone or to a fixed-dose combination is inadequate, use of fixed-dose clindamycin-tretinoin or a combined oral contraceptive agent may be considered.

Localized Mild-to-Moderate Papulopustular Acne

• The presentation of mild-to-moderate papulopustular acne can vary with regard to inflammation and lesion distribution.
• Topical therapies are a reasonable intervention for patients with mild papulopustular acne. Given the strong evidence for use of topical retinoids, benzoyl peroxide and fixed-dose combinations to treat inflammatory lesions, all three options are strongly recommended for this type of acne.
• The treatment choice would be determined by factors such as type of vehicle, ease of use and cost. For more extensive papulopustular acne or areas not amenable to topical therapy (such as the back), systemic therapies, in addition to the topical therapies, are recommended.
• For benzoyl peroxide in concentrations ranging from 2.5-10%, in gel, cream and lotion formulations, 11 grade A studies and three grade B studies showed superiority over placebo, with reductions in inflammatory lesion counts of 19-62%, compared with increases of 12-46% for vehicle (level 1 evidence).¹⁶ The onset of action of benzoyl peroxide may be superior to that of tretinoin.²⁰
• Topical retinoids (adapalene, tazarotene and tretinoin) can also be used as first-line agents. Several fixed-dose combinations can be used as initial treatment for localized mild-to-moderate papulopustular acne.
• The combination of clindamycin 1% and benzoyl peroxide 5% gel was superior to vehicle and the individual components in four grade A studies, with lesion count reductions of 48-63%, while changes with vehicle ranged from an increase of 3% to a reduction of 30% (level 1 evidence).¹⁶
• The fixed-dose combination of adapalene 0.1% and benzoyl peroxide 2.5% gel was superior to vehicle and the individual components in reduction of inflammatory lesion counts in all three grade A studies, with reduction of 62-70%, compared with 34-46% for vehicle (level 1 evidence).¹⁶

Extensive Moderate Papulopustular Acne

• Although tetracycline and minocycline have been shown to be superior to placebo in reducing inflammatory acne lesions,¹⁶ use of these agents on their own is discouraged because of concerns about selection of antibiotic-resistant bacteria.
• Other antibiotic classes, including penicillins, macrolides and fluoroquinolones, are also discouraged because they are indicated for use in community-acquired infections, such as pneumonia and urinary tract infections. Furthermore, given that minocycline is associated with an increased risk of drug-induced lupus and hepatitis,²¹ tetracycline or doxycycline is preferred.
• The combinations of ethinyl estradiol 20 µg and levonorgestrel 100 µg (level 3 evidence), ethinyl estradiol 20 µg and drospirenone 3 mg (level 1 evidence) and ethinyl estradiol 35 µg and norgestimate 180, 215 or 250 µg (level 2 evidence) have all shown superiority over placebo.
• The committee noted that adjunctive use of topical agents with oral contraceptive agents has been inadequately studied.

Severe Acne

• Isotretinoin is the prescription of choice for severe acne but the practice should be limited to physicians who are trained and experienced in its use, monitoring and appropriate pregnancy-prevention measures.
• For patients unwilling or unable to use oral isotretinoin and those with intolerance, systemic antibiotics in combination with topical benzoyl peroxide, with or without a topical retinoid, may be considered. For women, hormonal therapy with a combined oral contraceptive may also be considered.

Discussion

This document will be updated at a minimum of every five years as required to maintain validity.²² Updates may be provided sooner to include important new developments, such as evidence on benefits and harms of existing interventions, development of new treatments or changes in available treatments.

Uncertainties in acne treatment encompass both general and specific factors. General factors include absence of information related to efficacy in truncal acne (the outcome measure for almost all studies being facial acne); lack of certainty about a minimal effect size that is relevant for patients; lack of a current, universally applied standard for global severity grading of acne; and lack of knowledge about the potential role of adjunctive support, including psychotherapy, for patients with impaired quality of life. Specific factors include uncertainty about durations of use of oral antibiotics to minimize development of antibiotic-resistant bacteria (at cutaneous and extracutaneous sites) and lack of higher levels of evidence for often-used treatments, including fixed-dose erythromycin-tretinoin, spironolactone and isotretinoin.

Conclusion

Dermatology continues to be challenged by acne and its sequelae. It is to be hoped that clear guidelines such as these along with new therapies and improved conversation between specialists and family doctors will hasten the march of progress and prevent the mental and physical scarring caused by this often debilitating condition. Guidelines such as these are not perfect nor are they error proof. The community must commit itself to testing these guidelines and to formulating new guidelines that will take into account continuing developments in clinical trials that now have more standardized outcome measures.

References

1. White GM. J Am Acad Dermatol. 1998;39:S34-7.
2. Perkins AC, Cheng CE, Hillebrand GG, et al. J Eur Acad Dermatol Venereol. 2011;25:1054-60.
3. Tan JK. J Am Acad Dermatol. 2004;50:15.
4. James WD. N Engl J Med. 2005;352:1463-72.
5. Gollnick H. Drugs. 2003;63:1579-96.
6. Kellett SC, Gawkrodger DJ. Br J Dermatol. 1999;140:273-82.
7. Gupta MA, Gupta AK. Br J Dermatol. 1998;139:846-50.
8. Krowchuk DP, Stancin T, Keskinen R, et al. Pediatr Dermatol. 1991;8:332-8.
9. van der Meeren HL, van der Schaar WW, van den Hurk CM. Cutis. 1985;36:84-6.
10. Jones-Caballero M, Chren MM, Soler B, et al. J Eur Acad Dermatol Venereol. 2007;21:219-26.
11. Abdel-Hafez K, Mahran AM, Hofny ER, et al. Int J Dermatol. 2009;48:280-5.
12. Tan JK, Balagurusamy M, Fung K, et al. J Cutan Med Surg. 2009;13:204-8.
13. Sundström A, Alfredsson L, Sjolin-Forsberg G, et al. BMJ. 2010;341:c5812.
14. Layton AM, Henderson CA, Cunliffe WJ. Clin Exp Dermatol. 1994;19:303-8.
15. Tan JK, Tang J, Fung K, et al. J Cutan Med Surg. 2007;11:211-6.
16. Nast A, Dréno B, Bettoli V, et al. J Eur Acad Dermatol Venereol. 2012;26 (Suppl 1):1-29.
17. Woolf S, Grol R, Hutchinson A, et al. BMJ. 1999;28:527-30.
18. ADAPTE Collaboration; 2009. Available: www.g-i-n.net (accessed 2015 Oct. 29).
19. Jacobs A, Starke G, Rosumeck S, et al. Br J Dermatol. 2014;170:557-64.
20. Garner SE, Eady EA, Popescu C, et al. Cochrane Database Syst Rev. 2003;(1):CD002086.
21. Garcia LM, Sanabria AJ, Alvarez EG, et al. CMAJ. 2014;186:1211-9.

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

Introduction

Atopic dermatitis is a chronic inflammatory skin condition. It has a relapsing course characterized by flare-ups of acute eczema on a background of chronically dry skin. The association of atopic dermatitis (AD) with asthma and allergic rhinitis is referred to as the atopic triad. Conventional strategies have focused on avoidance of triggers and pharmacologic intervention during flares, however, with greater insights into disease etiopathogenesis, prophylaxis of flare-ups with topical immunosuppression and skin barrier protection represent recent changes in AD prevention and management.

Pathogenesis

• Atopic dermatitis is the most common pediatric chronic skin disease.
• AD occurs mainly in infants, with almost half of all cases occurring within the first 6 months of life, but can also be seen in children; AD can last into adult years in approximately 40% of those children.¹
• The prevalence of AD in Canada was estimated to be 8.5% for children aged 6-7 years and 9.4% for children aged 13-14 years. Lifetime prevalence is estimated to be up to 17%, but continues to increase.
• About 10-15% of cases are severe with the remainder split between mild and moderate.^2,3

Diagnosis

• The morphology of AD lesions is the same as that of any dermatitis and includes erythema, vesicle and papule formation, exudation, excoriation, crusting, scaling, and sometimes lichenification. Hence, one cannot use morphology alone to make the diagnosis. Instead, it is necessary to consider the constellation of features associated with AD, these include:
  1. Pruritus (the hallmark of AD; do not make the diagnosis without a history of itch)
  2. Early age of onset
  3. Typical morphology and distribution
  4. Personal or family history of atopy (50-70% of patients with AD have a first-degree relative with atopy)
  5. Xerosis
  6. Chronic relapsing course (no cure)
• The itch, which can be intractable, has important psychological implications. It causes emotional stress and sleep disturbances that significantly impact quality of life. In children, it can impact school performance and, in adults, work performance.
• AD usually begins at 3 months of age, sometimes earlier, with symmetrical involvement of the cheeks, forehead, scalp, and extensor aspects of the extremities.
  • On the torso it stops in the area covered by the diaper.
  • Dry skin is common but becomes more pronounced during the second year of life. After age 2 the lesions are more often located in the antecubital and popliteal fossae, as well as hands, feet, wrists, ankles, and folds of the neck.
• Most cases of AD seem to disappear during childhood, but
  when they last into teenage years, lichenification and dryness
  are typical. In the adult years, facial and hand involvement
  are typical.⁴

Pathogenesis

• Pathogenic factors include:
  • Genetic predisposition (filaggrin mutations)⁵
  • Skin barrier abnormalities
  • Inflammatory immune response
  • Environmental factors
• Patients with AD have skin barrier function defects that increase skin permeability⁶ and transepidermal water loss (TEWL), and allow the penetration of allergens through the skin.
  • These allergens induce activation of the immune system, driving dendritic cells to enhance Th2 polarization, which in turn produces inflammation and leads to further deterioration of skin barrier function. This is referred to as the outside-inside-outside theory of AD pathophysiology.
  • The dramatic increase in prevalence of AD since World War II suggests that environment-gene interactions must play an important role in its pathogenesis.
  • Additionally, increased exposure to soaps, bubble-baths, and water further aggravate an already damaged skin barrier.

General Skin Care

Caring for atopic skin must be as continuous as the disease is chronic. It is important to educate the patient or caregiver about AD and explain that the care cannot stop when the flare is over and that good skin care may reduce acute flares by improving the compromised skin barrier and reducing TEWL.⁷

• The mainstay of basic AD management is the regular use of moisturizers together with good skin hydration, and the avoidance of known triggers.
  • The amount of moisturizer used must be generous and the method of application should be demonstrated to the patient/caregiver as they tend to use too small a quantity.
• Practical tips for AD management:
  • Wash clothes with mild laundry detergent; double-rinse
  • Avoid fabric softener and bleach
  • Dress in cotton and soft fabrics, avoiding wool
  • Keep the humidity in the house around 45-55%
  • Bathe 1-3 times daily in lukewarm water for 5-10 minutes
  • Use emulsifying oil in the bathwater
  • Use mild syndets with adjusted pH for cleansing
  • Pat dry, do not rub, and apply moisturizer immediately after bathing while the skin is still damp

Treatment of Atopic Dermatitis

The common treatment approach for AD has been a reactive one with the use of moisturizers daily and the application of topical steroids or calcineurin inhibitors reserved for acute flares. An alternative treatment approach has been investigated in clinical trials and is known as proactive therapy, preventative therapy or maintenance therapy. This approach has been labelled a paradigm shift in the treatment of AD.⁸

Topical Steroids

• First-line therapy of AD in children consists of using a mild to moderately potent topical steroid combined with the general skin care previously described.
• To maximize benefit and reduce risk, one must choose a topical steroid strength and vehicle by considering the age of the patient, site of the dermatitis, extent and severity of the disease, morphology of the lesion (which guides in choice of the vehicle), and duration of therapy.
• Treating only acute flares, however, does not adequately control the disease since there is subclinical inflammation, epidermal barrier dysfunction, and immunological abnormalities present in the skin of patients with atopic dermatitis even where no lesion is seen. This provides a rationale for ongoing treatment to control that inflammation rather than wait for an acute flare.
• The long-term use of topical steroids is limited by potential local and systemic side-effects.
• Although an important tool in short courses for the treatment of severe AD flares, topical steroids can cause problems if used chronically, especially on the face or in the skin folds, causing atrophy, telangiectasia, and striae.
• If too potent a steroid is used over a large area, suppression of the hypothalamic pituitary axis can occur.
• Just as it is important to demonstrate the application of a moisturizer, it is important to demonstrate the application of topical steroids. When used properly side-effects can be avoided and patient education can reduce steroid phobia.
• There are a few studies looking at the long-term use (16-40 weeks) of topical steroids twice-weekly on unaffected skin to prevent flares of atopic dermatitis.^9-11

Topical Calcineurin Inhibitors (TCI)

The TCIs available in Canada, tacrolimus 0.03% and 0.1% ointments and pimecrolimus 1% cream, provide antiinflammatory steroid-free therapy for atopic dermatitis. They act by inhibiting the activity of calcineurin to dephosphorylate the nuclear factor of activated T cell, and thus, suppress T cell cytokine production.

• They are safe and effective treatment options for children and adults with atopic dermatitis.
• They are indicated for short-term and long-term intermittent therapy in non-immunocompromised patients aged ≥2 years.
• They are extremely effective in alleviating the itch of atopic dermatitis, thereby improving the quality of life of the patients and their family members.¹²
• Treatment with TCIs (and topical steroids) is associated with reduced colonization with Staphylococcus aureus (S. aureus) on the lesional skin of patients with AD.
• They can be used on any body surface including face, eyelids, and folds, and are not associated with atrophy. In fact, there is evidence to suggest that tacrolimus can reverse steroid induced atrophy.¹³
• The most common side-effect is local discomfort, described by some patients as increased itching, burning or stinging experienced during the first few days of therapy, which usually lasts only 10-15 minutes upon application.
• Absorption through the skin is low and there is no evidence of systemic toxicity.¹⁴

Maintenance Therapy

• To address the issues of subclinical inflammation, epidermal barrier dysfunction, and immunological abnormalities present in the non-lesional skin of AD patients, ongoing twice-weekly treatment with tacrolimus ointment was compared with conventional reactive therapy with tacrolimus ointment.
• Patients with any severity of AD received stabilization therapy with tacrolimus ointment for up to 6 weeks to control the disease. Once controlled, they were randomized to ongoing twice-weekly treatment with active drug or vehicle for 1 year. The vehicle arm represents the current standard regimen of treating disease flares. AD flares were treated with twice-daily tacrolimus ointment until resolution.^15,16
• Results showed that twice-weekly tacrolimus ointment reduced the number of flares, prolonged the flare-free interval, and was well tolerated without increasing the amount of ointment used. See Table 1.
• The trial results led to Health Canada’s approval of tacrolimus ointment 0.03% and 0.1% for a new indication. It can be prescribed for maintenance therapy to prevent flares and prolong flare-free intervals in patients with atopic dermatitis who experience a high frequency of flares (≥5 times per year).

Adjuvant Therapy

• Oral antihistamines can provide symptomatic relief of the itch, particularly at bedtime (due to their sedating properties), if topical therapy alone is inadequate.
• Topical or systemic antibiotics may be necessary to treat impetiginized atopic dermatitis. Both topical steroids and calcineurin inhibitors in the long-term will reduce staphylococcal colonization, but at times reducing colonization with the use of bleach baths and intranasal application of mupirocin ointment may be necessary.
• Patients with atopic dermatitis can develop wide-spread infection with herpes simplex, referred to as eczema herpeticum or Kaposi’s varicelliform eruption. Prompt recognition and treatment with oral acyclovir may prevent complications of this potentially life-threatening infection.

Conclusion

Atopic dermatitis is a common chronic inflammatory skin condition that can be difficult to treat. The key to successful therapy is education of the patient/caregiver in the principles of general skin care that have been discussed. Advancements in AD pathophysiology have led to improvements in therapy and the option of steroid-free treatment. The understanding of subclinical inflammation, epidermal barrier dysfunction, and immunological abnormalities in what appears to be normal looking skin has led to the use of maintenance or preventative therapy to keep the disease under control and break the cycle of repeated flares.

References

1. Bieber T. Atopic dermatitis. N Engl J Med. 2008 Apr 3;358(14):1483-94.
2. Barbeau M, Lalonde H. Burden of Atopic dermatitis in Canada. Int J Dermatol. 2006 Jan;45(1):31-6.
3. Lynde C, Barber K, Claveau J, et al. Canadian practical guide for the treatment and management of atopic dermatitis. J Cutan Med Surg. 2005; 8 (Suppl 5):1-9.
4. Leung AK, Hon K, Robson W. Atopic dermatitis. Adv Pediatr. 2007;54:241-73.
5. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011 Oct 6;365(14):1315-27.
6. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009 Aug;129(8):1892-908.
7. Loden M. The skin barrier and use of moisturizers in atopic dermatitis. Clin Dermatol. 2003 Mar-Apr;21(2):145-57.
8. Schmitt J, von Kobyletzki L, Svensson A, et al. Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. 2011 Feb;164(2):415-28.
9. Berth-Jones J, Damstra RJ, Golsch S, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. BMJ. 2003 Jun 21;326(7403):1367.
10. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol. 2002 Sep;147(3):528-37.
11. Van Der Meer JB, Glazenburg EJ, Mulder PG, et al. The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group. Br J Dermatol. 1999 Jun;140(6):1114-21.
12. Whalley D, Huels J, McKenna SP, et al. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents’ quality of life in the treatment of pediatric atopic dermatitis. Pediatrics. 2002 Dec;110(6):1133-6.
13. Boguniewicz M, Schmid-Grendelmeier P, Leung DY. Atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):40-3.
14. Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007 Apr;127(4):808-16.
15. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol. 2008 Dec;159(6):1348-56.
16. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy. 2008 Jun;63(6):742-50.

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.

Top

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.

Top

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).

Top

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.

Top

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.

Top

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

Top

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).

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.

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.

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 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.

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.

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

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).

Key Words:
acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, erythromycin, clindamycin, topical combination therapy

Background

The first description of benzoyl peroxide (BP) in the treatment of acneiform eruptions dates back to 1934, although its use as a topical agent in the management of various skin lesions was pioneered by Loevenhart in 1905.¹ In 1958, Fishman was the first to suggest benzoyl peroxide as a viable treatment for acne.² Pace presented findings of its efficacy before the members of the Canadian Dermatology Association at their meeting in Toronto in June of 1962 (later publishing the findings in 1965³) and after a suitable vehicle (it is insoluble in water) was found for the drug, benzoyl peroxide was adopted by clinicians. Its popularity has increased in recent years with the emergence of antibiotic-resistant strains of Propionibacterium acnes (P. acnes).

Benzoyl peroxide is available in various strengths (2.5-20%) and vehicles (gels, lotions, solutions, creams, soap bars, pads, masks, and washes), as well as in combination formulation with the topical antibiotics erythromycin or clindamycin phosphate. It is also combined with the topical retinoid adapalene in a formulation that was US FDA approved in December 2008, but is not yet available in Canada.

Pharmacokinetics and Pharmacodynamics

Benzoyl peroxide is lipophilic and when applied to the skin it is capable of penetrating into the pilosebaceous follicle. Within the skin, benzoyl peroxide releases free radical oxygen and benzoic acid. The free radicals oxidize bacterial proteins. Higher concentrations of benzoyl peroxide applied to the skin result in larger amounts of drug in the skin.⁴ The benzoic acid is cleared rapidly by the kidneys and excreted unchanged in the urine.⁵ A second peak of urinary excretion of benzoic acid is detected when the benzoyl peroxide is washed off 24 hours after its application. This was noted especially with higher concentrations of the drug, suggesting that it is retained in the stratum corneum and that hydration increases its penetration.⁴

Inhibiting Antibiotic Resistance

Since the introduction of topical antibiotics in the mid-1970s, antibiotic-resistant strains of P. acnes have emerged and increased in numbers over the years.⁶ There is some evidence to suggest that patients with these resistant strains clinically fail to respond to the corresponding oral antibiotic when it is used alone.^6,7

Benzoyl peroxide is a very effective broad-spectrum anti-bacterial agent. It was found to be more effective in reducing the concentration of free fatty acids in sebum than was systemic tetracycline, and efficacy was not affected by
P. acnes resistance.^8,9 BP has mild anti-inflammatory and comedolytic effects,¹⁰ thus, it influences three of the four factors involved in acne pathogenesis. BP was initially thought to have sebo-suppressive effects, but Cunliffe showed that a 5% concentration increased sebum secretion rates by 22.5% after 1-2 months, likely by reducing obstruction in the pilosebaceous follicle and allowing sebum to flow more freely to reach the skin surface rather than affecting the sebaceous gland cells.¹¹

Benzoyl peroxide is effective in controlling antibiotic-sensitive and antibiotic-resistant P. acnes. Significant reductions of P. acnes counts on the skin surface and in the follicle were noted after only 2 days of application of 5% benzoyl peroxide in an aqueous gel, with clinical improvement seen as early as 4 days.¹² Benzoyl peroxide 6% cleanser was shown to reduce counts of antibiotic-susceptible and antibiotic-resistant strains of P. acnes equally by at least 2 logs after only 3 weeks of once daily washing for 20 seconds.¹³

Three double-blind studies that enrolled 153 patients with mild to moderately severe acne compared the efficacy of 2.5%, 5%, and 10% benzoyl peroxide gel formulations with the gel vehicle applied twice daily for 8 weeks. The three strengths were significantly more effective than the gel vehicle. Though the three strengths were deemed similar in their ability to reduce inflammatory lesions, the study was inadequately powered. Consequently, a statistically significant difference between the 2.5% and 5% and the 2.5% and 10% could not be reached. The 2.5% gel was also formulated in a different vehicle than the 5% and 10% gels. Furthermore, the findings showed an increased incidence of irritation related to higher strengths of benzoyl peroxide.¹⁴

The rise of resistant strains of P. acnes has been associated with a failure to respond to antibiotic therapy. This resistance was first reported with the topical antibiotics, clindamycin and erythromycin.¹⁵ The combination of benzoyl peroxide and topical antibiotic should prevent the selection of antibiotic-resistant propionibacteria, as well as reduce the number of strains of existing antibiotic-resistant bacteria on the skin. Benzoyl peroxide has also been shown to reduce the amount of erythromycin required to inhibit sensitive propionibacteria by up to 50% less than if erythromycin was used alone.¹⁶

Additionally, benzoyl peroxide can prevent the selection of erythromycin-resistant Staphylococcus epidermidis (S. epidermidis). During a 16-week study,¹⁷ three groups of 20 patients were treated with benzoyl peroxide alone, BP in combination with 3% erythromycin (BP/E), or erythromycin alone. After 12 weeks of treatment with erythromycin alone, the S. epidermidis isolated was completely resistant to erythromycin. There was also an increase in resistance to clindamycin and tetracycline. Those treated with BP or BP/E showed no change in resistance patterns to erythromycin or other antibiotics. These results are of major significance as S. epidermidis can cause infections in immunosuppressed and hospitalized patients and can transfer resistance to Staphylococcus aureus.¹⁷

In a double-blind study, 37 patients with mild to moderate acne were treated with 5% benzoyl peroxide in combination with 3% erythromycin (BP/E) gel or 3% erythromycin gel alone for 12 weeks. The combination therapy resulted in a greater than 3 log reduction in total P. acnes counts and significantly reduced the number of erythromycin-resistant strains by 6 weeks. Erythromycin alone, however, produced less than a 1.5 log reduction in total P. acnes counts and did not reduce the number of resistant strains after the same amount of time.18 Of concern, five patients in each group developed erythromycin-resistant strains de novo at 6 and 12 weeks. In an open study of 21 patients with erythromycin-resistant strains of P. acnes, the total count and number of resistant strains were reduced by greater than 2.5 logs after
6 weeks of treatment with the BP/E gel.¹⁸

The combination of benzoyl peroxide and antibiotics has also been shown to have superior efficacy to either product alone. In two double-blind randomized, parallel, vehicle-controlled trials, patients were treated nightly with a combination 5% benzoyl peroxide + 1% clindamycin gel (BP/C), benzoyl peroxide, clindamycin, or vehicle gel. The combination gel was significantly superior to the two individual agents in global improvement and reduction of inflammatory lesions.¹⁹

In a ten week study, the combination of BP/C was more efficacious than benzoyl peroxide alone and statistically comparable to the BP/E combination.²⁰

Safety

Benzoyl peroxide can induce an irritant contact dermatitis that is related to the amount and type of product, its concentration, and its vehicle formulation. Reactivity may be more commonly seen in patients with atopic dermatitis. In combination with a topical antibiotic, BP produces less erythema than when used alone.²¹ The rates reported of true allergic contact dermatitis vary in the literature from 0.2% to 1%.^21,22 Patch testing to benzoyl peroxide can be difficult to interpret because of its irritant properties.²³

The carcinogenicity and photocarcinogenicity of benzoyl peroxide have been questioned for many years. An article reviewing two case-control epidemiological studies and 23 carcinogenicity studies in rodents concluded that there was no evidence to support an association between skin cancer in humans and the use of benzoyl peroxide.²⁴ Current data suggests that benzoyl peroxide is considered safe in humans and does not accelerate photocarcinogenesis, though more data is needed.²⁵

Benzoyl peroxide is assigned a Category C by the US FDA, and no studies on its use in pregnant women have been published. However, its metabolism and excretion would suggest that it should have no effect on the fetus.²⁶

Other Treatment Considerations

Benzoyl peroxide bleaches clothing and hair, and thus, patients should be warned accordingly when the drug is prescribed. Practical suggestions for patient management may include limiting use on the chest and back to nighttime due to its bleaching effect on clothing, or recommending that the patient wear a white T-shirt under clothing for daytime application.

Conclusion

Benzoyl peroxide is one of the most commonly used and efficacious topical acne agents. It is equally effective against antibiotic-resistant and antibiotic-sensitive strains of
P. acnes. To avoid antibiotic resistance, the prolonged use of topical or oral antibiotic monotherapy for acne is strongly discouraged without concomitant treatment with benzoyl peroxide. For topical acne therapy benzoyl peroxide can be used as a combination formulation with an antibiotic, and for systemic antibiotic therapy it can be used daily as a wash or leave-on product.²⁷ If found to be too irritating for daily use, even as a wash, a short course (5-7 days) of benzoyl peroxide used monthly may be effective in reducing resistant strains of
P. acnes. Limitations of benzoyl peroxide include an irritant contact dermatitis and, much less frequently, an allergic contact dermatitis.

References

1. Merker PC. Benzoyl peroxide: a history of early research and researchers. Int J Dermatol 41(3):185-8 (2002 Mar).
2. Fishman IM. Benzoyl peroxide in acne: reply. J Am Acad Dermatol 20(3):518 (1989 Mar).
3. Pace WE. A benzoyl peroxide-sulfur cream for acne vulgaris. Can Med Assoc J 93:252-4 (1965 Aug 7).
4. Yeung D, Nacht S, Bucks D, et al. Benzoyl peroxide: percutaneous penetration and metabolic disposition. II. Effect of concentration. J Am Acad Dermatol 9(6):920-4 (1983 Dec).
5. Nacht S, Yeung D, Beasley JN, et al. Benzoyl peroxide: percutaneous penetration and metabolic disposition. J Am Acad Dermatol 4(1):31-7 (1981 Jan).
6. Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol 8(1):41-5 (1983 Jan).
7. Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol 121(1):51-7 (1989 Jul).
8. Fulton JE Jr, Farzad-Bakshandeh A, Bradley S. Studies on the mechanism of action to topical benzoyl peroxide and vitamin A acid in acne vulgaris. J Cutan Pathol 1(5):191-200 (1974).
9. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet 364(9452):2188-95 (2004 Dec 18-31).
10. Burkhart CK. A re-examination of the function of benzoyl peroxide in acne. J Dermatol Allergy 5:23-6 (1982).
11. Cunliffe WJ, Stainton C, Forster RA. Topical benzoyl peroxide increases the sebum excretion rate in patients with acne. Br J Dermatol 109(5):577-9 (1983 Nov).
12. Bojar RA., Cunliffe WJ, Holland KT, et al. The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol 132(2):204-8 (1995 Feb).
13. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis 82(6):417-21 (2008 Dec).
14. Mills OH Jr, Kligman AM, Pochi P, et al. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 25(10):664-7 (1986 Dec).
15. Crawford WW, Crawford IP, Stoughton RB, et al. Laboratory induction and clinical occurrence of combined clindamycin and erythromycin resistance in Corynebacterium acnes. J Invest Dermatol 72(4):187-90 (1979 Apr).
16. Eady EA, Farmery MR, Ross JE, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from acne patients. Br J Dermatol 131(3):331-6 (1994 Sep).
17. Harkaway KS, McGinley KJ, Foglia AN, et al. Antibiotic resistance patterns in coagulase-negative staphylococci after treatment with topical erythromycin, benzoyl peroxide, and combination therapy. Br J Dermatol 126(6):586-90 (1992 Jun).
18. Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin-resistant propionibacteria. Br J Dermatol 134(1):107-13 (1996 Jan).
19. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol 37(4):590-5 (1997 Oct).
20. Leyden JJ, Hickman JG, Jarratt MT, et al. The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl peroxide/erythromycin combination product. J Cutan Med Surg 5(1):37-42 (2001 Jan-Feb).
21. Cunliffe WJ, Burke B. Benzoyl peroxide: lack of sensitization. Acta Derm Venereol 62(5):458-9 (1982).
22. Fulton JE Jr, Bradley S. The choice of vitamin A acid, erythromycin, or benzoyl peroxide for the topical treatment of acne. Cutis 17(3):560-4 (1976 Mar).
23. Ockenfels HM, Uter W, Lessmann H, et al. Patch testing with benzoyl peroxide: reaction profile and interpretation of positive patch test reactions. Contact Dermatitis 61(4):209-16 (2009 Oct).
24. Kraus AL, Munro IC, Orr JC, et al. Benzoyl peroxide: an integrated human safety assessment for carcinogenicity. Regul Toxicol Pharmacol 21(1):87-107 (1995 Feb).
25. Lerche CM, Philipsen PA, Poulsen T, et al. Photocarcinogenesis and toxicity of benzoyl peroxide in hairless mice after simulated solar radiation. Exp Dermatol 19(4):381-6 (2010 Apr).
26. Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy. J Am Acad Dermatol 19(3):431-42 (1988 Sep).
27. Del Rosso JQ. Benzoyl peroxide cleansers for the treatment of acne vulgaris: status report on available data. Cutis 82(5):336-42 (2008 Nov).