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Acne: Maximizing Effectiveness With Combination Therapy

Jerry Tan, MD, FRCPC
Department of Medicine, University of Western Ontario, Windsor, Ontario, Canada

Effective management of acne is contingent upon understanding the pathophysiologic features of this condition. At the level of the target organ, the pilosebaceous glands, the primary factors involved are:

  1. androgenic stimulation or hypersensitivity
  2. enlargement and increased function of sebaceous (oil) glands
  3. altered follicular epithelial growth and shedding
  4. proliferation of Propionibacterium acnes (P. acnes) within the follicle
  5. inflammation.

Types of Acne Lesions

Non-inflammatory lesions: Comedones

Basic acne lesion is a comedone

  • Enlarged, plugged pilosebaceous follicle
    - Whiteheads (plugged follicle)
    - Blackheads (plugged follicle with partially oxidized fatty acids).

Inflammatory Lesions – all of these can scar

Papules
  • Tender to the touch
  • Small, red bumps.
Pustules (pimples)
  • Papules topped by
  • pus-filled lesions
  • May be red at base.
Nodules
  • Large, painful, solid
  • Deep within skin.
Cysts
  • Deep, painful, pus-filled.

Educating the Patient

  • Dispel myths regarding inadequate facial cleansing, the use of steam or abrasives, and the effect of diet on acne (although dairy products may aggravate acne in a small group of patients).
  • Manage expectations: cure vs. control, most treatments take 8-12 weeks for noticeable improvement.
  • While medicines are effective at reducing the number of new lesions, treatment of stains and scars may require fading gels, facials, and surgical correction.
  • Cautions: avoid picking, vigorous scrubbing, and drying.
  • Routine skin care should be gentle.

Goals of Treatment

  1. Heal existing lesions and prevent scarring.
  2. Prevent new lesions from forming.
  3. Minimize psychological stress and embarrassment.
Aggravating Factors
  • Certain drugs (e.g., androgens, lithium)
  • Occlusive cosmetics may enhance comedogenesis
  • Premenstrual flares due to changes in hormone levels
  • Friction of rubbing or scrubbing skin
  • Occlusion from helmets, backpacks, or tight collars
  • Squeezing or picking at blemishes
  • Stress.

Mild Acne – Topical Therapy

Comedonal +/- a few inflammatory lesions

Topical Retinoids

  • 1st line therapy – most effective in preventing and treating microcomedones and comedones.
  • Use early for best results.
  • Add antimicrobial therapy when inflammatory lesions are present.
  • Should be applied to entire affected area.

Retinoid Mechanism of action

  • Inhibits the microcomedo formation.
  • Clears mature comedones and inflammatory lesions.
  • Maintains remission of acne.
  • Treating the microcomedo prevents disease progression.
  • Enhances collagen production and can be used to reduce acne scars.
  • Topical retinoids include: Tretinoin, Stieva A®, Retin A® (plus others); Tazarotene (Tazorac®); Adapalene (Differin®).

Topical Antibotics: Erythromycin and Clindamycin

  • Inexpensive
  • Useful for inflammatory, but not comedonal acne.
  • Mechanism of action: antimicrobial and anti-inflammatory.
  • Evidence of increasing antibiotic resistance due to over-use of antibiotics.
Combination Therapy for Mild-to-Moderate Acne
  • Topical retinoids, BPO and antibiotics can be used. They are now marketed in various combinations, i.e., Benzaclin®, Benzamycin®, Clindoxyl®, and Stievamycin®.
  • Should be used when inflammatory lesions are present (to help speed action of antibiotics).
  • Antibiotic should be discontinued when inflammatory lesions resolve (2-4 months).
  • Continue to use topical retinoids for maintainance when remission has been obtained.
  • Time for Results: 8-12 wks.

Antibiotic + Topical Retinoid is Better than Antibiotic Alone in Preventing Microcomedone Formation

  • Treats most mild-to-moderate acne with combination therapy (antibiotic + topical retinoid).
  • Targets more pathophysiologic factors.
  • Clearing is faster and greater than antibiotic therapy alone.

Non-responders

  • Add systemic antibiotics or hormones.
  • Treat non-responders as patients with moderate acne.

Tips for Topical Treatment

  • Apply to entire area, not just affected spots.
  • Use regularly; consistency is important.
  • Expect improvement after 8-12 wks.
  • If irritation occurs, reduce duration +/- frequency of application.
  • When possible use aqueous rather than alcohol-based products (less irritating).
  • Consider a gentle start-up schedule:
    - alternate night treatments with topicals
    - apply between dinner and bedtime
    - wash off prior to bedtime, do not sleep with products on skin
    - combine with mild, gentle cleansers
    - avoid the nose, eyes, and corners of the mouth.
  • Cosmetic Options:
    - includes cleansers and moisturizers
    - camouflage make-up: encourage cover-up and camouflage cosmetics to reduce embarrassment
    - products should be oil free and tested to be non-comedogenic
    - reduce use of hair products (conditioners, gels, hair spray, mousse) – may extend onto forehead, neck, back causing comedones

Moderate Acne – Topical/ Systemic Therapy

  • Means an increase in the number and extent of inflammatory lesions.
  • Greater involvement of the face and trunk.

Using topical preparations is preferable if moderate acne responds. However, systemic therapy, i.e., oral antibiotics or hormonal therapy, may be needed to clear moderate acne.

Rational Use of Oral Antibiotics

To minimize the development of resistant P. acnes:
  • Limit use to maximum 6 months to reduce risk of resistant bacteria
  • Restrict to tetracycline family if possible (i.e., tetracycline 1g/d, minocycline 100mg/d)
  • Use in combination with benzoyl peroxide.

Hormonal Therapy

  • An adjunctive therapy to topicals in mild acne in women desiring contraception.
  • Primary therapy in moderate nonscarring acne.
  • One of 2 preferred forms of contraception in severe acne treated with Accutane®.
  • For women desiring contraception: Diane 35®, Yasmin® Tricyclen®, Alesse®.
  • When contraception is not required consider spironolactone.
  • Maximum effectiveness seen at 4-6 months.
  • Add topicals to increase speed of improvement.

Mechanism of Action for Hormonal Therapy

Estrogen effects:
  • decreases adrenal and ovarian androgens
  • reduces 5-á reductase levels
  • increases sex hormone-binding globulin leading to lower testosterone levels.
Progestins vary in androgenic potential:
  • antiandrogenic: cyproterone acetate
  • low in androgenic potential: desogestrel, norgestimate

Severe Acne – Systemic Therapy

Inflammatory nodules
  • Extensive papulopustules
  • Ongoing scarring
  • Purulent and/ or serosanguinous drainage
  • Sinus tracts
  • Psychosocial/ occupational impact
  • Inadequate therapeutic response.

Oral isotretinoin (Accutane®)

  • Treatment of choice for severe acne
  • Reduces sebaceous gland function and sebum excretion
  • Secondarily reduces proliferation of P. acnes
  • Reduces follicular plugging.

Isotretinoin Adverse Events

  • Can cause dryness of facial skin
  • Isotretinoin is teratogenic
  • Women must be abstinent, permanently sterilized or use two separate effective forms of birth control
  • Monitor for depression and other mood changes
  • Other mucocutaneous side effects
  • Rarely: hepatitis, hypertriglyceridemia.

Agent

P. acnes

Sebum

Inflammation

Comedones

Benzoyl peroxide*

++

-

+

+

Topical antibiotics

++

-

+

+

Azeleic Acid

+

-

+

+/-

Topical retinoids

-

-

+

+++

Estrogenic OCs

-

+

-

-

Antiandrogens

-

++

-

-

Oral antibiotics

+++

-

++

-

Oral isotretinoin

++

++++

++

++

Table 1. Acne medications and mechanism of effect. *use with antibiotics to reduce risk of selecting for resistant P. acnes

Conclusion

Educate and counsel. Most patients with acne are teenagers who are very self-conscious about their looks and expect immediate treatment results. However, adult acne is becoming more common, and can be very distressing as well. It is critical that all patients be counseled about compliance with the treatment and to expect results no sooner than 8 weeks after beginning therapy.

Treatment choice should be based on pathophysiology, severity and the psychosocial impact of the disease:

  1. Mild: topical retinoids +/- topical antibiotics +/- topical BPO.
  2. Moderate: add oral antibiotics or hormones if the patient is unresponsive to topical treatments alone.
  3. Severe or unresponsive disease: oral isotretinoin.