Optimal Management of Acne to Prevent P. acnes Resistance

M. T. Haroun, MD, FRCPC
Assistant Professor of Medicine, Division of Dermatology, University of Toronto,
Sunnybrook and Women’s College Health Sciences Centre, Toronto, Canada

Acne Vulgaris

Acne vulgaris is a disease of the pilosebaceous follicle characterized by noninflammatory (open and closed comedones) and inflammatory lesions (papules, pustules, and nodules). Its pathogenesis is multifactorial, i.e., hormonal, bacterial and immunological (inflammatory) factors are involved, and their interaction results in the production of acne lesions. Although it is not a life-threatening condition, it can have a detrimental effect on a patient’s quality of life. It is readily responsive to treatment with the goals being to clear the lesions, prevent scarring, and reduce the psychological distress.

Possible Causes of Acne

Hormones are known to affect sebum production, but may well play a role in follicular hyperkeratinization independent of the effect on the sebaceous gland. During adrenarche, an increase in adrenal androgens leads to:

• an increase in the size of sebaceous glands and a resulting increase in sebum production
• abnormal desquamation and greater adhesion of the shed keratinocytes in the sebaceous follicle, leading to obstruction in the follicle, and resulting in production of the microcomedo: the precursor of all acne lesions.

Colonization of the pilosebaceous apparatus by the anaerobic diphtheroid Propionibacterium acnes (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
• inducing immune response (e.g., antibody production).

Topical Treatments

Topical antibiotics have been used to treat acne for more than 40 years and are still widely used. Their efficacy is partly due to their reduction of the P. acnes population and partly due to the reduction of inflammatory mediators. The emergence of resistant strains has in some cases been associated with a failure to respond to antibiotic therapy. This resistance was first reported with the topical antibiotics clindamycin and erythromycin.[Crawford WW, et al. J Invest Dermatol 72:187-90 (1979).] The use of benzoyl peroxide (BP) helps to reduce the occurrence of resistance and can be effective in the treatment of both nonresistant and resistant P. acnes strains. BP does not promote antimicrobial resistance and has been shown to prevent such resistance when used concomitantly with topical erythromycin.

Clinical Study	Treatment	Results
Double-blind study of patients with mild-tomoderate acne [Eady EA, et al. Br J Dermatol 134:107-13 (1996).]	5% BP/3% erythromycin (BP/E) gel vs. erythromycin alone applied for 6 weeks	The number of erythromycin-resistant strains was signifi cantly reduced in the BP/E group compared with the group who received erythromycin alone.
Open study of patients with erythromycin-resistant strains of P. acnes. [Eady EA, et al. Br J Dermatol 134:107-13 (1996).]	5% BP/3% erythromycin (BP/E) gel vs. erythromycin alone applied for 6 weeks	Highly signifi cant reductions were also seen in acne grade and lesion counts with the BP/E combination.
Two double-blind randomized, parallel, vehicle-controlled trials of acne patients [Lookingbill DP, et al. J Am Acad Dermatol 37:590-5 (1997).]	BP/clindamycin combination, BP, clindamycin or vehicle gels applied once nightly for 11 weeks	The combination gel was signifi cantly superior to the two individual agents in global improvement and reduction of infl ammatory lesions.
Randomized, multicenter, single-blind trial of moderate-to-severe acne patients [Leyden JJ, et al. J Cutan Med Surg 5:37-42. (2001).]	5% BP/1% clindamycin, 5% BP or 5% BP/3% erythromycin applied twice daily for 10 weeks	Compared with BP, BP/clindamycin demonstrated signifi cantly greater reductions in infl ammatory lesions. BP/clindamycin was comparable to BP/E.
Table 1: Clinical trials demonstrating efficacy for combination treatments with BP and clindamycin or erythromycin

Advantages of BP/Antibiotic Combination

1. less irritation than BP alone
2. increase tolerability to topical retinoid
3. better efficacy than BP alone.

There are many acne grading systems, but it may be easier to use a descriptive grading system using the terms mild, moderate, and severe with descriptors of comedonal, inflammatory, nodular, and scarring acne.

Comedonal Acne

Non-inflammatory (comedonal) acne is best treated with a topical retinoid. Options include tretinoin, adapalene, and tazarotene. Not only do retinoids inhibit comedo formation, they can usually clear all degrees of comedonal acne, but this may take a few months. BP has mild comedonal activity.

Oral Treatments

Acne that does not respond to topical therapy, causes scarring, or presents with nodular lesions should be treated orally. Options for oral therapies include antibiotics, hormonal therapy and isotretinoin. Isotretinoin is usually used as monotherapy. Both oral antibiotics and hormonal therapies should be used in combination with topical retinoids and BP.

Prescribing habits to minimize resistant strains of P. acnes

1. Antibiotics should not be used as monotherapy, nor should they be used to treat mild acne.
2. Avoid topical antibiotics if non-antibiotic topical preparations will suffice.
3. Use alternatives to antibiotics for maintenance.
4. Stop antibiotic treatment when the skin clears or if no further improvement is noted.
5. 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]).
6. If the antibiotic is needed again, use the same antibiotic.
7. Use full doses of antibiotics and do not taper.
8. Avoid concomitant topical and systemic use of different antibiotics to reduce the risk of developing resistance to both.
9. Do not switch or rotate antibiotics in nonresponders.
10. Use BP during antibiotic therapy.

Feature	Systemic Drugs	Topical Drugs
Sebum overproduction	Estrogen, spironolactone, other anti-androgens, isotretinoin	None.
Follicular keratinization	Isotretinoin, antibiotics (indirect effect), anti-androgens	Tretinoin, adapalene, tazarotene, salicylic acid Antibiotics and BP (indirect effects).
P. acnes proliferation	Tetracycline, minocycline, doxycycline, erythromycin, trimethoprim, isotretinoin	Clindamycin, erythromycin, BP, BP/antibiotics combos.
Inflammation	Corticosteroids, isotretinoin, dapsone, antibiotics, NSAIDS	Intralesional corticosteroids, topical antibiotics, BP/antibiotic combos, some retinoids.
Table 2: Major pathophysiologic features of acne and drugs that affect them

Side-Effects

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 population) should a topical retinoid be used with a topical antibiotic alone.

Conclusion

Since multiple factors are involved in the pathophysiology of acne, treatment that counteracts the majority of them can be expected to achieve the best results. When considering the options for reducing the P. acnes population, it is best to choose those that do not encourage resistance patterns.

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