Mechanism-based treatment of acne vulgaris: the value of combination therapy

Journal of Drugs in Dermatology, May-June, 2005 by Guy Webster

An overview of the pathophysiologic factors addressed by the different drug classes is presented in Table 2.

Treatment Approach: Combination Therapy

Because the genesis of acne is multifactorial, it is rational to use agents from different classes that address different pathophysiologic factors. It is sensible to treat the disease as efficiently as possible to limit expense and adverse events and to speed improvement. As seen in Table 1, topical retinoids as monotherapy are recommended as first-line therapy for comedonal acne. The recommended first-line therapy for mild papular/pustular acne is the combination of a topical retinoid and a topical antimicrobial. (1) This combination will address multiple pathophysiologic factors. The galenic stability and tolerability of the retinoid being used needs to be considered. Some formulations of tretinoin, for example, will be degraded in the presence of sunlight and oxidized in the presence of benzoyl peroxide. (23) This is not true of adapalene or the microsponge formulation of tretinoin. (23,24)

The recommended first-line treatment of moderate papular/pustular acne is a topical retinoid plus an oral antibiotic; topical benzoyl peroxide may also be necessary. This is different from a historical approach to treating inflammatory acne, which involved a combination of an oral and topical broad spectrum antibiotic. This strategy significantly increases the risk of bacterial resistance to antibiotics, both that of P. acnes in acne patients, and other organisms such as Staphylococcus aureus. Further, antibiotics have only weak effects on comedogenesis. (1)

Topical Retinoids Plus Antibiotics: Key Clinical Studies

Combined analysis of 6 controlled efficacy and safety trials conducted in Europe for registration of a fixed combination of clindamycin phosphate 1% and tretinoin 0.025% gel showed that the combination was significantly more effective than either clindamycin 1% or tretinoin 0.025% alone. The studies included a combined total of 769 patients aged 12 to 26 years. There were 680 patients included in the efficacy analysis after patients without post-baseline efficacy evaluations and patients with fewer than 10 inflammatory and 10 non-inflammatory lesions at study entry were excluded. Safety was evaluated in all patients. After 12 weeks of therapy, the combination was significantly better than either agent alone in reducing inflammatory, non-inflammatory, and total lesions. The combination was well-tolerated, with the most frequently reported adverse effects being application site reactions. (25)

In a 12-week randomized, multicenter trial of 249 patients with mild-to-moderate acne assessing the effects of dual therapy with adapalene gel 0.1% plus clindamycin 1% versus clindamycin plus vehicle, the combination again proved significantly better. Patients were at least 12 years old and had a global severity score ranging from 2 to 8 on the Leeds Revised Acne Grading Scale. They had 10 to 50 inflammatory facial lesions (no more than 3 nodules or cysts) and 20 to 150 non-inflammatory facial lesions. Not only did the combination result in significantly greater reduction in inflammatory lesions (P = .004) and non-inflammatory lesions (P < .001) at 12 weeks (Figure 1), but also in accelerated improvement of lesions. Those on the adapalene/clindamycin therapy showed a significantly greater improvement in the reduction of total and non-inflammatory lesions seen as early as week 4, and a reduction of total lesions counts at week 2 that was similar in proportion (23.6%) to that of clindamycin plus vehicle at week 12 (25.5%). Adverse events were similar in the combination group and the clindamycin monotherapy group in terms of overall incidence, nature, and severity, showing the low irritation potential of adapalene. Reports of scaling, dryness, and stinging/burning were greater in patients using the combination, but most were mild in severity. Of clinical note, there was no acne flare and little irritation in the combination group. (26)