Overview of New Therapeutic Developments for Acne

Anja Thielitz; Harald Gollnick

Disclosures

April 13, 2009

In This Article

Oral Antibiotics

Systemic antibiotics are a standard of care in the management of moderate and severe acne, acne that is resistant to topical treatment and acne that covers large parts of the body surface. There is evidence to support the use of tetracycycline, doxycycline, minocycline, trimethoprim-sulfomethoxazole, clindamycin and azithromycin, but tetracyclines are routinely considered as the first-line oral antibiotic therapy in acne.[51] The most commonly prescribed tetracyclines are first-generation cyclines (tetracycline HCl and oxytetracycline) and second-generation cyclines (doxycycline, minocycline and lymecycline), which have a better pharmacokinetic profile and may be taken with meals, but are more expensive. Beside their antimicrobial effects on P. acnes, tetracyclines also have potent anti-inflammatory effects, such as their ability to reduce neutrophil chemotaxis or inhibitory effects on cytokines and matrix metalloproteinases.[52] Recent studies have shown that subantimicrobial-dose doxycycline (40 mg/day) reduced the number of both inflammatory and noninflammatory lesions in patients with moderate acne.[53] No detectable antimicrobial effect on the skin flora was demonstrated. In 2006, a controlled-release 40-mg capsule formulation of doxycycline devoid of antibiotic activity was approved by the FDA for the treatment of inflammatory rosacea. However, such an approval is still lacking for acne therapy and current guidelines support the normal-dose regimens (doxycycline 100 mg/day) rather than commonly practiced prolonged low-dose treatments of 50 mg/day, which have borderline antimicrobial activity and might promote bacterial resistance.[6,8,54] In general, oral antibiotics should not be used as monotherapy and be combined with BPO at least when used longer than 6 weeks and with topical retinoids to increase and speed up clinical efficacy.

There is insufficient evidence to support one tetracycline over another in terms of efficacy.[55] In the range of investigated dosages, the antibiotic dosage seems to have no impact on efficacy. Adverse effects, such as gastrointestinal symptoms or vaginal candidiasis, can be seen with all oral tetracyclines. Doxycycline has the highest risk associated with photosensitivity.

Minocycline shows less resistance towards P. acnes[54] than first-generation tetracyclines and doxycycline and higher lipid solubility; however, minocycline seems to be almost unique within the group in causing potentially irreversible slate-grey hyperpigmentation of the skin, which has been very rarely seen with other tetracyclines, or acute vestibular adverse events. Furthermore, it is associated with a higher risk of inducing lupus-like syndrome.[56] The overall hazard ratio for the association of minocycline to lupus erythematosus (LE) was 2.64 (95% confidence interval: 1.51-4.66).[57] Another possible risk associated with minocycline is autoimmune hepatitis or other types of hepatotoxicity.[58] Related to these facts, minocycline is no longer recommended as first-line therapy in acne vulgaris.[59]

Based on the concept that lowered overall systemic exposure to minocycline should reduce unwanted side effects, an extended-release (ER) minocycline hydrochloride tablet formulation was developed that demonstrated a delayed time of maximum concentration (tmax: 3.5-4 h) compared with a nonmodified-release minocycline (tmax: 2.25-3 h), and a lower maximum concentration of drug in the blood compared with nonmodified-release formulations. In 2006, the FDA approved an ER formulation of minocycline hydrochloride tablets (Solodyn®, Medicis) for the treatment of inflammatory lesions of non-nodular moderate-to-severe acne vulgaris in patients aged 12 years and older based on large-scale Phase III clinical trials that evaluated efficacy and safety, dose-response analysis and long-term data.[60,61] Independently, each study showed that treatment with ER minocycline administered in a 1-mg/kg dose for 12 weeks significantly reduced (p < 0.001) the number of inflammatory lesions and significantly improved (p < 0.001) their Evaluator's Global Severity Assessment (EGSA) scores compared with the placebo group. The percentage of subjects reporting acute vestibular adverse events was comparable in both groups (~10% of subjects in each group). Further long-term studies and observations will have to demonstrate whether the incidence of rare severe side effects is lowered by ER formulations.

Azithromycin has been tested in several recent clinical trials for acne and might have comparable efficacy to doxycycline or tetracycline;[62,63] however, well-designed trials without methodological flaws (e.g., open-labeled, small patient numbers) are still lacking. There is also a huge diversity in the dosage regimens used throughout the studies and it is as yet unclear whether a pulse therapy or other regimens (every other day, three-times weekly) should be preferred. However, prolonged use of intermittent or low-dose regimens is highly questionable with regard to the induction of antibiotic resistance of this potent and widely used broad-spectrum antibiotic. A recently performed dose-finding study suggested that azithromycin in a total dose of 6.0 g in 10 weeks is superior to 4.5 g in 7 weeks and 7.0 g in 13 weeks and seems to be a promising agent in the treatment of papulopustular acne vulgaris with few side effects and good patient compliance.[64]

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