Azelaic Acid: Evidence-based Update on Mechanism of Action and Clinical Application

Azelaic acid is a complex molecule, and our knowledge of its clinical utility continually evolves. This dicarboxylic acid, a byproduct of pityrosporum fungal mycelia metabolism, first drew attention as an inducer of hypopigmentation via competitive inhibition of tyrosinase.¹ This observation inspired inquiry into the usage of azelaic acid as a topical treatment for disorders characterized by hyperpigmentation1. Subsequent investigation demonstrated both anti-inflammatory, as well as antibacterial properties, both in vitro, and in vivo.^2,3

In 2003, Azelaic acid was first approved for clinical use as a 15% gel in the treatment of rosacea.⁴ Since its introduction, it has also been approved for the treatment of acne as a 20% cream. Topical azelaic acid has been demonstrated as safe in pregnancy and is thus classified as a category B drug; the agent also appears safe for use during lactation.⁵

In this report, we review in some detail the various mechanisms of action ascribed to azelaic acid, and provide an update on its reported clinical utility.

Azelaic acid is bactericidal for Propionibacterium acnes, but also has demonstrable antibacterial activity against a number of other cutaneous microorganisms.⁶ Both in vitro and in vivo studies that azelaic acid has marked effect against S. aureus, and S. epidermidis.⁷a naturally occurring and nontoxic C9 dicarboxylic acid, possesses significant biologic properties and a potential as a therapeutic agent. These studies have shown that azelaic acid is a reversible inhibitor of tyrosinase and other oxidoreductases in vitro and that it inhibits mitochondrial respiration. It can also inhibit anaerobic glycolysis. Both in vitro and in vivo it has an antimicrobial effect on both aerobic and anaerobic (Propionibacterium acnes While the exact mechanism(s) of antimicrobial activity remains to be fully elucidated, azelaic acid has effects on metabolism, enzymatic activity, and intracellular pH.³ Furthermore, intracellular concentrations of azelaic acid in P. acnes have been found to be over 90 times greater than that of the ambient tissue environment, indicating that the molecule is actively transported into the cell.³ Studies suggest that intracelleular azelaic acid may disable the bacterium’s ability to maintain a pH difference across the cell membrane, thereby acting to decrease the efficiency of respiratory metabolism, and render the cell more susceptible to changes in the environmental pH.⁸ A lower environmental pH may also enhance this dicarboxyclic acid bactericidal effects.³ Even at 313μM, azelaic acid has been shown to reduce microbial protein synthesis by over fifty percent.³ Meanwhile, 12-30 fold greater concentrations of azelaic acid are required to inhibit DNA and RNA replication to a similar degree.³

Recent in vitro data suggests that azelaic acid might possess a wider spectrum of anti-infective activity than previously known or expected. Following appropriate standard culture of Bacillus oleronius, S. aureus, S. epidermidis, Malassezia furfur, and P. acnes with azelaic acid, significantly impeded growth was seen in a disk diffusion model. (Table 1; Data on file, Bayer Pharmaceutical).

To date, no resistant strains of P. acnes to azelaic acid have been identified using both in vitro or in vivo studies.⁶

Many clinical results of azelaic acid use lead to visibly reduced inflammation. It appears that this may be a consequence of not only mitigating disease staes, but also due to a direct role in reducing the production of pro-inflammatory factors, and reactive