Non-antibiotic doxycycline new paradigm in rosacea treatment

November 1, 2006

Available evidence from basic science and clinical research support the conclusion that when an antibiotic is not an antibiotic, it may still be a safe and effective agent for the treatment of rosacea, says James Q. Del Rosso, D.O., clinical associate professor of dermatology, University of Nevada School of Medicine, Las Vegas.

Dr. Del Rosso is referring to the use of doxycycline in a dosage formulation that is devoid of antibiotic activity yet is capable of exhibiting anti-inflammatory properties relevant to the treatment of rosacea. This formulation, a 40 mg controlled release doxycycline monohydrate capsule (Oracea, CollaGenex) administered once daily, is referred to specifically as anti-inflammatory dose doxycycline.

TRIALS PROVE IT The randomized, double-blind placebo-controlled trials provide proof that anti-inflammatory dose doxycycline is safe and effective treatment for rosacea.

"Dermatologists write about six million prescriptions for tetracyclines each year, most of which are for patients with acne and rosacea. However, it is still unknown whether microorganisms are important in the etiology of rosacea, and while tetracyclines at conventional antibiotic doses have acquired a time-tested role in rosacea management based on years of clinical experience, there is a paucity of evidence indicating that an antibiotic effect is needed for treatment of rosacea. Furthermore, although clinically meaningful side effects of long-term tetracycline treatment for rosacea appear to be relatively uncommon, the potential for emergence of bacterial resistance is an important concern. Considering that information and because rosacea is a chronic disease requiring long-term therapy, it seems reasonable to avoid exposing patients to antibiotics unnecessarily provided other forms of therapy are effective," Dr. Del Rosso says.

"Treatment with anti-inflammatory dose doxycycline is a first step toward separating out the antibacterial and anti-inflammatory effects of 'antibiotic' drugs. Although likely not the last, it is a major advance for harnessing the therapeutic benefits of doxycycline with advantages relating to safety and once-daily dosing convenience."

BELOW THE RADAR As outlined in a recently published article (j am acad dermatol 2006;54:258-65), accumulating research demonstrates that tetracyclines exert a range of nonantibiotic activities that include the ability to reduce release of pro-inflammatory cytokines, scavenge reactive oxygen species, downregulate matrix metalloproteinases, inhibit nitric oxide synthetase, inhibit angiogenesis and reduce pro-inflammatory activity of phospholipase A2.

Those effects can be achieved at doses below the level needed for antibacterial activity and make the tetracyclines drugs of interest for the treatment of a variety of non-infectious diseases, including rosacea. At present, doxycycline is the only tetracycline antibiotic for which a dosage separation between antibiotic and anti-inflammatory effects has been established.

"The pathogenesis of rosacea is not fully understood, but several lines of evidence support a contributory role for chronic photodamage. Clearly, excessive UV exposure can lead to telangectasias, but it also promotes increases in reactive nitrogen species, reactive oxygen species and MMPs, as well as dermal matrix degradation, angiogenesis and loss of vascular integrity. The spectrum of pharmacologic activity of the tetracyclines can be considered to provide an excellent match for addressing those mechanisms," Dr. Del Rosso tells Dermatology Times.

Research with doxycycline has led to characterization of its dose-related pharmacologic spectrum of activities and identification of the dose threshold for achieving anti-inflammatory effects without antibacterial activity. In describing the dose-ranging effects of doxycycline, Dr. Del Rosso notes the importance of discriminating between low-dose and anti-inflammatory dose doxycycline.

"Low-dose doxycycline, defined as 50 to 100 mg per day, is not synonymous with a non-antibiotic effect because even at a daily dose of 50 mg, doxycycline can achieve serum levels for two to four hours that can exert antibiotic selection pressure against sensitive bacteria," he explains.

ROSACEA DOSAGE The pivotal trials that led to FDA approval of once daily controlled release doxycycline monohydrate for the treatment of moderate to severe rosacea consisted of two, identically designed phase 3 trials randomizing a total of 537 adult patients to treatment with placebo (n = 268) or anti-inflammatory dose doxycycline 40 mg daily (n = 269).