Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics

Journal of Drugs in Dermatology, May, 2007 by Jennifer F. Conde, Christopher B. Yelverton, Rajesh Balkrishnan, Alan B. Fleischer, Jr., Steven R. Feldman

Abstract

Background: Rosacea is an extremely common chronic dermatosis affecting an estimated 14 million Americans. Rosacea is most commonly managed with topical metronidazole, sometimes in combination with oral antibiotics.

Purpose: To review published studies about topical metronidazole therapy for rosacea, both as a monotherapy and in conjunction with oral antibiotics.

Methods: Medline searches were conducted for clinical trials using metronidazole, tetracycline, and doxycycline for rosacea.

Results: Topical metronidazole has been well studied as a rosacea therapy. Twice-daily dosing of metronidazole 1.0% cream is as effective as 250 mg tetracycline twice daily. Metronidazole 1.0% gel used once daily is as effective as azelaic acid 15% gel dosed twice daily. When dosed at subantimicrobial levels, doxycycline 20 mg taken twice daily is effective in decreasing inflammatory lesions and erythema associated with rosacea. Metronidazole 0.75% lotion is more effective when used in combination with doxycycline 20 mg dosed twice daily.

Discussion: Metronidazole in 0.75% strength lotion, cream, and gel and 1.0% metronidazole cream and gel are all efficacious in treating rosacea. Combination treatment with oral antibiotics at both antimicrobial and subantimicrobial doses is an efficacious means of treating rosacea. Maintenance treatment with topical metronidazole decreases relapses and allows for longer intervals between flares.

Introduction

Rosacea is a common chronic dermatologic condition affecting an estimated 14 million Americans. Rosacea has a higher prevalence for fair-skinned individuals, mostly of Celtic and northern European origin and most commonly affects individuals between the ages of 30 and 50 with women being affected more often than men. (1,2)

The National Rosacea Society has standard classification criteria to provide consistency in research and clinical trials. The features of rosacea most commonly affect the convex surfaces of the face with the primary features of rosacea including persistent erythema, transient (flushing) erythema, inflammatory lesions consisting of papules, pustules, and nodules, and telangiectasias. (3) Secondary features of rosacea include dryness, burning, stinging, plaques, edema, ocular manifestations such as conjunctiva or lid irritation, phymatous changes especially of the nose, as well as poorly understood peripheral changes. (3)

Four subtypes of rosacea along with one variant are recognized. The four subtypes are erythematotelangiectatic, papu-lopustular, phymatous, and ocular. (3) Granulomatous rosacea is a variant form consisting of lesions ranging in color from brown to yellow to red, which are hard and not inflammatory in nature. (3)

The main goals of treatment (as well as the end outcomes in most clinical trials) are to reduce the number and severity of inflammatory lesions, reduce erythema, and reduce telangiectasias (although treatments are minimally successful at treating this component). The most widely used rosacea treatment is topical metronidazole, either as monotherapy or in combination with other treatments. This article reviews available evidence for use of topical metronidazole in the treatment of rosacea.

Methods

We conducted Medline searches for clinical trials using the keywords rosacea, metronidazole, tetracycline(s), doxycycline, and minocycline. We examined trials in English dealing with topical metronidazole, either as monotherapy or in conjunction with oral antibiotics.

Results

Topical Metronidazole

Metronidazole was the first topical treatment approved solely for the treatment of rosacea. (4) Since its approval in the late 1980s, metronidazole has been studied in many randomized controlled trials and remains a first-line therapy for the treatment of rosacea (Table 1). The formulations of metronidazole currently available are 0.75% gel, lotion, and cream as well as 1.0% gel and cream. Metronidazole is well-tolerated with side effects encompassing a range of local skin reactions including dryness, redness, pruritus, aggravation of acne or rosacea, burning, and stinging. (5) True allergic contact dermatitis from the use of metronidazole is extremely rare. (5) A review of all vehicles of metronidazole found that local skin reactions typically occur in less than 2% of subjects. (6)

The reason for topical metronidazole's effectiveness in treating rosacea is not clearly understood. Metronidazole is a broad-spectrum antibacterial and antiparasitic agent. Although it has been thought that metronidazole may have effects on the Demodex folliculorum mite, its mechanism is more likely due to its anti-inflammatory, antioxidant, or immunosuppressive properties. (7,8) Metronidazole may affect neutrophil migration and activity as well as the production of reactive oxygen species. (8)

In 1983, 81 subjects with rosacea were treated with either metronidazole 1% cream twice daily or vehicle. (9) Overall clinical assessment, as well as erythema scores and papule and pustule counts were significantly improved (P<0.05) in the metronidazole group when compared to vehicle at 2 months. (9)