Topical metronidazole combination therapy in the clinical management of rosacea

Journal of Drugs in Dermatology, July-August, 2005 by James Q. Del Rosso, Joseph Bikowski

Abstract

Metronidazole was the first topical agent approved by the US Food and Drug Administration for the treatment of rosacea. Several controlled studies have confirmed the efficacy and safety of topical metronidazole 0.75% gel, lotion and cream and 1% cream for rosacea. At present, little data exists regarding the use of combination topical therapy in rosacea management, although anecdotal evidence and preliminary studies suggest at least some additive benefit when topical metronidazole is used in combination with sulfacetamide 10%/sulfur 5%. In this paper, the results of observational experience evaluating topical metronidazole 0.75% gel used in combination with other topical rosacea therapies and/or subantimicrobial dose doxycycline are reported.

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Introduction

Topical metronidazole 0.75% gel has been available for the treatment of rosacea since 1988. Several studies inclusive of the 0.75% gel, lotion, and cream, 1% cream, and a new 1% gel formulation have established favorable efficacy and tolerability in over 2,200 actively treated patients; data from all but a few of the most recently completed studies have been published elsewhere. (1,2) A recently completed multicenter, open-label, 12-week trial evaluating 612 patients treated with metronidazole 0.75% gel for papulopustular rosacea provides additional community-based experience confirming efficacy, safety, and favorable tolerability. In this trial, severity was graded as moderately severe in 23%, moderate in 58%, and mild in 19% of patients. Results at study endpoint (week 12 interim analysis) include a 77% reduction in papules and 80% reduction in pustules (p<.001), greater than 50% reduction in mean combined facial erythema score (p<.0001), significant improvement in telangiectasia rating (p=.0001), less than 2% incidence of local tolerability reactions, and significant improvement from baseline in several quality of life indices including symptoms (p<.0001), embarrassment (p<.0001), and impact on social activities (p < .0001). (3)

Regardless of the topical agent under evaluation for rosacea, almost all clinical trials have studied efficacy and tolerability with monotherapy. There is a conspicuous absence of data evaluating the potential benefit of combination topical therapy for rosacea. This paper reports on combination topical therapy using metronidazole 0.75% gel with a topical sulfacetamide 10%/sulfur 5% cleanser or "leave on" formulation, or with subantimicrobial-dose doxycycline hyclate (20 mg twice daily).

Reported Clinical Data

Combination with Therapeutic Cleansers

Sulfacetamide-sulfur cleansers are commonly used as adjunctive therapy for rosacea in combination with other topical and/or systemic agents and are also beneficial in treating rosacea-seborrheic dermatitis overlap (Figures 1A and 1B). (4) An 8-week, investigator-blinded study of sulfacetamide-sulfur cleanser used twice daily with and without metronidazole 0.75% gel reported reduction in papule counts, erythema and overall severity of rosacea in both study arms, with optimal response noted using the combination of both active agents. (4) Similar results were observed in a 4-week open-trial utilizing a fragrance-free sulfacetamide-cleanser formulation in combination with topical metronidazole. (5)

Combination with Subantimicrobial-Dose Doxycycline

A double-blind, randomized study, compared the efficacy of metronidazole 0.75% lotion in combination with doxycycline hyclate 20 mg twice daily vs metronidazole 0.75% lotion alone in patients with rosacea of moderate severity (Figures 2A and 2B). (6,7) At week 12, the group receiving the combination regimen demonstrated a 64% mean reduction in inflammatory lesions versus 44% in the patients using topical therapy alone; erythema reduction was also noted in both study arms. This data suggests additive benefit when topical metronidazole is combined with subantimicrobial-dose oral doxycycline therapy.

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Observational Experience

Patient Inclusion and Methods

Office-based experience from 2003 through September 2004 using topical metronidazole 0.75% gel in combination with another topical agent or subantimicrobial-dose doxycycline was evaluated (n=87). Included were adult patients with mild or moderate inflammatory rosacea who had not received any medical or physical modality treatments for rosacea for at least 12 weeks and had not used topical antibiotics, topical corticosteroids, topical retinoids or topical niacinamide-containing preparations on the face, or systemic antibiotics or corticosteroids for at least 12 weeks. Patients with a history of intolerance to topical metronidazole, topical sulfacetamide, topical sulfur, or oral doxycycline were excluded.

Patients were treated with one of the following regimens:

* Sulfacetamide 10%/sulfur 5% cleanser and topical metronidazole 0.75% gel twice daily (n=30)

* Sulfacetamide 10%/sulfur 5% with sunscreens cream once daily in the morning and topical metronidazole 0.75% gel once daily in the evening (n=22)