C. Zip, MD, FRCPC

Department of Medicine, University of Calgary, Calgary, Alberta, Canada

ABSTRACT

Topical metronidazole (Noritate® 1% Cream, Dermik; MetroCream™ 0.75% Cream, MetroLotion® 0.75% Lotion, Metrogel® 0.75% and 1% Topical Gel, Galderma) has been used for the treatment of rosacea for over 30 years. Several placebo-controlled trials have demonstrated its effectiveness in the treatment of moderate-to-severe rosacea. It is also effective in preventing relapses of disease and is well tolerated by most patients. A growing number of formulations are available.

Key Words:
rosacea, metronidazole, antibiotic, anti-inflammatory

Rosacea is one of the most common conditions seen by dermatologists. Its etiology and pathogenesis are unknown despite its high prevalence. Topical metronidazole, which was first reported to be effective in the treatment of rosacea in 1983,1 remains a cornerstone of therapy. Although the use of metronidazole in the treatment of rosacea has been reviewed previously,2,3 continued research has prompted this updated review.

Mechanism of Action

The mechanism of action of metronidazole in the treatment of rosacea is unclear. The efficacy of this broad spectrum antibiotic has been attributed to its antimicrobial and anti-inflammatory effects. In vitro studies have shown that metronidazole interferes with neutrophil release of reactive oxygen species that cause tissue injury at sites of inflammation.4 This antioxidant activity may be the basis of its anti-inflammatory effect in rosacea.

Pharmacokinetics

Metronidazole is poorly absorbed after topical application, with either undetectable or trace serum concentrations reported after topical use.1,5 Based on pharmacokinetic data on the original 0.75% gel formulation, it was originally thought that the optimal application frequency should be twice daily. More recent research has shown that metronidazole is degraded into active metabolites that may prolong the clinical efficacy of the parent drug.6

Placebo-Controlled Trials

Metronidazole has been shown to be effective for the treatment of moderate-to-severe rosacea in a number of placebo-controlled trials (Table 1).5,7-13 In a recent trial comparing metronidazole 1% gel, 1% cream, and gel vehicle applied once daily for 10 weeks, the efficacy of the 1% gel was at least that of the 1% cream and superior to the gel vehicle.8

Comparative Trials With Other Rosacea Treatments

A number of studies have compared topical metronidazole with other treatment options for rosacea. These are summarized in Table 2. Regardless of the formulation, studies have shown a significant reduction of papulopustular lesions and erythema scores compared with placebo. Although most studies have not shown improvement of telangiectasias, Tan, et al. reported a significant reduction in the telangiectasia score in patients with moderate-to-severe rosacea using metronidazole 1% cream with sunscreen SPF 15 (Rosasol®, Steifel Canada) for 12 weeks.12 In their review of randomized controlled trials of patients with moderate-to-severe rosacea in the Cochrane Database of Systemic Reviews, van Zuuren, et al. concluded that topical metronidazole is more effective than placebo, but that the quality of studies evaluating rosacea treatments was generally poor, and that good randomized controlled trials that include quality of life assessments are needed.14

Comparative Trials Between Different Formulations of Metronidazole

Metronidazole is currently available in a variety of formulations, and comparative studies have shown equal efficacy. In a study comparing commercially available formulations of both metronidazole 0.75% and 1% cream, applied once daily for 12 weeks for the treatment of moderate-to-severe rosacea, both were equally effective.15


Formulation

Study
Design

Frequency
and
Duration

Number of
Patients

Percent
Reduction
in Lesion
Count vs.
Placebo**

Significant
Reduction
in Erythema

Adverse
Effects

Onset of
Efficacy
(Weeks)
Metronidazole
0.75% gel
Aronson, et al.5		R, SF, DBb.i.d.
9 wks		4751 vs. 4YesNone3
Metronidazole
0.75% gel
Bleicher, et al.7		R, SF, DBb.i.d.
9 wks		4065 vs. 15YesNone3
Metronidazole
1% gel
Beutner, et al.8		R, PG, SB,
1% gel vs.
1% cream
vs. gel
vehicle		q.d.
10 wks		>1200 total67 (1%
gel) vs. 58
(1% cream)
vs. 46 (gel
vehicle)		3% (1% gel),
4% (1%
cream and
gel vehicle)
Metronidazole
0.75% cream
Drake, et al.9		R, PG, DBb.i.d.
12 wks		143 total62.5 vs. 43
Metronidazole
1% cream
Breneman, et
al.10		R, PG, DBq.d.
10 wks		8953 vs. 17Yes2% had
adverse skin
effects		2-4
Metronidazole
1% cream
Jorizzo, et al.11		R, PG, DBb.i.d.
12 wks		6165 vs. 25YesMild
application
site reactions		4
Metronidazole
1% cream with
Sunscreen
Tan, et al.12		R, PG, DBb.i.d.
12 wks		6165 vs. 25YesMild
application
site reactions		4
Metronidazole
0.75% lotion
Breneman, et al.13		R, PG, DBb.i.d.
12 wks		6557 vs. 27
Table 1:
Placebo-controlled trials of metronidazole for rosacea*
R=randomized, SF=split-face, PG=parallel group, DB=double-blind, SB=single-blind, P=Placebo
* table includes studies using commercially available products
**all changes in lesion count were significant compared with placebo


Trial

Results

Comment
Azelaic acid 15% gel vs. metronidazole 0.75% gel16,17Azelaic acid superior in improving
lesion counts and erythema		Study design has been criticized
Azelaic acid 20% cream vs. metronidazole
0.75% cream18		Similar reductions in lesions but
better global improvement with
azelaic acid		Split-face design
Sodium sulfacetamide 10% and
sulfur 5% lotion or cream vs. metronidazole
0.75% gel or cream19,20		Greater reduction in lesions
and erythema with sodium
sulfacetamide/sulfur		More treatment related adverse
effects with sodium sulfacetamide/
sulfur
Metronidazole 1% cream or 0.75%
gel vs. tetracycline 250 mg b.i.d.-
t.i.d.21,22		No significant difference in
efficacy		Tetracycline may have a more rapid
onset of action
Table 2: Comparative trials with other rosacea treatments.

Remission and Relapse

In a study of patients who achieved remission of rosacea with the use of systemic tetracycline, two thirds relapsed within 6 months of treatment cessation.23 Nielsen reported that metronidazole 1% cream applied daily or every other day is at least as effective in preventing relapses as tetracycline 250mg taken twice daily.24 In a more recent study, metronidazole 0.75% gel applied twice daily maintained remission compared with vehicle after successful treatment with a combination of metronidazole gel and oral tetracycline.25

Adverse Effects

Metronidazole is generally well tolerated, with adverse events reported in less than 5% of patients. Local reactions include dryness, redness, pruritus, aggravation of acne or rosacea, burning, and stinging. True allergic contact dermatitis is rare.26

Conclusion

Topical metronidazole remains a cornerstone in the treatment of rosacea. Several placebo-controlled trials have confirmed its ability to reduce both inflammatory lesions and erythema. Daily dosing has been shown to be effective in numerous clinical trials. As well, metronidazole is effective is preventing relapses of rosacea.

References

  1. Nielsen PG. Treatment of rosacea with 1% metronidazole cream. A double-blind study. Br J Dermatol 108(3):327-32 (1983 Mar).
  2. McClellan KJ, Noble S. Topical Metronidazole. A review of its use in rosacea. Am J Clin Dermatol 1(3):191-9 (2000 May-Jun).
  3. Gupta AK, Chaudhry M. Topical metronidazole for rosacea. Skin Therapy Lett 7(1):1-3,6 (2002 Jan).
  4. Miyachi Y, Imamura S, Niwa Y. Anti-oxidant action of metronidazole: a possible mechanism of action in rosacea. Br J Dermatol 114(2):231-4 (1986 Feb).
  5. Aronson IK, Rumsfield JA, West DP, Alexander J, Fischer JH, Paloucek FP. Evaluation of topical metronidazole gel in acne rosacea. Drug Intell Clin Pharm 21(4):346-51 (1987 Apr).
  6. Lamp KC, Freeman CD, Klutman NE, Lacy MK. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet 36(5):353-73 (1999 May).
  7. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol 123(5):609-14 (1987 May).
  8. Beutner K, Calvarese B, Graeber M. A multi-center, investigator-blind clinical trial to assess the safety and efficacy of metronidazole gel 1% as compared to metronidazole gel vehicle and metronidazole cream 1% in the treatment of rosacea. Presented at: American Academy of Dermatology 63rd Annual Meeting; 2005 Feb 18-22; New Orleans, P101.
  9. Drake L, Leyden J, Lucky A, et al. Evaluation of topical metronidazole cream in rosacea. Presented at: American Academy of Dermatology 55th Annual Meeting; 1997 Mar 21-26; San Francisco, P65.
  10. Breneman DL, Stewart D, Hevia O, Hino PD, Drake LA. A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea. Cutis 61(1):44-7 (1998 Jan).
  11. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial. J Am Acad Dermatol 39(3):502-4 (1998 Sep).
  12. Tan JKL, Girard C, Krol A, et al. Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. J Cutan Med Surg 6(6):529-34 (2002 Nov-Dec).
  13. Breneman D, Bucko A, Friedman D, et al. Evaluation of topical metronidazole lotion in rosacea. Presented at: American Academy of Dermatology 56th Annual Meeting; 1998 Feb 27-Mar 4; Orlando, P289.
  14. van Zuuren EJ, Graber MA, Hollis S, Chaudhry M, Gupta AK, Gover M. Interventions for rosacea. Cochrane Database Syst Rev (3):CD003262 (2005 May 20).
  15. Dahl MV, Jarratt M, Kaplan D, Tuley MR, Baker MD. Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea. J Am Acad Dermatol 45(5):723-30 (2001 Nov).
  16. Elewski BE, Fleischer AB Jr, Pariser DM. A comparison of 15% azaleic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol 139(11):1444-50 (2003 Nov).
  17. Czernielewski J, Liu Y. Comparison of 15% azelaic acid gel and 0.75% metronidazole gel for the topical treatment of papulopustular rosacea. Arch Dermatol 140(10):1282-3 (2004 Oct).
  18. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol 40(6 Pt 1):961-5 (1999 Jun).
  19. Lebwohl MG, Medansky RS, Russo CL, Plott RT. The comparative efficacy of sodium sulfacetamide 10%/sulfur 5% lotion and metronidazole 0.75% in the treatment of rosacea. J Geriatr Dermatol 3(5):183-5 (1995).
  20. Torok HM, Webster G, Dunlap FE, Egan N, Jarratt M, Stewart D. Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea. Cutis 75(6):357-63 (2005 Jun).
  21. Schachter D, Schachter RK, Long B, et al. Comparison of metronidazole 1% cream versus oral tetracycline in patient with rosacea. Drug Invest 3(4):220-4 (1991).
  22. Monk BE, Logan RA, Cook J et al. Topical metronidazole in the treatment of rosacea. J Dermatolog Treat 2:91-3 (1991).
  23. Knight AG, Vickers CFH. A follow-up of tetracycline-treated rosacea. Br J Dermatol 93(5):577-80 (1975 Nov).
  24. Nielsen PG. The relapse rate for rosacea after treatment with either oral tetracycline or metronidazole cream. Br J Dermatol 109(1):122 (1983 Jul).
  25. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintains remissions of rosacea. Arch Dermatol 134(6):679-83 (1998 Jun).
  26. Jappe U, Schnuch A, Uter W. Rosacea and contact allergy to cosmetics and topical medicaments-retrospective analysis of multicentre surveillance data 1995-2002. Contact Dermatitis 52(2):96-101 (2005 Feb).
STL Volume 11 Number 2

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