Mechanism of action

The exact mechanism of action of metronidazole remains unknown. The drug possesses demonstrable antibacterial and antiprotozoal effects but no activity against Demodex folliculorum, staphylococci, Propionibacterium, and Malassezia species. It also has direct antiinflammatory effects that may be key to its efficacy in several dermatologic conditions. Metronidazole inhibits inflammatory mediators generated by neutrophils, inhibits lymphocyte chemotaxis, and suppresses aspects of cell-mediated immunity. It decreases reactive oxygen species (ROS) in the skin and hence acts as an antioxidant by decreasing ROS production and scavenging existing free radicals.

Pharmacology

Topical metronidazole is minimally absorbed after topical application to the skin, with either undetectable or trace serum concentrations reported after topical use. It is classified as US Food and Drug Administration (FDA) pregnancy risk category B. FDA-approved uses of topical metronidazole include, in addition to inflammatory lesions of rosacea, Grade III or IV anaerobically infected decubitus ulcers, perioral dermatitis, and bacterial vaginosis.

Pharmacology

Topical metronidazole is minimally absorbed after topical application to the skin, with either undetectable or trace serum concentrations reported after topical use. It is classified as US Food and Drug Administration (FDA) pregnancy risk category B. FDA-approved uses of topical metronidazole include, in addition to inflammatory lesions of rosacea, Grade III or IV anaerobically infected decubitus ulcers, perioral dermatitis, and bacterial vaginosis.

Optimal use of metronidazole in the treatment of rosacea

Topical metronidazole was FDA approved for the treatment of rosacea in 1988 and remains a first-line therapy. Its effectiveness in the treatment of moderate to severe rosacea has been shown in several placebo-controlled trials. Although studies have demonstrated a significant reduction in papulopustular lesions and perilesional erythema, topical metronidazole has no effect on telangiectasias. The medication is well tolerated, with local reactions, such as stinging, dryness, and burning, reported in up to 2% of patients. Allergic contact dermatitis to metronidazole has rarely been reported. One study comparing the cumulative irritancy potential of metronidazole 0.75% gel and cream and metronidazole 1% cream in healthy volunteers showed no significant difference in the relative irritancy of the different formulations. Metronidazole 1% gel was found to be nonirritating in a 21-day cumulative irritation study. Metronidazole cream, gel, and lotion formulations have similar efficacy, as have the 0.75% and 1% concentrations currently available. Hence, patient preference for vehicle may be an important factor in maximizing clinical efficacy by improving patient adherence to the suggested regimen.

Although it was originally thought that the optimal frequency of application of metronidazole should be twice daily based on pharmacokinetic data for the original 0.75% gel formulation, more recent research has shown that metronidazole is degraded into active metabolites that may prolong the clinical efficacy of the parent drug. Jorizzo and colleagues studied the efficacy of metronidazole 1% cream when applied once compared with twice daily and found both treatment regimens to be of equal efficacy. Metronidazole 1% gel is FDA approved for once daily use. More studies are necessary to determine if twice-daily dosing of other available formulations of metronidazole is truly more effective than once-daily use.

Several studies have compared metronidazole to other topical therapies in the treatment of rosacea ( Table 1 ). Comparative studies have shown topical metronidazole and azelaic acid to be of similar efficacy. Elewski and colleagues compared azelaic acid 15% gel to metronidazole 0.75% gel in subjects with moderate papulopustular rosacea, and found azelaic acid to be superior in improving lesion counts and erythema. Maddin compared azelaic acid 20% cream and metronidazole 0.75% cream in a double-blind split-face comparative trial of subjects with papulopustular rosacea. Both groups had similar reductions in lesions but better global improvement was seen with azelaic acid. More recently, Wolf and colleagues compared once-daily metronidazole 1% gel to twice-daily azelaic acid 15% gel in subjects with moderate rosacea. The efficacies of the two medications were similar. Azelaic acid 15% gel has more potential for irritation compared with metronidazole 0.75% and 1% gel. Topical sodium sulfacetamide 10% with sulfur 5% is also FDA approved for the treatment of rosacea and has been compared with topical metronidazole treatment.

An investigator-blinded study comparing sodium sulfacetamide 10% and sulfur 5% cream with sunscreens to metronidazole 0.75% cream showed a greater reduction in lesions and erythema with sodium sulfacetamide/sulfur, but also more treatment-related adverse effects with this medication compared with treatment with topical metronidazole. A recent, small, open-label study compared topical pimecrolimus 1% cream and metronidazole 1% cream in subjects with papulopustular rosacea. Both treatments were equally effective and well tolerated. Clearly lacking in the literature are studies evaluating the efficacy of combination topical therapy in the treatment of rosacea, although preliminary data suggests the potential for improved clinical outcomes.

Topical metronidazole is often combined with oral tetracycline derivatives in the management of more severe rosacea. The combination of topical metronidazole and doxycycline has been shown to result in a more rapid onset of effect and to be more effective compared with topical monotherapy. However, it is not clear from the literature if the combination of topical metronidazole and oral tetracycline is actually superior to an oral tetracycline alone. In one non-blinded retrospective study, relapse rates after treatment with oral tetracycline were not lower than after treatment with metronidazole 1% cream, with most subjects relapsing within 6 months. There is evidence to support the efficacy of topical metronidazole in maintaining remissions of rosacea, after initial successful treatment with a combination of topical metronidazole and a tetracycline. Given the frequency of relapse after cessation of treatment, and patients’ tendency to self-discontinue treatment when their rosacea is controlled, maintenance therapy with topical metronidazole should be encouraged.

Innovative uses

The remainder of this article reviews novel uses of topical metronidazole that are supported in the peer-reviewed literature. The data supporting its use in the treatment of seborrheic dermatitis, periorificial dermatitis, epidermal growth factor receptor (EGFR) inhibitor-associated skin toxicity, malodorous wounds, and topical provocation of fixed drug eruption and acute generalized exanthematous pustulosis are discussed ( Box 1 ).

Seborrheic dermatitis

Four double-blind, placebo-controlled studies and two comparative studies support the use of topical metronidazole in the treatment of seborrheic dermatitis ( Table 2 ). Parsad and colleagues treated 44 subjects with seborrheic dermatitis involving the scalp, face, and chest with either metronidazole 1% gel or its vehicle twice daily for 8 weeks. Metronidazole gel was significantly more effective than its vehicle, with significant improvement noted as early as week two. Koca and colleagues treated 84 subjects with mild to moderate facial seborrheic dermatitis with either metronidazole 0.75% gel or its vehicle gel twice daily for 8 weeks. Both treatments showed similar efficacy. Siadat and colleagues compared the efficacy of metronidazole 1% gel to its vehicle gel in a double-blind clinical trial of 55 subjects with facial seborrheic dermatitis. As in the previous studies, subjects were treated twice daily for 8 weeks. Metronidazole gel was significantly more effective than its vehicle as early as week two. Finally, Ozcan and colleagues treated 67 subjects with mild to moderate seborrheic dermatitis involving the scalp, face, and chest with either metronidazole 0.75% gel or its vehicle twice daily for 4 weeks. Both treatment arms showed equivalent and statistically significant improvement. Topical metronidazole gel was well tolerated in all four studies.

Seckin and colleagues compared metronidazole 0.75% gel and ketoconazole 2% cream in a double-blind study of 60 consecutive subjects with mild to moderate facial seborrheic dermatitis. Subjects were randomized to receive either ketoconazole 2% cream and metronidazole gel vehicle or metronidazole 0.75% gel and ketoconazole cream vehicle each applied once daily for 4 weeks. Both treatments were equally effective and well tolerated. More recently, Cicek and colleagues compared the efficacy and safety of pimecrolimus 1% cream, methylprednisolone aceponate 0.1% cream, and metronidazole 0.75% gel in the treatment of facial seborrheic dermatitis. In this open study, 64 consecutive subjects were randomized into one of the three treatment arms and applied their medication twice daily for 8 weeks. All three drugs were found to be effective, although pimecrolimus was significantly more effective than either methylprednisolone aceponate, or topical metronidazole. Significantly more subjects in the metronidazole group developed side effects, including erythema and burning.

Is topical metronidazole effective in the treatment of seborrheic dermatitis? Although more studies are needed, several trials support the use of metronidazole gel in the treatment of seborrheic dermatitis. Although its mechanism of action in seborrheic dermatitis is not clear, it may be acting through inherent antiinflammatory effects. Although treatment with anti-Malassezia agents, such as ketoconazole, is usually sufficient, some patients do not respond. Thus, at the very least, topical metronidazole offers a viable therapeutic alternative to reliance on topical steroids in this group of patients.

Periorificial dermatitis

Periorificial dermatitis consists of monomorphous grouped erythematous papules around the mouth, nose, and eyes. The spectrum of disease includes perioral dermatitis; granulomatous periorificial dermatitis; and facial Afro-Caribbean childhood eruption (FACE).

Several case series support the use of topical metronidazole in the treatment of periorificial dermatitis in children. Manders and Lucky reported 14 consecutive cases of perioral dermatitis in children seen in one pediatric dermatology practice. Eight of the cases were managed with metronidazole 0.75% gel alone, applied once, or more commonly, twice daily. Five of the children were treated with metronidazole gel in combination with other medications, including topical or oral erythromycin and hydrocortisone 1% cream. One case was treated with hydrocortisone 1% cream alone. All of the children cleared after 1 to 8 weeks of treatment, with a mean of 5 weeks to clearance. No relapses were seen in up to 16 months of follow-up. Miller and Shalita reported three children with perioral dermatitis treated with metronidazole 0.75% gel twice daily. All three subjects completely cleared after 14 weeks of therapy and were significantly improved after 2 months. Boeck and colleagues treated seven pediatric subjects with perioral dermatitis with metronidazole 1% emulsion. The dosage was increased to 2% emulsion applied twice daily after 2 weeks. All children completely cleared after 3 to 6 months, with significant improvement seen at 4 to 6 weeks. No side effects were noted and all subjects remained clear during 2 years of follow-up. Nguyen and Eichenfield reported a retrospective chart review of 79 cases of periorificial dermatitis in children and adolescents. Treatment with metronidazole cream or gel, oral erythromycin, or both was associated with resolution of the rash, whereas treatment with a calcineurin inhibitor, sulfacetamide, hydrocortisone, or an antifungal agent was associated with persistent disease. The investigators suggest initial treatment of periorificial dermatitis in children with topical metronidazole for 1 to 2 months, with addition of oral erythromycin if the rash persists.

Veien and colleagues compared the efficacy of topical metronidazole and oral tetracycline in the treatment of adults with perioral dermatitis. In a double-blind, double-dummy, randomized multicenter trial, 108 adults with perioral dermatitis were treated with metronidazole 1% cream or tetracycline 250 mg twice daily for 8 weeks. Although both treatments were effective, oral tetracycline was significantly more effective and resulted in more rapid improvement.

Weber and colleagues used guidelines of evidence-based medicine to evaluate the quality of studies on the treatment of perioral dermatitis. They found only two therapeutic trials of medium-range quality; the other studies were rated as low quality. Most support was found for treatment of perioral dermatitis with oral tetracycline. There was inconsistency in the literature reviewed with respect to the efficacy of topical therapy. The data also supported avoidance of topical corticosteroids and cosmetics. Support was also found for the option of no therapy, because spontaneous clearance has been documented.

What is the role of topical metronidazole in the treatment of periorificial dermatitis? Based on the current literature, when treating children with periorificial dermatitis, an initial trial of topical metronidazole for 1 to 2 months is reasonable and justifiable. If the condition persists, oral erythromycin should be considered. For the treatment of adults with perioral dermatitis, oral tetracycline (or doxycycline) is the treatment of choice. Topical metronidazole is an option for therapy in adults if there is a compelling need to avoid tetracyclines or if patients would prefer topical treatment.

Epidermal growth factor receptor inhibitor-associated cutaneous toxicity

Epidermal growth factor receptor inhibitors are being used with increasing frequency to treat advanced epithelial tumors. EGFR plays an important role in control of cell growth and differentiation and is overexpressed in various epithelial cancers. Currently, EGFR inhibitors are FDA approved for the treatment of non-small cell lung cancer, pancreatic cancer, colorectal cancer, and head and neck cancer. There are two main classes of agents that target EGFR ( Table 3 ). The tyrosine kinase inhibitors, which include erlotinib, gefitinib, and lapatinib, bind the intracellular protein kinase portion of the receptor and hence prevent its activation. The monoclonal antibodies, including cetuximab and panitumumab, block ligand-dependent activation of EGFR. EGFR is present in keratinocytes, the follicular epithelium, and sweat and sebaceous glands and plays an important role in normal development and function of the epidermis. The most common adverse effect associated with the use of EGFR inhibitors is skin and adnexal toxicity. Because cutaneous toxicity has been observed with all agents that target EGFR, it is considered a class effect. However, the monoclonal antibodies tend to be associated with more frequent and severe skin toxicity.

Table 3

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