Chapter 218. Topical Antibiotics

Topical antibiotics play an important role in the management of many common dermatologic conditions (Table 218-1). They are prescribed most often by dermatologists for the management of mild-to-moderate acne vulgaris or as adjunctive treatment with oral agents. For localized superficial infections, such as impetigo, the use of a topical agent (e.g., mupirocin or retapamulin) may eliminate the need for oral antibiotics and the accompanying problems of compliance, gastrointestinal side effects, and potential drug interactions. Topical antibiotics are still frequently prescribed as prophylactic agents after minor surgery or cosmetic procedures (chemical peel or laser resurfacing) to reduce the risk of postoperative wound infection and to speed wound healing. The use of topical antibiotics for prophylaxis after such minor procedures has been proven to be unnecessary and incurs risk of inducing allergy. Petrolatum is recommended for use after clean surgical procedures.

The efficacy of topical antibiotics for the treatment of acne vulgaris and rosacea may be due to their direct antibiotic effect, but many of the topical antibiotics exhibit anti-inflammatory properties by suppressing neutrophil chemotactic factor or by other mechanisms.1 There are concerns about the use of topical antibiotics in the treatment of acne vulgaris because of the increasing levels of antibiotic resistance. Combining the antimicrobial benzoyl peroxide with antibiotics reduces the development of antibiotic resistance.

Erythromycin

Erythromycin belongs to the group of macrolide antibiotics and is active against both Gram-positive cocci and Gram-negative bacilli. It is used principally as a topical agent in the treatment of acne. Erythromycin binds to the bacterial 50S ribosome and blocks translocation of the peptidyl-transfer RNA (tRNA) molecule from the acceptor to the donor site, interfering with the formation of the polypeptide chain and inhibiting protein synthesis. In addition to its antibacterial properties, erythromycin has anti-inflammatory activity. Erythromycin is available as a 1.5% to 2.0% solution, gel, pledgets, and ointment as a single agent. It is also available in combination with benzoyl peroxide.

Clindamycin

Clindamycin is a semisynthetic lincosamide antibiotic that is derived from lincomycin. The mechanism of action is very similar to that of erythromycin, with binding to the 50S ribosome and suppression of bacterial protein synthesis. Clindamycin is used topically as a 1% gel, solution, suspension (lotion), and foam primarily for the treatment of acne. It is also available as a combination with benzoyl peroxide, which may slow the development of antibiotic resistance to clindamycin. Pseudomembranous colitis rarely has been reported to occur with the topical use of clindamycin.2

Metronidazole

Metronidazole, a topical nitroimidazole, is currently available as a 0.75% gel, cream, or lotion and as a 1% cream or gel for the topical treatment of rosacea. In the lower strength, it is applied twice daily, and in the higher strength, it is used once daily. Orally, metronidazole has broad-spectrum activity against many protozoal organisms and anaerobes.

Azelaic Acid

Azelaic acid is a dicarboxylic acid found in food (whole-grain cereals and animal products). There is a normal human plasma level (20–80 ng/mL); topical application does not significantly alter this level. The mechanism of action is thought to be normalization of the keratinization process (decreased thickness of the stratum corneum, decreased number and size of keratohyaline granules, and decreased amount of filaggrin). There are reports of in-vitro activity against Propionibacterium acnes and Staphylococcus epidermidis, which may be due to protein synthesis inhibition. In aerobic microorganisms, there is inhibition of oxidoreductive enzymes (such as tyrosinase, mitochondrial enzymes of the respiratory chain, 5α-reductase, and DNA polymerases). In anaerobic bacteria, there is disruption of glycolysis. Azelaic acid is used principally in the treatment of acne vulgaris and rosacea, although there are some advocates for its use in the treatment of hyperpigmentation (such as melasma for which it was initially developed). However, the US Food and Drug Administration has not approved the drug for this indication. Azelaic acid is available as a 15% gel or 20% cream preparation.

Sulfonamides (Sulfacetamide)

Sulfacetamide is a topical sulfonamide used in the treatment of rosacea and acne. The antibacterial mechanism of action for most sulfonamides is competition with para-aminobenzoic acid (PABA) during the synthesis of folic acid. The mechanism of action for topical treatment of rosacea is not understood. Sulfacetamide is available as a 10% lotion and in combination with 5% sulfur in a gel, cream, suspension, cleanser, cloths, and mask.

Dapsone

Topical 5% dapsone gel is approved by the FDA for the topical treatment of acne. The mechanism of action of dapsone in acne vulgaris is not known at this time; however, it is possible that inhabitation of neutrophils activity may be important. If benzoyl peroxide is applied after topical dapsone, temporary orange/yellow discoloration of skin and facial hair have been noted.

Localized impetigo, superficial dirty abrasions, and secondarily infected chronic dermatoses are commonly treated with topical antibiotics. However, widespread impetigo, infection of the lower extremities, or disease occurring in immunocompromised individuals should be treated with systemic antibiotics to reduce the risk of serious complications. Topical antibiotics are still at times used following minor surgical procedures. The result of a large study comparing bacitracin and petrolatum in more than 1,200 minor surgical procedures demonstrated that bacitracin did not statistically decrease the already low rate of infection. Several patients were, however, shown to be allergic to bacitracin. Petrolatum proved to be cheaper, of equal efficacy and to have fewer side effects than bacitracin.3 When clean wounds are made during minor surgery, there is no need to use antibacterial ointment to aid in healing or prevent infection. Because burns produce a fertile ground for life-threatening secondary infection, prophylactic topical therapy is often used.

Mupirocin

Mupirocin, which was formerly known as pseudomonic acid A, is a topical antibiotic agent derived from Pseudomonas fluorescens. The drug reversibly binds to isoleucyl-tRNA synthetase and inhibits bacterial protein synthesis. The activity of mupirocin is limited to Gram-positive bacteria, especially staphylococci and most streptococci. Its activity is enhanced in an acid pH environment (5.5), which is the normal pH of the skin. Mupirocin is somewhat temperature-sensitive, and thus loses efficacy if exposed to high temperatures. Mupirocin ointment 2% is applied three times daily and is principally indicated for the treatment of localized impetigo caused by S. aureus and Streptococcus pyogenes. One study in the Tennessee Veterans’ Affairs Hospital demonstrated that prolonged use of mupirocin ointment to control methicillin-resistant S. aureus (MRSA) carriage, especially in bedridden patients with decubitus ulcers, led to significant resistance.4 Furthermore, Japanese researchers found that low serum concentrations of mupirocin are achieved after intranasal application and postulated that this might explain the selection of mupirocin-resistant strains of S. aureus.5 A small pilot study using intranasal application of a combination antibiotic ointment containing bacitracin, polymyxin B, and gramicidin successfully decolonized 80% (9 out of 11) of MRSA-positive patients who remained clear after a mean follow-up of 2 months. All cases of mupirocin-sensitive MRSA were eradicated, whereas only three of five cases of mupirocin-resistant were eliminated.6 New formulations that involve the use of the calcium salt of mupirocin (the calcium salt aids in chemical stability in the intranasal preparation) are available for intranasal use as a 2% ointment and a 2% topical cream.

Retapamulin

Retapamulin is approved for topical treatment of impetigo in patients older than 9 months of age. It is a semisynthetic pleuromotilin antibiotic derived from fermentation in Clitopilus paseckerianus with activity against staphylococci. The antibacterial mechanism of action is inhibition of protein synthesis via 50S bacterial ribosomes at protein L3, near the peptidyl tranferase center. Retapamulin binding inhibits peptidyl tranferase and partial inhibition of binding of initiator tRNA to P-site of ribosome. Allergic contact dermatitis to the active ingredient has been reported.7

Bacitracin

Bacitracin is a topical polypeptide antibiotic originally isolated from the Tracy-I strain of Bacillus subtilis. Bacitracin is a cyclic polypeptide with multiple components (A, B, and C). Bacitracin A is the major component of commercial products and is often used as the zinc salt. Bacitracin interferes with bacterial cell wall synthesis by binding to and inhibiting the dephosphorylation of a membrane-bound lipid pyrophosphate. It is active against Gram-positive cocci such as staphylococci and streptococci. Most Gram-negative organisms and yeast are resistant to the drug. It is available as bacitracin ointment and as zinc bacitracin, with 400 to 500 units per gram.

Topical bacitracin is effective for the treatment of superficial bacterial infections of the skin such as impetigo, furunculosis, and pyodermas. It is often combined with polymyxin B and neomycin as a triple antibiotic ointment applied several times daily for the treatment of secondarily infected eczematous dermatitis such as atopic dermatitis, nummular dermatitis, or stasis dermatitis. Unfortunately, the topical application of bacitracin carries with it the risk of allergic contact sensitization and, rarely, anaphylactic shock.8

Polymyxin B

Polymyxin B is a topical antibiotic derived from a spore-forming soil aerobe B. polymyxa. Polymyxin B is a mixture of polymyxin B1 and B2, which are both cyclic polypeptides. They function as cationic detergents that interact strongly with bacterial cell wall membrane phospholipids, thus disrupting the integrity of the cell membrane.

Polymyxin B is active against a wide range of Gram-negative organisms, including P. aeruginosa, Enterobacter, and Escherichia coli. Polymyxin B is available in ointment form (5,000 to 10,000 units per gram) in combination with bacitracin or as triple antibiotic ointment with bacitracin and neomycin. It should be applied one to three times a day.

Topical Aminoglycosides (Neomycin and Gentamicin)

The aminoglycosides are an important group of antibiotics used both topically and systemically for the treatment of infections caused by Gram-negative bacilli. Aminoglycosides exert their bactericidal effects by binding to the 30S ribosomal subunit and interfering with protein synthesis.

Neomycin sulfate, the aminoglycoside most often used topically, is a fermentation product ofStreptomyces fradiae. Commercial neomycin is a mixture of neomycin B and C, whereas framycetin, used in Canada and some European countries, is pure neomycin B.9 Neomycin sulfate has activity against aerobic Gram-negative bacteria and is used most commonly for prophylaxis against infection in superficial abrasions, cuts, and burns. It is available in ointment form (3.5 mg/g) and is also packaged in combination with other antibiotics such as bacitracin, polymyxin, and gramicidin. Other agents, such as lidocaine, pramoxine, or hydrocortisone, also are available in combination with neomycin.

Neomycin is not recommended by many dermatologists because it is responsible for a large number of cases of allergic contact dermatitis. The prevalence of contact dermatitis is high, with 6% to 8% of patients undergoing patch testing being positive.10 Neomycin sulfate (20%) in petrolatum is used to assess for contact allergy.

Gentamicin sulfate is derived as a fermentation product from Micromonospora purpurea. It is available as a topical 0.1% cream or ointment. It is used by some dermatologic surgeons when operating on the ear, especially in diabetic or other immunocompromised patients, to provide prophylaxis against malignant otitis externa due to P. aeruginosa. The ophthalmic formulation is useful in caring for operative wounds in the periorbital area.

Sulfonamides (Silver Sulfadiazine and Mafenide Acetate)

The sulfonamides are structurally similar to PABA and compete with it during the synthesis of folic acid. Sulfonamides are used to treat acne vulgaris, acne rosacea, and burns. Silver sulfadiazine is thought to release silver slowly and exerts its effect on the bacterial cell walls and membranes. The mechanism of action of mafenide is not the typical sulfonamide mechanism of action because PABA does not antagonize its performance. Mafenide acetate, if used over large areas of skin, has the potential to cause metabolic acidosis, and it can cause intense pain on topical administration. Both agents are broad-spectrum antibacterials useful in the treatment of burns. Candida superinfection may be a problem with mafenide cream.

Nitrofurazone

Nitrofurazone (Furacin) is a nitrofuran derivative used for the treatment of burn patients. The mechanism of action involves the inhibition of bacterial enzymes involved in the aerobic and anaerobic degradation of glucose and pyruvate. Nitrofurazone is available as a 0.2% cream, solution, or soluble dressing, and its spectrum of activity includes staphylococci, streptococci, E. coli, Clostridium perfringens, and Proteus sp.

Gramicidin

Gramicidin is a topical antibiotic derived from B. brevis. The gramicidins are linear peptides that form stationary ion channels in susceptible bacteria. The antibiotic activity of gramicidin is restricted to Gram-positive bacteria.

Clioquinol

Clioquinol (also known as iodochlorhydroxyquin) is a broad-spectrum antibacterial/antifungal topical that is currently indicated for the treatment of inflammatory skin disorders and tinea pedis and has been used for minor bacterial infections. It is a synthetic hydroxyquinoline whose mechanism of action is unknown. The disadvantages of clioquinol include discoloration of clothing, skin, hair, and nails and the potential to cause irritation. Clioquinol may interfere with thyroid function determination when taken orally and possibly topically if used extensively. The iodine moiety interferes with tests that rely on iodine uptake (this effect can last for up to 3 months after application). However, clioquinol does not interfere with testing for T3 or T4.