Topical Antibacterial Agents

Microbiologic Activity (see Table 41.1 )

Bacitracin is active against Staphylococcus aureus , Streptococcus pneumoniae , Neisseria spp, Haemophilus influenzae , Treponema pallidum , Actinomyces , and Fusobacterium spp. It has minimal Gram-negative coverage and is not active against Pseudomonas , Nocardia , Enterobacteriaceae, Candida , or Cryptococcus .

Dermatologic Uses

Bacitracin, in combination with cetrimide (an antiseptic) and polymyxin B and possibly neomycin, significantly reduces S. aureus contamination in artificially inoculated normal skin and wounds. Q41.1 However, bacitracin is only 44% effective for eliminating nasal carriage of S. aureus , compared with 94% reduction with mupirocin. In a randomized trial comparing topical mupirocin, topical bacitracin, and oral cephalexin for the treatment of impetigo, bacitracin was significantly inferior and associated with frequent treatment failure.

Q41.2 A double-blind study comparing bacitracin with white petrolatum found no statistical difference in the postoperative infection rate in dermatologic surgery patients. In this study, 90% of the wound infections in the petrolatum group were because of methicillin-sensitive S. aureus (MRSA), whereas the patients treated with bacitracin grew ciprofloxacin-sensitive Gram-negative bacteria. Given the higher cost of treating Gram-negative infections, the 0.9% rate of contact dermatitis, and the higher cost of bacitracin, it is less expensive to treat clean dermatologic surgical wounds with white petrolatum.

Adverse Effects

There have been no published reports on the topical absorption of bacitracin into skin. However, no significant systemic absorption of bacitracin occurs after bladder irrigation. Common AE include localized itching and burning. Q41.2 The North American Contact Dermatitis Group (NACDG) found that 9.2% of patients with allergic contact dermatitis (ACD) had a positive patch test to bacitracin. Bacitracin is a frequent allergen in patients with chronic stasis dermatitis or keratoconjunctivitis. Over 12% of patients with stasis dermatitis and 24% of patients with chronic leg ulcers have positive patch tests to bacitracin. Barrier disruption and chronicity of use in these clinical settings may allow the development of contact dermatitis. Thus, long-term use on nonintact skin, encountered in stasis ulcers or chronic inflammatory dermatoses, may lead to an increased risk of contact allergy. In dermatologic surgery, postoperative use of bacitracin is associated with an 8% overall incidence of ACD. Patch testing is performed with 20% bacitracin in petrolatum ( Table 41.4 ). Given that zinc bacitracin is less soluble than bacitracin, it may provide false-negative test results. In addition, a 48-hour patch test reading may miss a positive reaction, which may not be manifest until 96 hours.

Q41.3 To date, there has been a significant number of reported cases of anaphylactic shock because of topical bacitracin. Most cases involved patients who had used bacitracin on nonintact skin such as ulcers. Q41.4 Bacitracin often co-reacts—but does not cross-react—with neomycin, such that patch testing to both may uncover a neomycin allergy. It is believed that the co-reacts is attributed to coincidental sensitization, as bacitracin is chemically unrelated to neomycin, but both antibacterial agents are commonly found in combination ( Table 41.5 ).

Microbiologic Activity (see Table 41.1 )

Polymyxin B is bactericidal in vitro against Gram-negative bacteria including Proteus mirabilis , P. aeruginosa , and Serratia marcescens . In vitro activity has also been demonstrated against Acinetobacter baumannii , a multidrug-resistant Gram-negative organism associated with wound infections leading to septicemia. This antibacterial agent is not effective against Gram-positive bacteria or fungi.

Dermatologic Uses

Polymyxin B is usually combined with other topical antibacterial agents to broaden its bacterial coverage. For example, the ‘triple antibiotic’ combination of neomycin, bacitracin, and polymyxin B is a popular, inexpensive, over-the-counter formulation for the treatment of minor skin wounds.

Adverse Effects

Contact allergy to polymyxin B in the absence of concomitant positive reactions to neomycin, bacitracin, or oxytetracyclines is very rare. Additionally, polymyxin B is not a significant allergen in postoperative wounds in dermatologic surgery patients. Because polymyxin B binds avidly to cell membranes, there is little systemic absorption and few systemic reactions even when applied to open wounds, although one case of reversible acute renal failure was reported. When contact allergy is suspected, patch testing may be done with 3% polymyxin B in petrolatum (see Table 41.4 ).

Microbiologic Activity (see Table 41.1 )

Neomycin has good coverage against most clinically important Gram-negative and some Gram-positive organisms, including Escherichia coli , H. influenzae , Klebsiella spp, Proteus spp, S. aureus , and Serratia spp. It does not cover P. aeruginosa or anaerobic bacteria such as Bacteroides spp. Moreover, neomycin has only weak activity against streptococci. Because resistance to neomycin has been reported in both Gram-positive and Gram-negative bacteria, neomycin is virtually always used in combination with other topical antibacterial agents. Bacitracin is typically added for its Gram-positive coverage, whereas polymyxin B is added to provide coverage of Pseudomonas spp.

Dermatologic Uses

Neomycin is useful for treating minor wounds and cutaneous infections. It is used in combination with bacitracin to achieve optimal staphylococcal and streptococcal coverage.

Adverse Effects

As with other aminoglycosides, systemic toxicity to neomycin includes ototoxicity and nephrotoxicity. Systemic absorption and toxicity do not occur when the antibacterial agent is used topically on minor skin lesions. Neomycin-related deafness has been reported, usually involving a neomycin solution to irrigate a large wound. There have been rare reported cases of deafness from using ear drops containing neomycin. Ear drops containing an ototoxic agent should not be used in patients with tympanic membrane perforation. To reduce the potential for sensitization, resistance, or toxicity, it is recommended that no more than 1 g per day of a topical preparation containing neomycin be used, for a maximum of 7 days.

Q41.2 The overall prevalence of allergic contact sensitivity to neomycin in the United States has been reported to range from 0.09% to 1.1%, but 10% of patients with ACD have positive patch testing to neomycin. In dermatologic surgery, neomycin is the most common cause of postoperative ACD and should be avoided. Regarding chronic use, studies indicate that in patients suffering from leg ulcers, between 9% and 13% of patients patch-tested positive to neomycin. Patch testing is done by applying 20% neomycin sulfate in petrolatum under occlusion for 48 hours (see Table 41.4 ). Although the majority of tests are positive in 96 hours, it may take 7 days to become positive. Neomycin potentially cross-reacts with streptomycin, kanamycin, gentamicin, paromomycin, spectinomycin, and tobramycin. Q41.4 As previously mentioned, neomycin often co-reacts, but does not cross-react, with bacitracin. Therefore, patch testing to both may uncover a bacitracin allergy, and this co-reaction represents coincidental sensitization.

Microbiologic Activity (see Table 41.1 )

Mupirocin has excellent activity against S. aureus , Staphylococcus epidermidis , Streptococcus pyogenes , and β-hemolytic streptococci. In addition, it covers MRSA. Mupirocin is not active against anaerobic bacteria, P. aeruginosa , Enterococcus faecalis , Enterococcus faecium , Streptococcus bovis , fungi, or normal skin flora such as Corynebacterium , Micrococcus , and Propionibacterium spp.

Q41.5 Mupirocin resistance, encountered almost exclusively in strains of MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE), has increased recently, and prior exposure to mupirocin is a strong predictor for resistance. Low-level resistance results from mutations in the native ileS gene encoding isoleucyl t-RNA synthetase, whereas high-level resistance is mediated by transfer of the plasmid-encoded ileS-2 gene, which results in expression of another isoleucyl t-RNA synthetase. Resistance to mupirocin does not negatively affect the ability of these bacteria to survive or reproduce, and it is estimated that 3.1% of MRSA strains demonstrate high-level resistance.

Cutaneous Bacterial Infections

Mupirocin is used to treat skin infections frequently initiated by staphylococci and streptococci, including impetigo, folliculitis, impetiginized eczema, burns, lacerations, and leg ulcers. In a Cochrane systematic review of 57 trials, topical mupirocin was more effective than oral erythromycin for impetigo. Mupirocin ointment is effective for almost all patients with staphylococcal folliculitis and results in cure for 75% of patients.

Staphylococcal Colonization

Q41.1 Intranasal mupirocin is effective for the elimination of staphylococci, even MRSA, from chronic carriers. Most recent studies advocate twice-daily application for 5 days. Prolonged suppression of nasal staphylococcal carriage is achieved by weekly dosing or monthly courses. In healthy adults, intranasal mupirocin is effective in decolonizing nasal, but not extranasal, sites. To eliminate carriage of MRSA in immunocompetent patients with recurrent pyoderma caused by S. aureus, the best regimen is mupirocin ointment applied to the nares two to three times per day in combination with dilute bleach baths or chlorhexidine body washes daily, each for 5 days per month. Nonetheless, recurrent infections still occur in over 30% of patients after 4 months of eradication. For a history of four or more episodes of furunculosis, nasal application of mupirocin for 5 days, chlorhexidine disinfection daily for 21 days, and oral clindamycin for 21 days is 87% effective for preventing recurrence.

Data regarding the efficacy of nasal mupirocin in reducing the overall rate nosocomial S. aureus infections have been conflicting. A large trial found that intranasal mupirocin, in combination with chlorhexidine soap, reduced nosocomial S. aureus surgical-site infections from 7.7% to 3.4% in nasal carriers. Q41.2 Among nasal MRSA carriers undergoing Mohs surgery, no postoperative MRSA infections occurred in patients who used intranasal mupirocin and trimethoprim/sulfamethoxazole for 5 to 7 days.

Q41.6 In children and adults with atopic dermatitis, S. aureus colonization is very frequent and is a risk factor for exacerbations of disease or recurrent S. aureus infections. Furthermore, S. aureus colonization is directly proportional to disease severity. Colonization occurs in lesional and nonlesional skin, and up to 65% of lesional strains of S. aureus produce superantigenic exotoxins which can stimulate large numbers of T lymphocytes, provoking disease exacerbations. There is a high prevalence of MRSA and multidrug resistance among strains of S. aureus in pediatric patients with atopic dermatitis. In children with a superimposed bacterial infection, intermittent intranasal mupirocin, dilute bleach baths, and oral cephalexin reduced the severity of atopic dermatitis compared with cephalexin alone. In adults, treatment of skin and nasal S. aureus carriage with intranasal mupirocin, oral cephalexin, and chlorhexidine ointment also led to significant improvement in atopic dermatitis. In two studies, use of mupirocin ointment combined with a topical corticosteroid (CS) ointment (either hydrocortisone butyrate 0.1% or fluticasone 0.005%) reduced the severity of atopic dermatitis for 1 week, but this improvement was not sustained. More than 50% of patients with mycosis fungoides and Sézary syndrome have skin and/or nasal colonization with S. aureus , with erythrodermic patients affected most frequently. Intranasal mupirocin combined with oral antibacterial agents has produced clinical improvement in 58% of S. aureus -colonized patients in this demographic.

The use of mupirocin for S. aureus decolonization in immunocompromised patients has also been studied. Monthly intranasal mupirocin for 8 consecutive months significantly reduced the rate of S. aureus colonization among human immunodeficiency virus (HIV)-positive patients in a long-term care setting, but did not affect the rate of S. aureus infection. In hemodialysis patients, intranasal mupirocin has been shown to reduce the incidence of S. aureus bacteremia, but serial retreatment may be necessary for sustained decolonization.

Burns

In burn patients without baseline colonization, nasal mupirocin reduced the risk of acquiring S. aureus in burn wounds. Compared with silver sulfadiazine, silver nitrate, mafenide acetate, and honey, mupirocin was the most highly active topical antimicrobial against clinical isolates of MRSA recovered from burn wounds. In addition, twice-daily mupirocin under occlusion for fewer than 5 days was effective in eliminating MRSA in burn wounds encompassing <20% of body surface area. Thus, mupirocin appears to be advantageous for topical treatment of Staphylococcus -infected burns, especially those colonized with MRSA. Although there are no reports of systemic toxicity caused by topical mupirocin, the safety of mupirocin on burns exceeding 20% of body surface area has not been addressed.

Adverse Effects

Most reactions are local and include pain, burning, and itching. This is attributed to the vehicle base (polyethylene glycol) because the incidence is no greater than with the vehicle alone. The nasal formulation does not contain polyethylene glycol; thus, it is less irritating on mucosal surfaces. Because of its unique structure, mupirocin does not cross-react with other topical antibacterials. Q41.2 True allergic contact sensitivity to mupirocin is extremely rare. Unlike bacitracin and neomycin, mupirocin is an uncommon cause of postoperative ACD following dermatologic surgery.

Microbiologic Activity (see Table 41.1 )

Retapamulin demonstrates excellent in vitro activity against multiple Gram-positive aerobic cocci, including methicillin-susceptible and methicillin- and mupirocin-resistant S. aureus , S. epidermidis , S. pyogenes , Streptococcus agalactiae , S. pneumoniae , and viridans group streptococci. Retapamulin inhibits 91% of anaerobes tested in vitro, including multidrug-resistant Propionibacterium species. Q41.7 Because of its unique target of action, retapamulin has no clinically relevant cross-resistance with other antibacterials, including oxacillin, erythromycin, or mupirocin. Stepwise mutations in the gene encoding protein L3 or an increased production of Vga proteins (adenosine triphosphate [ATP]-binding cassette proteins involved in drug efflux) are required to confer reduced susceptibility. Thus, retapamulin has a low propensity to select for resistant strains of S. aureus and S. pyogenes .

Dermatologic Uses

Retapamulin is US Food and Drug Administration (FDA)-approved for the treatment of primary impetigo attributed to S. aureus (methicillin-susceptible isolates only) or S. pyogenes in adults and children 9 months of age or older. Topical retapamulin is over 85% effective for impetigo caused by methicillin-sensitive Staphylococcus aureus (MSSA), and it may also be used for staphylococcal folliculitis.

Retapamulin is as clinically effective in the treatment of secondarily infected dermatitis and secondarily infected traumatic wounds as oral cephalexin twice daily for 10 days. The recommended dosing for the 1% ointment in the treatment of impetigo is twice daily for 5 days. Although retapamulin is active in vitro against MRSA, it is only 64% effective for impetigo caused by MRSA. Thus, retapamulin is not FDA-approved for the treatment of impetigo caused by MRSA.

Adverse Effects

The most frequent AE are local reactions, including pruritus, paresthesia, irritation, or pain at the site of application. ACD has been reported and confirmed by patch testing.

Microbiologic Activity

Ozenoxacin has demonstrated a broad antimicrobial spectrum against both Gram-positive and Gram-negative organisms including the major pathogenic bacteria of acne vulgaris ( Propionibacterium acnes ) and superficial skin infections ( S. aureus , S. epidermidis , and S. pyogenes ). Ozenoxacin has activity against levofloxacin-susceptible and resistant P. acnes and S. aureus . Quinolone resistance in P. acnes and S. aureus is mediated by amino acid substitutions in the quinolone resistance determining regions (QRDR) of GyrA. Dual inhibition of DNA gyrase and topoisomerase IV in S. aureus allows for activity against these quinolone-resistant bacteria.

Dermatologic Uses

Ozenoxacin is FDA-approved for the treatment of impetigo caused by S. aureus (methicillin-susceptible isolates only) or S. pyogenes in adults and children 2 months of age or older. In two clinical trials, ozenoxacin demonstrated a 34.8% and 54.4% clinical response rate compared with 19.2% and 37.9% for placebo. Ozenoxacin demonstrated a 90.8% bacterial success rate compared with 69.8% for placebo. In a head-to-head trial, ozenoxacin produced more rapid microbiologic clearance than retapamulin. Based on these studies, the recommended dosing for the 1% cream is twice daily for 5 days. Ozenoxacin 2% lotion is used in Japan as an effective treatment of levofloxacin-susceptible and resistant P. acnes .