Topical antimicrobials are used to prepare the skin for surgical procedures or to locally treat cutaneous infections. Topical therapy is especially attractive to clinicians treating cutaneous infections in infants and children, because the risks of systemic drug exposure can be minimized. Parents may also be spared the frustration that accompanies administration of oral medications to reluctant children.
The risks of topical agents are different from those of commonly prescribed systemic antimicrobials. Topical use does not guarantee safety, as demonstrated by the history of topical antiseptic use in infants. Neonates were bathed with hexachlorophene in the 1950s and 1960s to help control nursery epidemics of Staphylococcus aureus. This practice was banned in the early 1970s after reports that seizures, and even death, associated with vacuolar encephalopathy could occur. Premature and low-birth-weight infants were most susceptible to this neurotoxicity.1,2
Other than systemic absorption and toxicity, risks of topical antimicrobials include local irritation, chemical burns, sensitization and allergic contact dermatitis, and accidental ingestion and poisoning. Pediatricians must keep in mind the potential for poisoning from any agent used in the home and counsel families appropriately about prevention.
Many topical antibacterial agents are safe and effective. Topical mupirocin, the best example, has replaced systemic antibiotic therapy as the treatment of choice for localized impetigo.3 This article reviews the safety and efficacy of topical antibacterial agents used for the prevention and treatment of pediatric skin infections. The emphasis is on use in neonates and infants, who are at greatest risk for adverse reactions.
Antimicrobial antiseptics, otherwise known as preparation agents or "preps," are used in hospital settings to cleanse the skin prior to invasive procedures or surgery. Infants in intensive care nurseries are exposed frequently to these agents, often over large surface areas. The potential for systemic absorption and toxicity is significant, especially in premature infants. Preparation agents are also used for care of the umbilical cord, and are applied to the maternal perineum before and during delivery to reduce postpartum infections. This may affect newborns through the percutaneous absorption of the agent from the mother, or by its direct contact with the infant during delivery.
Alcohol is an omnipresent antiseptic, both in the home and in the hospital. This agent may be applied to the skin of infants before procedures, to the umbilicus in routine care of the cord, and to children's skin in an attempt to control fever. Alcohol usually evaporates before it is absorbed by normal skin. When applied to immature or diseased skin, or with occlusion, alcohol can cause local burns or be absorbed with resultant systemic toxicity. Adverse systemic effects include dysfunction of the central nervous system, metabolic acidosis, and hypoglycemia.2'45 Alcohol pads are ubiquitous in neonatal intensive care units, and tend to be used more frequently for smaller, sicker infants.6 Unfortunately, these premature, low-birth-weight infants are at greatest risk for toxicity because of their poor cutaneous barrier.
Term infants are at risk from inappropriate use of alcohol in the home as well. Care of the umbilical cord with gauze or cotton balls soaked with isopropyl alcohol after diaper changes, followed by a dressing of alcohol under occlusion, resulted in acute alcohol toxicity in an infant 21 days old.7 Pediatricians should counsel parents to limit or avoid isopropyl alcohol for cord care and fever control, and to prevent poisoning among older siblings at risk for accidental ingestion.
Povidone-iodine is another common topical preparation in neonatal intensive care units. When absorbed in significant amounts, this agent may cause excess iodine, leading to perturbation of production of neonatal thyroid hormone and hypothyroidism. Disturbance of thyroid function in infants is associated with intraventricular hemorrhage, growth and motor retardation, and death.2,8-10 Some authors dispute that excess iodine causes hypothyroidism in infants in the United States because this phenomenon has been observed primarily in Europe, an area of relative iodine deficiency.11,12 However, it is clear that premature infants are at high risk of percutaneous absorption and excess iodine because of their immature skin barrier and high surface area to weight ratios. Therefore, exposure to skin preparation agents and antibiotics that contain iodine should be strictly limited or avoided in this group of infants.9,10 The use of a topical ointment that contains iodine on open wounds resulted in hypothyroidism in 4 infants with spina bifida,13 so ointments or solutions containing iodine should not be used on open wounds or under occlusion in any infant. They should also be used with caution in pregnant women - elevated thyroid-stimulating hormone in cord blood was reported because of maternal preparation with povidone-iodine before cesarean delivery.14
Chlorhexidine is a skin preparation agent with a broad spectrum of activity against gram-negative and gram-positive bacteria and some yeast.15 It is commonly used in hospital wards, including neonatal intensive care units. In some studies, it was as effective as povidone-iodine in reducing bacterial flora when used to disinfect skin at intravenous catheter sites in preterm and term infants.16,17
However, there have been reports of gramnegative bacterial resistance to Chlorhexidine, including one outbreak of Serratia marcescens in a pediatric oncology unit that was traced to contaminated Chlorhexidine.18 Systemic absorption was reported in preterm infants but not in term infants with the use of 1% Chlorhexidine solution in ethanol for cord care and before procedures. However, no toxic effects were seen after absorption.15 Local reactions were reported in preterm infants with occlusive chlorhexidine-impregnated dressings placed over central venous lines.19 Systemic anaphylaxis occurred in one adult following a Chlorhexidine bath.20
Although safety data in preterm infants are somewhat limited, Chlorhexidine is generally safe when used as a topical preparation agent without occlusion. If Chlorhexidine is used with alcohol in the vehicle, the safety of the alcohol component should be considered also.
Triclosan and Triclocarban
Triclosan is a phenolic antibacterial agent in many household products and surgical soap. It is bactericidal against gram-positive, gram-negative, and acid-fast bacteria. Specific safety data for neonates are not available.21 Bathing infants and washing hands with triclosan helped control a methicillin-resistant Staphylococcus aureus (MRSA) epidemic in one neonatal nursery.21 Neonatal conjunctivitis has been reported to be caused by triclosan soap contaminated with Serratia in a nursery.22 Nonmedicated liquid soap contaminated with Serratia has also been a source of nosocomial Serratia infection.23 Soaps containing triclosan should be investigated as sources of nosocomial outbreaks of Serratia.
Triclocarban is another antimicrobial agent used in home skin care products. Its range of bactericidal activity is more limited than that of triclosan, as it is effective against only gram-positive bacteria. It was helpful in the treatment of adult atopic dermatitis in one study, presumably by reducing S. aureus colonization of the skin.24
TOPICAL ANTIBACTERIAL AGENTS
These agents are used for the local treatment of bacterial skin infections and to eradicate the intranasal carrier state of S. aureus in hospital and family outbreaks. They are also used for acne treatment and infection prophylaxis on traumatic or surgical wounds and burns. Discussion of acne and burn therapy is beyond the scope of this article and is not included.
Many factors affect the antimicrobial power of topical antibacterial agents. These include the species of infecting bacteria, depth and extent of infection in the skin, presence of commensal organisms, and development of resistance and superinfection. Safety depends on avoiding systemic absorption, local irritation and tissue destruction, and hypersensitivity. Therefore, the ideal topical antibiotic is formulated in a non-irritating, nontoxic vehicle, and contains an agent with a range of activity, targeting specific pathogens without greatly disrupting commensal skin flora.25
Mupirocin is used for the treatment of local skin infections caused by gram-positive bacteria, especially S. aureus and Group A streptococci. It is not as active against other gram-positive or most gram-negative bacteria. Mupirocin is not readily absorbed from the skin, even when occluded.25 It is an effective treatment for localized, superficial impetigo in children when compared with oral erythromycin ethylsuccinate.26 Mupirocin is more expensive than oral erythromycin, but was more cost-effective than oral erythromycin in the treatment of impetigo because it reduced overall costs of the illness (ie, fewer lost work and school days and fewer side effects).27 More widespread superficial infections, or deeper skin infections, such as folliculitis and cellulitis, should be treated with systemic antibiotics such as cephalexin.25,28
Mupirocin has also been used to treat the nasal carrier state of S. aureus, including colonization by MRSA. Re-colonization after 6 to 12 months is common.26 Mupirocin was used intranasally in hospital staff to control an S. aureus outbreak in a children's hospital.29 It has been used topically in neonates to help control an outbreak of MRSA in a neonatal intensive care unit.30 It was effective for candidal diaper dermatitis in infants when used three times a day for 7 days. In this study, Candida albicans showed good in vitro sensitivity to mupirocin when compared with nystatin.31 It has also been used successfully to treat perianal streptococcal cellulitis.32
Resistance to mupirocin has emerged, especially after prolonged use in attempts to limit the spread of endemic MRSA. To prevent resistance, mupirocin should be used only for outbreaks and not for blanket prevention during long periods of time.33
Allergic contact dermatitis to mupirocin is rare, but has been reported.34 In some cases, the allergy was to the vehicle and not the mupirocin itself.35 In general, topical mupirocin has been a safe and effective addition to the pediatric topical antibacterial armamentarium.
Other Topical Antibacterial Agents
Bacitracin is a wide-spectrum topical antibiotic, available since the 1940s, that inhibits bacterial cell wall synthesis (Table). It is commonly used for infection prophylaxis in traumatic and surgical wounds. It is not an effective agent for the treatment of impetigo when compared with topical mupirocin or oral cephalexin, nor is it efficacious in the treatment of S. aureus nasal carriage.28,35 Bacitracin is inferior to systemic therapy for impetigo, even in combination with neomycin and polymyxin B (the so-called "triple antibiotic").36 When used three times daily on areas of mild skin trauma, this combination "triple" topical antibiotic was effective for preventing endemic impetigo in a day care center in one study.37 Bacitracin can cause allergic contact dermatitis and immediate urticarial eruptions. It has rarely caused anaphylaxis.38
Topical Antibacterial Agents Used for the Treatment of Cutaneous Infections in Pediatric Patients
Neomycin is active against staphylococci and has broader gram-negative coverage than bacitracin (Table). Similar to bacitracin, it is less effective for impetigo than oral antibiotics and is more often used on wounds for infection prophylaxis. It was inferior to topical mupirocin when used for cutaneous infections in adults in one study.39 Compared with other topical antibiotics, neomycin is more likely to cause allergic contact dermatitis. It is one of the most common of all sensitizers in children. Again, systemic antibiotics are more effective than topical bacitracin, neomycin, polymyxin, or combinations thereof in the treatment of impetigo, and are the preferred treatment except for localized lesions, which are best treated with mupirocin.36
An outbreak of gentamicin-resistant S. aureus infection occurred in a neonatal intensive care unit and corresponded with the indiscriminate use of gentamicin ointment for wound care. Topical preparations of the same antibiotics that are used systemically should be avoided because of the emergence of resistance.40
Although used medicinally by Australian Aborigines for thousands of years, tea tree oil has only recently become popular in the United States for the topical treatment of fungal and bacterial skin infections.41 There are considerable data regarding its antibacterial and antifungal efficacy. It is active in vivo against MRSA and has been used to treat dermatophyte infections (eg, tinea pedis), candidal infections, and acne.41-43 Data on its safety in infants and children are limited. Cases of poisoning in infants have been reported. These children presented with neurologic symptoms, such as confusion and ataxia, but all recovered completely.44,45
Topical antimicrobials can be useful for prevention and treatment of cutaneous bacterial infections in infants and children. However, the potential for adverse local and systemic reactions must be recognized. In addition, as with systemic antibiotics, the use of these agents should be specific and thoughtful. Indiscriminate, widespread use leads inevitably to the emergence of resistance, rendering these tools powerless against the bacteria we are attempting to control.
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3. Leyden JJ. Review of mupirocin ointment in the treatment of impetigo. Clin Pediatr (Phila). 1992;31:549-553.
4. Watkins AM, Keogh EJ. Alcohol burns in the neonate. J Paediatr Child Health. 1992;28:306-308.
5. Schick JB, Milstein JM. Burn hazard of isopropyl alcohol in the neonate. Pediatrics. 1981;68:587-588.
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12. Gordon CM, Rowitch DH, Mitchell ML, Kohane IS. Topical iodine and neonatal hypothyroidism. Arch Pediatr Adolesc Med. 1995;149:1336-1339.
13. Barakat M, Carson D, Hetherton AM, Smyth P, Leslie H. Hypothyroidism secondary to topical iodine treatment in infants with spina bifida. Acta Paediatr. 1994;83:741-743.
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16. Garland JS, Buck RK, Maloney P, et al. Comparison of 10% povidone-iodine and 0.5% Chlorhexidine gluconate for the prevention of peripheral intravenous catheter colonization in neonates: a prospective trial. Pediatr Infect Dis J. 1995;14:510-516.
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19. Garland JS, Alex CP, Mueller CD, Cisler-Kahill LA. Local reactions to a Chlorhexidine gluconate-impregnated antimicrobial dressing in very low birth weight infants. Pediatr Infect Dis J. 1996;15:912-914.
20. Snellman E, Rantanen T. Severe anaphylaxis after a Chlorhexidine bath. J Am Acad Dermatol. 1999;40:771-772.
21. Zafar AB, Butler RC, Reese DJ, Gaydos LA, Mennonna PA. Use of 0.3% triclosan (Bacti-Stat) to eradicate an outbreak of methicillin-resistant Staphylococcus aureus in a neonatal nursery. Am J Infect Control. 1995;23:200-208.
22. McNaughton M, Mazinke N, Thomas E. Newborn conjunctivitis associated with triclosan 0.5% antiseptic intrinsically contaminated with Serratia marcescens. Canadian Journal of Infection Control. 1995;10:7-8.
23. Sartor C, Jacomo V, Duvivier C, Tissot-Dupont H, Sambuc R, Drancourt M. Nosocomial Serratia marcescens infections associated with extrinsic contamination of a liquid nonmedicated soap. Infect Control Hosp Epidemiol. 2000;21:196199.
24. Breneman DL, Hanifin JM, Berge CA, Keswick BH, Neumann PB. The effect of antibacterial soap with 1.5% triclocarban on Staphylococcus aureus in patients with atopic dermatitis. Cutis. 2000;66:296-300.
25. Ward A, Campoli-Richards DM. Mupirocin: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1986;32:425-444.
26. Darmstadt GL, Lane AT. Impetigo: an overview. Pediatr Dermatol. 1994;11:293-303.
27. Rice TD, Duggan AK, DeAngelis C. Cost-effectiveness of erythromycin versus mupirocin for the treatment of impetigo in children. Pediatrics. 1992;89:210-214.
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33. Cookson BD. The emergence of mupirocin resistance: a challenge to infection control and antibiotic prescribing practice. J Antimicrob Chemother. 1998;41:11-18.
34. Zappi EG, Brancaccio RR. Allergic contact dermatitis from mupirocin ointment. J Am Acad Dermatol. 1997;36:266.
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36. Hirschmann JV. Topical antibiotics in dermatology. Arch Dermatol. 1988;124:1691-1700.
37. Maddox JS, Ware JC, Dillon HC. The natural history of streptococcal skin infection: prevention with topical antibiotics. J Am Acad Dermatol. 1985;13:207-212.
38. Katz BE, Fisher AA. Bacitracin: a unique topical antibiotic sensitizer. J Am Acad Dermatol. 1987;17:1016-1024.
39. Wilkinson RD, Carey WD. Topical mupirocin versus topical neosporin in the treatment of cutaneous infections. Int J Dermatol. 1988;27:514-515.
40. Graham DR, Correa- Villasenor A, Anderson RL, Vollman JH, Baine WB. Epidemic neonatal gentamicin-methicillin-resistant Staphylococcus aureus infection associated with nonspecific topical use of gentamicin. J Pediatr. 1980;97:972-978.
41. Carson CF, Riley TV, Cookson BD. Efficacy and safety of tea tree oil as a topical antimicrobial agent. J Hosp Infect. 1998;40:175-178.
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43. Tong MM, Airman PM, Barnetson RS. Tea tree oil in the treatment of tinea pedis. Australas J Dermatol. 1992;33:145149.
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Topical Antibacterial Agents Used for the Treatment of Cutaneous Infections in Pediatric Patients