Neonates and Topical Antimicrobials: What Should We Be Using?

Bacterial skin infections account for one of the most common topics discussed among medical professionals. In the hospital, cutaneous breaks (intended or unintended) are daily occurrences. Consequently, skin colonization with an organism’s potential entry into the deeper compartments and, eventually, hematogenous spread are feared complications of a patient’s stay. Due to a rise in antimicrobial resistance, due mostly to systemic antibiotics use, the role of topical antimicrobials is increasing. 

Prevention and treatment of skin infections can involve the application of an antibiotic or an antiseptic. Antiseptics are disinfectants that can be used on intact skin and some open wounds to kill or inhibit microorganisms.¹ They often have multiple microbial targets, a broad antimicrobial spectrum, and residual anti-infective activity, but are often toxic to host tissues (fibroblasts, keratinocytes).¹ Antibiotics are chemicals produced either naturally (by a microorganism) or synthetically, which in dilute solution inhibit or kill other microorganisms.^1,2 They usually act on a specific cell target, have a narrower spectrum of activity, are relatively nontoxic, and are more susceptible to losing their effectiveness to bacterial resistance.^1,2 Common topical antiseptics include compounds such as acetic acids, iodine derivatives, silver formulations, hydrogen peroxide, chlorhexidine gluconate, sodium hypochlorite, and hypochlorous acid. 

Theoretically, topical antibiotics offer several advantages over systemic administration, including delivery of high concentrations of the antimicrobial at the required site of action and a reduction in systemic toxicity. However, the widespread use of commonly used topical antibiotics (particularly mupirocin, polymyxin, and neomycin) has led to increasing bacterial resistance in some settings, limiting the potential efficacy of such agents.^1–3 Given global concerns regarding antibiotic resistance and relatively limited therapeutic options, especially for some species, such as Staphylococcus aureus, the appropriate use of topical agents and the prevention of further resistance are critical. Important questions to ask are 1) if topical antibiotics should be used in pediatrics and, more importantly, in neonatology and 2) if so, when? Before answering those questions, a review of a few of the common topical antibiotics is in order.

Neomycin. Neomycin is an aminoglycoside antimicrobial that is produced by Streptomyces fradiae and was first described in 1949.³ Neomycin comprises 3 major chemically related compounds; namely, neomycin A (neamine), neomycin B (framycetin, also called neomycin sulfate), and neomycin C, with the quantity of each varying with the manufacturing process.^1–3 Due to its relative toxicity when administered systemically, neomycin is generally used only topically, either alone or in combination with polymyxin B and/or bacitracin. 

Similar to other aminoglycosides, neomycin acts by binding to the 30S subunit of the bacterial ribosome to inhibit protein synthesis. Resistance is mediated through a number of mechanisms, with the most significant being enzymatic inactivation of the drug by chromosomally or plasmid-encoded aminoglycoside-modifying enzymes. Topical neomycin-containing formulations are most commonly used for treatment of localized skin infections. In general, however, neomycin formulations perform less well than other topical antimicrobials, such as fusidic acid and mupirocin, for the treatment of common skin infections such as impetigo.^1–3 In addition, one of the major concerns regarding the use of topical neomycin is its high prevalence of allergic contact dermatitis, which has been estimated at 1% to 6%, but is thought to be higher in patients with a compromised skin barrier, such as atopic dermatitis, preterm skin, and an open wound, or in immunocompromised patients.⁴ Neomycin can adversely affect the kidneys and auditory system. Topical application to wounds can result in hearing loss, especially in patients with renal impairment because neomycin, similar to aminoglycosides, can cause apoptotic cell death of hair cells, mainly in the cochlea.^1–4 Eardrum perforation can occur when neomycin eardrops are administered. 

Neomycin should not be prescribed to patients with renal impairment. In addition, systemic hypersensitivity reactions occurring from topical application were reported from both a neomycin-only formulation and a combination neomycin–bacitracin formulation.¹ Some patients who are allergic to neomycin are also allergic to bacitracin. An allergy to neomycin often translates into a cross-reaction from other aminoglycosides such as gentamycin and amikacin, which are both extremely common antibiotics used in the neonatal intensive care unit. Both neomycin and bacitracin have won the “Allergen of the Year” award from the American Academy of Dermatology in the past.⁵ 

Neomycin, by itself or in combination with other antibiotics, is effective against gram-negative (GN) bacteria, except Pseudomonas aeruginosa. Its gram-positive (GP) coverage includes S aureus but not Streptococcus. The polymyxin component is bactericidal against many GN and GP organisms, including P aeruginosa. Neomycin is applied 1 to 3 times per day and comes in variety of preparations. 

Bacitracin. Bacitracin is a cyclic polypeptide antimicrobial derived from the bacterium Bacillus subtilis and is approved by the U.S. Food and Drug Administration for the treatment of superficial bacterial skin infections. Complexing with zinc results in a stable form of bacitracin. It is bactericidal by complexing with C₅₅-isoprenyl pyrophosphate, which is a bacterial cell wall component that normally transports peptidoglycan across the bacterial cell membrane.^1–3 Inhibition of C₅₅-isoprenyl pyrophosphate subsequently blocks cell wall formation. Its antimicrobial spectrum covers many GP (Staphylococcus/Streptococcus/Corynebacterium) anaerobic cocci, but it is inactive against many GN organisms. 

Resistance in isolates of staphylococci and streptococci is thought to be low.^1–3 In vitro studies suggest that other beta-hemolytic streptococci are either resistant or display reduced susceptibility.^1–3 The majority of GN bacteria are resistant. Due to systemic toxicity (nephrotoxicity and thrombophlebitis), use is restricted to topical administration. Local application can result in pain, burning, itching, hypersensitivity, and rarely anaphylactic reactions. 

Bacitracin is used extensively in the emergency, dermatology, and plastic surgery departments as well as in general care. Providers of pediatric care often are unaware of its potential for allergic and anaphylactic reactions. It must be applied 2 to 3 times a day and can cause overgrowth of antibiotic-resistant organisms, including fungi. It is the most widespread topical antibiotic used in the pediatric hospital, starting with neonatal lacerations during the birth process, skin irritations in the newborn nursery, and cutaneous repair in the emergency department. It is also the “ointment of choice” during or after surgical procedures and is prescribed as “discharge ointment” after office procedures.

Metronidazole. Metronidazole works on anaerobic bacteria. It is applied 1 to 2 times per day. It is not widely used in pediatric practice. However, in the author’s institution it is a common choice for topical application in ulcerated hemangiomas and other overgrowth masses.

Silver sulfadiazine. Silver sulfadiazine, a combination of sulfonamide and silver ions, covers both GN and GP organisms. It is applied 1 to 2 times per day, is known to cross-react with other sulfonamides, causes skin staining (especially in neonates), and is known to induce antimicrobial resistance. The use of silver has been discussed in many other “Children With Wounds” articles as it pertains to neonatology and pediatrics. The most common pediatric indication for silver sulfadiazine is burn injury; in neonatology, the most common indication is a topical application to giant omphaloceles. As discussed in previous articles, most neonatal and pediatric practitioners caution against silver-based applications due to its potential toxicity.

Mupirocin. Mupirocin ointment is a short fatty acid side chain linked to monic acid by an ester linkage produced by submerged fermentation of Pseudomonas fluorescens. The major metabolite is pseudomonic acid A, which is responsible for most of the activity, whereas 3 other minor metabolites (pseudomonic acids B, C, and D) have similar chemical structures and antimicrobial spectra.^1–3 Its activity can be decreased if the pH increases above the normal skin pH of 5.5,³ which can be an issue in extremely preterm babies because they have reduced acid mantle and more alkalotic skin pH for the first few weeks of life. The enteric instability of mupirocin has restricted its use to a topical application, notably for soft skin injuries, impetigo, and off-label use in decolonizing intranasal S aureus, where it remains active in nasal secretions (as shown by studies performed in adults).⁶ 

There is some concern about the theoretical cytotoxic mechanism of mupirocin. A study by Balin et al⁷ showed growth inhibition of fibroblasts after 4 to 6 days’ exposure to 700 µg/mL mupirocin. The clinical concentration of mupirocin is 2% or 20,000 µg/mL, which is much higher than that used in the study. However, the concentration of mupirocin in tissue from topical application is unknown. Topical application may cause burning, itching, reddening, and allergic contact dermatitis.³ Conjunctival application is contraindicated because it may cause irritation. Irritation and an unpleasant or abnormal taste, which are minor side effects, have also been recorded from nasal application. Mupirocin can be absorbed through the skin, especially when skin lesions are present. Because mupirocin is rapidly metabolized in plasma, the percutaneous absorption of mupirocin can be measured from its metabolite monic acid. Urinary monic acid was evaluated after repeated applications of mupirocin, and the measured concentration of monic acid is very inconsistent in studies.^8,9 

Although no systemic adverse effects resulting from mupirocin administration have been reported, it is recommended that pregnant and breastfeeding women should use mupirocin with caution due to unknown potential systemic effects if transferred to infants. Because mupirocin can be absorbed, it may be able to pass into breast milk and may affect the infant. Polyethylene glycol from the ointment base can be absorbed through open wounds or damaged skin, resulting in renal toxicity.^3,10 Therefore, topical application may not be suitable for patients with a large open wound or those with renal impairment. Mupirocin should not be applied for longer than 10 days, as chances of bacterial resistance increase after that and, in recent years, have been as high as 30% for S aureus.¹¹

Despite the availability of various topical antimicrobials, most practitioners are not sure what to use on acute and chronic neonatal and pediatric wounds, especially due to a lack of robust supporting literature regarding concerns and side effects. 

Skin infections. Impetigo is a common superficial bacterial skin infection that is often caused by S aureus and/or Streptococcus pyogenes. Clinically, there are 2 main syndromes: the more common nonbullous impetigo (impetigo contagiosa) and the less common bullous (blistering) impetigo. Nonbullous impetigo typically manifests as small intraepidermal blisters, which subsequently form yellow-brown crusted lesions around the face, particularly the nose and mouth. It is most common in children aged 2 to 5 years, and although self-limiting, it is generally treated with antibiotics to reduce symptom duration and to prevent further transmission of causative bacteria.³ Impetigo can be treated with topical antibiotics and/or systemic antibiotics, and the decision of which therapy to use is generally based on the number and extent of lesions, with minor disease usually treated with topical agents.³

Despite an estimated global prevalence in children of approximately 162 million, there is limited high-quality evidence to guide the appropriate empirical topical treatment of impetigo.³ A meta-analysis conducted in 2012 to assess interventions for impetigo included 24 randomized controlled trials (RCTs) that compared topical antibiotic therapy (mupirocin or fusidic acid) to placebo.¹² Overall, the authors of that analysis concluded that topical antibiotic therapy achieved significantly higher cure rates than those with placebo and that there was no significant difference between the 2 main topical antibiotics used. However, the quality of the included studies was variable, with most being conducted more than a decade ago, making resistance patterns noncontemporary. 

There remain several knowledge gaps regarding the most appropriate topical treatment for impetigo. For example, given that impetigo is generally regarded as a self-limiting condition, there are relatively few trials comparing topical antibiotic treatment to treatment with placebo. Normally, laboratory testing is not a part of the routine work-up for mild impetigo; therefore, true rates of resistance in causative pathogens are largely unknown. Thus, caution should be exercised in extrapolating results of studies conducted in low-resistance settings, as it is possible that clinical and microbiological cure rates differ among settings.³ Given the current evidence, it is important for practitioners to consider prescribing topical antibiotics for impetigo for the shortest possible duration of therapy and being aware of the microbial local resistance patterns.

Wounds. Whether surgical, traumatic, or iatrogenic, wounds have always been the primary target of topical antimicrobials. Both chronic and acute wounds in pediatrics are commonly covered by bacitracin or Neosporin (neomycin, polymyxin, and bacitracin zinc; Johnson & Johnson). Almost every cutaneous procedure in the emergency department or an outpatient office is followed by the application of one of those antibiotics, and they are included in the discharge instructions. Many studies have shown their efficacy over placebo in decreasing skin colonization and infection development, yet others demonstrated no difference and enhanced epithelization just from the presence of an emollient base.^1–3 

In addition to traumatic wounds, infections following burn injuries represent a major area of interest. Cutaneous injury, coupled with vascular insufficiency and often an inadequate immune system, may create a perfect storm for colonization and multiplication of microbes. Numerous topical antimicrobial agents have been used for infection prophylaxis, but the strength of data is moderate. A systematic review in 2013 reviewed the effectiveness of topical prophylaxis for burn-related infections in adults; it included 26 RCTs, evaluating a range of topical agents such as silver sulfadiazine, neomycin, bacitracin, polymyxin B, and mafenide acetate.¹⁰ The authors found no evidence to support the use of topical antimicrobials (compared with either no intervention or any other intervention) for the prevention of infections. Moreover, a subanalysis of 11 RCTs (with 645 participants) involving the use of 1% topical silver sulfadiazine found that patients treated with silver sulfadiazine actually had a higher risk of infection and a longer hospital stay than those treated with either dressings or skin substitutes.³ Frequent and potentially painful applications of these topical agents complicate care even further. It is the author’s opinion that modern dressings, including impregnated foams, skin substitutes, surfactant-based burn gel, medical grade honey, and hydrophobic gel-based dressings, offer safer, noncytotoxic, and patient-friendly solutions.

Prevention of postsurgical wound infections is another area of concern. Most practitioners will administer preoperative antibiotics, followed by postoperative systemic antibiotics. Some may recommend topical antibiotics to the incision area as prophylaxis. There is limited evidence to support the administration of topical antibiotics directly at the surgical site.¹² In adults, an analysis concluded that locally applied topical antibiotics had a probable benefit in reducing postsurgical infection rates in joint arthroplasties and ophthalmic surgery and a possible benefit in reducing the rates in cosmetic breast augmentation and in obese patients undergoing abdominal surgery.⁸ In addition, a  Cochrane review¹³ evaluated the use of locally applied topical antibiotics in the prevention of surgical wound healing by primary intention. The overall quality of the evidence was poor, however, but a mild positive effect was elucidated in the surgical site infection rate. Personally, the author worries about this practice in pediatrics because data are limited and it may continually add to antimicrobial resistance.

Decolonization. In addition to systemic antibiotics, contemporary infection prevention strategies often involve the application of a topical antibiotic (mupirocin) to the nasal mucosa to eradicate preoperative S aureus carriage and antiseptic body washes (chlorhexidine) to reduce the bacterial load on the skin. The available evidence suggests that prophylactic nasal and skin decolonization is an effective strategy for preventing S aureus infections following surgical procedures, predominantly orthopedic and cardiac surgeries. This reduction is observed for both methicillin-susceptible S aureus (MSSA) and methicillin-resistant S aureus (MRSA).³ MRSA colonization in the general population is widespread (approximately 1.5% of the population).^6,8 Neonates are likely to acquire S aureus through the birth canal, breastfeeding, and contact with people and the surrounding environment.^6,11 Neonatal colonization rates of S aureus were reported to be 40% to 50% during the first 8 weeks of life, followed by a gradual decrease to around 20% at 6 months of age, with anterior nares being the predominant site of MRSA colonization.⁶ Other parts of the body, such as the umbilicus, pharynx, axilla, groin, and perineum, harbor MRSA to a lesser extent. Current data demonstrate a higher MRSA colonization rate in hospitalized neonates than in the general neonatal population, ranging from 3.9% to 32% among institutions.^11,14 Approximately 1 of 5 neonates colonized with MRSA may develop an infection, with the onset ranging from 4 to 9 days.⁸ Prematurity is the single largest predisposing factor.⁸ 

The clinical manifestations of MRSA infections range from mild focal infections to more severe forms, such as toxic shock syndrome, and invasive infections, such as sepsis, necrotizing pneumonia, meningitis, endocarditis, osteomyelitis, liver abscesses, and urinary tract infections. The mortality rate of MRSA infections varies widely among institutions, ranging from about 2.9% to 28%.^8,14 Although there seems to be no difference between MRSA and MSSA in terms of their clinical presentation and mortality rate, neonates infected with MRSA may have a higher readmission rate and a longer infection course than those with MSSA.¹⁴ 

Untreated colonization increases the risk of MRSA infection by 6% daily.¹⁵ Therefore, most neonatal intensive care units have adopted active surveillance cultures plus MRSA decolonization strategies using nasal mupirocin with or without antiseptic bath along with frequent handwashing. Many studies have shown the success of this practice in both children and adults, but frequent recolonization occurs in neonates.^11,14–17 In the author’s experience, many neonates require a second and third course of mupirocin, leading to the current 30% mupirocin-resistant rate. Most neonates tolerate the application well; therefore, many courses are easily administered without always checking strain sensitivity or the potential effectiveness of mupirocin. 

It is known that the mupirocin molecule is unstable in the enteric form.^9,15 In cutaneous application, it is successful in eradicating MRSA/MSSA by targeting bacterial isoleucyl-tRNA synthetase.⁹ In adults little evidence exists for transcutaneous absorption, based on the level of monic acid (the cleavage of the mupirocin molecule produces monic acid) in the urine or the lack thereof.^8,9 Neonates may absorb mupirocin to a greater extent, given their skin immaturity, leading to a greater exposure and potentially more widespread resistance. While it is important to prevent MRSA infections and eliminate MRSA/MSSA colonization, practitioners have to be cognizant of resistance development, minimalize unnecessary exposure, develop tests helpful in determining mupirocin efficacy, and adhere to strict hygiene measures.