Cutaneous bacterial infections in the newborn

April A. Larsona,c and James G.H. Dinulosa,b,c

Departments of aMedicine, bPediatrics, and cDermatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
 

Current Opinion in Pediatrics 2005, 17: 481—485 2005 Lippincott Williams & Wilkins

Abbreviations AMP antimicrobial peptide MRSA methicillin-resistant Staphylococcus aureus

Traducción libre : Dr Carlos González        Pediatra    Puerto Montt Chile

Purpose of review

This review examines neonatal bacterial skin infections with respect to host immunity, bacterial pathogens, patterns of  infection, and new therapeutic approaches.

Recent findings

Advances have been made in our understanding of innate host defense and the emerging role of cutaneous antimicrobial peptides of the cathelicidin and defensin families. Toll-like receptors are being investigated with respect to their interactions with bacteria and other components of the innate immune defense, such as the antimicrobial peptides. The epidermal barrier remains an active area of research. Studies confirm that maintaining an intact epidermal barrier by minimizing exposure to soap and by not removing vernix caseosa are simple measures to improve skin barrier function. Active barrier-enhancing measures such as the application of topical emollients have shown mixed results in the prevention of nosocomial infection. A meta-analysis of studies performed in developed countries showed a trend of increasing risk for coagulase-negative staphylococcal infection. By contrast, a randomized controlled trial showed that infants treated with sunflower oil are less likely to experience nosocomial infections than are control infants. Infants with bacteremia and no known source of infection should be carefully examined because cutaneous abscesses have been shown to be an important nidus of infection. Methicillin-resistant Staphylococcus aureus is reaching epidemic proportions, making surface cultures an essential part of the evaluation of cutaneous bacterial infection.

Introduction

Although most cutaneous bacterial infections in newborns are superficial and respond nicely to topical antimicrobial therapy, bacteria under certain conditions are able to penetrate the skin, causing serious life-threatening infections. The skin and mucous membranes are the first lines of defense against invading bacteria. Prematurity, malnutrition, and immunodeficiency are factors negatively influencing an infant’s ability to defend against serious bacterial illness.  This review examines innate immune defense, clinical patterns of cutaneous infection, important bacterial pathogens, and new therapies for bacterial skin infections in the newborn period.

Innate host immune defenses: the epidermal barrier

The epidermal barrier is the first line of protection against bacterial cutaneous infection. Most of the protection is afforded by the uppermost layer of the epidermis, the stratum corneum. The stratum corneum consists of a complex organization of proteins and lipids. Lamellar bilayers of hydrophobic lipids, principally fatty acids, cholesterol, and ceramides, are tightly formed between protein-rich cornified cells. The principle lipids in the stratum corneum, the ceramides, have at least nine types or subclasses and perform an essential role in epidermal barrier function, especially in the prevention of transepidermal water loss. More recently, evidence suggests that ceramides may have immunomodulatory properties as well [1•]. Alterations in cutaneous ceramide function are seen in skin conditions in which there is an increase in cutaneous bacterial infections, such as atopic dermatitis. Ceramide-rich emollients have been used successfully to clinically improve atopic dermatitis, supporting the concept that ceramides are essential to normal skin function.

An infant’s gestational age has a great impact on epidermal barrier function as measured by transepidermal water loss.

Preterm infants younger than 28 weeks show decreased functioning of the epidermal barrier, placing them at risk for cutaneous bacterial infection [2]. The skin barrier attains full function, similar to adult skin, by 2 to 4 weeks of age but can take as long as 8 weeks in extremely premature infants [2]. This postnatal epidermal barrier maturation corresponds to a significant rise in total skin ceramide concentration and is thought to be an adaptive response to the change from a moist environment to a dry environment [3].

The lipid content of the skin is not the only known adaptive response occurring in postnatal skin. Within 2 weeks of birth, skin surface pH drops from neutral to a range of 5 to 5.5, consistent with the pH of normal adult skin. This acid pH is referred to as the acid mantle and is thought to provide an environment favoring the colonization of commensal bacteria and discouraging the growth of pathologic organisms [4]. Soap alters the pH of the skin and thus has the potential to alter the delicate balance between pathogenic and commensal bacteria. A recent study examined the role of bathing with neutral pH soap on cutaneous bacterial colonization in infants admitted to a neonatal intensive care unit. In that study, 73 premature infants were randomized at day 3 of life to one of two groups: daily bath with water alone or daily bath with water and neutral pH liquid soap [5•]. Before entering the study, the infants in both groups were bathed with a liquid soap and water. Seven days after randomization, axillary quantitative bacterial cultures were obtained before and 30 minutes after bathing. The investigators found no difference in type or number of colony-forming units of bacteria between groups. Both groups showed a high prevalence of coagulasenegative Staphylococcus before bathing (88–90%) as well as a significant decrease in colony-forming units of both gram-positive and gram-negative bacteria after bathing.

Three infants experienced sepsis. Two of the infants with sepsis showed congruent surface and blood cultures. The sample size was too small to detect whether the addition of soap decreased the rate of sepsis. These results indicate that liquid neutral pH soap does not alter the bacterial colonization of the skin after bathing for 1 week. This study should prompt close evaluation of bathing practices in neonatal intensive care units and special care nurseries. Daily use of soap may not be necessary for adequate skin hygiene.

Vernix caseosa

Vernix caseosa continues to intrigue investigators and during the past several years has been the focus of several studies. Produced by fetal sebaceous glands and keratinocytes, vernix caseosa consists of a complex mixture of water, protein, and lipids. The true function of vernix caseosa remains largely unknown. Vernix caseosa is believed to maintain skin hydration and influence the development of the acid mantle after birth. Recently, Visscher et al. [6•] examined the role of vernix caseosa in these and other neonatal adaptive responses, including the surface distribution of vernix caseosa at birth, thermal regulation, skin surface adaptation after birth, and antioxidant properties.

Vernix caseosa distribution correlated inversely with birth weight: vernix caseosa covered larger surface areas in infants weighing less than 2000 g. Removal of vernix caseosa did not show a significant effect on thermal regulation in this study. Vernix caseosa significantly aided with skin hydration and skin acidification. Vitamin E was recovered from vernix caseosa by quantitative analysis, suggesting that vernix may be important in protection from oxidative stress. This study shows that vernix caseosa improves neonatal adaptive responses that are likely to assist with protection from cutaneous bacterial infection [6]. These results correspond to a previous study of the content of epidermal barrier lipids. Hoeger et al. [3] analyzed the content of epidermal barrier lipids in vernix and fetal skin and found that the ceramide concentration in vernix corresponded to that in fetal skin at a similar gestational age. These data support the idea that vernix caseosa plays a central role in adaptive cutaneous  responses, including epidermal barrier formation. Vernix caseosa, like the epidermis, contains antimicrobial peptides and has a direct role in defense against bacteria.

Antimicrobial peptides

In addition to acting as a physical barrier to pathogenic bacteria, the epidermis harbors key components of the immune system. Recent work has focused on elements of the innate immune defense within the epidermis, specifically antimicrobial peptides (AMPs) [7••]. AMPs are small proteins that are highly preserved in many organisms, including animals, insects, and plants. In humans, they are produced in part by activated keratinocytes within the epidermis. These cationic proteins, termed cathelicidins and defensins, are attracted to the negatively charged surfaces of bacteria, fungi, and viruses, enabling them to not only directly kill bacteria but also recruit slower adaptive immune defenses. This broad mechanism of action is thought to aid in avoiding the development of resistance in bacterial pathogens.

In adult skin, the baseline expression of AMPs is low and increases significantly in the presence of inflammation. Interestingly, studies of normal neonatal skin in mice and humans revealed increased baseline levels of cathelicidin and b-defensin 2, in comparison with adults, suggesting that AMPs play a more crucial role in the immature immune system of newborns [8]. Alpha-defensins have also been found to be active antimicrobial components of vernix and amniotic fluid in three studies [9,10,11•]. The presence of human cathelicidin and b- defensins in these fluids has been inconsistent, however; one study showed no detectable LL-37, the mature protein product of cathelicidin, in 25 vernix samples, and another demonstrated LL-37 positivity by Western blot in all six vernix extracts [9,11•]. Vernix extracts in one study were found to be active against gram-positive bacteria; however, in two studies, extracts of vernix and amniotic fluids did not show activity against Escherichia coli, presumably because of low levels of AMPs in crude extract [9,10]. Cathelicidins have also been isolated in human breast milk and mouse mammary glands, and may in part explain lower infection rates of breast-fed infants [12•].

Toll-like receptors

Most infectious disease research regarding toll-like receptors focuses on viral infections or cutaneous bacterial  pathogens that rarely affect newborns, such as Mycobacteria, Borrelia burgdorfei, and Treponema pallidum. It is likely, however, that new research will focus on toll-like receptors important in the recognition of other bacterial pathogens and interaction with antimicrobial peptides, which may have relevance in this pediatric population.

Mammalian toll-like receptors are also elements of the innate immune system and are found on the surface of many cells, including keratinocytes. By binding specific bacterial pathogens, these pattern recognition receptors act as inducers of the innate immune system. Toll-like receptors 2 and 4 have been demonstrated on the surface of keratinocytes and may be an integral step in the activation of certain antimicrobial peptides [13].

Types of neonatal cutaneous infection

Bacterial cutaneous infections can be classified according to the clinical pattern of infection and the type of bacteria. Different clinical patterns include superficial infection, such as impetigo and paronychia, and subcutaneous infections, such as cellulitis, abscesses, and necrotizing fasciitis. Neonates can also show diffuse skin erythema and scaling (e.g., scalded skin syndrome) caused by cutaneous or extracutaneous infection with a toxin-producing organism [14].

Mandel et al. [15•] conducted a retrospective analysis of the role of cutaneous abscess in sepsis. They found that in 22% of the newborn infants with nosocomial sepsis, cutaneous abscess was the underlying cause. Persistent bacteremia preceded the diagnosis of cutaneous abscess, suggesting that infants with persistent bacteremia should have careful skin examinations.

The umbilical cord is one of the first cutaneous areas to be  colonized with bacteria. Omphalitis, or infection of the umbilical stump, is one of the more common bacterial infections seen in newborn infants and remains an important clinical issue. Premature infants seem to be at increased risk for omphalitis. A study conducted in Oman found that omphalitis was more common with home births, in pregnancies with high risk for early neonatal sepsis (prolonged rupture of membranes, maternal fever, chorioamnionitis), and in infants weighing less than 2500 g [16•]. Staphylococcus aureus was the most common pathogen isolated from the umbilical stump, followed by E. coli and Klebsiella spp. Janssen et al. [17] conducted a trial comparing dry cord care (cleansing with soap and water when the umbilicus becomes soiled) with cord care using triple dye/alcohol. They noted that infants with dry cord care were more likely to be colonized with E. coli, coagulasenegative Staphylococcus, and group B Streptococcus. They concluded that infants receiving dry cord care should be monitored closely for omphalitis.

Pathogens

Cutaneous bacterial infections in developed countries are overwhelmingly caused by gram-positive bacteria. The incidence of methicillin-resistant S. aureus (MRSA) in pediatric patients is reaching epidemic proportions, both in the hospital and in community settings. This topic has recently been reviewed in this journal and will not be repeated in depth here [18•]. Briefly, MRSA infection is particularly pertinent to infants with atopic dermatitis, in which S. aureus carriage is common. A retrospective review of 150 children with infected atopic dermatitis and skin surface cultures revealed 100% carriage of S. aureus [19]. Of 36 infants younger than 12 months, 2 (6%) infants had MRSA. The rate of MRSA carriage increased with age. We recommend routine skin surface culture of all impetigo patients, especially when impetigo occurs in conjunction with atopic dermatitis.

Treatment

Treatment may consist of emollients and other topical therapies, or some antibiotic agents.

Emollients and other topical therapies

Recent studies have focused on methods to assist with the epidermal barrier. A meta-analysis included four randomized controlled trials evaluating the role of topical emollients in the prevention of infection in preterm infants [20••]. The inclusion criteria included infants younger than 37 weeks gestation treated within 96 hours of birth. A total of 1304 infants were studied in these nonblinded trials. Infants in the treatment group received twice-daily application of an emollient for an average of 2 weeks. Although daily application of a topical ointment or cream improved the overall skin condition, an increased risk of coagulasenegative staphylococcal infection was found in infants treated with prophylactic ointment in comparison with the control groups (relative risk 1.31, CI 1.02–1.70). The trials included in this meta-analysis were all conducted in developed countries. These results may not apply to developing countries.

Two studies conducted in developing countries demonstrated a protective effect of prophylactic topical emollients. Darmstadt et al. [21••] conducted a randomized controlled trial of preterm infants in Bangladesh. A population of 497 infants younger than 33 weeks’ gestation was randomized to three groups: topical treatment with sunflower seed oil, Aquaphor, or control. The treatment arms received three times daily application of emollient for 14 days, followed by twice-daily application until discharge. The control group did not receive a control emollient because none could be found without a proposed effect on the epidermal barrier. The primary outcome was the rate of nosocomial infection, specifically sepsis or meningitis, demonstrated by blood or spinal fluid culture.

The incidence of systemic nosocomial infection was lower in both treatment groups; treatment with sunflower seed oil had a significant relative risk of 0.59, whereas treatment with Aquaphor carried a relative risk of 0.60, although this result was not statistically significant. The relative risk was reduced even further in extremely low birthweight (<1250 g) neonates. This confirmed previous results of a study in Egypt performed by the same group [22•]. It is notable, however, that treatment with emollients did not reduce the risk of infection by Klebsiella, the primary pathogen in nosocomial infection.

It should be pointed out that although the emollients applied in these studies may mimic natural emollients such as vernix, they lack active antibacterial properties. Promising new therapies in the future will likely combine structural barrier-enhancing properties with active immunomodulatory or antimicrobial agents. These ‘smart’ emollients may not be that far removed from clinical application. A European group recently created new lipid mixtures using synthetic ceramides to more closely resemble the stratum corneum lipid barrier [23]. Izadpanah and Gallo [7•] suggest that synthetic topical AMPs will likely be pursued as a new generation of topical antibiotics.

New antibiotics

With the increasing rate of MRSA requiring more use of vancomycin and linezolid, it is only a matter of time before significant resistance is seen to these antibiotics as well. Linezolid-resistant strains of Enterococcous faecium, E. faecalis, and S. aureus have already been reported [24]. Daptomycin is a recently approved lipopeptide antibiotic for use in skin and soft tissue infections in the United States.  It is active against susceptible and resistant strains of S. aureus and is currently under investigation for use in vancomycin-resistant Enterococcus infections as well as other serious gram-positive infections. There has already been a report of confirmed daptomycin resistance in a patient being treated with daptomycin for MRSA bacteremia [25•]. Other antibiotics being investigated for use in resistant S. aureus infections include oritavancin, dalbavancin, and tigecycline [26].

Conclusion

The skin serves a central role in protecting infants from life-threatening bacterial infection. Basic science research continues to forge ahead with respect to our understanding of the structural and immunologic mechanisms important for protection from invading bacterial organisms. Meticulous care of the skin is critical to maintaining skin integrity and prevention of bacterial sepsis. New emollients are being formulated based on the lipid structure of the skin. Recent research has focused on creating simple and culturally sensitivemethods to assist in augmenting the epidermal barrier. These methods may prove to be highly effective in developing countries such as Egypt and Bangladesh. Antibiotic-resistant organisms such as MRSA are increasing in global clinical relevance, putting into question basic skin care, such as how we care for the umbilical cord. As we move forward in the area of bacterial skin infections, we will see new treatments for bacterial skin infections; however, the old adage ‘an ounce of prevention is worth a pound of cure’ will always remain paramount in the study of neonatal bacterial skin infections.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest •• of outstanding interest •

1. Yang J, Yu Y, Sun S, et al. Ceramide and other sphingolipids in cellular responses. Cell Biochem Biophys 2004; 40:323—350. This is an excellent review of ceramide biology and the multiple cellular functions of these lipids. This is a comprehensive review for one interested in understanding the basic science of sphingolipids.

2. Kalia YN, Nonato LB, Lund CH, et al. Development of skin barrier function in premature infants. J Invest Dermatol 1998; 111:320— 326.

3. Hoeger PH, Schreiner V, Klaassen IA, et al. Epidermal barrier lipids in human vernix caseosa: corresponding ceramide pattern in vernix and fetal skin. Br J Dermatol 2002; 146:194—201.

4. Rippke F, Schreiner V, Schwanitz HJ. The acidic milieu of the horny layer: new findings on the physiology and pathophysiology of skin pH. Am J Clin Dermatol 2002; 3:261—272. •

5. da Cunha ML, Procianoy RS. Effect of bathing on skin flora of preterm newborns. J Perinatol 2005 This interesting study examined the role of neutral lipid soap in cutaneous bacterial colonization. The results support the idea that soap is not necessary each time an infant is bathed. •

6. Visscher MO, Narendran V, Pickens WL, et al. Vernix caseosa in neonatal adaptation. J Perinatol 2005 The authors combined four studies in one article, making systematic review difficult. The results point to a vital role for vernix caseosa in neonatal adaptation. Further studies will need to be conducted to enable us to learn more about the underlying mechanisms responsible for these findings. ••

7. Izadpanah A, Gallo RL. Antimicrobial peptides. J Am Acad Dermatol 2005; 52:381—390; quiz 391—392. This is an excellent review on antimicrobial peptides written by experts in this field. The article is very well written and has supporting illustrations.

8. Dorschner RA, Lin KH, Murakami M, et al. Neonatal skin in mice and humans expresses increased levels of antimicrobial peptides: innate immunity during development of the adaptive response. Pediatr Res 2003; 53:566—572.

9. Marchini G, Lindow S, Brismar H, et al. The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa. Br J Dermatol 2002; 147:1127—1134.

10. Yoshio H, Tollin M, Gudmundsson GH, et al. Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: implications for newborn innate defense. Pediatr Res 2003; 53:211—216. •

11. Akinbi HT, Narendran V, Pass AK, et al. Host defense proteins in vernix caseosa and amniotic fluid. Am J Obstet Gynecol 2004; 191:2090—2096. These investigators used molecular techniques to characterize antimicrobial peptides in vernix caseosa. More studies such as this one should be done to assist us in understanding the role of vernix caseosa in antimicrobial defense. •

12. Murakami M, Dorschner RA, Stern LJ, et al. Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk. Pediatr Res 2005; 57:10—15.  The cathelicidin group of antimicrobial peptides is one of the major classes of cutaneous antimicrobial peptides. This article examines the content of cathelicidins in human milk, which may be protective against bacterial infection.

13. Pivarcsi A, Bodai L, Rethi B, et al. Expression and function of Toll-like receptors 2 and 4 in human keratinocytes. Int Immunol 2003; 15:721—730.

14. Chao SC, Richard G, Lee JY. Netherton syndrome: report of two Taiwanese siblings with staphylococcal scalded skin syndrome and mutation of SPINK5. Br J Dermatol 2005; 152:159—165.  •

15. Mandel D, Littner Y, Mimouni FB, et al. Nosocomial cutaneous abscesses in septic infants. Arch Dis Child Fetal Neonatal Ed 2004; 89:F161—F162. The vast majority of skin infections are superficial. These authors show that deeper infections such as cutaneous abscesses are able to produce bacteremia. An infant with bacteremia without a known cause should be examined for cutaneous abscesses. •

16. Sawardekar KP. Changing spectrum of neonatal omphalitis. Pediatr Infect Dis J 2004; 23:22—26. This article reports on the impact of home deliveries on the incidence of omphalitis in Oman. A decrease in home deliveries resulted in a decrease in the spectrum and severity of omphalitis.

17. Janssen PA, Selwood BL, Dobson SR, et al. To dye or not to dye: a randomized, clinical trial of a triple dye/alcohol regime versus dry cord care. Pediatrics 2003; 111:15—20. •

18. Buescher ES. Community-acquired methicillin-resistant Staphylococcus aureus in pediatrics. Curr Opin Pediatr 2005; 17:67—70. This is an excellent review of MRSA as an emerging problem in children.

19. Arkwright PD, Daniel TO, Sanyal D, et al. Age-related prevalence and antibiotic resistance of pathogenic staphylococci and streptococci in children with infected atopic dermatitis at a single-specialty center. Arch Dermatol 2002; 138:939—941. ••

20. Conner JM, Soll RF, Edwards WH. Topical ointment for preventing infection in preterm infants. Cochrane Database Syst Rev 2004:CD001150. This meta-analysis examines the role of prophylactic application of emollients in infants. The reviewed studies were all conducted in industrialized countries, and the results may thus not be as applicable to developing countries. ••

21. Darmstadt GL, Saha SK, Ahmed AS, et al. Effect of topical treatment with skin barrier-enhancing emollients on nosocomial infections in preterm infants in  Bangladesh: a randomised controlled trial. Lancet 2005; 365:1039—1045. This is one of the first studies to examine the role of topical emollients in the prevention of sepsis. A culturally sensitive emollient such as sunflower oil in Bangladesh may be a simple and effective measure to prevent sepsis. •

22. Darmstadt GL, Badrawi N, Law PA, et al. Topically applied sunflower seed oil prevents invasive bacterial infections in preterm infants in Egypt: a randomized, controlled clinical trial. Pediatr Infect Dis J 2004; 23:719—725. This study was conducted in Egypt and showed that topical therapy with emollients may be a cost-effective measure to prevent sepsis in developing countries.

23. de Jager MW, Gooris GS, Dolbnya IP, et al. Novel lipid mixtures based on synthetic ceramides reproduce the unique stratum corneum lipid organization. J Lipid Res 2004; 45:923—932.

24. Segreti J. Efficacy of current agents used in the treatment of Gram-positive infections and the consequences of resistance. Clin Microbiol Infect 2005; 11(Suppl 3): 29—35. •

25. Mangili A, Bica I, Snydman DR, et al. Daptomycin-resistant, methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2005; 40:1058— 1060. This article describes a new antibiotic that may become applicable for bacterial cutaneous infections in newborns.

26. Anstead GM, Owens AD. Recent advances in the treatment of infections due to resistant Staphylococcus aureus. Curr Opin Infect Dis 2004; 17:549— 555.