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The role of Staphylococcus epidermidis in neonatal sepsis: Guarding angel or pathogenic devil?

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Abstract

Neonatal late-onset sepsis (LOS) is a serious problem in neonatal intensive care. Coagulase-negative staphylococci, especially Staphylococcus epidermidis, have emerged as the predominant pathogen of LOS in very low birth weight (VLBW) infants, accounting for up to 77.9% of neonatal LOS in industrialized countries and 46.5% in some developing regions. VLBW neonates with indwelling medical devices are most susceptible for S. epidermidis sepsis, the incidence rate of which is approximately 25%. However, S. epidermidis primarily plays a commensal role on human host and is of evolutionary importance to newborns, by inhibiting virulent pathogens and educating the innate immune system. Recent advances in molecular microbiology show that S. epidermidis is a bacterial species equipped with remarkable genetic flexibility, and can employ a multitude of mechanisms to become adapted to the changing environment. Extrinsic factors in the neonatal ward, such as the interruption of skin barrier by medical devices and the selective pressure due to antibiotics, contribute to the conversion of S. epidermidis from a member of the skin microflora to an infectious agent. Furthermore, neonates are predisposed for S. epidermidis infections due to their distinct immunological characteristics. A better understanding of the dichotomy of S. epidermidis and the underlying mechanisms may inspire new anti-infectious strategies.

Introduction

Advances in neonatal intensive care have dramatically reduced the mortality rate of premature infants during the last two decades [Sweet et al., 2013]. However, the increasing survival of preterm infants is complicated by a growing burden of short-term and long-term problems associated with nosocomial infections [Marchant et al., 2013]. The last two decades have seen coagulase-negative staphylococci (CONS), especially Staphylococcus epidermidis, emerge as the predominant pathogen responsible for neonatal late-onset sepsis mainly in industrialized countries [Bizzarro et al., 2005, Marchant et al., 2013]. S. epidermidis is permanently present in the nosocomial environment and can disseminate widely among hospitals in different regions, adding to the morbidity, mortality and medical cost [Strunk et al., 2007, Power Coombs et al., 2013]. The evolving paradigm of S. epidermidis sepsis is a significant change from the traditionally held view, which envisioned S. epidermidis as a harmless skin inhabitant. Interdisciplinary collaborations at the interface of microbiology and immunology have generated new insights into the nature of S. epidermidis, showing that S. epidermidis mostly engages itself in a beneficial way in host defense and immune maturation, but may adopt an infectious lifestyle under certain circumstances [Cogen et al., 2008, Otto, 2009]. A thorough and comprehensive understanding of how S. epidermidis successfully establishes itself as the most widespread pathogen in the nosocomial environment may help to expand our armamentarium of anti-infectious strategies.

Section snippets

Clinical aspects of S. epidermidis neonatal sepsis

Neonatal sepsis is one of the leading causes of neonatal death [Qazi and Stoll, 2009]. Early-onset sepsis (EOS), reflecting trans-placental, or more frequently, ascending infections from the maternal genital tract, occurs within 72 h of age [Behrman et al., 2004]. In contrast, late-onset sepsis (LOS) is associated with the postnatal healthcare environment and usually presents after 72 postnatal hours, with the peak incidence between the 15th and 17th day of life [Stoll et al., 2002, Hira et al.,

The beneficial function of S. epidermidis on neonates

S. epidermidis normally maintains a benign relationship with the host and primarily has not evolved to become a pathogen [Otto, 2009]. In contrast to the abundant information on the infectious role of S. epidermidis, our understanding of the beneficial role of S. epidermidis on neonates is considerably limited. S. epidermidis colonizes on the skin immediately after birth, and rapidly dominates the microflora of various body sites within the first month of life [Capone et al., 2011]. Although

S. epidermidis as a pathogen in neonatal sepsis

Nosocomial factors, such as the disruption of the skin barrier by medical devices and the selection pressure due to the widespread use of antibiotics, may drive the conversion of S. epidermidis from a mutualistic microbe toward a pathogen [Otto, 2009]. Epidemiological studies in the past decade showed that the dissemination of S. epidermidis in hospitals including neonatal wards was attributable to several clonal lineages [Kozitskaya et al., 2004, Hira et al., 2007, Klingenberg et al., 2007, Li

Neonatal immune response to S. epidermidis

It is widely believed that the susceptibility of neonates to nosocomial sepsis arises, at least in part, from an immature immunity, marked by deficiencies in numerous components of the immune system. However, this view is challenged by accumulating evidence which demonstrates that the neonatal immune system is not simply immature, but rather specifically regulated for the early postnatal life [Ghazal et al., 2013, Levy and Wynn, 2014]. A highly tolerant immune reaction, characterized by

Therapeutic prospect of neonatal sepsis caused by S. epidermidis

The dual role of S. epidermidis as both a beneficial symbiont and a potential pathogen, the dwindling arsenal of antibiotics to combat increasingly resistant bacteria and the particularities of the neonatal immune system are major factors contributing to the difficulties in treatment of S. epidermidis sepsis. Eradication of S. epidermidis from skin would be undesirable and even counterproductive, given the beneficial functions of S. epidermidis in defending against other pathogens and educating

Conclusion

As the predominant component of human skin microbiome, S. epidermidis contributes fundamentally to the well-being of neonates, and the immune system has evolved to tolerate S. epidermidis on the uppermost layer of body. However, several extrinsic factors associated with the nosocomial environment may disturb this delicate host-microbe balance, resulting in a lifestyle conversion of S. epidermidis from mutualism to pathogenicity. In other words, the very interventions used to treat premature

Acknowledgements

Dr Ying Dong received a scholarship under the State Scholarship Fund organized by the China Scholarship Council (CSC) (No. 201308500098).

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    Present address: Children's Hospital of Fudan University, Shanghai, China.

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