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Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 586076, 10 pages
http://dx.doi.org/10.1155/2013/586076
Review Article

Neonatal Sepsis due to Coagulase-Negative Staphylococci

1Child and Family Research Institute, 4th Floor, Translational Research Building, 950 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4
2Department of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1ZA
3Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada V6T 1ZA
4Department of Pediatrics, Children’s Hospital, University of Oxford, Oxford OX3 9DU, UK

Received 12 March 2013; Revised 27 April 2013; Accepted 27 April 2013

Academic Editor: Robert Bortolussi

Copyright © 2013 Elizabeth A. Marchant et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neonates, especially those born prematurely, are at high risk of morbidity and mortality from sepsis. Multiple factors, including prematurity, invasive life-saving medical interventions, and immaturity of the innate immune system, put these infants at greater risk of developing infection. Although advanced neonatal care enables us to save even the most preterm neonates, the very interventions sustaining those who are hospitalized concurrently expose them to serious infections due to common nosocomial pathogens, particularly coagulase-negative staphylococci bacteria (CoNS). Moreover, the health burden from infection in these infants remains unacceptably high despite continuing efforts. In this paper, we review the epidemiology, immunological risk factors, diagnosis, prevention, treatment, and outcomes of neonatal infection due to the predominant neonatal pathogen CoNS.

1. Epidemiology of Neonatal Sepsis

Neonatal sepsis is defined as infection in the first 28 days of life, or up to 4 weeks after the expected due date for preterm infants [1]. Epidemiologists defined two types of infections in neonates: early-onset neonatal sepsis (EONS), which manifests in the first 72 hours of life (up to 7 days) and late-onset neonatal sepsis (LONS), whose incidence peaks in the 2nd to 3rd week of postnatal life [1]. The mortality from neonatal sepsis has dramatically decreased over the last century, because of medical advances. In the preantibiotic era (<1940), the case fatality rate of neonatal sepsis was extremely high, exceeding 80% [2]. By the late 1960s, the introduction of antibiotics and the development of modern perinatal care had lowered this case fatality rate to less than 20% overall [2]. The composition of pathogens causing neonatal sepsis has also changed dramatically over the last century [26]. In the early 1930s, Streptococcus pneumoniae and group A streptococci were responsible for almost half of the cases of LONS [2, 3]. By the 1960s, gram-negative bacilli had become major pathogens [3], along with the emergence of group B streptococci (GBS) as a predominant cause of EONS [2]. In North America, gram-positive organisms account for the majority of neonatal sepsis cases (up to 70%). Sepsis due to gram-negative organisms (~15 to 20%) and fungi (~10%) is less common, and polymicrobial bloodstream infections contribute to less than 15% of cases [2, 7, 8]. Coagulase-negative staphylococci (CoNS) are the major pathogen involved in LONS, particularly in infants born at a lower gestational age. According to more recent data from the National Institutes of Child Health and Development (NICHD), infection-related mortality in very low-birth-weight (VLBW) infants (birth weight < 1500 grams) averages 10% [7] but can reach 40% depending on the pathogen involved [911]. Preterm neonates have a high risk of developing neonatal infections, resulting in high mortality and serious long-term morbidities [5, 7, 12]. In North America, it is estimated that each episode of sepsis prolongs the duration of a neonate’s hospital stay by about 2 weeks, resulting in an incremental cost of USD$25,000 per episode [13]. In a more recent study, authors estimated that nosocomial bloodstream infections increase the neonatal hospitalization cost for VLBW infants in the lowest birth weight group (401–750 grams) by 26%, and that of the highest birth weight group (1251–1500 grams) by 80% [14]. This study also estimated that the duration of hospital stay increased by four to seven days in all VLBW categories with a nosocomial bloodstream infection [14].

1.1. Burden of Neonatal Sepsis in Developing Countries

In developed countries, advances in medical care have enabled a greater proportion of premature infants to survive, albeit with an increased risk of infection [15]. However, because the greatest burden of neonatal sepsis falls on low-resource developing countries, the global economic impact is difficult to estimate [16]. Globally, infections still cause an estimated 1.6 million neonatal deaths annually, representing 40% of all neonatal deaths [1618]. About 12% of children are born prematurely worldwide, including about 2% of VLBW. Together, prematurity and neonatal infections account for the greatest burden of neonatal deaths overall [16]. The limited access to medical resources combined with geographical comorbidities (e.g., severe malnutrition) can lead to mortality from neonatal sepsis remaining unacceptably high in developing countries [16].

2. Pathogenesis

Within the first week of life, neonates become rapidly colonized by microorganisms originating from the environment [1922]. During this period, the risk of CoNS infection increases substantially with the use of central venous catheters (CVC), mechanical ventilation, and parenteral nutrition, and with exposure to other invasive skin- or mucosa-breaching procedures [8, 15, 2328]. CoNS are common inhabitants of the skin and mucous membranes; although a small proportion of neonates acquire CoNS by vertical transmission, acquisition primarily occurs horizontally [22, 29]. Consequently, infants admitted to a hospital obtain most of their microorganisms from the hospital environment, their parents, and staff [30, 31]. Transmission via the hands of hospital staff can lead to endemic strains circulating for extended periods [29, 3235]. Because CoNS is a ubiquitous skin commensal, authors have assumed that colonizations of the skin and of indwelling catheters are important sources of sepsis [34, 36]. However, recent studies suggest that epithelial loci other than the skin, such as the nares, may be important access points of infection [34, 36]. Antibiotic resistance in skin-residing strains has been found to be low at birth but to increase rapidly during the first week of hospitalization [37]. Selective pressure as a result of perinatal antibiotic exposure, therefore, is an additional major factor influencing the spectrum and antibiotic resistance pattern of microorganisms isolated from neonates.

2.1. Host Immunological Factors

Some components of the immune response are particularly important in preventing sepsis due to CoNS (reviewed in [38]). The immune system is traditionally described in terms of the innate and the adaptive immune systems. The innate immune system is responsible for the “naïve,” more rapid, first-line response to infection. At birth, the neonate’s own adaptive immune system is largely uneducated. To protect against infection, neonates must therefore rely heavily on innate immune responses and on passive adaptive immune mechanisms acquired from the mother (e.g., transplacental transfer of antibodies), which are deficient in preterm neonates [3943]. Specific host innate immune factors have been studied in the context of neonatal CoNS infections: mucosal barriers, including antimicrobial peptides (AMP), cells (neutrophils), and pattern recognition receptors (PRR, e.g., Toll-like receptors), as detailed below.

2.1.1. Mucosal Barriers

The outermost layer of the skin (stratum corneum) acts as a physical barrier and first line of defense against bacterial invasion. The skin secretes AMP, which are early-response factors creating a microbicidal shield particularly effective against CoNS [4348]. In preterm neonates, the immature stratum corneum only fully matures at one to two weeks after birth [42, 43, 46]. The vernix caseosa, a waxy coating on neonates’ skin, provides additional antimicrobial protection in mature neonates. It is mainly formed during the last trimester of gestation, leaving extremely premature neonates far more vulnerable to infection [4951]. Immunity against CoNS is also limited in other mucosal surfaces in preterm neonates, for example, because of a thinner glycocalyx layer coating the intestinal epithelium [52, 53], lower secretory IgA [53], and reduced AMP production by Paneth cells [5456]. Necrotizing enterocolitis (NEC) is a progressive ischemic necrosis of the neonatal intestine that occurs in preterm infants [57]. The cause of NEC is unclear but is believed to develop as a result of gut injury, with a key role for bacteria in its pathogenesis [5759]. Frequent isolation of enterotoxin-producing CoNS from the intestinal flora of infants with NEC has led authors to propose that overgrowth of CoNS plays a role in this complication [6062]. A poor barrier function and an overall immaturity of the premature gastrointestinal immune system [63, 64] contribute largely to the development of NEC, possibly by favoring bacterial overgrowth and translocation [57, 63, 65].

2.1.2. Cells

Neutrophils also play a major role in protection against neonatal sepsis, including CoNS, as first-responder leukocytes in the blood [6669]. Certain characteristics of neonatal neutrophils have been proposed as mechanisms of increased susceptibility to CoNS sepsis [70]: their relatively inefficient recruitment and extravasation to the site of infection [69]; their reduced bacterial killing capacity, in part due to the failure to upregulate their oxidative burst response [71]; and the reduced ability of neonatal neutrophils to form “extracellular traps” [50].

2.1.3. Pattern Recognition Receptors

PRR detect the presence of microorganisms in the tissue through the recognition of conserved molecular structures specific to microbes (known as pathogen-associated molecular patterns: PAMP). To date, the best characterized PRR are the Toll-like receptors (TLR), which include ten receptors in humans [7275]. Recent studies in mice have suggested that Toll-like receptor 2 (TLR2), an extracellular member of the TLR family, plays an important role in the immune recognition of CoNS [76]. Additionally, S. epidermidis induces an upregulation of TLR2 and MyD88, and a systemic increase in proinflammatory cytokines (e.g., interleukin (IL)-6) [77]. As inflammatory stimuli, the PAMP produced by the gram-positive CoNS are less potent than PAMP expressed at the surface of gram-negative bacteria (e.g., lipopolysaccharide, LPS). However, the most prevalent clinical isolate of CoNS, S. epidermidis, is known to produce a complex of bacterial peptides called phenol-soluble modulins, which induce a considerable proinflammatory response through TLR2 [7880]. Interestingly, activation of TLR2 by a yet unidentified product of S. epidermidis triggers the enhanced production of the human AMP family of -defensins from keratinocytes and underscores a potential role of AMP in the control of staphylococcal infections [81, 82]. Reliance on TLR-induced CoNS immunity has important implications, since preterm neonates exhibit marked defects in TLR signaling cascades and cytokine responses [39, 83]. Indeed, monocytes of premature neonates display a gestational age-dependent reduction in TLR-induced production of proinflammatory cytokines [84], whereas other monocyte functions related to phagocytosis and intracellular bacterial killing develop earlier, well before 30 weeks of gestation [85].

2.2. Bacterial Virulence Factors

CoNS lacks several of the virulence factors shared with the closely related species S. aureus [31]. Compared with S. aureus, S. epidermidis produces lower levels of cytolytic toxins [86]. Therefore, S. epidermidis must rely on other mechanisms, such as biofilms and the anionic polymer poly- -DL-glutamic acid (PGA) to evade hosts’ immune responses.

Biofilm formation serves as the primary mode of immune evasion of CoNS [87]. These multilayered bacterial aggregates strongly adhere to inanimate objects such as indwelling medical devices. CoNS are particularly adept at biofilm formation, and this capacity is a key mechanism of their pathogenesis, particularly in relation to catheter-related infections [88, 89]. Biofilms act as nonselective physical barriers that obstruct antibiotic diffusion and hinder the cellular and humoral host immune responses [86, 9093]. In addition, biofilms provide protection from antimicrobial therapy [30, 31, 94, 95]. Poly-N-acetylglucosamine surface polysaccharide, also termed polysaccharide intercellular adhesin (PIA), is crucial in facilitating cellular aggregation during biofilm formation and is the most extensively studied biofilm molecule [31, 90]. In rat models, PIA defective mutants have been shown to exhibit decreased virulence [31]. Lack of PIA in S. epidermidis results in mutants susceptible to phagocytosis and killing by human neutrophils as well as enhanced AMP susceptibility [92]. Additionally, the expression of an ATP-binding cassette transporter allows for the export of AMP out of the bacterial cell, thus contributing to AMP resistance [86, 96]. Other components help CoNS evade immune defenses; for example, a glutamyl endopeptidase from S. epidermidis is expressed specifically in biofilms and degrades the complement-derived chemoattractant C35 [31].

The secreted anionic extracellular polymer PGA also plays an important role in immune evasion of S. epidermidis [91]. However, PGA is not specific to S. epidermidis, and is also secreted by other staphylococcal species and Bacillus strains [91, 97]. PGA appears to play an important role in the persistence of S. epidermidis colonization on medical devices [91]. Moreover, PGA contributes to resistance against phagocytosis and microbicidal action of AMP like LL-37 and human β-defensin 3, as demonstrated by increased susceptibility to neutrophils and AMP activity; however, the precise mechanisms of this PGA-mediated resistance remain unclear [91]. To avoid antistaphylococcal human AMP, S. epidermidis is also equipped with resistance mechanisms such as the Aps (antimicrobial peptide sensing) system and the AMP-degrading protease SepA [86, 96].

Finally, bacteria have multiple creative antibiotic resistance mechanisms, including modification of target structures (e.g., altered penicillin-binding proteins in staphylococci) and production of antibiotic-inactivating enzymes (e.g., beta-lactamases to hydrolyze penicillins, cephalosporins and/or carbapenems). Genes encoding proteins responsible for these mechanisms often reside on mobile genetic elements, enabling transfer of resistance between bacteria of the same or different species. In a recent study, authors proposed that CoNS may be a significant reservoir of methicillin resistance genes that can be transferred horizontally to other common related neonatal pathogens such as S. aureus [98].

3. Diagnosis

Neonatal sepsis is clinically diagnosed by a combination of clinical signs, nonspecific laboratory tests and microbiologically confirmed by detection of bacteria in blood by culture. Clinical signs of sepsis in neonates are usually nonspecific and often inconspicuous. They include the presence of fever or hypothermia (in the preterm neonate, this is more commonly seen as a general disturbance in thermoregulation); lethargy; poor feeding; respiratory distress or apnea; pallor; jaundice; tachycardia or bradycardia; hypotension; disturbances in gastrointestinal function (diarrhea, bloody stools, abdominal distention, and ileus); and thrombocytopenia [30, 31, 99, 100]. With CoNS, such clinical signs are often more subtle because of the low virulence of these organisms. However more serious, often persistent illness due to more virulent strains can occur in a considerable minority of cases, in association with severe thrombocytopenia [101].

The gold standard for diagnosis of neonatal sepsis remains blood culture. However, in many situations this test is fraught with practical problems, including the small blood volumes obtainable, especially in the smallest of preterm neonates. Indeed, this volume is often below the recommended 1 mL lower limit of detection, leading to a high proportion of false negative test results [102105]. Conversely, the nonspecific nature of clinical signs in neonates probably leads to frequent overuse of broad-spectrum antibiotics with the potential to select for resistant bacteria and fungi, especially in preterm neonates. Therefore, there is a great need for better rapid diagnostic tests to differentiate infants with sepsis from those who are sick from other causes.

Hematological indices (e.g., numbers of white blood cells, neutrophils, platelets) [106] and biochemical markers of inflammation, such as C-reactive protein [107], and procalcitonin [108] are routinely used in clinical practice and can aid in the diagnosis of neonatal sepsis. This is particularly useful in cases of persisting clinical symptoms and in the absence of a confirmatory positive blood culture, or in situations where localized sources of infection are being considered [105]. Furthermore, the abundance of CoNS as a natural skin commensal often leads to blood culture contamination and a subsequent overestimation of neonatal sepsis cases [109, 110].

CVC, which are often used in smallest preterm neonates, provide a sanctuary for CoNS, leading to persistence of an infection. A number of methods to determine if the CVC is the source of an infection have been suggested, including observing a positive culture from the CVC but not from a peripheral site [111, 112] and reduced “time to positivity” of a CVC culture (as opposed to a peripheral site). A higher bacterial load in the CVC [113, 114] and a three- to fivefold differential magnitude of colony-forming units between a quantitative CVC and peripheral culture are indicative of a CVC as the primary focus of infection [99, 115]. However, these methods are impractical when applied to neonates. The small lumen size of the CVC makes removal of blood, and therefore CVC culture, impossible in most cases. Furthermore, any comparison of CVC and peripheral cultures would rely on identical sample volumes from both sites being taken and processed at exactly the same time, which is often not feasible.

In the future, new diagnostic technologies involving microfluidics may considerably reduce the amount of blood volumes required for diagnosis [116]. At present, the relatively high cost of this technique limits its routine use in the clinical setting [117]. In some instances, polymerase chain reaction (PCR) can be useful to characterize subspecies [118, 119]. Adjunctive use of nucleic acid-based technologies with blood cultures can facilitate a faster diagnostic turnaround time and easier antibiotic susceptibility profile identification. Molecular typing techniques, such as pulsed field gel electrophoresis and multilocus sequence typing [99], are also useful in subspecies differentiation [120]. PCR-based diagnostic methods may be most useful clinically in the short term by providing clinicians with the ability to detect the presence of genetic markers of antibiotic resistance [118].

4. Prevention and Treatment

4.1. Prevention

In the hospital setting, the mainstay of prevention against neonatal sepsis includes strict hand-washing practices; careful aseptic procedures in the management of intravenous lines; skin care; judicious use of antibiotics; promoting early enteral (as opposed to parenteral) nutrition, preferably using breast milk (i.e., to enhance the infant’s own gastrointestinal immune defenses); and minimizing invasive interventions (e.g., prompt removal of CVCs, reducing mechanical ventilation) [7, 121123]. Hand washing is a widely accepted and cost-effective measure to decrease the occurrence of nosocomial infections including CoNS [15, 124127]; yet universal compliance is difficult to achieve [3]. Minimizing the indwelling time and number of CVCs decreases the risk of CoNS and other pathogens of LONS [15, 128]. In some studies, more than half of all cases of CoNS sepsis occurred while indwelling CVCs were in place [129]. The number of central lines experienced by the neonate from birth, rather than the duration of insertion, was an important predictor of CoNS sepsis [28]. Some authors have proposed the use of prophylactic antibiotics immediately before and for 12 hours after removal of a CVC in preterm neonates [129].

Clinical trials of vancomycin added to parenteral nutrition solutions have demonstrated decreases in the incidence of CoNS sepsis in preterm neonates [130, 131], without reduction in mortality or duration of hospital stay [132]. Others have proposed using antibiotic-coated devices for CVC [133135]. However, these measures carry a risk of increasing antimicrobial resistance and have not been universally adopted. Antimicrobial “locks,” that is, leaving a microbicidal substance within the catheters in between administration of other drugs represents another proposed solution to decrease bacterial colonization. Antiseptics (e.g., alcohol, taurolidine), anticoagulants (e.g., heparin, EDTA), and antibiotics (e.g., vancomycin, rifamycin) have all been studied [105, 136139]. Two studies reported a reduction in catheter-related sepsis in critically ill neonates through the use of either fusidic acid and heparin, or vancomycin locks [140, 141]. The benefit of antibiotic lock over prophylactic antibiotic administration is the avoidance of systemic effects of antibiotics in the patient, since the solution remains within the catheter. A similar measure incorporates antiseptic-impregnated catheters to decrease cutaneous bacterial load and catheter colonization [134, 135, 139, 142]. However, clinical experience with these methods is very limited in VLBW infants. In the absence of more definitive evidence, the standard of care is to use strict hand hygiene and skin antisepsis protocols prior to, during, and after catheter insertion [8, 143].

4.2. Treatment

The subtle, nonspecific nature of clinical signs and the rapid progression of neonatal sepsis make prompt diagnosis and antibiotic treatment crucial. Any delay in antimicrobial therapy places a neonate with sepsis at greater risk of mortality. Empirical antibiotic therapy should be based on knowledge of local epidemiology and antibiotic resistance patterns of neonatal sepsis, since geographic variation can be influential. Because colonization of infants with CoNS is unusual in the first 48 hours after birth, the preferred empirical treatment of EONS is mainly based on the use of ampicillin and gentamicin to cover more predominant GBS and gram-negative bacilli, and, to a lesser extent, L. monocytogenes. For LONS, administration of antistaphylococcal penicillin (e.g., oxacillin) or an alternative agent such as vancomycin is indicated. The advantage of a penicillin is the low toxicity and potent in vivo bactericidal activity, even in difficult infections such as endocarditis [30, 31]. In areas with widespread beta-lactam resistance in CoNS and/or a high prevalence of methicillin-resistant S. aureus, vancomycin is often preferred [144]. Although not as bactericidal as oxacillin, little resistance has been reported to vancomycin. Considerable rates of gram-negative organisms in LONS dictate that empirical treatment cannot consist solely of antistaphylococcal antibiotics. Therefore, aminoglycosides are frequently used in addition, as in EONS, and may have a synergistic antistaphylococcal effect when administered with penicillins and vancomycin, although the in vivo significance of this is not entirely clear [145147]. Linezolid, another class of antibiotics, possesses potent antistaphylococcal activity comparable to that of vancomycin, with little reported resistance [148, 149]. Once culture results are available, antibiotics can be modified to specifically target the isolated pathogen according to the results of susceptibility testing.

The presence of a CVC or other indwelling foreign material is highly associated with persistence of infection despite appropriate antibiotic therapy, because of biofilm formation. In vivo antibiotic action is also antagonized by the neutralization of pharmaceuticals like vancomycin by the polysaccharides of CoNS biofilms [150]. In addition, the low metabolic activity of biofilms limits the activity of many antibiotics which require rapid metabolism of growing bacteria to exert their microbicidal effect [151]. Antibiotic resistance and biofilm formation are among selective factors for the persistence of endemic nosocomial strains and probably contribute to the predominance of S. epidermidis and S. haemolyticus as clinical isolates on NICU infants [37, 100, 152]. In such cases, it may be imperative to remove the CVC.

5. Long-Term Sequelae

Multiple studies show that neonatal sepsis has major long-term neurodevelopmental consequences in survivors, particularly in preterm infants [153]. In modern intensive care, about half of extremely preterm neonates born at 24 weeks’ gestation and the majority of neonates over 25 weeks’ gestation generally survive [154]. The risk of such morbidity in extremely premature neonates is inversely proportional to their gestational age [4, 155158]. In VLBW infants, neonatal sepsis dramatically increases the long-term risk of motor, cognitive, neurosensory and visual impairments [157159]. The risk of adverse neurodevelopmental outcome in VLBW neonates with sepsis is further increased with other comorbidities such as bronchopulmonary dysplasia [157, 160]. This increased risk of neurodevelopmental impairment in preterm infants with sepsis has several reasons, including a high risk of meningitis; heightened adverse effect of sepsis-associated cardiovascular instability during a vulnerable period for the developing brain; and increased neurotoxic effects of inflammatory mediators [153]. Surprisingly, the risk of adverse neurodevelopmental outcome in VLBW infants surviving from neonatal sepsis does not appear to depend on the infecting organism [157], although in some studies extremely premature infants who experienced sepsis had a greater risk of a hearing impairment when the infection involved gram-negative, fungal, or combined infections [157].

6. Future Therapies

Despite limited natural antibody immune protection in preterm neonates, meta-analyses of intravenous immunoglobulin administration have so far failed to demonstrate sufficient therapeutic benefits [31, 161163]. Other immunomodulatory therapies designed to improve neonatal immune deficits, such as granulocyte transfusions, or administration of granulocyte-macrophage colony stimulating factor which increases neutrophils and enhances their antimicrobial activity, have also not yet translated into concrete benefits in clinical trials [161]. Finally, lactoferrin, an antimicrobial glycoprotein that sequesters iron, may be useful in reducing the incidence of late-onset sepsis in low-birth-weight neonates [164]. The future of antistaphylococcal immunotherapy and immunoprophylaxis requires more research. This may require a combined use of adjunctive immunomodulatory treatments to enhance the innate immune system of neonates while disabling virulence factors that enable resistance to conventional antibiotic treatment of CoNS.

7. Conclusion

The 20th century saw CoNS emerge as the foremost pathogen of neonatal sepsis in developed countries. VLBW neonates contribute disproportionately to CoNS-related morbidity and mortality, in stark contrast to their full-term counterparts who usually suffer milder symptoms. Several reasons make prematurity the single most important factor for neonatal sepsis: innate immunological deficiencies; prolonged stays in the NICU; and, notably, the higher use of indispensable but invasive medical interventions in these developmentally immature neonates. Advances in medical technology have dramatically increased the survival rate of premature neonates. This corresponds to a growing burden of both short- and long-term problems associated with neonatal sepsis. Effective prophylactic measures, prompt and accurate diagnoses, and subsequent administration of targeted therapy are vital to curb the excessive burden of disease that CoNS infection imposes upon this highly vulnerable age group.

Authors’ Contribution

E. A. Marchant and G. K. Boyce contributed equally to this paper.

Acknowledgments

The authors thank Rosemary Delnavine for revising the paper. G. Boyce is supported by a graduate studentship from the BC Transplant Training Program. P. M. Lavoie is supported by a Clinician-Scientist Award from the Child & Family Research Institute and a Career Investigator Award from the Michael Smith Foundation for Health Research.

References

  1. S. A. Qazi and B. J. Stoll, “Neonatal sepsis: a major global public health challenge,” The Pediatric Infectious Disease Journal, vol. 28, supplement 1, pp. S1–S2, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. M. J. Bizzarro, C. Raskind, R. S. Baltimore, and P. G. Gallagher, “Seventy-five years of neonatal sepsis at Yale: 1928–2003,” Pediatrics, vol. 116, no. 3, pp. 595–602, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. L. G. Donowitz, “Nosocomial infection in neonatal intensive care units,” American Journal of Infection Control, vol. 17, no. 5, pp. 250–257, 1989. View at Scopus
  4. B. J. Stoll, N. I. Hansen, E. F. Bell et al., “Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network,” Pediatrics, vol. 126, no. 3, pp. 443–456, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. B. J. Stoll, N. Hansen, A. A. Fanaroff et al., “Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants,” The New England Journal of Medicine, vol. 347, no. 4, pp. 240–247, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. S. Vergnano, E. Menson, N. Kennea et al., “Neonatal infections in England: the neonIN surveillance network,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 96, no. 1, pp. F9–F14, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. B. J. Stoll, N. Hansen, A. A. Fanaroff et al., “Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network,” Pediatrics, vol. 110, no. 2, part 1, pp. 285–291, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. P. L. Graham, M. D. Begg, E. Larson, P. Della-Latta, A. Allen, and L. Saiman, “Risk factors for late onset gram-negative sepsis in low birth weight infants hospitalized in the neonatal intensive care unit,” The Pediatric Infectious Disease Journal, vol. 25, no. 2, pp. 113–117, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. C. P. Hornik, P. Fort, R. H. Clark et al., “Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units,” Early Human Development, vol. 88, supplement 2, pp. S69–S74, 2012. View at Publisher · View at Google Scholar
  10. I. R. Makhoul, P. Sujov, T. Smolkin, A. Lusky, and B. Reichman, “Pathogen-specific early mortality in very low birth weight infants with late-onset sepsis: a national survey,” Clinical Infectious Diseases, vol. 40, no. 2, pp. 218–224, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. E. J. Weston, T. Pondo, M. M. Lewis et al., “The burden of invasive early-onset neonatal sepsis in the United States, 2005–2008,” The Pediatric Infectious Disease Journal, vol. 30, no. 11, pp. 937–941, 2011.
  12. T. M. O'Shea, “Cerebral palsy in very preterm infants: new epidemiological insights,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 8, no. 3, pp. 135–145, 2002. View at Publisher · View at Google Scholar · View at Scopus
  13. J. E. Gray, D. K. Richardson, M. C. McCormick, and D. A. Goldmann, “Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome,” Pediatrics, vol. 95, no. 2, pp. 225–230, 1995. View at Scopus
  14. N. R. Payne, J. H. Carpenter, G. J. Badger, J. D. Horbar, and J. Rogowski, “Marginal increase in cost and excess length of stay associated with nosocomial bloodstream infections in surviving very low birth weight infants,” Pediatrics, vol. 114, no. 2, pp. 348–355, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. I. Adams-Chapman and B. J. Stoll, “Prevention of nosocomial infections in the neonatal intensive care unit,” Current Opinion in Pediatrics, vol. 14, no. 2, pp. 157–164, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. UNICEF, The State of the World’s Health 2009: Maternal and Newborn Health, 2009.
  17. WHO, World Heath Statistics: 2010, 2010.
  18. L. Liu, H. L. Johnson, S. Cousens et al., “Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000,” The Lancet, vol. 379, no. 9832, pp. 2151–2161, 2012.
  19. M. T. Brady, “Health care-associated infections in the neonatal intensive care unit,” American Journal of Infection Control, vol. 33, no. 5, pp. 268–275, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. D. A. Goldmann, “Bacterial colonization and infection in the neonate,” The American Journal of Medicine, vol. 70, no. 2, pp. 417–422, 1981.
  21. R. D. Feigin, J. Cherry, G. Demmler, and S. Kaplan, Textbook of Pediatric Infectious Diseases. Volume 1, Saunders (Elsevier), Philadelphia, Pa, USA, 2004.
  22. S. L. Hall, S. W. Riddell, W. G. Barnes, L. Meng, and R. T. Hall, “Evaluation of coagulase-negative staphylococcal isolates from serial nasopharyngeal cultures of premature infants,” Diagnostic Microbiology and Infectious Disease, vol. 13, no. 1, pp. 17–23, 1990. View at Publisher · View at Google Scholar · View at Scopus
  23. A. H. Sohn, D. O. Garrett, R. L. Sinkowitz-Cochran et al., “Prevalence of nosocomial infections in neonatal intensive care unit patients: results from the first national point-prevalence survey,” Journal of Pediatrics, vol. 139, no. 6, pp. 821–827, 2001. View at Publisher · View at Google Scholar · View at Scopus
  24. F. Bolat, S. Uslu, G. Bolat et al., “Healthcare-associated infections in a Neonatal Intensive Care Unit in Turkey,” Indian Pediatrics, vol. 49, no. 12, pp. 951–957, 2012.
  25. J. Freeman, D. A. Goldmann, N. E. Smith, D. G. Sidebottom, M. F. Epstein, and R. Platt, “Association of intravenous lipid emulsion and coagulase-negative staphylococcal bacteremia in neonatal intensive care units,” The New England Journal of Medicine, vol. 323, no. 5, pp. 301–308, 1990. View at Scopus
  26. A. C. V. Távora, A. B. Castro, M. A. M. Militão, J. E. Girão, K. D. C. Ribeiro, and L. G. F. Távora, “Risk factors for nosocomial infection in a Brazilian neonatal intensive care unit,” The Brazilian Journal of Infectious Diseases, vol. 12, no. 1, pp. 75–79, 2008.
  27. D. Isaacs, C. Barfield, T. Clothier et al., “Late-onset infections of infants in neonatal units,” Journal of Paediatrics and Child Health, vol. 32, no. 2, pp. 158–161, 1996. View at Scopus
  28. C. M. Healy, C. J. Baker, D. L. Palazzi, J. R. Campbell, and M. S. Edwards, “Distinguishing true coagulase-negative Staphylococcus infections from contaminants in the neonatal intensive care unit,” Journal of Perinatology, vol. 33, no. 1, pp. 52–58, 2013.
  29. C. H. Patrick, J. F. John, A. H. Levkoff, and L. M. Atkins, “Relatedness of strains of methicillin-resistant coagulase-negative Staphylococcus colonizing hospital personnel and producing bacteremias in a neonatal intensive care unit,” The Pediatric Infectious Disease Journal, vol. 11, no. 11, pp. 935–940, 1992. View at Scopus
  30. J. Huebner and D. A. Goldmann, “Coagulase-negative staphylococci: role as pathogens,” Annual Review of Medicine, vol. 50, pp. 223–236, 1999. View at Publisher · View at Google Scholar · View at Scopus
  31. J. S. Remington, J. O. Klein, C. B. Wilson, V. Nizet, and Y. A. Maldonado, “Staphylococcal infections,” in Infectious Diseases of the Fetus and Newborn, pp. 489–505, Saunders (Elsevier), Philadelphia, Pa, USA, 2011.
  32. J. Huebner, G. B. Pier, J. N. Maslow et al., “Endemic nosocomial transmission of Staphylococcus epidermidis bacteremia isolates in a neonatal intensive care unit over 10 years,” Journal of Infectious Diseases, vol. 169, no. 3, pp. 526–531, 1994. View at Scopus
  33. O. Lyytikäinen, H. Saxén, R. Ryhänen, M. Vaara, and J. Vuopio-Varkila, “Persistence of a multiresistant clone of Staphylococcus epidermidis in a neonatal intensive-care unit for a four-year period,” Clinical Infectious Diseases, vol. 20, no. 1, pp. 24–29, 1995. View at Scopus
  34. M. Björkqvist, M. Liljedahl, J. Zimmermann, J. Schollin, and B. Söderquist, “Colonization pattern of coagulase-negative staphylococci in preterm neonates and the relation to bacteremia,” European Journal of Clinical Microbiology & Infectious Diseases, vol. 29, no. 9, pp. 1085–1093, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. V. Milisavljevic, F. Wu, J. Cimmotti et al., “Genetic relatedness of Staphylococcus epidermidis from infected infants and staff in the neonatal intensive care unit,” American Journal of Infection Control, vol. 33, no. 6, pp. 341–347, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. S. F. Costa, M. H. Miceli, and E. J. Anaissie, “Mucosa or skin as source of coagulase-negative staphylococcal bacteraemia?” Lancet Infectious Diseases, vol. 4, no. 5, pp. 278–286, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. V. Hira, R. F. Kornelisse, M. Sluijter et al., “Colonization dynamics of antibiotic-resistant coagulase-negative Staphylococci in neonates,” Journal of Clinical Microbiology, vol. 51, no. 2, pp. 595–597, 2013.
  38. T. Strunk, P. Richmond, K. Simmer, A. Currie, O. Levy, and D. Burgner, “Neonatal immune responses to coagulase-negative staphylococci,” Current Opinion in Infectious Diseases, vol. 20, no. 4, pp. 370–375, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. A. A. Sharma, R. Jen, A. Butler, and P. M. Lavoie, “The developing human preterm neonatal immune system: a case for more research in this area,” Clinical Immunology, vol. 145, no. 1, pp. 61–68, 2012.
  40. B. Adkins, C. Leclerc, and S. Marshall-Clarke, “Neonatal adaptive immunity comes of age,” Nature Reviews. Immunology, vol. 4, no. 7, pp. 553–564, 2004. View at Scopus
  41. H. Zaghouani, C. M. Hoeman, and B. Adkins, “Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells,” Trends in Immunology, vol. 30, no. 12, pp. 585–591, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. O. Levy, “Innate immunity of the newborn: basic mechanisms and clinical correlates,” Nature Reviews. Immunology, vol. 7, no. 5, pp. 379–390, 2007.
  43. J. L. Wynn and O. Levy, “Role of innate host defenses in susceptibility to early-onset neonatal sepsis,” Clinics in Perinatology, vol. 37, no. 2, pp. 307–337, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. O. Levy, “Innate immunity of the human newborn: distinct cytokine responses to LPS and other toll-like receptor agonists,” Journal of Endotoxin Research, vol. 11, no. 2, pp. 113–116, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. A. Jackson, “Time to review newborn skincare,” Infant, vol. 4, no. 5, pp. 168–171, 2008.
  46. V. A. Harpin and N. Rutter, “Barrier properties of the newborn infant’s skin,” The Journal of Pediatrics, vol. 102, no. 3, pp. 419–425, 1983.
  47. N. J. Evans and N. Rutter, “Development of the epidermis in the newborn,” Biology of the Neonate, vol. 49, no. 2, pp. 74–80, 1986. View at Scopus
  48. V. P. Walker, H. T. Akinbi, J. Meinzen-Derr, V. Narendran, M. Visscher, and S. B. Hoath, “Host defense proteins on the surface of neonatal skin: implications for innate immunity,” Journal of Pediatrics, vol. 152, no. 6, pp. 777–781, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. M. O. Visscher, V. Narendran, W. L. Pickens et al., “Vernix caseosa in neonatal adaptation,” Journal of Perinatology, vol. 25, no. 7, pp. 440–446, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. C. C. Yost, M. J. Cody, E. S. Harris et al., “Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates,” Blood, vol. 113, no. 25, pp. 6419–6427, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. A. A. Larson and J. G. H. Dinulos, “Cutaneous bacterial infections in the newborn,” Current Opinion in Pediatrics, vol. 17, no. 4, pp. 481–485, 2005. View at Publisher · View at Google Scholar · View at Scopus
  52. S. J. McElroy and J. H. Weitkamp, “Innate immunity in the small intestine of the preterm infant,” NeoReviews, vol. 12, no. 9, pp. e517–e526, 2011.
  53. C. N. Emami, M. Petrosyan, S. Giuliani et al., “Role of the host defense system and intestinal microbial flora in the pathogenesis of necrotizing enterocolitis,” Surgical Infections, vol. 10, no. 5, pp. 407–417, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Yoshio, M. Tollin, G. H. Gudmundsson et al., “Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: implications for newborn innate defense,” Pediatric Research, vol. 53, no. 2, pp. 211–216, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. E. B. Mallow, A. Harris, N. Salzman et al., “Human enteric defensins: gene structure and developmental expression,” Journal of Biological Chemistry, vol. 271, no. 8, pp. 4038–4045, 1996. View at Scopus
  56. M. P. Sherman, S. H. Bennett, F. F. Y. Hwang, J. Sherman, and C. L. Bevins, “Paneth cells and antibacterial host defense in neonatal small intestine,” Infection and Immunity, vol. 73, no. 9, pp. 6143–6146, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. H. J. L. Brooks, M. A. Mcconnell, and R. S. Broadbent, “Microbes and the inflammatory response in necrotising enterocolitis,” in Preterm Birth, O. Erez, Ed., pp. 137–174, InTech, 2013.
  58. E. C. Claud and W. A. Walker, “Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis,” FASEB Journal, vol. 15, no. 8, pp. 1398–1403, 2001. View at Publisher · View at Google Scholar · View at Scopus
  59. W. Hsueh, M. S. Caplan, X. W. Qu, X. D. Tan, I. G. de Plaen, and F. Gonzalez-Crussi, “Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts,” Pediatric and Developmental Pathology, vol. 6, no. 1, pp. 6–23, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. D. L. Mollitt, J. J. Tepas, and J. L. Talbert, “The role of coagulase-negative Staphylococcus in neonatal necrotizing enterocolitis,” Journal of Pediatric Surgery, vol. 23, no. 1, part 2, pp. 60–63, 1988. View at Scopus
  61. D. W. Scheifele, G. L. Bjornson, R. Dyer, and J. E. Dimmick, “Delta-like toxin produced by coagulase-negative staphylococci is associated with neonatal necrotizing enterocolitis,” Infection and Immunity, vol. 55, no. 9, pp. 2268–2273, 1987. View at Scopus
  62. D. W. Scheifele and G. L. Bjornson, “Delta toxin activity in coagulase-negative Staphylococci from the bowels of neonates,” Journal of Clinical Microbiology, vol. 26, no. 2, pp. 279–282, 1988. View at Scopus
  63. K. L. Schnabl, J. E. van Aerde, A. B. R. Thomson, and M. T. Clandinin, “Necrotizing enterocolitis: a multifactorial disease with no cure,” World Journal of Gastroenterology, vol. 14, no. 14, pp. 2142–2161, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. E. J. Israel, “Neonatal necrotizing enterocolitis, a disease of the immature intestinal mucosal barrier,” Acta Paediatrica. Supplement, vol. 396, pp. 27–32, 1994. View at Scopus
  65. S. F. Wu, M. Caplan, and H. C. Lin, “Necrotizing enterocolitis: old problem with new hope,” Pediatrics and Neonatology, vol. 53, no. 3, pp. 158–163, 2012.
  66. J. M. Voyich, K. R. Braughton, D. E. Sturdevant et al., “Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils,” Journal of Immunology, vol. 175, no. 6, pp. 3907–3919, 2005. View at Scopus
  67. J. S. Cho, E. M. Pietras, N. C. Garcia et al., “IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice,” Journal of Clinical Investigation, vol. 120, no. 5, pp. 1762–1773, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. L. S. Miller, E. M. Pietras, L. H. Uricchio et al., “Inflammasome-mediated production of IL-1β is required for neutrophil recruitment against Staphylococcus aureus in vivo,” Journal of Immunology, vol. 179, no. 10, pp. 6933–6942, 2007. View at Scopus
  69. J. M. Koenig and M. C. Yoder, “Neonatal neutrophils: the good, the bad, and the ugly,” Clinics in Perinatology, vol. 31, no. 1, pp. 39–51, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Björkqvist, M. Jurstrand, L. Bodin, H. Fredlund, and J. Schollin, “Defective neutrophil oxidative burst in preterm newborns on exposure to coagulase-negative staphylococci,” Pediatric Research, vol. 55, no. 6, pp. 966–971, 2004. View at Publisher · View at Google Scholar · View at Scopus
  71. G. E. Schutze, M. A. Hall, C. J. Baker, and M. S. Edwards, “Role of neutrophil receptors in opsonophagocytosis of coagulase-negative staphylococci,” Infection and Immunity, vol. 59, no. 8, pp. 2573–2578, 1991. View at Scopus
  72. O. Takeuchi and S. Akira, “Pattern recognition receptors and inflammation,” Cell, vol. 140, no. 6, pp. 805–820, 2010.
  73. K. Takeda and S. Akira, “TLR signaling pathways,” Seminars in Immunology, vol. 16, no. 1, pp. 3–9, 2004.
  74. T. Kawai and S. Akira, “The role of pattern-recognition receptors in innate immunity: update on toll-like receptors,” Nature Immunology, vol. 11, no. 5, pp. 373–384, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. T. Kawai and S. Akira, “Toll-like receptors and their crosstalk with other innate receptors in infection and immunity,” Immunity, vol. 34, no. 5, pp. 637–650, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. T. Strunk, P. Richmond, A. Prosser et al., “Method of bacterial killing differentially affects the human innate immune response to Staphylococcus epidermidis,” Innate Immunity, vol. 17, no. 6, pp. 508–516, 2011.
  77. K. D. Kronforst, C. J. Mancuso, M. Pettengill et al., “A neonatal model of intravenous Staphylococcus epidermidis infection in mice <24 h old enables characterization of early innate immune responses,” PloS One, vol. 7, no. 9, Article ID e43897, 2012.
  78. A. M. Hajjar, D. S. O'Mahony, A. Ozinsky et al., “Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin,” Journal of Immunology, vol. 166, no. 1, pp. 15–19, 2001. View at Scopus
  79. W. C. Liles, A. R. Thomsen, D. S. O'Mahony, and S. J. Klebanoff, “Stimulation of human neutrophils and monocytes by staphylococcal phenol-soluble modulin,” Journal of Leukocyte Biology, vol. 70, no. 1, pp. 96–102, 2001. View at Scopus
  80. C. Mehlin, C. M. Headley, and S. J. Klebanoff, “An inflammatory polypeptide complex from Staphylococcus epidermidis: isolation and characterization,” Journal of Experimental Medicine, vol. 189, no. 6, pp. 907–917, 1999. View at Publisher · View at Google Scholar · View at Scopus
  81. L. S. Miller and J. S. Cho, “Immunity against Staphylococcus aureus cutaneous infections,” Nature Reviews Immunology, vol. 11, no. 8, pp. 505–518, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. Y. Lai, A. L. Cogen, K. A. Radek et al., “Activation of TLR2 by a small molecule produced by staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections,” Journal of Investigative Dermatology, vol. 130, no. 9, pp. 2211–2221, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. T. Strunk, A. Currie, P. Richmond, K. Simmer, and D. Burgner, “Innate immunity in human newborn infants: prematurity means more than immaturity,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 24, no. 1, pp. 25–31, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. P. M. Lavoie, Q. Huang, E. Jolette et al., “Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis,” The Journal of Infectious Diseases, vol. 202, no. 11, pp. 1754–1763, 2010.
  85. T. Strunk, A. Prosser, O. Levy et al., “Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation,” Pediatric Research, vol. 72, no. 1, pp. 10–18, 2012.
  86. G. Y. C. Cheung, K. Rigby, R. Wang et al., “Staphylococcus epidermidis strategies to avoid killing by human neutrophils,” PLoS Pathogens, vol. 6, no. 10, Article ID e1001133, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. T. J. Foster, “Immune evasion by staphylococci,” Nature Reviews. Microbiology, vol. 3, no. 12, pp. 948–958, 2005.
  88. C. von Eiff, G. Peters, and C. Heilmann, “Pathogenesis of infections due to coagulase-negative staphylococci,” Lancet Infectious Diseases, vol. 2, no. 11, pp. 677–685, 2002. View at Publisher · View at Google Scholar · View at Scopus
  89. D. Mack, A. P. Davies, L. G. Harris, H. Rohde, M. A. Horstkotte, and J. K. M. Knobloch, “Microbial interactions in Staphylococcus epidermidis biofilms,” Analytical and Bioanalytical Chemistry, vol. 387, no. 2, pp. 399–408, 2007. View at Publisher · View at Google Scholar · View at Scopus
  90. H. Rohde, S. Frankenberger, U. Zähringer, and D. Mack, “Structure, function and contribution of polysaccharide intercellular adhesin (PIA) to Staphylococcus epidermidis biofilm formation and pathogenesis of biomaterial-associated infections,” European Journal of Cell Biology, vol. 89, no. 1, pp. 103–111, 2010. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Kocianova, C. Vuong, Y. Yao et al., “Key role of poly-γ-DL-glutamic acid in immune evasion and virulence of Staphylococcus epidermidis,” Journal of Clinical Investigation, vol. 115, no. 3, pp. 688–694, 2005. View at Publisher · View at Google Scholar · View at Scopus
  92. C. Vuong, J. M. Voyich, E. R. Fischer et al., “Polysaccharide intercellular adhesin (PIA) protects Staphylococcus epidermidis against major components of the human innate immune system,” Cellular Microbiology, vol. 6, no. 3, pp. 269–275, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. F. Guenther, P. Stroh, C. Wagner, U. Obst, and G. M. Hänch, “Phagocytosis of staphylococci biofilms by polymorphonuclear neutrophils: S. aureus and S. epidermidis differ with regard to their susceptibility towards the host defense,” International Journal of Artificial Organs, vol. 32, no. 9, pp. 565–573, 2009. View at Scopus
  94. C. Klingenberg, E. Aarag, A. Rønnestad et al., “Coagulase-negative staphylococcal sepsis in neonates: association between antibiotic resistance, biofilm formation and the host inflammatory response,” The Pediatric Infectious Disease Journal, vol. 24, no. 9, pp. 817–822, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. Y. Qu, A. J. Daley, T. S. Istivan, S. M. Garland, and M. A. Deighton, “Antibiotic susceptibility of coagulase-negative staphylococci isolated from very low birth weight babies: comprehensive comparisons of bacteria at different stages of biofilm formation,” Annals of Clinical Microbiology and Antimicrobials, vol. 9, article 16, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. M. Otto, “Staphylococcus colonization of the skin and antimicrobial peptides,” Expert Review of Dermatology, vol. 5, no. 2, pp. 183–195, 2010. View at Publisher · View at Google Scholar · View at Scopus
  97. F. Oppermann-Sanio and A. Steinbüchel, “Occurrence, functions and biosynthesis of polyamides in microorganisms and biotechnological production,” Naturwissenschaften, vol. 89, no. 1, pp. 11–22, 2002. View at Publisher · View at Google Scholar · View at Scopus
  98. W. Ziebuhr, S. Hennig, M. Eckart, H. Kränzler, C. Batzilla, and S. Kozitskaya, “Nosocomial infections by Staphylococcus epidermidis: how a commensal bacterium turns into a pathogen,” International Journal of Antimicrobial Agents, vol. 28, supplement 1, pp. S14–S20, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. K. L. Rogers, P. D. Fey, and M. E. Rupp, “Coagulase-negative Staphylococcal infections,” Infectious Disease Clinics of North America, vol. 23, no. 1, pp. 73–98, 2009. View at Publisher · View at Google Scholar · View at Scopus
  100. B. Neumeister, S. Kastner, S. Conrad, G. Klotz, and P. Bartmann, “Characterization of coagulase-negative staphylococci causing nosocomial infections in preterm infants,” European Journal of Clinical Microbiology & Infectious Diseases, vol. 14, no. 10, pp. 856–863, 1995.
  101. M. Khashu, H. Osiovich, D. Henry, A. Al Khotani, A. Solimano, and D. P. Speert, “Persistent bacteremia and severe thrombocytopenia caused by coagulase-negative Staphylococcus in a neonatal intensive care unit,” Pediatrics, vol. 117, no. 2, pp. 340–348, 2006. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Paolucci, M. P. Landini, and V. Sambri, “How can the microbiologist help in diagnosing neonatal sepsis?” International Journal of Pediatrics, vol. 2012, Article ID 120139, 14 pages, 2012. View at Publisher · View at Google Scholar
  103. R. L. Schelonka, M. K. Chai, B. A. Yoder, D. Hensley, R. M. Brockett, and D. P. Ascher, “Volume of blood required to detect common neonatal pathogens,” Journal of Pediatrics, vol. 129, no. 2, pp. 275–278, 1996. View at Publisher · View at Google Scholar · View at Scopus
  104. T. G. Connell, M. Rele, D. Cowley, J. P. Buttery, and N. Curtis, “How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children's hospital,” Pediatrics, vol. 119, no. 5, pp. 891–896, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. A. Craft and N. Finer, “Nosocomial coagulase negative staphylococcal (CoNS) catheter-related sepsis in preterm infants: definition, diagnosis, prophylaxis, and prevention,” Journal of Perinatology, vol. 21, no. 3, pp. 186–192, 2001. View at Publisher · View at Google Scholar · View at Scopus
  106. T. B. Newman, K. M. Puopolo, S. Wi, D. Draper, and G. J. Escobar, “Interpreting complete blood counts soon after birth in newborns at risk for sepsis,” Pediatrics, vol. 126, no. 5, pp. 903–909, 2010.
  107. J. D. M. Edgar, V. Gabriel, J. R. Gallimore, S. A. McMillan, and J. Grant, “A prospective study of the sensitivity, specificity and diagnostic performance of soluble intercellular adhesion molecule 1, highly sensitive C-reactive protein, soluble E-selectin and serum amyloid A in the diagnosis of neonatal infection,” BMC Pediatrics, vol. 10, article 22, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. E. K. Vouloumanou, E. Plessa, D. E. Karageorgopoulos, E. Mantadakis, and M. E. Falagas, “Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic review and meta-analysis,” Intensive Care Medicine, vol. 37, no. 5, pp. 747–762, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. K. K. Hall and J. Lyman, “Updated review of blood culture contamination,” Clinical Microbiology Reviews, vol. 19, no. 4, pp. 788–802, 2006.
  110. S. E. Beekmann, D. J. Diekema, and G. V. Doern, “Determining the clinical significance of coagulase-negative staphylococci isolated from blood cultures,” Infection Control and Hospital Epidemiology, vol. 26, no. 6, pp. 559–566, 2005. View at Publisher · View at Google Scholar · View at Scopus
  111. F. Blot, G. E. Nitenberg, E. Chachaty et al., “Diagnosis of catheter-related bacteraemia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures,” The Lancet, vol. 354, no. 9184, pp. 1071–1077, 1999. View at Publisher · View at Google Scholar · View at Scopus
  112. F. M. Parvez and W. R. Jarvis, “Nosocomial infections in the nursery,” Seminars in Pediatric Infectious Diseases, vol. 10, no. 2, pp. 119–129, 1999. View at Publisher · View at Google Scholar · View at Scopus
  113. A. H. Gaur, P. M. Flynn, M. A. Giannini, J. L. Shenep, and R. T. Hayden, “Difference in time to detection: a simple method to differentiate catheter-related from non-catheter-related bloodstream infection in immunocompromised pediatric patients,” Clinical Infectious Diseases, vol. 37, no. 4, pp. 469–475, 2003. View at Publisher · View at Google Scholar · View at Scopus
  114. I. Raad, H. A. Hanna, B. Alakech, I. Chatzinikolaou, M. M. Johnson, and J. Tarrand, “Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections,” Annals of Internal Medicine, vol. 140, no. 1, pp. 18–I39, 2004. View at Scopus
  115. I. Chatzinikolaou, H. Hanna, R. Hachem, B. Alakech, J. Tarrand, and I. Raad, “Differential quantitative blood cultures for the diagnosis of catheter-related bloodstream infections associated with short- and long-term catheters: a prospective study,” Diagnostic Microbiology and Infectious Disease, vol. 50, no. 3, pp. 167–172, 2004. View at Publisher · View at Google Scholar · View at Scopus
  116. P. Yager, T. Edwards, E. Fu et al., “Microfluidic diagnostic technologies for global public health,” Nature, vol. 442, no. 7101, pp. 412–418, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. K. Edmond and A. Zaidi, “New approaches to preventing, diagnosing, and treating neonatal sepsis,” PLoS Medicine, vol. 7, no. 3, Article ID e1000213, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. N. Mancini, S. Carletti, N. Ghidoli, P. Cichero, R. Burioni, and M. Clementi, “The era of molecular and other non-culture-based methods in diagnosis of sepsis,” Clinical Microbiology Reviews, vol. 23, no. 1, pp. 235–251, 2010. View at Publisher · View at Google Scholar · View at Scopus
  119. M. Venkatesh, A. Flores, R. A. Luna, and J. Versalovic, “Molecular microbiological methods in the diagnosis of neonatal sepsis,” Expert Review of Anti-Infective Therapy, vol. 8, no. 9, pp. 1037–1048, 2010. View at Publisher · View at Google Scholar · View at Scopus
  120. O. Raimundo, H. Heussler, J. B. Bruhn et al., “Molecular epidemiology of coagulase-negative staphylococcal bacteraemia in a newborn intensive care unit,” Journal of Hospital Infection, vol. 51, no. 1, pp. 33–42, 2002. View at Publisher · View at Google Scholar · View at Scopus
  121. A. Borghesi and M. Stronati, “Strategies for the prevention of hospital-acquired infections in the neonatal intensive care unit,” Journal of Hospital Infection, vol. 68, no. 4, pp. 293–300, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. J. D. Horbar, J. Rogowski, P. E. Plsek et al., “Collaborative quality improvement for neonatal intensive care. NIC/Q Project Investigators of the Vermont Oxford Network,” Pediatrics, vol. 107, no. 1, pp. 14–22, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. W. H. Lim, R. Lien, Y. C. Huang et al., “Prevalence and pathogen distribution of neonatal sepsis among very-low-birth-weight infants,” Pediatrics and Neonatology, vol. 53, no. 4, pp. 228–234, 2012.
  124. O. K. Helder, J. Brug, C. W. N. Looman, J. B. van Goudoever, and R. F. Kornelisse, “The impact of an education program on hand hygiene compliance and nosocomial infection incidence in an urban Neonatal Intensive Care Unit: an intervention study with before and after comparison,” International Journal of Nursing Studies, vol. 47, no. 10, pp. 1245–1252, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. B. C. C. Lam, J. Lee, and Y. L. Lau, “Hand hygiene practices in a neonatal intensive care unit: a multimodal intervention and impact on nosocomial infection,” Pediatrics, vol. 114, no. 5, pp. e565–e571, 2004. View at Publisher · View at Google Scholar · View at Scopus
  126. L. Saiman, “Strategies for prevention of nosocomial sepsis in the neonatal intensive care unit,” Current Opinion in Pediatrics, vol. 18, no. 2, pp. 101–106, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. E. Kane and G. Bretz, “Reduction in coagulase-negative staphylococcus infection rates in the NICU using evidence-based research,” Neonatal Network, vol. 30, no. 3, pp. 165–174, 2011.
  128. S. G. Golombek, A. J. Rohan, B. Parvez, A. L. Salice, and E. F. LaGamma, “‘Proactive’ management of percutaneously inserted central catheters results in decreased incidence of infection in the ELBW population,” Journal of Perinatology, vol. 22, no. 3, pp. 209–213, 2002. View at Publisher · View at Google Scholar · View at Scopus
  129. M. A. C. Hemels, A. van den Hoogen, M. A. Verboon-Maciolek, A. Fleer, and T. G. Krediet, “Prevention of neonatal late-onset sepsis associated with the removal of percutaneously inserted central venous catheters in preterm infants,” Pediatric Critical Care Medicine, vol. 12, no. 4, pp. 445–448, 2011. View at Publisher · View at Google Scholar · View at Scopus
  130. R. J. Baier, J. A. Bocchini, and E. G. Brown, “Selective use of vancomycin to prevent coagulase-negative staphylococcal nosocomial bacteremia in high risk very low birth weight infants,” The Pediatric Infectious Disease Journal, vol. 17, no. 3, pp. 179–183, 1998. View at Publisher · View at Google Scholar · View at Scopus
  131. P. S. Spafford, R. A. Sinkin, C. Cox, L. Reubens, and K. R. Powell, “Prevention of central venous catheter-related coagulase-negative staphylococcal sepsis in neonates,” Journal of Pediatrics, vol. 125, no. 2, pp. 259–263, 1994. View at Publisher · View at Google Scholar · View at Scopus
  132. A. P. Craft, N. N. Finer, and K. J. Barrington, “Vancomycin for prophylaxis against sepsis in preterm neonates,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD001971, 2000. View at Scopus
  133. C. von Eiff, B. Jansen, W. Kohnen, and K. Becker, “Infections associated with medical devices: pathogenesis, management and prophylaxis,” Drugs, vol. 65, no. 2, pp. 179–214, 2005. View at Publisher · View at Google Scholar · View at Scopus
  134. J. Timsit, Y. Dubois, C. Minet et al., “New materials and devices for preventing catheter-related infections,” Annals of Intensive Care, vol. 1, no. 1, p. 34, 2011. View at Publisher · View at Google Scholar
  135. M. T. McCann, B. F. Gilmore, and S. P. Gorman, “Staphylococcus epidermidis device-related infections: pathogenesis and clinical management,” Journal of Pharmacy and Pharmacology, vol. 60, no. 12, pp. 1551–1571, 2008. View at Publisher · View at Google Scholar · View at Scopus
  136. M. P. Venkatesh, F. Placencia, and L. E. Weisman, “Coagulase-negative staphylococcal infections in the neonate and child: an update,” Seminars in Pediatric Infectious Diseases, vol. 17, no. 3, pp. 120–127, 2006. View at Publisher · View at Google Scholar · View at Scopus
  137. M. B. Bestul and H. L. VandenBussche, “Antibiotic lock technique: review of the literature,” Pharmacotherapy, vol. 25, no. 2, pp. 211–227, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. M. Maiefski, M. E. Rupp, and E. D. Hermsen, “Ethanol lock technique: review of the literature,” Infection Control and Hospital Epidemiology, vol. 30, no. 11, pp. 1096–1108, 2009. View at Publisher · View at Google Scholar · View at Scopus
  139. E. Y. Huang, C. Chen, F. Abdullah et al., “Strategies for the prevention of central venous catheter infections: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review,” Journal of Pediatric Surgery, vol. 46, no. 10, pp. 2000–2011, 2011.
  140. L. Filippi, M. Pezzati, S. di Amario, C. Poggi, and P. Pecile, “Fusidic acid and heparin lock solution for the prevention of catheter-related bloodstream infections in critically ill neonates: a retrospective study and a prospective, randomized trial,” Pediatric Critical Care Medicine, vol. 8, no. 6, pp. 556–562, 2007. View at Publisher · View at Google Scholar · View at Scopus
  141. J. S. Garland, C. P. Alex, K. J. Henrickson, T. L. McAuliffe, and D. G. Maki, “A vancomycin-heparin lock solution for prevention of nosocomial bloodstream infection in critically ill neonates with peripherally inserted central venous catheters: a prospective, randomized trial,” Pediatrics, vol. 116, no. 2, pp. e198–e205, 2005. View at Publisher · View at Google Scholar · View at Scopus
  142. J. S. Garland, C. P. Alex, C. D. Mueller et al., “A randomized trial comparing povidone-iodine to a chlorhexidine gluconate-impregnated dressing for prevention of central venous catheter infections in neonates,” Pediatrics, vol. 107, no. 6, pp. 1431–1437, 2001. View at Publisher · View at Google Scholar · View at Scopus
  143. G. L. Darmstadt and J. G. Dinulos, “Neonatal skin care,” Pediatric Clinics of North America, vol. 47, no. 4, pp. 757–782, 2000. View at Scopus
  144. J. F. John and A. M. Harvin, “History and evolution of antibiotic resistance in coagulase-negative staphylococci: susceptibility profiles of new anti-staphylococcal agents,” Therapeutics and Clinical Risk Management, vol. 3, no. 6, pp. 1143–1152, 2007. View at Scopus
  145. S. A. Shelburne, D. M. Musher, K. Hulten et al., “In vitro killing of community-associated methicillin-resistant Staphylococcus aureus with drug combinations,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 10, pp. 4016–4019, 2004. View at Publisher · View at Google Scholar · View at Scopus
  146. S. Rochon-Edouard, M. Pestel-Caron, J. F. Lemeland, and F. Caron, “In vitro synergistic effects of double and triple combinations of β-lactams, vancomycin, and netilmicin against methicillin-resistant Staphylococcus aureus strains,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 11, pp. 3055–3060, 2000. View at Publisher · View at Google Scholar · View at Scopus
  147. T. Brilene, H. Soeorg, M. Kiis et al., “In vitro synergy of oxacillin and gentamicin against coagulase-negative staphylococci from blood cultures of neonates with late-onset sepsis,” APMIS: Acta Pathologica, Microbiologica et Immunologica Scandinavica, 2013. View at Publisher · View at Google Scholar
  148. J. G. Deville, S. Adler, P. H. Azimi et al., “Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates,” The Pediatric Infectious Disease Journal, vol. 22, no. 9, supplement, pp. S158–S163, 2003. View at Scopus
  149. V. G. Meka and H. S. Gold, “Antimicrobial resistance to linezolid,” Clinical Infectious Diseases, vol. 39, no. 7, pp. 1010–1015, 2004. View at Publisher · View at Google Scholar · View at Scopus
  150. B. F. Farber, M. H. Kaplan, and A. G. Clogston, “Staphylococcus epidermidis extracted slime inhibits the antimicrobial action of glycopeptide antibiotics,” Journal of Infectious Diseases, vol. 161, no. 1, pp. 37–40, 1990. View at Scopus
  151. N. Høiby, T. Bjarnsholt, M. Givskov, S. Molin, and O. Ciofu, “Antibiotic resistance of bacterial biofilms,” International Journal of Antimicrobial Agents, vol. 35, no. 4, pp. 322–332, 2010. View at Publisher · View at Google Scholar · View at Scopus
  152. C. Klingenberg, A. Rønnestad, A. S. Anderson et al., “Persistent strains of coagulase-negative staphylococci in a neonatal intensive care unit: virulence factors and invasiveness,” Clinical Microbiology and Infection, vol. 13, no. 11, pp. 1100–1111, 2007. View at Publisher · View at Google Scholar · View at Scopus
  153. I. Adams-Chapman and B. J. Stoll, “Neonatal infection and long-term neurodevelopmental outcome in the preterm infant,” Current Opinion in Infectious Diseases, vol. 19, no. 3, pp. 290–297, 2006. View at Publisher · View at Google Scholar · View at Scopus
  154. J. M. Lorenz, “The outcome of extreme prematurity,” Seminars in Perinatology, vol. 25, no. 5, pp. 348–359, 2001. View at Scopus
  155. D. Moster, R. T. Lie, and T. Markestad, “Long-term medical and social consequences of preterm birth,” The New England Journal of Medicine, vol. 359, no. 3, pp. 262–273, 2008. View at Publisher · View at Google Scholar · View at Scopus
  156. B. E. Stephens and B. R. Vohr, “Neurodevelopmental outcome of the premature infant,” Pediatric Clinics of North America, vol. 56, no. 3, pp. 631–646, 2009.
  157. B. J. Stoll, N. I. Hansen, I. Adams-Chapman et al., “Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection,” Journal of the American Medical Association, vol. 292, no. 19, pp. 2357–2365, 2004. View at Publisher · View at Google Scholar · View at Scopus
  158. M. Wheater and J. M. Rennie, “Perinatal infection is an important risk factor for cerebral palsy in very-low-birthweight infants,” Developmental Medicine and Child Neurology, vol. 42, no. 6, pp. 364–367, 2000. View at Publisher · View at Google Scholar · View at Scopus
  159. S. Saigal and L. W. Doyle, “An overview of mortality and sequelae of preterm birth from infancy to adulthood,” The Lancet, vol. 371, no. 9608, pp. 261–269, 2008. View at Publisher · View at Google Scholar · View at Scopus
  160. L. Singer, T. Yamashita, L. Lilien, M. Collin, and J. Baley, “A longitudinal study of developmental outcome of infants with bronchopulmonary dysplasia and very low birth weight,” Pediatrics, vol. 100, no. 6, pp. 987–993, 1997. View at Scopus
  161. J. L. Wynn, J. Neu, L. L. Moldawer, and O. Levy, “Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis,” Journal of Perinatology, vol. 29, no. 2, pp. 79–88, 2009. View at Publisher · View at Google Scholar · View at Scopus
  162. A. King, E. Juszczak, U. Kingdom et al., “Treatment of neonatal sepsis with intravenous immune globulin,” The New England Journal of Medicine, vol. 365, no. 13, pp. 1201–1211, 2011. View at Publisher · View at Google Scholar
  163. M. Otto, “Novel targeted immunotherapy approaches for staphylococcal infection,” Expert Opinion on Biological Therapy, vol. 10, no. 7, pp. 1049–1059, 2011.
  164. P. Manzoni, M. Rinaldi, S. Cattani et al., “Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial,” Journal of the American Medical Association, vol. 302, no. 13, pp. 1421–1428, 2009. View at Publisher · View at Google Scholar · View at Scopus