The Changing Spectrum of Neonatal Infectious Disease

Home , Neonatal meningitis

LRW Plano Departments of Pediatrics and Microbiology & Immunology, University of Miami, Miller School of Medicine, Miami, FL, USA

were not previously accepted as true potential pathogens, such To understand the changing spectrum of neonatal infectious disease, one as the coagulase-negative staphylococci (CONS).1–3 From the must first be familiar with the history, the variety of organisms and the 1960s through the 1990s, Streptococcus agalactiae, group B progression of change of neonatal infections over the years. As progressively streptococcus (GBS), overtook S. aureus as the primary more immature neonates are surviving, the spectrum of infectious disease Gram-positive infecting organism.4–7 Over the course of the has changed in response to current medical practice responsible for this following years, the list of not uncommon pathogens has success and to selective pressures on the microorganisms. The surviving very continued to grow and be influenced by current medical practices low birth weight infants are at a significant risk for contracting infections and the pressures applied on these microorganisms from the from this expanding repertoire of pathogens. Microorganisms once thought rampant use of antimicrobials, including many broad-spectrum seemingly benign and nonpathogenic are now commonly accepted as drugs that have contributed to the selection for multidrug-resistant pathogens and are among the most likely organisms to cause infections in organisms in and out of the hospital settings. CONS are now the this extremely vulnerable patient population. When considering the possible most prevalent infecting organism in the neonatal setting, identity of infecting organisms and attempting to tailor specific therapies to owing this distinction to the late-onset infection rate in neonatal decrease unwanted consequences, one must consider the level of maturity intensive care units.8–10 Joining these organisms are E. coli, and and the age of neonate, as well as the intensity of care necessary for a multidrug-resistant Gram-negative organisms including successful outcome. This brief review focuses primarily on the changing Pseudomonas, Klebsiella and the fungi.3–12 Although systemic spectrum of bacterial and fungal infections and will not substantially infection of the term newborn indeed occurs, severe sepsis is now address viral infections. primarily a complication of preterm delivery. Journal of Perinatology (2010) 30, S16–S20; doi:10.1038/jp.2010.92

Keywords: neonatal infectious disease; neonatal sepsis; early-onset sepsis; late-onset sepsis Early versus late infections Infections of newborns were classically divided into early-onset sepsis (EOS), occurring within the first 7 days of life, and late-onset sepsis (LOS), occurring within the neonatal period after the 7th day of life. Early-onset infections are associated with intrapartum Historical perspectives exposure to the infecting organisms. This includes In the 1950s, when there were few surviving very low birth weight in utero or transplacental acquisition, as well as acquisition of (VLBW) infants, our therapeutic armamentarium was limited for these organisms during labor and delivery. Today, the majority of 13 those who did survive and, as a result, neonatal infection was EOS, approaching 90%, will present within the first 24 h of life. essentially a condition of the term infant. At that time the The route of transmission or type of exposure can influence the organisms most likely to cause infection were Staphylococcus timing of presentation. The earliest in utero exposure can come aureus and Escherichia coli. As our ability to support the as a result of a maternal subclinical infection at any time during survival of smaller, less mature infants progressed, the variety of the pregnancy. This is seen in classic TORCH infections that microorganisms with the potential to cause infection expanded to may persist through the neonatal period, in which the mother may include more opportunistic infecting organisms and those that be unaware that she had any significant infections. These in utero infections are beyond the scope of this discussion except to Correspondence: Dr LRW Plano, Departments of Pediatrics and Microbiology & Immunology, make the point that the timing of in utero infection affects the University of Miami, Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA. consequences and ultimate outcomes. Early in utero infections E-mail: [email protected] may result in spontaneous abortions, preterm delivery, stillbirths, This paper resulted from the Evidence vs Experience in Neonatal Practices conference, intrauterine growth retardation, congenital malformations or overt 19 to 20 June 2009, sponsored by Dey, LP. symptomatology at birth consistent with a long-standing infection. Neonatal infectious disease LRW Plano S17

In utero or transplacental acquisition that occurs in the undergo some invasive intervention during their routine care and immediate peripartum period, as well as acquisition of organisms the more likely they are to be exposed to the organisms associated during labor and delivery, can also result in early-onset infections. with infections. Immunological deficits of newborn and especially This may occur with or without the rupture of fetal membranes preterm infants significantly contribute to the risk of becoming (ROM). Early-onset infection with Listeria monocytogenes is infected after exposure to an organism. Components of the associated with hematogenous or transplacental transmission with neonatal immune system lack preexisting memory and have both intact fetal membranes. Prolonged ROM increases the risk of qualitative and quantitative deficiencies. Dysfunction in the naı¨ve infection by ascending organisms from the maternal vaginal flora, neutrophil has also been implicated in contributing to the including GBS, enteric Gram-negative organisms, gonococci, pathology and severity of neonatal sepsis.25–28 Although term Chlamydia and some viral pathogens. The risk of infection infants can mount adult-like immune responses,29–32 these occur increases with increasing length of time between ROM and delivery. under specific sets of circumstances and cannot be relied upon to Many investigations have addressed this and clearly established an be protective. Adding to the risk of infection in the preterm infant is increased risk of EOS after 18 h of ROM.14–16 Acquisition of EOS is the fact that they have failed to acquire protective maternal also associated with a number of other well-described factors that, antibodies that would have been transferred during the late third if present, would support the need to consider observation or trimester of pregnancy. evaluation of the newborn for infection. These include a maternal fever >38 1C, chorioamnionitis, prolonged or preterm ROM, poor prenatal care, poor maternal nutrition, a history of recurrent Impact of gestational age on infection: term versus abortion, low birth weight, maternal substance abuse, difficulty in preterm infections delivery, birth asphyxia and meconium staining.17,18 The changing spectrum of neonatal infectious disease is infection Knowledge of the risks and timing of exposure to GBS that of the VLBW infant with opportunistic and aggressive multidrug- would result in early-onset infection has allowed for recommendations resistant pathogens. VLBW infants accounted for 1.48% of all for interventions that have resulted in the successful decrease of deliveries in 2006 for a total of 63 136 births.33 Approximately early-onset GBS disease. After the implementation of the American one-third of these infants weighed <1000 g. The risk of infections College of Obstetricians and Gynecologists and Centers for Disease for this population is significant. Where only an estimated 0.1% of Control and Prevention recommendations for maternal screening for term infants will have an infection in the neonatal period, 20% of colonization and intrapartum antibiotic prophylaxis during labor for VLBW infants will be infected during their hospital stay.24,34,35 The women with known GBS colonization or other risk factors, incidence of sepsis increases with decreasing gestational age. the occurrence of early-onset GBS disease was dramatically Stratified by weight, 10% of 1000 to 1500 g infants, 35% of <1000 g decreased.19–23 Late-onset disease has, however, not been similarly infants and 50% of <750 g infants will have the diagnosis of sepsis affected as it is associated with postpartum acquisition of GBS. during the neonatal period. Most bouts of sepsis in this population Infection that is acquired in the postpartum period is primarily will occur after the third day of life. The NICHD Neonatal Research through horizontal transmission from family members or Network survey from 1998 to 2000 and the Vermont Oxford caregivers or through environmental exposures. Infections can be Network 2001 database summary reported similar rates (of 1.5 and acquired through breast-feeding (human immunodeficiency virus 2%, respectively), of VLBW infants with EOS, and both reported 21% and CMV) or by direct contact with family members or health-care for VLBW infants with LOS. The NICHD also reported that 46% of workers. These types of contacts and exposures are especially infants born at <25 weeks gestation had LOS.24 Although most important in infants, primarily preterm, with prolonged VLBW infants who have sepsis will have only a single infection, hospital stays, where they are more likely to be exposed to 28% will have more than one, 20% will have two, 6% will have multidrug-resistant hospital-associated organisms potentially from three and 2% will have more than three. Multiple episodes of sepsis contact with caregivers or contaminated equipment. increase with lower birth weights, and 40% of infants weighing Preterm infants are at an extremely increased risk for both <750 g will have two or more episodes of sepsis.24 Most strikingly, early- and late-onset infections secondary to multiple contributing sepsis is responsible for B50% of neonatal deaths after 2 weeks of factors. New definitions have been applied to EOS and LOS in life10 and VLBW infants who have sepsis have a mortality rate that the VLBW infant (<1500 g). As defined by the NICHD Neonatal approaches three times that of those without sepsis.24 Network,24 EOS is an infection that occurs up to 72 h of life and LOS beyond 72 h. Included among these are the degree of prematurity and the associated medical interventions necessary for Routes of infection appropriate care, as well as increased risk of exposure to pathogens There are many avenues through which a newborn might become associated with extended stays in the hospital. The greater the infected. Initially, during a vaginal delivery the infant is exposed to degree of an infant’s prematurity, the more likely they are to all the organisms in the birth canal and the physical barrier of

Journal of Perinatology Neonatal infectious disease LRW Plano S18 intact skin protects them from infection. At this time the infant Although it is generally accepted that infection may be a may become colonized or, if the skin is not intact owing to external predisposing factor as well as a result of necrotizing enterocolitis, monitors, abrasions or injury suffered during the delivery, infected. it is clear that its etiology extends beyond simple infection and Other potential routes of infection include the umbilical cord, as such an extensive discussion is beyond this review. UTIs are conjunctiva, oropharynx, gastrointestinal and respiratory tracts. diagnosed when organisms are present in appropriately collected Infants who require extended hospital stays and advanced support urine samples. The overall incidence of UTI in VLBW is reported at with indwelling foreign bodies such as persistent intravenous lines, 8.1%, stratified as 5.7% for infants weighing 1000 to 1500 g and endotracheal tubes, urinary catheters and shunts are at increased increasing to 12.5% for those <1000 g.43 Depending on the risk. Even respiratory support with something as seemingly benign organism, at least 100 colony-forming units (CFU) ml–1 from as a nasal cannula can increase the risk if surrounding tissues are a suprapubic bladder aspiration or 10 000 CFU ml–1 from allowed to become eroded due to contact with foreign material. a sterile bladder catheterization is required for diagnosis, or less for Additional contributing factors to late-onset infection in VLBW Gram-negative organisms or fungi.43,44 Evaluation for a UTI is not infants are the repeated courses of broad-spectrum antibiotics that indicated for VLBW infants in the first 72 h of life.45 However, initially delay the establishment of probiotic normal flora and beyond this period, when urine is no longer considered sterile, select for drug-resistant organisms and fungal infection in it should be included in the evaluation of a symptomatic infant. individual hosts. Repeated blood draws and other invasive procedures may also contribute to the high LOS rates, especially in VLBW infants, in whom routine blood draws may be difficult, Organisms associated with EOS and LOS in VLBW infants requiring multiple attempts. Timing of the onset of infection in the VLBW infant can also suggest the etiological agent and the associated morbidity and mortality. However, the clinical presentation is not unique to the individual organisms and therefore may not be helpful in determining the Types of infections causative agent. The primary organisms responsible for EOS in VLBW Although dominating this discussion, neonatal infections are not may vary at different centers and over time, but remain primarily limited to severe systemic infections such as sepsis. VLBW neonates E. coli, GBS and CONS.8,46,47 Data compiled from these and additional also succumb to a variety of focal infections, some associated with studies34,47–49 and reviewed8 show that in sepsis that presents in sepsis, including pneumonia, meningitis, urinary tract infections <72 h, about 61% were caused by Gram-negative organisms, with an (UTIs) and superficial skin infections. These infections can be associated mortality of 41, and 37% were caused by Gram-positive caused by the same bacterial and fungal agents that are responsible organisms, with an associated mortality of 26%. Fungal infections for causing sepsis and likewise may be challenging to diagnose, with Candida albicans accounted for only 2.4% of EOS. Of the and are briefly discussed here. Pneumonia in the endotracheally Gram-negative organisms causing EOS, 44% were E. coli,over8% intubated VLBW infant may be the most difficult focal infection to were Haemophilus influenza and Citrobacter,andBacteroides and diagnose. Radiographic findings and clinical presentation in Klebsiella accounted for B6% of the infections. Of the Gram-positive pneumonia may be indistinguishable from bronchopulmonary organisms causing EOS, GBS and CONS each were responsible for 9% dysplasia or chronic lung disease.36–38 Distinguishing colonization of infections, followed by Viridans streptococci and other streptococci from infection based on white blood cell counts, Gram stains and (8.4%), L. monocytogenes (2.4%) and S. aureus (1.2%). cultures obtained from endotracheal tube aspirates is unreliable. Sepsis that occurred after 72 h of life was primarily caused by Meningitis in the VLBW infant, defined as a positive cerebral Gram-positive bacteria24,49,50 with an overall mortality of 11.2%. Of spinal fluid (CSF) culture, has been and remains a difficult these, the majority of events were caused by CONS, with the lowest diagnosis to make.39–42 Many factors contribute to the mortality (9.1%) associated with any infecting organism. However, underdiagnoses and potential inadequate treatment of this when sepsis was caused by GBS, there was an associated 21.9% condition. Often, attempts at CSF collection for microorganism mortality. The other Gram-positive organisms causing LOS were isolation are delayed due to the patient’s clinical status and S. aureus (7.8%), with 17.2% mortality, and Enterococcus species antimicrobial therapies are initiated in the interim further (3.3%). Only 17.6% of LOS was associated with Gram-negative decreasing the chance of isolating viable bacteria. In recent studies, organisms, but with a reported 36% mortality. The greatest risk for investigators have confirmed that meningitis in the VLBW infant death was associated with Pseudomonas sepsis, with 2.7% of the can occur without associated bacteremia or abnormalities infections but 74% mortality. Other LOS-associated Gram-negative in CSF.39 They further showed that CSF parameters, used to support organisms were E. coli, representing 4.9% of infections with or exclude the diagnosis in older children, and peripheral white 34% mortality; Klebsiella, 4% of infections with 22.6% mortality; blood cell counts were not helpful in making the diagnosis Enterobacter, 2.5% of infections with 26.8% mortality; and in VLBW infants and that a positive CSF culture was critical. Serratia, 2.2% of infections with 35.9% mortality. Lastly, fungal

Journal of Perinatology Neonatal infectious disease LRW Plano S19 infections accounted for 12.2% of the LOS with 31.8% mortality. total number of births of VLBW infants remains high, the C. albicans accounted for 5.8% of LOS infections with 43.9% challenges are now to develop strategies and practices to prevent mortality and C. parapsilosis accounted for 4.1% of infections with neonatal infections; to develop novel speciﬁc therapies to eradicate 15.9% mortality. infecting organisms without selecting for worse pathogens; and to develop better diagnostic tools.

Diagnosis and treatment Diagnosis of neonatal infections is challenging. Most infants will have some risk factors and the presenting symptoms are many and Conflict of interest nonspecific, including poor feeding, breathing difficulty, apneas The author declares no conflict of interest. and bradycardia, gastrointestinal problems, increased oxygen requirement or ventilator support needs, lethargy or hypotension, decreased or elevated temperature, unusual skin rash or color References change, persistent crying or irritability. Adding to the challenge of correctly identifying the infection, the list of conditions to consider 1 Gladstone IM, Ehrenkranz RA, Edberg SC, Baltimore RS. A ten-year review of neonatal sepsis and comparison with the previous fifty-year experience. Pediatr Infect Dis J in the differential diagnosis is extensive, including metabolic and 1990; 9: 819–825. congenital abnormalities. As a result, the most common presenting 2 Philip AG. The changing face of neonatal infection: experience at a regional medical symptoms have low positive predictive value (PPV) for center. Pediatr Infect Dis J 1994; 13: 1098–1102. culture-proven sepsis, only 14 to 20%, and the symptom with the 3 Levine EM, Ghai V, Barton JJ, Strom CM. Intrapartum antibiotic prophylaxis increases highest PPV, hypotension (PPV 31%), is present only in 5% of the incidence of gram-negative neonatal sepsis. Infect Dis Obstet Gynecol 1999; 7: culture-proven events.50 Although isolation of a microorganism from 210–213. 4 Baker CJ, Barrett FF, Gordon RC, Yow MD. Suppurative meningitis due to streptococci the blood is the standard for diagnosis of sepsis, this is challenging of Lancefield group B: a study of 33 infants. J Pediatr 1973; 82: 724–729. as well. Only one in five evaluations for sepsis will produce a positive 5 Barton LL, Feigin RD, Lins R. Group B beta hemolytic streptococcal meningitis in blood culture. Therefore, when considering a possible diagnosis, the infants. J Pediatr 1973; 82: 719–723. chances of getting a false-negative culture from an infant 6 Franciosi RA, Knostman JD, Zimmerman RA. Group B streptococcal neonatal and with significant risk factors and strong clinical indicators support infant infections. J Pediatr 1973; 82: 707–718. 7 McCracken Jr GH. Group B streptococci: the new challenge in neonatal infections. the diagnosis of clinical sepsis. In one report of autopsy data of J Pediatr 1973; 82: 703–706. ELBW infants, 61% of infections diagnosed at necropsy were not 8 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very- 51 diagnosed before death. Other complicating factors include low-birth-weight infants. Clin Microbiol Rev 2004; 17: 638–680, table of contents. maternal antimicrobial therapy before birth as well as the low 9 Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR et al. Late-onset blood volume often collected for these cultures.52 In one recent sepsis in very low birth weight neonates: a report from the National Institute of Child study there was a 60% false-negative culture rate if <4 CFU of Health and Human Development Neonatal Research Network. J Pediatr 1996; 129: 63–71. bacteria were present per ml and if <0.5 ml of blood was collected. 10 Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Altogether, empirical therapy is given 80% of the time, with no Research Network. Semin Perinatol 2003; 27: 293–301. identified microorganism.24 Another recent study investigating the 11 Bromiker R, Arad I, Peleg O, Preminger A, Engelhard D. Neonatal bacteremia: patterns value of single versus multiple blood cultures for the diagnosis of antibiotic resistance. Infect Control Hosp Epidemiol 2001; 22: 767–770. of sepsis showed that two-site blood cultures were not better than 12 Cordero L, Sananes M, Ayers LW. Bloodstream infections in a neonatal intensive-care X 53 unit: 12 years’ experience with an antibiotic control program. Infect Control Hosp a single culture if 1 ml of blood was collected. Standard Epidemiol 1999; 20: 242–246. laboratory evaluations for white blood cell counts with differential 13 Law MR, Palomaki G, Alfirevic Z, Gilbert R, Heath P, McCartney C et al. The prevention determination and platelet counts as well as adjunctive tests may of neonatal group B streptococcal disease: a report by a working group of the Medical be helpful to support the diagnosis of sepsis and useful to follow Screening Society. J Med Screen 2005; 12: 60–68. the progression, but are not diagnostic. 14 Boyer KM, Gadzala CA, Kelly PD, Gotoff SP. Selective intrapartum chemoprophylaxis of neonatal group B streptococcal early-onset disease. III. Interruption of mother-to-infant transmission. J Infect Dis 1983; 148: 810–816. 15 Stewardson-Krieger PB, Gotoff SP. Risk factors in early-onset neonatal group b Conclusions streptococcal infections. Infection 1978; 6: 50–53. Despite significant advances in health care, infection in the 16 Yancey MK, Duff P, Kubilis P, Clark P, Frentzen BH. Risk factors for neonatal sepsis. neonate, especially in the preterm VLBW newborn, remains an Obstet Gynecol 1996; 87: 188–194. extremely important cause of morbidity and mortality. Adequate 17 Benitz WE, Gould JB, Druzin ML. Risk factors for early-onset group B streptococcal sepsis: estimation of odds ratios by critical literature review. Pediatrics 1999; 103: e77. diagnosis in this unique population can be extremely challenging. 18 Martius JA, Roos T, Gora B, Oehler MK, Schrod L, Papadopoulos T et al. Risk factors Successful treatment relies on early recognition, diagnosis and associated with early-onset sepsis in premature infants. Eur J Obstet Gynecol Reprod appropriate targeted supportive and antimicrobial therapies. As the Biol 1999; 85: 151–158.

Journal of Perinatology Neonatal infectious disease LRW Plano S20

19 Centers for Disease Control and Prevention (CDC). Hospital-based policies for 37 Baltimore RS. The difficulty of diagnosing ventilator-associated pneumonia. Pediatrics prevention perinatal Group B streptococcal diseaseFUnited States, 1999. MMWR Morb 2003; 112: 1420–1421. Mortal Wkly Rep 2000; 49: 936–940. 38 Cordero L, Ayers LW, Miller RR, Seguin JH, Coley BD. Surveillance of ventilator- 20 Centers for Disease Control Prevention (CDC). Adoption of perinatal group B associated pneumonia in very-low-birth-weight infants. Am J Infect Control 2002; 30: streptococcal disease prevention recommendations by prenatal-care providersF 32–39. Connecticut and Minnesota, 1998. MMWR Morb Mortal Wkly Rep 2000; 49: 228–232. 39 Garges HP, Moody MA, Cotten CM, Smith PB, Tiffany KF, Lenfestey R et al. Neonatal 21 Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep 2002; 51: and cerebrospinal fluid parameters? Pediatrics 2006; 117: 1094–1100. 1–22. 40 Kumar S. Missed and delayed diagnosis of neonatal meningitis. Indian Pediatr 2004; 22 Schrag SJ, Zywicki S, Farley MM, Reingold AL, Harrison LH, Lefkowitz LB et al. Group B 41: 959–960. streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 41 Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA et al. To tap or 2000; 342: 15–20. not to tap: high likelihood of meningitis without sepsis among very low birth weight 23 Makhoul IR, Kassis I, Smolkin T, Tamir A, Sujov P. Review of 49 neonates with infants. Pediatrics 2004; 113: 1181–1186. acquired fungal sepsis: further characterization. Pediatrics 2001; 107: 61–66. 42 Wiswell TE, Baumgart S, Gannon CM, Spitzer AR. No lumbar puncture in the 24 Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA et al. Late-onset evaluation for early neonatal sepsis: will meningitis be missed? Pediatrics 1995; 95: sepsis in very low birth weight neonates: the experience of the NICHD Neonatal 803–806. Research Network. Pediatrics 2002; 110: 285–291. 43 Eliakim A, Dolfin T, Korzets Z, Wolach B, Pomeranz A. Urinary tract infection in 25 Ahmad M, Fleit HB, Golightly MG, La Gamma EF. In vivo effect of recombinant premature infants: the role of imaging studies and prophylactic therapy. J Perinatol human granulocyte colony-stimulating factor on phagocytic function and oxidative 1997; 17: 305–308. burst activity in septic neutropenic neonates. Biol Neonate 2004; 86: 48–54. 44 Bauer S, Eliakim A, Pomeranz A, Regev R, Litmanovits I, Arnon S et al. Urinary tract 26 Koenig JM, Yoder MC. Neonatal neutrophils: the good, the bad, and the ugly. Clin infection in very low birth weight preterm infants. Pediatr Infect Dis J 2003; 22: 426–430. Perinatol 2004; 31: 39–51. 45 Tamim MM, Alesseh H, Aziz H. Analysis of the efficacy of urine culture as part of sepsis 27 Petrova A, Mehta R. Dysfunction of innate immunity and associated pathology in evaluation in the premature infant. Pediatr Infect Dis J 2003; 22: 805–808. neonates. Indian J Pediatr 2007; 74: 185–191. 46 Baltimore RS. Neonatal sepsis: epidemiology and management. Paediatr Drugs 2003; 28 Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML et al. Impaired 5: 723–740. neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of 47 Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR et al. Early-onset human neonates. Blood 2009; 113: 6419–6427. sepsis in very low birth weight neonates: a report from the National Institute of Child 29 Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Health and Human Development Neonatal Research Network. J Pediatr 1996; 129: Rev Immunol 2004; 4: 553–564. 72–80. 30 Forsthuber T, Yip HC, Lehmann PV. Induction of TH1 and TH2 immunity in neonatal 48 Brodie SB, Sands KE, Gray JE, Parker RA, Goldmann DA, Davis RB et al. Occurrence of mice. Science 1996; 271: 1728–1730. nosocomial bloodstream infections in six neonatal intensive care units. Pediatr Infect 31 Ridge JP, Fuchs EJ, Matzinger P. Neonatal tolerance revisited: turning on newborn Dis J 2000; 19: 56–65. T cells with dendritic cells. Science 1996; 271: 1723–1726. 49 Clark R, Powers R, White R, Bloom B, Sanchez P, Benjamin Jr DK. Nosocomial 32 Sarzotti M, Robbins DS, Hoffman PM. Induction of protective CTL responses in infection in the NICU: a medical complication or unavoidable problem? J Perinatol newborn mice by a murine retrovirus. Science 1996; 271: 1726–1728. 2004; 24: 382–388. 33 Martin JA, Kung HC, Mathews TJ, Hoyert DL, Strobino DM, Guyer B et al. Annual 50 Fanaroff AA, Korones SB, Wright LL, Verter J, Poland RL, Bauer CR et al. Incidence, summary of vital statistics: 2006. Pediatrics 2008; 121: 788–801. presenting features, risk factors and significance of late onset septicemia in very low 34 Sohn AH, Garrett DO, Sinkowitz-Cochran RL, Grohskopf LA, Levine GL, Stover BH et al. birth weight infants. The National Institute of Child Health and Human Development Prevalence of nosocomial infections in neonatal intensive care unit patients: results Neonatal Research Network. Pediatr Infect Dis J 1998; 17: 593–598. from the first national point-prevalence survey. J Pediatr 2001; 139: 821–827. 51 Barton L, Hodgman JE, Pavlova Z. Causes of death in the extremely low birth weight 35 Stover BH, Shulman ST, Bratcher DF, Brady MT, Levine GL, Jarvis WR. Nosocomial infant. Pediatrics 1999; 103: 446–451. infection rates in US children’s hospitals’ neonatal and pediatric intensive care units. 52 Neal PR, Kleiman MB, Reynolds JK, Allen SD, Lemons JA, Yu PL. Volume of blood Am J Infect Control 2001; 29: 152–157. submitted for culture from neonates. J Clin Microbiol 1986; 24: 353–356. 36 Apisarnthanarak A, Holzmann-Pazgal G, Hamvas A, Olsen MA, Fraser VJ. Ventilator- 53 Sarkar S, Bhagat I, DeCristofaro JD, Wiswell TE, Spitzer AR. A study of the role of associated pneumonia in extremely preterm neonates in a neonatal intensive care unit: multiple site blood cultures in the evaluation of neonatal sepsis. J Perinatol 2006; 26: characteristics, risk factors, and outcomes. Pediatrics 2003; 112: 1283–1289. 18–22.

Journal of Perinatology