OVERVIEW: What every practitioner needs to know

Late onset sepsis (LOS) remains an important cause of neonatal morbidity and mortality. The presenting signs and symptoms are often subtle and mimic other neonatal conditions; however, many affected infants may develop a rapidly progressing and overwhelming sepsis syndrome with associated multiple organ dysfunction and death.

Gram-positive organisms are the most common pathogens. Gram-negative pathogens are frequently associated with fulminant presentation and have a higher attributable mortality rate. Fungal and viral pathogens may also cause infection.

Prematurely born infants are at increased risk for infection, often related to conditions associated with preterm delivery, including premature and prolonged rupture of membranes, maternal infection, or maternal colonization with pathogenic bacteria. These infants are also at risk for healthcare-associated infections.

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A diagnosis of septicemia is confirmed by a positive blood culture obtained from a normally sterile body fluid. Other laboratory data (CBC, CRP, coagulation studies) may be helpful in overall management; however, they are non-specific and cannot be used to confirm or exclude a diagnosis of septicemia. Meningeal involvement should be considered as a part of the diagnostic evaluation of any neonate with confirmed septicemia.

Early administration of antimicrobials may be lifesaving. Do not delay antimicrobial therapy awaiting results of cultures in a neonate with suspected septicemia.

Are you sure your patient has septicemia? What are the typical findings for this disease?

Clinical signs and symptoms of septicemia can be highly variable in the neonate. Some neonates have subtle findings that overlap with other neonatal conditions, while other neonates present with signs of overwhelming septic shock. The key symptoms and signs of the disease include:

  • Respiratory distress

  • Apnea

  • Temperature instability

  • Poor feeding

  • Feeding intolerance

  • Lethargy

  • Irritability

  • Seizures

  • Loss of glucose homeostasis – hypoglycemia or hyperglycemia

  • Hypotension

Healthcare-Associated Infections (HAIs)


Healthcare associated infections (HAIs) are an important cause of infection-associated morbidity and mortality in hospitalized neonates in the first month of life. Approximately 7%-24% of NICU patients will develop a HAI. The risk increases with increased complexity and invasiveness of supportive care due to the disruption of natural barriers and the use of medical devices. Infections are associated with an increased length of hospital stay and healthcare costs.

Creating an environment that minimizes the risk of HAI has become an important quality metric in neonatology and in most hospital settings. Local surveillance to monitor incidence and antimicrobial sensitivity patterns is critically important to identify opportunities for improvement. Multi-faceted programs for education, surveillance and care management protocols have been designed to decrease the risk of various HAIs in this population.

Gram-positive organisms cause the majority of HAI blood stream infections during the neonatal period, with coagulase-negative Staphylococcus being the most common pathogen. Gram-negative pathogens are more commonly associated with ventilator-associated pneumonia (VAP). Fungal infections continue to be an important pathogen and are associated with an increased risk of death and/or disability among survivors.

Centers for Disease Control and Prevention (CDC) definitions for Healthcare-Associated Infections(Table I)

Table I.n

CDC Definitions for Healthcare Associated Infections

A healthcare-associated infection (HAI) is defined by the CDC as a localized or systemic infection resulting from an infectious agent and/or its toxins that was not present at the time of hospital admission. Endogenous sources of HAIs are body sites normally inhabited by microorganisms (i.e., skin, eye, gastrointestinal tract, or vagina). Exogenous sources are considered things external to the patient (i.e., hospital personnel, visitors, devices, equipment, or healthcare environment). Infections that occur during passage through the birth canal can be considered HAIs if they manifest after 48 hours of age.

What is NOT considered a HAI?

Some conditions and infections are already present before 48 hours of age even if they manifest clinically later in the hospitalization. It is important to appropriately classify the most likely source of these infections to ensure that the incidence of HAI is accurate. The CDC has defined several circumstances that should not be considered a HAI, including: infections present at the time of admission, infections that occur transplacentally but do not manifest within 48 hours, reactivation of latent infections, colonization with organisms but no clinical evidence of disease or inflammation associated with trauma or tissue injury.

Catheter-Related Blood Stream Infections (CRBSI)

Catheter-related blood stream infections (CRBSI) are the most common type of HAI in the newborn. The majority are caused by coagulase-negative Staphylococcus. The risk is inversely related to gestational age and birth weight. The National Health Survey Network reports rates of 4.4 to 6.4 cases per 1000 catheter days among infants < 1000 grams.

Extraluminal or intraluminal contamination of catheters is the most common cause of CRBSI. Multifaceted prevention strategies to decrease CRBSI include emphasis on minimizing catheter days and appropriate care and maintenance of catheters.

Ventilator-Associated Pneumonia (VAP)

The incidence of VAP varies between NICUs, but ranges from 1 to 14 cases per 1000 ventilator days. Risk factors include days of mechanical ventilation, gestational age, birth weight, and multiple reintubations.

The CDC and the National Health Survey Network have established guidelines for the diagnosis of VAP that include worsening of gas exchange within 48 hours of the suspected episode, 2 or more radiographs showing new infiltrates, and at least 3 clinical signs (change in secretions, tachypnea, wheezing, cough, abnormal CBC) (Table II).

Table II.n

CDC Guidelines for Diagnosis of Hospital Acquired Pneumonia in Infants

Tracheal aspirates are often obtained, but are of limited utility since most chronically ventilated patients are colonized with bacteria.

What other disease/condition shares some of these symptoms?

The signs and symptoms of septicemia in a neonate are variable and often overlap with other conditions. Careful evaluation of the infant, combined with appropriate analysis of laboratory and diagnostic data, guide the decision-making process. Diseases/conditions that can mimic septicemia in the neonate between 5-28 days of age include:

Respiratory distress syndrome

Congenital heart disease (particularly ductal dependent lesions)

Congenital pneumonia



Metabolic acidosis

Severe anemia

Hemolytic anemia

Inborn error of metabolism

Congenital adrenal hyperplasia


Septic arthritis


Differential Diagnosis

The signs and symptoms of septicemia during the first month of life are very non-specific and could easily represent serious life-threatening diseases in other organ systems.

Careful and thorough evaluation of infants with suspected sepsis is necessary to avoid delay in appropriate treatment.

Many forms of congenital heart disease may not be evident immediately after birth. Ductal dependent lesions may not become symptomatic until partial or complete ductal closure.

Delayed diagnosis of metabolic disorders may impact long-term outcome.

What caused this disease to develop at this time?

The majority of late onset infections in neonates are related to healthcare-associated risk factors. Hospitalized and prematurely born infants are more likely to develop septicemia.

Careful review of the medical history will also alert you to any previous infections or colonization patterns that would be a potential source of systemic disease, for example, known colonization of mucosal or surface tissues with methicillin-resistant
Staphylococcus aureus (MRSA).

Review of the maternal history is very important. Known maternal colonization with GBS or documented Chlamydia infection typically present as active disease after 2 weeks of age in previously asymptomatic infants.

Use of broad spectrum empiric antibiotic usage has been associated with an increased risk of infection.The CDC has provided a list of guidelines to help minimize unnecessary antibiotic usage (Table III).

Table III.n

CDC Guidelines to minimize antibiotic usage

Various devices necessary to support the immature preterm neonate also increase the risk of infection. Bacteria frequently colonize the surfaces of devices, resulting in colonization of otherwise sterile tissue. Guidelines for acceptable duration to leave catheters in situ are unclear; however, judicious use and removal as soon as they are no longer clinically necessary are strongly recommended. Use of devices such as intravenous catheters (central venous catheters, peripherally inserted central catheters, umbilical lines), ventilators, and devices that bypass natural barriers (i.e., feeding tubes, Foley catheters) are associated with an increased risk of septicemia in the neonatal period.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The clinical signs and symptoms of neonatal sepsis can be subtle. Laboratory data should be included in the decision-making process to confirm or rule out a diagnosis of septicemia. Laboratory tests that may be used to confirm a diagnosis of septicemia in a neonate include blood culture, complete blood count with differential, coagulation studies, urine culture, cerebrospinal fluid sample, respiratory culture, tissue or wound culture, and C-reactive protein.

In the absence of a positive blood, urine or CSF culture, other data should be used as supportive information (rather than diagnostic information) due to the modest sensitivity and specificity of any single test. The predictive value of multiple abnormal laboratory indices is greater than a single measure.

It is important for the clinician to remember not to delay treatment with antibiotics in a patient with a clinical picture consistent with sepsis pending laboratory data.

A blood culture is the “gold standard” diagnostic tool to confirm a diagnosis of sepsis. The predictive value is affected by prior antibiotic treatment before collection of the sample and the volume of blood in the sample. The yield increases when at least 1 ml of blood is collected for the sample.

What is the evidence for the management and treatment options you’ve recommended?” The average time to positivity is typically between 48-72 hours. Antibiotic sensitivity panels are obtained on positive cultures, and can be very helpful in selection of antibiotics.

A complete blood count (CBC) is a frequently utilized laboratory test obtained in a neonate with suspected sepsis. Caution is advised in interpretation of these results due to the wide range of normal values at various ages and the modest positive and negative predictive values of the test. Results from a CBC should not be used as the sole determinant to confirm a diagnosis of septicemia.

Neutropenia (ANC < 1500) is associated with higher predictive value for a diagnosis of septicemia in a neonate. The ratio of immature/total neutrophil count > 0.2 has also been associated with an increased likelihood of infection.

Abnormalities in coagulation profiles are not uncommon in the neonate with overwhelming sepsis. Some newborns have evidence of increased platelet destruction and/or increased peripheral consumption. Patients with suspected sepsis should be evaluated for evidence of thrombocytopenia, hypofibrinogenemia, or abnormal coagulation studies.

A urine culture should be considered a potential source of infection in neonates > 5 days of age. The concordance with positive blood cultures is low. The risk of bacterial colonization is higher in patients with a history of urinary catheterization or structural renal disease.

A lumbar puncture to obtain a cerebrospinal fluid (CSF) culture should be considered in any neonate with suspected sepsis. This diagnostic tool is underutilized in the low birth weight population because these infants are often unstable. The concordance with blood cultures is variable, partially because infants have often been treated with antibiotics prior to obtaining the CSF sample. A Gram stain, cell count, glucose, protein, and aerobic and anaerobic CSF cultures should be obtained. Viral cultures or PCR tests may be useful in patients with suspected viral pathogens. Characteristic findings are often present in patients with meningitis (elevated cell count, elevated protein, and decreased glucose); however, some patients have normal CSF indices but positive cultures.

A respiratory culture should be considered in patients with signs and symptoms of respiratory disease. In general, this test has limited utility and low predictive value. It can be difficult to differentiate between bacterial colonization in chronically ventilated patients and actual infection. Respiratory viral cultures can be helpful in patients with suspected viral syndromes, some of which have seasonal variation.

A tissue and wound culture should be obtained on any patient with evidence of a superficial abscess or fluid collection. Samples of deep tissue fluid collections may be performed under ultrasound guidance. Joint aspiration should be considered in patients with evidence of painful or swollen extremities, which often manifest clinically as decreased spontaneous movement in the affected joint.

C-reactive protein is a commercially available acute phase reactant suggestive of an inflammatory process. Elevated levels are not diagnostic and must be evaluated in the context of the clinical picture and other laboratory data. Levels increase within 6 hours of an inflammatory insult. The positive predictive value of a single measurement is limited; however, when combined with other laboratory tests, the predictive value increases. Serial measurements may be more useful to monitor response to therapy.

Would imaging studies be helpful? If so, which ones?

Ragiographic studies can help identify the source of infection. Frequently, patients develop disseminated disease affecting multiple organ systems. Many of these imaging studies are necessary for overall support and care of critically ill neonates who develop multiple organ system dysfunction as part of their sepsis syndrome.

A chest radiograph is useful in the evaluation of a neonate with suspected sepsis because such patients frequently have associated respiratory symptoms. X-rays are low-cost, portable, and associated with minimal radiation exposure. Targeted radiographs of long bones and joints can be useful in the evaluation of the neonate with clinical signs of a septic joint and/or osteomyelitis.

Various types of ultrasounds can be useful in the evaluation of a neonate with suspected sepsis. Ultrasounds can be useful in the evaluation for fluid collection or in deep tissue spaces, such as the abdomen or the chest. Cranial ultrasounds can identify evidence of intracranial pathology, including bleeding or abscesses. Ultrasounds are portable and can typically be performed at the bedside. The cost is relatively low and the yield is high when used selectively.

A CT scan is rarely used as a first-line diagnostic study in the evaluation of neonatal sepsis; however, it can be useful in specific situations. The cost and radiation exposure are higher than standard radiographs. Some hospitals may have the capability of performing portable scans; however, the patient may need to be transported to radiology to have this test performed.

The MRI scan is a non-invasive imaging study that does not involve ionizing radiation. It is rarely used in the initial evaluation of neonates with suspected sepsis. In most hospitals, the patient has to be transported to the scanner, and sedation is frequently required to prevent motion artifact. This study may be useful in the evaluation of the patient with suspected meningitis or osteomyelitis.

If you are able to confirm that the patient has septicemia, what treatment should be initiated?

Antimicrobial therapy should be initiated as soon as possible in the neonate with suspected sepsis. Treatment should not be delayed awaiting results of laboratory studies. Choice of empiric antimicrobial agent should be based on known sensitivity patterns of the most likely pathogen for an individual patient.

Once an organism has been identified and the antibiotic sensitivity profile is known, the clinician should change to the most appropriate antibiotic with the most narrow spectrum. Consult published guidelines for antibiotic dosing based on postnatal age and gestation, such as NeoFax® (New York: Thomson Reuters, Inc., 2012) and Lexicomp® (Lexi-Comp, Inc., Hudson, OH). Supportive therapy is also critically important.

Antimicrobial agents for consideration in neonatal sepsis:

  • Ampicillin

  • Gentamicin

  • Cephalosporins

  • Oxacillin

  • Vancomycin – strong consideration in hospitalized patients and those at risk for healthcare-acquired infections

  • Amphotericin B

  • Fluconazole

Many neonates with septicemia have evidence of end-organ system dysfunction. Supportive therapies include administration of: intravenous fluids, respiratory support (oxygen, CPAP, mechanical ventilation), cardiovascular support (inotropes) and management of hematologic abnormalities (transfusions with platelets, fresh frozen plasma, packed red blood cells or cryoprecipitate)

Therapies NOT shown to be helpful include intravenous gammaglobulin (IVIG) and granulocyte colony-stimulating factor (G-CSF).

What are the adverse effects associated with each treatment option?

There is minimal toxicity associated with the use of antimicrobial agents if used within the appropriate dosage ranges adjusted for birth weight and gestational age. Serum levels of some agents (i.e., gentamicin and vancomycin) can be measured to ensure adequacy of dose and minimize the risk of toxicity. Duration of antibiotic therapy should be tailored to the clinical scenario. Prolonged empiric use of broad spectrum antibiotics has been associated with colonization with multi-drug resistant bacteria and Candida infection.

The goal of supportive treatment is to minimize additional end-organ injury. There is a small risk of barotrauma and secondary lung injury in patients requiring high concentrations of inspired oxygen or high ventilator pressures for prolonged periods of time.

The exposure to ionizing radiation is minimized in neonates by limiting the area exposed and using protective equipment. The potential benefits outweigh the potential risks associated with limited exposure to radiographic studies, particularly in the critically ill neonate.

What are the possible outcomes of septicemia?

What will you tell the family about prognosis?

Counseling the family of a neonate with suspected septicemia can be difficult. Families often want to know about prognosis, length of treatment, and potential long-term consequences.

Most infants with neonatal sepsis survive; however, the mortality rate may be as high as 15%. The mortality is higher in preterm infants and those with Gram-negative infections and systemic candidiasis.

It is important to monitor the infant closely for signs of response to therapy. Typically, most infants show signs of improvement within 24-48 hours. It is important to monitor the neonate for signs of systemic disease.

Duration of therapy varies based on the source and site of infection. The average length of antibiotic therapy is 7-10 days; however, infants with Gram-negative sepsis, meningitis, or candidiasis may require a more prolonged course of antimicrobial therapy, up to 21 days. Infants with persistently positive cultures may require a longer course of therapy.

Many term neonates with septicemia who survive do not appear to have long-term sequelae. However, prematurely-born neonates with septicemia and those with meningitis have an increased risk of long-term neurodevelopmental difficulties. All newborns with septicemia will have a hearing evaluation prior to hospital discharge. It is often easier to give parents information about potential long-term consequences prior to hospital discharge.

Term and preterm neonates with meningitis are at increased risk for long-term neurologic difficulties including cerebral palsy, learning difficulties, hearing loss and neurocognitive impairment. These infants should be considered at high risk, and appropriate developmental follow-up should be arranged.

What will you tell the family about risks/benefits of the available treatment options?

The benefits of treatment with antimicrobial and supportive treatment far outweigh the risks of non-treatment in this disease. The likelihood of spontaneous recovery without intervention is exceedingly low, and delay in therapy has been associated with worse outcomes.

What causes this disease and how frequent is it?


The rate of neonatal septicemia is highly variable across the country and in different nurseries. It is unclear if this simply reflects different population risks or variations in local practice that might be modifying the risk of infection. The overall incidence varies from 0.3 to 8 cases per 1000 live births. The risk is higher among prematurely-born infants. In a report from the National Institute of Child Health & Human Development (NICHD) Neonatal Research Network of 9575 infants <1500 grams birth weight, the overall incidence was 37%, but the risk varied inversely with gestational age and birth weight (58% at 22 wks vs 22% at 28 wks).

Risk Factors

Risk factors for septicemia in neonates between 5-28 days include: maternal colonization with Group B Streptococcus, hospital-acquired colonization with pathogenic bacteria (i.e., MRSA), exposure to contaminated healthcare equipment/healthcare workers, and translocation from other infected sites.


The distribution of pathogens that cause sepsis in the preterm infant are different from those causing sepsis in the term infant. In the preterm infant, the most common pathogen causing late onset sepsis is coagulase-negative Staphylococcus. In the term infant, the most common pathogen causing late onset sepsis is Group B Streptococcus. There is not a seasonal variation for either pathogen. Table IV shows the distribution of pathogens for late onset sepsis in very low birth weight infants.

Table IV.n

Distribution of Pathogens Associated with the First Episode of Late-Onset Sepsis Among VLBW Infants

Gram-positive pathogens

  • Coagulase-negative

  • Enterococcus

  • Listeria monocytogenes

  • Group B

  • S. pneumoniae

Gram-negative pathogens

  • E. coli

  • Enterobacter species

  • Haemophilus species (typically non-typeable in neonates)

  • Serratia

  • Klebsiella species

  • Pseudomonas species

  • Acinetobacter

Fungal pathogens

  • Candida species

Viral pathogens

  • Respiratory syncytial virus (RSV)

  • Influenza

Late Onset Group B Streptococcus

Group B Streptococcus (GBS) is an important cause of late onset infection during infancy. This Gram-positive bacteria typically causes disease between 7 days of age and 3 months of age. Although there are 10 known serotypes of GBS, Type III is most commonly associated with late onset infection in the newborn, particularly among infants with meningitis. The incidence of late onset GBS sepsis is 0.25 cases per 1000 live births. Intrapartum antibiotic administration to GBS-colonized mothers has been an effective strategy to decrease the incidence of early onset GBS disease; however, this therapy has not affected the incidence of late onset GBS disease. Rates have remained relatively stable over the past decade.

The most common clinical manifestations of late onset GBS disease in the neonate are bacteremia and meningitis. Other clinical symptoms include: osteomyelitis, septic arthritis, necrotizing fasciitis, pneumonia, and cellulitis.

Recent reports suggest that acute mortality rates secondary to GBS meningitis have decreased to approximately 5%. These infants are at risk for death after hospital discharge, and at least 50% have long-term neurologic impairment.

How do these pathogens/genes/exposures cause the disease?

Sepsis is defined by the presence of bacteria in an otherwise sterile fluid, including blood, urine, and cerebrospinal fluid. Infection results in both a local and a systemic inflammatory response, causing downstream activation of various cytokines that further exacerbate the inflammatory response, with some cytokines causing local cytotoxic injury. This systemic response often manifests as organ failure in distant tissues, which correlates with clinical symptoms of respiratory distress, hypotension, poor cardiac output, and coagulopathy.

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?

Long-term complications of late septicemia vary based on the gestational age. Preterm infants with a history of late onset sepsis (LOS) are at increased risk for long-term neurodevelopmental delay and growth impairment in early infancy. The risk for long-term neurodevelopmental delay in term infants with a history of LOS is unclear.

Meningitis is associated with an increased risk of long-term developmental difficulties and hearing impairment. Seizures may occur in patients with structural CNS injury or hemorrhage related to the infection.

Neonates diagnosed with a urinary tract infection may have a slightly increased risk of problems with structural renal abnormalities or vesicoureteral reflux, particularly if they have had repeated infections.

Infants with late onset GBS meningitis are at risk for abnormal long-term neurologic sequelae, particularly among those with documented CNS abnormalities, hearing impairment, and an abnormal neurological exam at hospital discharge. Imaging performed near discharge appears to be more predictive than neuroimaging obtained during the acute presentation of disease.

Are additional laboratory studies available; even some that are not widely available?

Various pro- and anti-inflammatory mediators have been identified in patients with sepsis, including CRP, TNF-α, IL-1β, IL-8 and IL-10. The majority of these regulatory cytokines are not readily available for testing in routine clinical laboratories.

How can septicemia be prevented?

Prevention of Late Onset Group B Streptococcus Disease

The majority of late onset infections in neonates occur in hospitalized and prematurely born infants, with the notable exception of late onset Group B Streptococcus. Intrapartum antibiotic administration to GBS colonized mothers has decreased the rate of early onset GBS disease by 80%; however, this treatment has no effect on the rates of late onset GBS disease. Researchers are working to develop an effective vaccine to prevent GBS disease. In preliminary studies, vaccination decreased the rates of maternal GBS colonization and increased the amount of transplacental anti-GBS antibody to the developing fetus.

Prevention of blood stream infections

Hand antisepsis is the single most cost-effective strategy to reduce the risk of hospital-acquired infections. The cost of hand antisepsis is extremely low. Compliance by all healthcare workers continues to be a challenge. Most blood stream infections in this setting are catheter-related; therefore, bundled care plans to minimize CRBSI focus on hand antisepsis, judicious use of broad spectrum antibiotics, and minimizing the number of catheter days. In addition, bundled care plans for catheter care and maintenance include: dedicated insertion team, site antisepsis, dressing changes, minimization of catheter manipulations, and minimization of line entry

Prevention of ventilator-associated pneumonia (VAP)

There are limited data regarding effective strategies for the prevention of VAP in the neonatal population; therefore, many guidelines have been extrapolated from adult and older pediatric populations.

Most occurrences of VAP are associated with colonization of equipment used for respiratory management of the neonate with respiratory disease. Key prevention strategies to prevent VAP include: hand antisepsis, daily assessment of extubation readiness, elevation of head of bed 30 degrees to prevent aspiration, comprehensive mouth care to minimize colonization, closed system suction devices, heated ventilator circuits, and systematic ventilator circuit changes.

Prophylactic drugs and vaccines

The use of prophylactic antibiotics and antibiotic lock therapy have not been shown to be effective in the prevention of CRBSI in neonatal populations. Prophylactic fluconazole has been shown to be effective in reducing rates of colonization with Candida. The use of fluconazole is recommended in targeted high-risk populations, particularly at sites with high rates of systemic candidiasis.

Behavioral factors

Nursery design can impact the risk of hospital-acquired infection (HAI) in neonatal populations. Efforts to minimize overcrowding and maintain a higher staff-to-patient ratio have both been shown to decrease the risk for HAI. Easy accessibility to hand antisepsis agents in a variety of forms is critically important. Dedicated catheter insertion teams and standardization of clinical practice pathways for care and maintenance of catheters are vital components of decreasing the incidence of CRBSI in neonates. (See Table V.)

Table V.n

Prevention of Nosocomial Infections in NICU

Genetic counseling

Recent evidence suggests that response and risk for infection may be related to specific newly recognized genetic markers. However, these are not readily available in a clinical setting, and they are not modifiable.

Nutritional factors

Early introduction of trophic feedings has been associated with improved longer term feeding tolerance and decreased catheter days. Breastfeeding is associated with a reduced risk of infection and necrotizing enterocolitis (NEC) in premature infants.

What is the evidence?

Schelonka, RL, Chai, MK, Yoder, BA. “Volume of blood required to detect common neonatal pathogens”. J Pediatr. vol. 129. 1996. pp. 275-8.

Garcia-Prats, JA, Cooper, TR, Schneider, VF. “Rapid detection of microorganisms in blood cultures of newborn infants utilizing an automated blood culture system”. Pediatircs. vol. 105. pp. 523-7.

Kumar, Y, Qunibi, M, Neal, TJ, Yoxall, CW. “Time to positivity of neonatal blood cultures”. Arch Dis Child Fetal Neonatal Ed. vol. 85. 2001. pp. F182-6.

Xanthou, M. “Leucocyte blood picture in ill newborn babies”. Arch Dis Child. vol. 47. 1972. pp. 741-6.

Stoll, BJ, Hansen, N, Fanaroff, AA. ” To tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants”. Pediatrics. vol. 113. 2004. pp. 1181-6.

Benjamin, DK, Stoll, BJ, Gantz, MG. “Neonatal candidiasis: epidemiology, risk factors, and clinical judgment”. Pediatrics. vol. 126. 2010. pp. E865-73.

Vohr, BR, Wright, LL, Dusick, AM. “Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994”. Pediatrics. vol. 105. 2000. pp. 1216-26.

Benjamin, DK, Stoll, BJ, Fanaroff, AA. “Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months”. Pediatrics. vol. 117. 2006. pp. 84-92.

Schelonka, RL, Maheshwari, A, Carlo, WA. “T cell cytokines and the risk of blood stream infection in extremely low birth weight infants”. Cytokine. vol. 53. 2011. pp. 249-55.

Adams-Chapman, I, Stoll, BJ. “Prevention of nosocomial infections in the neonatal intensive care unit”. Curr Opin Pediatr. vol. 14. 2002. pp. 157-64.

Carlo, WA, McDonald, SA, Tyson, JE. “Cytokines and neurodevelopmental outcomes in extremely low birth weight infants”. J Pediatr. vol. 159. 2011. pp. 919-25. (This study showed that cerebral palsy in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.)

Horan, T, Andrus, CM, Dudeck, MA. “CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting”. Am J Infect Control. vol. 36. 2008. pp. 309-32.

Kestenbaum, LA., Ebberson, J, Zorc, JJ. “Defining cerebrospinal fluid white blood cell count reference values in neonates and young infants”. Pediatrics. vol. 125. 2010. pp. 257-64. (These investigators determined age-specific CSF WBC reference values in a large cohort of neonates and young infants that can be used to interpret accurately the results of lumbar punctures in this population.)

Libster, R, Edwards, KM, Levent, F. “Long-term outcomes of group B streptococcal meningitis”. Pediatrics. vol. 130. 2012. pp. e8-e15.

Mermel, LA, Allon, M, Bouza, E. “Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 49. 2009. pp. 1-45.

Schelonka, RL, Yoder, BA, desJardins, SE. “Peripheral leukocyte count and leukocyte indexes in healthy newborn term infants”. J Pediatr. vol. 125. 1994. pp. 603-6.

Stoll, BJ, Hansen, N, Fanaroff, AA. “Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network”. Pediatrics. vol. 110. 2002. pp. 285-91. (This study showed that late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.)

Stoll, BJ, Hansen, NI, Adams-Chapman, I. “Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection”. JAMA. vol. 292. 2004. pp. 2357-65. (This large cohort study suggests that neonatal infections among ELBW infants are associated with poor neurodevelopmental and growth outcomes in early childhood. Additional studies are needed to elucidate the pathogenesis of brain injury in infants with infection so that novel interventions to improve these outcomes can be explored.)

Ongoing controversies regarding etiology, diagnosis, treatment

There are few ongoing controversies regarding etiology of late onset septicemia in neonates.

Researchers continue to investigate the utility and feasibility of measuring various cytokines to predict the risk of infection in neonates. Many hospitals do not have the capability to routinely measure many of the cytokines under clinical investigation.

Much of the work on late onset septicemia has focused on prevention and treatment strategies. Some strategies used in adult populations have not proven effective in neonates at preventing the risk for blood stream infections.

Prophylactic antibiotic locks to prevent central line infections seemed promising, but have not been shown to be efficacious in neonates.

The use of IVIG has not been shown to be effective in changing outcomes in newborns with clinical signs of sepsis, likely because of the low levels of circulating antibody to the pathogens that typically cause disease in neonates. Researchers are evaluating the benefits of organism-specific immune globulin preparations.

The use of probiotics in low birth weight populations to prevent infection remains controversial. Current data are limited by small sample size and variability in the products used. Even though probiotics are being used, routine use is not supported due to concerns regarding efficacy and safety.

Breastfeeding has been associated with a decreased risk of late onset infections and necrotizing enterocolitis among preterm infants. Donor milk banks have been proposed as an alternative to preterm formula for those infants who do not have maternal milk available. Various researchers are investigating the feasibility and cost-effectiveness of the routine use of donor milk in these populations.