bacteraemia reliably.
Most negative blood cultures are true negatives.
4.1.1.2 Multiple-site blood cultures
North American epidemiologic studies often define true CoNS bacteraemia as two or more positive blood cultures from different sites. In Europe and Australia, multiple-site blood cultures are rarely performed. A retrospective study of 460 newborns with suspected sepsis reported that paired cultures from different sites were helpful in confirming infection in eight infants and excluding it in 10 infants, but the retrospective nature casts doubt on the study’s validity.5 A prospective Canadian study found discordant blood cultures for CoNS in 5 of 100 paired cultures,5 but the study design has been criticized.6 In a prospective US study of 216 neonates with suspected sepsis, 269 paired blood cultures (≥1 mL) were taken from different sites. There was one early-onset Listeria infection and 22 late-onset infections, seven with CoNS.6 Blood cultures were completely concordant for culture-negative and culture-positive infants, for both early- and late-onset sepsis and for all organisms. The authors conclude that two blood cultures from different sites are no more accurate than one blood culture of at least 1 mL volume for detecting neonatal infection.6
Blood cultures from central lines are prone to contamination, so simultaneous peripheral blood cultures should also be sent.
4.1.1.3 Time to positive blood cultures
At least 96% of positive blood cultures considered clinically significant grow within 48 hours and 97–99% within 72 hours; organisms which took >72 hours to grow are almost always contaminants.3,7-15 The higher the level of bacteraemia, the quicker the blood cultures grow, so Gram-negative bacilli grow quicker in blood cultures than Gram-positive organisms.2,7,15,16 Thus the time to positivity of blood cultures is a clinically useful surrogate measure of the level of bacteraemia and hence the likelihood of true infection.
4.1.1.4 Polymicrobial blood cultures
Polymicrobial paediatric blood cultures are usually but not always contaminated. However, a review of 15 episodes of polymicrobial blood or CSF cultures (3.9% of all culture-proven sepsis) found a significantly higher mortality associated with late-onset polymicrobial sepsis (7 of 10; 70%) than with late-onset monomicrobial sepsis (86 of 370; 23%). Group D streptococci were recovered in eight cases (53%). Five of 10 infants with late-onset polymicrobial infection had gastrointestinal foci; four of five with early-onset infection had prolonged rupture of membranes.17 A larger study compared 105 episodes of polymicrobial bacteraemia in 102 infants (10% of all neonatal bacteraemia) with episodes of bacteraemia due to a single organism, mainly CoNS.18 Infants with polymicrobial bacteraemia presented later (mean 37.5 vs. 24 days; p <; 0.001) and were more likely to have a severe underlying condition and prolonged central venous catheterization. There was no difference in outcome or mortality.18
It is potentially hazardous to assume polymicrobial cultures are contaminants. The nature of the organisms isolated may give an important clue to their origin. Gram-negative bacilli suggest bowel or urinary tract origin. Exclusive skin organisms (e.g. CoNS, particularly multiple strains, α-haemolytic streptococci, micrococci, diphtheroids), increase the likelihood of contamination. GBS, Gram-negative bacilli or Candida grown in polymicrobial blood cultures should always be treated. Similarly, an infant with severe gastrointestinal pathology who grows one or more enteric organisms should always be treated. Repeated polymicrobial blood cultures may indicate genuine pathology, but should also raise the sinister possibility of factitious infection (Munchhausen syndrome by proxy).
4.1.2 Surface cultures
The term ‘surface cultures’ can be confusing. Some use it to mean only cultures from skin (e.g. ear, umbilicus) while some also include mucosal cultures (e.g. nose, nasopharynx, rectum).
Surface cultures can guide decisions regarding antibiotic cessation in suspected early sepsis. Ear and/or umbilical swab cultures may indicate the need for continuing antibiotic therapy in blood-culture-negative infants with suspected early-onset sepsis who are heavily colonized with GBS or Listeria (see Section 5.5.1). Negative surface and systemic cultures effectively exclude early-onset sepsis.
The use of surface cultures for routine surveillance is considered in Chapter 20.
4.1.3 Lumbar puncture
This section considers whether or not to perform lumbar puncture (LP) in suspected or proven sepsis. CSF fluid microscopy, biochemistry and culture interpretation is covered in Chapter 7.
Reasons for performing an immediate LP at the time of a ‘septic screen’ include the following.
- LP is a ‘ biopsy’: a rapid Gram stain test often alters empiric antibiotic choice
- Infants with meningitis may have negative blood cultures, so delaying LP and only doing LP if blood cultures are positive will miss some infants with meningitis
Arguments for not performing an immediate LP include the following.
- Neonatal meningitis is rare
- LP is potentially harmful, for example, respiratory compromise from manipulating the infant,19 bleeding, infection
- Delaying LP, treating empirically and only doing LP on infants with positive blood cultures minimizes harms from LP
- Symptomatic infants <;72 hours old: immediate LP is strongly recommended, because the incidence of meningitis is 1–2% and about a third of infants with meningitis have negative blood cultures
- Pre-term infants with RDS and no other clinical signs of infection: LP debatable as the risk of meningitis is low, but not zero, and blood cultures do not reliably identify infants with meningitis
- Developing countries: the risk of early-onset meningitis is probably high although the data are inconclusive
- If blood cultures are positive with an organism that causes meningitis and LP was not done, we recommend LP to guide the duration of therapy
- Routine LP is strongly recommended in the evaluation of infants with suspected late-onset sepsis, because the incidence of meningitis is 1.3–4% and about a third of infants with meningitis have negative blood cultures
- In developing countries, the risk of late-onset meningitis is probably high, although data are scanty
- LP is strongly recommended for infants with late-onset sepsis and blood cultures positive with an organism that causes meningitis who had no LP, to guide the duration of therapy and prognosis
4.1.4 Urine culture
Neonatal UTI is primarily a late-onset infection. In early-onset sepsis positive urine cultures are rare and usually reflect concomitant bacteraemia with presumed embolic renal spread, rather than primary UTI.32 Urine culture is not routinely recommended in suspected early-onset sepsis.
In contrast, urine culture should be routine when evaluating infants for suspected late-onset sepsis. The incidence of neonatal UTI is 0.1–1% and may be up to 10% in low birth-weight infants. Concomitant bacteraemia is relatively uncommon, so UTI will be missed if urine culture is omitted and empiric antibiotics given. This will delay the diagnosis of any associated structural urinary tract abnormalities.
4.1.5 Gastric aspirates
Gastric aspirate microscopy for pus cells and/or bacteria has a low sensitivity (71–89%) and specificity (49–87%) for rapid diagnosis of early sepsis.37 An infant with early-onset respiratory distress whose gastric aspirate is negative for pus cells and bacteria on microscopy is at low risk for early-onset infection, which is potentially useful for deciding not to treat with empiric antibiotics. Often, however, timeliness in obtaining the microscopy result to help clinical decision-making is a problem, particularly outside normal laboratory working hours.
4.1.6 Tracheal aspirates
There is research interest in identifying the biomarkers of neutrophil activation in tracheal aspirates to predict which mechanically ventilated infants will develop sepsis.41
4.2 Rapid tests for sepsis
Various haematologic, biochemical and microbiologic tests have been studied or are being developed in order to identify rapidly infants with neonatal sepsis and also to identify non-infected infants.
A reliable abnormal test result can be used as a basis to ‘rule in’ sepsis and start empiric antibiotics. A reliable normal test can be used to ‘rule out’ sepsis.
The danger of over-reliance on a normal test result to rule out sepsis is that septic babies may be missed and treatment delayed. In clinical practice, the clinician can only afford to rely on a test or combination of tests with 100% sensitivity (i.e. identifies every infected infant) and none has been described.
There is often a trade-off between sensitivity and specificity: more sensitive tests are less specific. Combining tests as a ‘sepsis screen’ increases sensitivity at the cost of decreased specificity. Many authors have reported using sepsis screens to decrease antibiotic use by improving identification of uninfected babies. However, sepsis screens are expensive.
An arguably safer and more cost-effective approach is to start many infants on antibiotics but stop them after 48–72 hours if systemic cultures are negative (see Section 5.5.1).
4.3 Haematologic tests
4.3 1 White cell counts
Manroe’s seminal study of peripheral blood white cell counts identified early-onset neutropenia and the immature to total (I:T) neutrophil ratio as the two best predictors of neonatal infection.42
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