Professional Documents
Culture Documents
CLINICAL REPORT
KEY WORDS
early-onset sepsis, antimicrobial therapy, group B streptococcus,
meningitis, gastric aspirate, tracheal aspirate, chorioamnionitis,
sepsis screen, blood culture, lumbar puncture, urine culture,
body surface cultures, white blood count, acute phase reactants,
prevention strategies
ABBREVIATIONS
CFUcolony-forming units
CRPC-reactive protein
CSFcerebrospinal uid
GBSgroup B streptococci
I/Timmature to total neutrophil (ratio)
PMNpolymorphonuclear leukocyte
PPROMpreterm premature rupture of membranes
This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors
have led conict of interest statements with the American
Academy of Pediatrics. Any conicts have been resolved through
a process approved by the Board of Directors. The American
Academy of Pediatrics has neither solicited nor accepted any
commercial involvement in the development of the content of
this publication.
The guidance in this report does not indicate an exclusive
course of treatment or serve as a standard of medical care.
Variations, taking into account individual circumstances, may be
appropriate.
INTRODUCTION
Suspected sepsis is one of the most common diagnoses made in the
NICU.1 However, the signs of sepsis are nonspecic, and inammatory
syndromes of noninfectious origin mimic those of neonatal sepsis. Most
infants with suspected sepsis recover with supportive care (with or
without initiation of antimicrobial therapy). The challenges for clinicians
are threefold: (1) identifying neonates with a high likelihood of sepsis
promptly and initiating antimicrobial therapy; (2) distinguishing highrisk healthy-appearing infants or infants with clinical signs who do not
require treatment; and (3) discontinuing antimicrobial therapy once
sepsis is deemed unlikely. The purpose of this clinical report is to
provide a practical and, when possible, evidence-based approach to the
diagnosis and management of early-onset sepsis, dened by the National Institute of Child Health and Human Development and Vermont
Oxford Networks as sepsis with onset at 3 days of age.
1006
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0541
doi:10.1542/peds.2012-0541
All clinical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reafrmed,
revised, or retired at or before that time.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2012 by the American Academy of Pediatrics
PATHOGENESIS AND
EPIDEMIOLOGY OF EARLY-ONSET
SEPSIS
Before birth, the fetus optimally is
maintained in a sterile environment.
Organisms causing early-onset sepsis
ascend from the birth canal either
when the amniotic membranes rupture
or leak before or during the course of
labor, resulting in intra-amniotic infection.2 Commonly referred to as chorioamnionitis, intra-amniotic infection
indicates infection of the amniotic uid,
membranes, placenta, and/or decidua.
Group B streptococci (GBS) can also
enter the amniotic uid through occult
tears. Chorioamnionitis is a major risk
factor for neonatal sepsis. Sepsis can
begin in utero when the fetus inhales
or swallows infected amniotic uid.
The neonate can also develop sepsis in
the hours or days after birth when
colonized skin or mucosal surfaces are
compromised. The essential criterion
for the clinical diagnosis of chorioamnionitis is maternal fever. Other
criteria are relatively insensitive. When
dening intra-amniotic infection (chorioamnionitis) for clinical research
studies, the diagnosis is typically based
on the presence of maternal fever of
greater than 38C (100.4F) and at least
two of the following criteria: maternal
leukocytosis (greater than 15 000 cells/
mm3), maternal tachycardia (greater
than 100 beats/minute), fetal tachycardia (greater than 160 beats/minute),
uterine tenderness, and/or foul odor of
the amniotic uid. These thresholds are
associated with higher rates of neonatal and maternal morbidity.
Nonetheless, the diagnosis of chorioamnionitis must be considered even
when maternal fever is the sole abnormal nding. Although fever is common
in women who receive epidural anesthesia (15%20%), histologic evidence
of acute chorioamnionitis is very common in women who become febrile
after an epidural (70.6%).3 Furthermore,
1007
1008
Platelet Counts
Acute-Phase Reactants
A wide variety of acute-phase reactants
have been evaluated in neonates with
suspected bacterial sepsis. However, only
C-reactive protein (CRP) and procalcitonin concentrations have been investigated in sufciently large studies.72,73 CRP
concentration increases within 6 to 8
hours of an infectious episode in neonates and peaks at 24 hours.74,75 The
sensitivity of a CRP determination is
low at birth, because it requires an
inammatory response (with release
of interleukin-6) to increase CRP concentrations.76 The sensitivity improves
dramatically if the rst determination
is made 6 to 12 hours after birth. Benitz
et al have demonstrated that excluding
a value at birth, 2 normal CRP determinations (824 hours after birth and
24 hours later) have a negative predictive accuracy of 99.7% and a negative likelihood ratio of 0.15 for proven
neonatal sepsis.76 If CRP determinations remain persistently normal, it is
strong evidence that bacterial sepsis is
unlikely, and antimicrobial agents can be
safely discontinued. Data are insufcient
to recommend following sequential CRP
1009
2. Unknown maternal colonization status with gestation <37 weeks, rupture of membranes >18 hours, or
temperature >100.4F (>38C)
3. GBS bacteriuria during the current
pregnancy
4. Previous infant with invasive GBS
disease
Management guidelines for the newborn infant have been published93 and
are available online (http://www.cdc.
gov/groupbstrep/guidelines/index.html).
CLINICAL CHALLENGES
Challenge 1: Identifying Neonates
With Clinical Signs of Sepsis With
a High Likelihood of Early-Onset
Sepsis Who Require Antimicrobial
Agents Soon After Birth
Most infants with early-onset sepsis
exhibit abnormal signs in the rst 24
FIGURE 1
Evaluation of asymptomatic infants <37 weeks gestation with risk factors for sepsis. aThe diagnosis
of chorioamnionitis is problematic and has important implications for the management of the
newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical
colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with
a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, response to treatment, and laboratory results. IAP, intrapartum antimicrobial prophylaxis; WBC, white
blood cell; Diff, differential white blood cell count.
1011
initiating antimicrobial treatment generally decreases with increasing numbers of risk factors for infection and
greater degrees of prematurity. Suggested algorithms for management of
healthy-appearing, high-risk infants are
shown in Figs 1, 2, and 3. Screening
blood cultures have not been shown to
be of value.21
CONCLUSIONS
The diagnosis and management of neonates with suspected early-onset sepsis
are based on scientic principles modied by the art and experience of the
practitioner. The following are wellestablished concepts related to neonatal sepsis:
1. Neonatal sepsis is a major cause of
morbidity and mortality.
2. Diagnostic tests for early-onset
sepsis (other than blood or CSF cultures) are useful for identifying infants with a low probability of sepsis
but not at identifying infants likely to
be infected.
3. One milliliter of blood drawn before
initiating antimicrobial therapy is
needed to adequately detect bacteremia if a pediatric blood culture bottle is used.
FIGURE 2
Evaluation of asymptomatic infants 37 weeks gestation with risk factors for sepsis. The diagnosis
of chorioamnionitis is problematic and has important implications for the management of the
newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical
colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with
a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, response to treatment, and laboratory results. WBC, white blood cell; Diff, differential white blood cell
count.
a
FIGURE 3
Evaluation of asymptomatic infants 37 weeks gestation with risk factors for sepsis (no
chorioamnionitis). aInadequate treatment: Dened as the use of an antibiotic other than penicillin,
ampicillin, or cefazolin or if the duration of antibiotics before delivery was <4 h. bDischarge at 24 h
is acceptable if other discharge criteria have been met, access to medical care is readily accessible,
and a person who is able to comply fully with instructions for home observation will be present. If
any of these conditions is not met, the infant should be observed in the hospital for at least 48 h and
until discharge criteria are achieved. IAP, intrapartum antimicrobial prophylaxis; WBC, white blood
cell; Diff, differential white blood cell count.
1012
Richard A. Polin, MD
LEAD AUTHOR
Vinod K. Bhutani, MD
FORMER LIAISON
LIAISONS
CAPT Wanda Denise Bareld, MD, MPH Centers
for Disease Control and Prevention
George Macones, MD American College of
Obstetricians and Gynecologists
STAFF
Jim Couto, MA
REFERENCES
1. Escobar GJ. The neonatal sepsis work-up:
personal reections on the development of
an evidence-based approach toward newborn
infections in a managed care organization.
Pediatrics. 1999;103(1, suppl E):360373
2. Polin RA, St Geme JW III. Neonatal sepsis.
Adv Pediatr Infect Dis. 1992;7:2561
3. Riley LE, Celi AC, Onderdonk AB, et al. Association of epidural-related fever and noninfectious inammation in term labor. Obstet
Gynecol. 2011;117(3):588595
4. Stoll BJ, Hansen NI, Bell EF, et al; Eunice
Kennedy Shriver National Institute of Child
Health and Human Development Neonatal
Research Network. Neonatal outcomes of
extremely preterm infants from the NICHD
Neonatal Research Network. Pediatrics.
2010;126(3):443456
5. Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin
Perinatol. 2010;37(2):339354
6. Gibbs RS, Duff P. Progress in pathogenesis
and management of clinical intraamniotic
infection. Am J Obstet Gynecol. 1991;164(5
pt 1):13171326
7. Romero R, Quintero R, Oyarzun E, et al.
Intraamniotic infection and the onset of
labor in preterm premature rupture of the
membranes. Am J Obstet Gynecol. 1988;159
(3):661666
8. DiGiulio DB, Romero R, Kusanovic JP, et al.
Prevalence and diversity of microbes in the
amniotic uid, the fetal inammatory response,
and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J
Reprod Immunol. 2010;64(1):3857
9. DiGiulio DB, Romero R, Amogan HP, et al.
Microbial prevalence, diversity and abundance in amniotic uid during preterm
labor: a molecular and culture-based investigation. PLoS ONE. 2008;3(8):e3056
10. Viscardi RM. Ureaplasma species: role in
diseases of prematurity. Clin Perinatol.
2010;37(2):393409
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
1013
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
1014
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
at: www.pediatrics.org/cgi/content/full/123/
6/e967
Rajesh NT, Dutta S, Prasad R, Narang A. Effect
of delay in analysis on neonatal cerebrospinal
uid parameters. Arch Dis Child Fetal
Neonatal Ed. 2010;95(1):F25F29
Christensen RD, Rothstein G, Hill HR, Hall RT.
Fatal early onset group B streptococcal
sepsis with normal leukocyte counts.
Pediatr Infect Dis. 1985;4(3):242245
Engle WD, Rosenfeld CR. Neutropenia in
high-risk neonates. J Pediatr. 1984;105(6):
982986
Manroe BL, Weinberg AG, Rosenfeld CR,
Browne R. The neonatal blood count in
health and disease. I. Reference values for
neutrophilic cells. J Pediatr. 1979;95(1):8998
Schelonka RL, Yoder BA, desJardins SE, Hall
RB, Butler J. Peripheral leukocyte count
and leukocyte indexes in healthy newborn
term infants. J Pediatr. 1994;125(4):603606
Mouzinho A, Rosenfeld CR, Snchez PJ, Risser
R. Revised reference ranges for circulating
neutrophils in very-low-birth-weight neonates.
Pediatrics. 1994;94(1):7682
Schmutz N, Henry E, Jopling J, Christensen
RD. Expected ranges for blood neutrophil
concentrations of neonates: the Manroe
and Mouzinho charts revisited. J Perinatol.
2008;28(4):275281
Christensen RD, Rothstein G. Pitfalls in the
interpretation of leukocyte counts of newborn
infants. Am J Clin Pathol. 1979;72(4):608611
Lambert RM, Baer VL, Wiedmeier SE, Henry
E, Burnett J, Christensen RD. Isolated elevated blood neutrophil concentration at
altitude does not require NICU admission if
appropriate reference ranges are used.
J Perinatol. 2009;29(12):822825
Christensen RD, Rothstein G. Exhaustion of
mature marrow neutrophils in neonates
with sepsis. J Pediatr. 1980;96(2):316318
Schelonka RL, Yoder BA, Hall RB, et al. Differentiation of segmented and band neutrophils during the early newborn period.
J Pediatr. 1995;127(2):298300
Lloyd BW, Oto A. Normal values for mature
and immature neutrophils in very preterm
babies. Arch Dis Child. 1982;57(3):233235
Gerdes JS, Polin RA. Sepsis screen in neonates with evaluation of plasma bronectin. Pediatr Infect Dis J. 1987;6(5):443446
Newman TB, Puopolo KM, Wi S, Draper D,
Escobar GJ. Interpreting complete blood
counts soon after birth in newborns at risk
for sepsis. Pediatrics. 2010;126(5):903909
Rozycki HJ, Stahl GE, Baumgart S. Impaired
sensitivity of a single early leukocyte count
in screening for neonatal sepsis. Pediatr
Infect Dis J. 1987;6(5):440442
79. Chiesa C, Natale F, Pascone R, et al. C reactive protein and procalcitonin: reference
intervals for preterm and term newborns
during the early neonatal period. Clin Chim
Acta. 2011;412(11-12):10531059
80. Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in
hospitalized patients. Clin Infect Dis. 2011;
52(10):12321240
81. Rodwell RL, Leslie AL, Tudehope DI. Early
diagnosis of neonatal sepsis using a hematologic scoring system. J Pediatr. 1988;
112(5):761767
82. Baker CN, Thornsberry C, Facklam RR. Synergism, killing kinetics, and antimicrobial
susceptibility of group A and B streptococci.
Antimicrob Agents Chemother. 1981;19(5):
716725
83. MacGowan A, Wootton M, Bowker K, Holt
HA, Reeves D. Ampicillin-aminoglycoside interaction studies using Listeria monocytogenes. J Antimicrob Chemother. 1998;41
(3):417418
84. Bryan CS, John JF, Jr, Pai MS, Austin TL.
Gentamicin vs cefotaxime for therapy of neonatal sepsis. Relationship to drug resistance.
Am J Dis Child. 1985;139(11):10861089
85. Manzoni P, Farina D, Leonessa M, et al. Risk
factors for progression to invasive fungal
infection in preterm neonates with fungal
colonization. Pediatrics. 2006;118(6):2359
2364
86. Bgu P, Floret D, Mallet E, et al. Pharmacokinetics and clinical evaluation of cefotaxime in children suffering with purulent
meningitis. J Antimicrob Chemother. 1984;
14(suppl B):161165
87. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, Wilson
Christopher B, Nizet V, eds. Infectious Diseases of the Fetus and Newborn Infant. 7th
ed. Philadelphia, PA: Saunders; 2010:222275
88. Pickering LK, Baker CJ, Kimberlin DW, Long
SS, eds. Red Book: 2009 Report of the
Committee on Infectious Diseases. 28th ed.
Elk Grove Village, IL: American Academy of
Pediatrics; 2009
89. Cordero L, Ayers LW. Duration of empiric
antibiotics for suspected early-onset sepsis in extremely low birth weight infants.
Infect Control Hosp Epidemiol. 2003;24(9):
662666
90. Cotten CM, Taylor S, Stoll B, et al; NICHD
Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of
necrotizing enterocolitis and death for
extremely low birth weight infants. Pediatrics. 2009;123(1):5866
91. Kuppala VS, Meinzen-Derr J, Morrow AL,
Schibler KR. Prolonged initial empirical
antibiotic treatment is associated with adverse outcomes in premature infants.
J Pediatr. 2011;159(5):720725
92. Alexander VN, Northrup V, Bizzarro MJ.
Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr. 2011;159(3):
392397
93. Centers for Disease Control and Prevention.
Prevention of perinatal group B streptococcal diseaserevised guidelines from
CDC, 2010. MMWR Recomm Rep. 2010;59
(RR-10):136
1015
References
Citations
Post-Publication
Peer Reviews (P3Rs)
Subspecialty Collections
Reprints
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/129/5/1006.full.html