management and outcome of sepsis in term and late preterm infants
TRANSCRIPT
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Offi cial reprint from UpToDatewww.uptodate.com ©2015 UpToDate
Author Morven S Edwards, MD
Section EditorsLeonard E Weisman, MDSheldon L Kaplan, MD
Deputy Editor Carrie Armsby, MD, MPH
Management and outcome of sepsis in term and late preterm infants
All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Aug 2015. | This topic last updated: Jul 13, 2015.
INTRODUCTION — Sepsis is an important cause of morbidity and mortality among newborn infants. Although the
incidence of sepsis in term and late preter m infants is low, the potential for serious adverse outcomes, including
death, is of such great consequence that caregivers should have a low threshold for evaluation and treatment for
possible sepsis in neonates. The approach discussed below is consistent with guidelines published by the
American Academy of Pediatrics (AAP) and the Center for Disease Control (CDC) [1,2].
The treatment and outcome of sepsis in term and late preterm infants will be reviewed here. T he epidemiology,
clinical features, diagnosis, and evaluation of sepsis in term and late preterm infants, neonatal sepsis in preterm
infants, the management of well-appearing infants at risk for group B streptococcal infection, and the evaluation of
febrile or ill-appearing newborns are discussed separately:
TERMINOLOGY — The following terms will be used throughout this discussion on neonatal sepsis:
Neonatal sepsis is classified accor ding to the infant's age at the onset of symptoms:
SUPPORTIVE CARE — Symptomatic infants should be treated in a care setting with full cardiopulmonary
monitoring and support, because the clinical course of these infants can deteriorate rapidly. Although there are no
data demonstrating the importance of supportive care measures in neonates with sepsis, it is generally accepted
that the following supportive measures are critical components of management:
®
®
(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants".)
(See "Clinical features and diagnosis of bacterial sepsis in the preterm infant" .)
(See "Treatment and prevention of bacterial sepsis in the preterm infant".)
(See "Management of the infant whose mother has received group B streptococcal chemoprophylaxis".)
(See "Evaluation and management of fever in the neonate and young infant (younger than three months of
age)", section on 'Neonates (0 to 28 days)'.)
(See "Approach to the septic-appearing infant".)
Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested by systemic signs
of infection and isolation of a bacterial pathogen from the blood stream [ 3]. A consensus definition for
neonatal sepsis is lacking [4]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late
preterm infants", section on 'Diagnosis'.)
Term infants are those born at a gestational age of 37 weeks or greater.
Late preterm infants (also called near-term infants) are those born between 34 and 36 completed weeks of
gestation [5]. (See "Late preterm infants".)
Preterm infants are those born at less than 34 weeks of gestation [5].
Early-onset sepsis is defined as the onset of symptoms before 7 days of age, although some experts limit
the definition to infections occurring within the first 72 hours of life [ 6].
Late-onset sepsis is defined as the onset of symptoms at ≥7 days of age [6]. Similarly to early-onset
sepsis, there is variability in its definition, ranging from an onset at >72 hours of life to ≥7 days of age [6,7].
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Severely ill patients may require ventilatory, volume, and/or vasopressor support to maintain adequate oxygenation
and perfusion. (See "Mechanical ventilation in neonates" and "Etiology, clinical manifestations, and evaluation of
neonatal shock".)
ONGOING DIAGNOSTIC EVALUATION
Other diagnostic considerations — In infants with suspected sepsis, additional testing for other conditions may
be warranted based on clinical signs and symptoms (table 1). It is often difficult to differentiate neonatal sepsis
from other diseases; however, given the morbidity and mortality of neonatal sepsis, empiric antibiotic therapy
should be provided (after cultures are obtained) to infants with suspected sepsis pending definitive culture-based
diagnosis. Alternative diagnoses should be entertained when an infant with suspected sepsis has negative
cultures. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on
'Differential diagnosis'.)
Lumbar puncture — If not done during the initial evaluation, a lumbar puncture (LP) should be performed in
infants, whenever possible, with culture-proven or culture-negative clinical sepsis. Clinical signs suggestingmeningitis can be lacking and blood culture may be negative in infants with meningitis. (See "Bacterial meningitis
in the neonate: Clinical features and diagnosis".)
ANTIBIOTIC THERAPY
Whom to treat — The decision to start antibiotic therapy is based on assessment of risk factors, clinical
evaluation, and laboratory tests. Indications for empiric antibiotic therapy include (see "Clinical features,
evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Evaluation and initial
management'):
Initial empiric therapy — The initial choice of parenteral antimicrobials for suspected sepsis in term and late
preterm neonates is based on the infant's age, likely pathogens, the susceptibility patterns of organisms in a
particular nursery, and the presence of an apparent source of infection (eg, skin, joint, or bone involvement) (table
3).
Early-onset sepsis — The recommended empiric regimen for suspected early-onset sepsis in a term or late
preterm infant is ampicillin 150 mg/kg per dose intravenously (IV) every 12 hours and gentamicin 4 mg/kg per dose
IV every 24 hours [7,8]. We generally obtain baseline renal function tests (ie, blood urea nitrogen and creatinine
levels) at the initiation of treatment with gentamicin. Serum gentamicin levels should be obtained in infants
receiving a full course of antibiotics, but are not required if a treatment course of only 48 hours is anticipated and
Maintaining adequate oxygenation and perfusion (see "Oxygen monitoring and therapy in the newborn")
Prevention of hypoglycemia and metabolic acidosis (see "Management and outcome of neonatal
hypoglycemia")
Maintenance of normal fluid and electrolyte status (see "Fluid and electrolyte therapy in newborns")
Ill-appearance (see "Approach to the septic-appearing infant")
Concerning symptoms, including temperature instability, or respiratory, cardiocirculatory, or neurologic
symptoms (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants",
section on 'Clinical manifestations')
Cerebrospinal fluid (CSF) pleocytosis (white blood cell [WBC] cell count of >20 to 30 cells/microL) (table 2)
(see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of CSF')
Confirmed or suspected maternal chorioamnionitis (see "Clinical features, evaluation, and diagnosis of
sepsis in term and late preterm infants", section on 'Maternal risk factors' )
Positive blood, urine, or CSF culture (see "Clinical features, evaluation, and diagnosis of sepsis in term and
late preterm infants", section on 'Blood culture')
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renal function is normal [3,7].
The combination of ampicillin and gentamicin is effective in treating most common pathogens that cause early-
onset sepsis, including group B Streptococcus (GBS), Listeria, Enterococcus, and most isolates of Escherichia
coli (E. coli ) (table 4) [1,9].
In a national surveillance study (2006 to 2008), 94 percent of all isolates in neonates were susceptible to the
combination of penicillin and gentamicin [10]. In a 10-year review from a single center, 90 percent of early-onset
sepsis pathogens in term and late preterm infants were susceptible to ampicillin and/or gentamicin [11]. Among six
infants with early-onset S. aureus bacteremia that was not susceptible to ampicillin and gentamicin, there were nocomplications before or after antibiotic therapy was adjusted based upon antibiotic susceptibility.
Ampicillin and gentamicin are preferred over ampicillin and a third-generation cephalosporin (eg, cefotaxime) based
upon the following:
The addition of a third-generation cephalosporin to the regimen of ampicillin and gentamicin is warranted for infantswith suspected meningitis and critically ill neonates with risk factors associated with ampicillin-resistant infections
(ie, prolonged rupture of membranes and/or prolonged antenatal maternal ampicillin treatment).
Late-onset sepsis — The choice of empiric therapy for late-onset sepsis depends upon whether the infant is
admitted from the community, and thus is at lower risk for infection caused by a multidrug-resistant pathogen, or is
hospitalized since birth and thus at a higher risk.
Admitted from the community — Neonates admitted from the community are at lower risk for infection
caused by a multidrug-resistant pathogen than are infants who remain hospitalized since birth. The combination of
ampicillin and gentamicin or ampicillin and cefotaxime are regimens for empiric treatment of sepsis without an
apparent focus of infection in this setting (table 3) [6].
Ampicillin and gentamicin is generally the preferred regimen; however, local antibiotic resistance patterns must be
considered. The dosing for ampicillin is 75 mg/kg per dose intravenously every six hours; the dosing of gentamicin
is 4 mg/kg per dose intravenously every 24 hours [7,8]. We generally obtain baseline renal function tests (ie, blood
urea nitrogen and creatinine levels) at the initiation of treatment with gentamicin. Serum gentamicin levels should
be obtained in infants receiving a full course of antibiotics, but are not required if a treatment course of only 48
hours is anticipated and renal function is normal [3,7].
In a national surveillance study (2006 to 2008), 96 percent of isolates from late-onset bacteremia were susceptible
to the combination of amoxicillin and gentamicin [10]. The addition of a third-generation cephalosporin to an
ampicillin and gentamicin regimen is warranted for neonates with suspected meningitis. (See 'Special
The regimen of ampicillin and a third-generation cephalosporin is not more effective than the combination of
ampicillin and gentamicin [12].
The emergence of cephalosporin-resistant gram-negative organisms (eg, Enterobacter cloacae, Klebsiella,
and Serratia species) can occur when cefotaxime is used routinely [1,13].
Ampicillin and gentamicin are synergistic in treating infections caused by GBS and Listeria monocytogenes.Cephalosporins are not active against L. monocytogenes.
In a large cohort study, infants who received ampicillin plus cefotaxime had a 1.5-fold increase in mortality
compared with those treated with ampicillin plus gentamicin (4.2 versus 1.9 percent, adjusted odds ratio 1.5,
95% CI 1.4-1.7) [12].
Ceftriaxone is highly bound to albumin and appears to displace bilirubin [14,15]. Although displacement of
free bilirubin by ceftriaxone has not been reported, avoidance of ceftriaxone in neonates at risk for acute
bilirubin encephalopathy is recommended [1]. (See "Clinical manifestations of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.)
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circumstances' below.)
Hospitalized since birth — Infants who continue to be hospitalized since birth are at higher risk for
multidrug-resistant organisms, and therefore vancomycin is substituted for ampicillin (table 3). For infants >7 days
of life, the dosing of vancomycin is dependent on postmenstrual age (PMA) [8]:
Special circumstances — Alternative regimens based upon specific clinical circumstances include thefollowing (table 3):
Culture-proven sepsis — In neonates with culture-proven sepsis, the usual course of therapy is 10 days
[1,3,13,17,18]. Longer treatment courses may be warranted if a specific focus of infection is identified (eg,
meningitis, osteomyelitis, or septic arthritis). Antimicrobial therapy should be altered based upon the susceptibility
profile of the pathogen isolated.
Pathogen-specific therapy — Guidelines for the treatment of the most common causative organisms of
neonatal sepsis are (table 3):
Group B streptococcus — The drug of choice for GBS is penicillin. Thus, when GBS is identified, and
resolution of bacteremia is documented by a repeat blood culture and, in infants with meningitis, the CSF is sterile,
we recommend discontinuing gentamicin and continuing therapy with penicillin G alone (table 5A-B). (See "Group
B streptococcal infection in neonates and young infants", section on 'Definitive therapy'.)
Escherichia coli — In patients with Escherichia coli (E. coli ) sepsis sensitive to ampicillin who have
improved clinically and in whom meningitis has been excluded, ampicillin monotherapy is administered for a 10-
day course.
For patients with ampicillin-resistant E. coli , the choice of definitive therapy is based upon the susceptibility profile.
Cefotaxime is often employed if the isolate is susceptible.
Other gram-negative bacilli — Nonmeningeal infections caused by E. coli , Klebsiella, Proteus,
Salmonella, or Shigella should be treated with a single agent, based upon the antimicrobial susceptibility profile.
30 to 37 weeks PMA – 15 mg/kg per dose every 12 hours
>37 weeks PMA – 15 mg/kg per dose every 8 hours
Suspected meningitis – When lumbar puncture suggests meningitis, cefotaxime should be included in the
regimen to provide an extended spectrum for enteric gram-negative rods and for optimal activity in the CSF
against pneumococci. Treatment of bacterial meningitis in neonates is discussed in detail separately. (See
"Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empirical therapy'.)
Suspected pneumonia − Empiric regimens for treatment of infants with a pulmonary focus of infection include
ampicillin and gentamicin, ampicillin and cefotaxime, vancomycin and cefotaxime, or vancomycin and
gentamicin. Treatment of pneumonia in neonates is discussed in detail separately. (See "Neonatal
pneumonia", section on 'Treatment'.)
If there is a focus of infection involving the soft tissues, skin, joints, or bones (in which case S. aureus is a
likely pathogen), vancomycin should be substituted for ampicillin [16]. In a toxic-appearing infant, nafcillin
should also be added.
If intravascular catheter-related infection is a concern, treatment should be initiated with vancomycin and
gentamicin to provide empiric coverage for coagulase-negative staphylococci, S. aureus, and gram-negative
bacteria.
If infection is thought to arise from the gastrointestinal tract (eg, anaerobic bacteria), clindamycin or another
suitable agent, such as metronidazole, should be added to the therapeutic regimen to improve coverage for
these pathogens.
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Antimicrobial treatment for infections caused by Enterobacter , Serratia, or Pseudomonas should be selected based
upon the susceptibility profile of the organism.
Infections caused by multidrug-resistant gram-negative bacilli, including those caused by extended-spectrum beta-
lactamase-producing organisms, or those with hyperproduction of beta-lactamases, should be treated with
meropenem.
Listeria monocytogenes — The combination of ampicillin and gentamicin is used for initial therapy.
Treatment with both agents is more effective than ampicillin alone in vitro and in animal models of Listeria
infection. Cephalosporins are not active against L. monocytogenes. Duration of therapy usually is 10 days. (See"Treatment, prognosis, and prevention of Listeria monocytogenes infection", section on 'Antibiotic regimens' .)
Staphylococcus species — Directed therapy for infection caused by staphylococci is determined by the
sensitivity of the isolate to specific antibiotic agents:
Probable but unproven sepsis — In infants with a negative blood culture but a clinical status that remains
concerning for a systemic infection (eg, ongoing temperature instability; ongoing respiratory, cardiocirculatory, or
neurologic symptoms not explained by other conditions; or laboratory abnormalities suggestive of sepsis),antibiotic therapy can be extended for as long as a total of 5 to 10 days.
After 48 hours, the empiric regimen is altered based upon whether or not meningitis has been excluded:
Alternative diagnoses should also be entertained when an infant with suspected sepsis has negative cultures
(table 1). Antibiotics should be discontinued when another diagnosis is established. (See "Clinical features,
evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Differential diagnosis'.)
Infection unlikely — Empiric antibiotics are initiated in many infants with maternal risk factors, abnormal
laboratory values, and/or mild to moderate symptoms that subsequently resolve. Sepsis is unlikely in these infants
if they remain well and the blood culture is sterile at 48 hours. Empiric antibiotic therapy should be discontinued
after 48 hours in these neonates [1,19].
Response to therapy — In most cases, symptomatic infants with proven sepsis improve clinically within 24 to 48
hours.
In infants with bacteremia, a repeat blood culture should be obtained after 24 to 48 hours of therapy to document
S. aureus – Vancomycin or, in a toxic-appearing infant, vancomycin plus nafcillin should be employed for S.
aureus infection until the susceptibility profile is available. The regimen then should be adjusted according to
the susceptibility profile:
Methicillin-susceptible S. aureus (MSSA) – Treatment of MSSA infection should be completed with
nafcillin. Cefazolin is an alternative for treatment of most MSSA infections outside the central nervous
system (CNS) and not involving endocarditis. (See "Staphylococcus aureus bacteremia in children:Management and outcome".)
•
Methicillin-resistant S. aureus (MRSA) – Treatment should be completed with vancomycin. (See
"Methicillin-resistant Staphylococcus aureus in children: Treatment of invasive infections", section on
'Treatment of neonates'.)
•
Coagulase-negative staphylococci – Coagulase-negative staphylococcal infections require treatment with
vancomycin.
If meningitis has been excluded, the ampicillin regimen can be changed to 75 mg/kg every 12 hours.
If lumbar puncture has not been performed, ampicillin should be continued at a meningitic dose.
Management of infants with cerebrospinal fluid (CSF) pleocytosis and/or positive CSF culture is discussed
separately. (See "Bacterial meningitis in the neonate: Treatment and outcome" .)
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sterility. Failure to sterilize the bloodstream suggests that the antimicrobial(s) chosen are not active against the
infecting pathogen or that there is an unrecognized focus of infection. Consultation with a pediatric infectious
disease specialist may be warranted.
ADJUNCTIVE THERAPIES — The following adjunctive immunotherapeutic interventions have been studied in
neonatal sepsis, but should NOT be routinely administered as they have not been shown to conclusively improve
outcomes [17,18,20]:
PREVENTION — The primary intervention to prevent neonatal sepsis is the use of intrapartum antibiotic
prophylaxis (IAP) in mothers with group B streptococcal (GBS) colonization and other risk factors. Although IAP
has resulted in a decrease in the incidence of early-onset GBS invasive neonatal infection, it has not had a similar
impact on the rate of late-onset GBS disease. (See "Neonatal group B streptococcal disease: Prevention" and
"Group B streptococcal infection in neonates and young infants", section on 'Epidemiology' .)
Comprehensive prevention of neonatal sepsis will require a multi-interventional program including effectivematernal vaccination, reduction in preterm delivery, and limited exposure of term infants to potential pathogens.
(See "Vaccines for the prevention of group B streptococcal disease" .)
OUTCOME — Overall mortality in term and late preterm infants with neonatal sepsis is approximately 2 to 4
percent [12,28]. Mortality estimates vary depending on gestational age of the infant (lower gestational age is
associated with higher mortality), pathogen (E. coli is associated with higher mortality than GBS), and sepsis
definition (lower mortality rates tend to be reported if infants with culture-negative clinical sepsis are included
compared with cases of culture-proven sepsis only).
Mortality rates for GBS sepsis in term infants after the introduction of IAP and routine use of empirical antibiotic
therapy range from 2 to 3 percent for early-onset disease and 1 to 2 percent for late-onset disease. The risk of
mortality is higher in infants with birth weight less than 2500 g, absolute neutrophil count less than 1500
cells/microL, hypotension, apnea, and pleural effusion [29]. (See "Group B streptococcal infection in neonates and
young infants", section on 'Outcome'.)
The risk of mortality is particularly high in neonates with early-onset sepsis caused by E. coli . Estimated mortality
rates for term neonates with E. coli sepsis are 6 to 10 percent [9,28,30].
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SUMMARY AND RECOMMENDATIONS
Intravenous immunoglobulin (IVIG) infusions [21,22]
Granulocyte transfusions [23]
Granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) [ 24,25]
Pentoxifylline [26]
Lactoferrin [27]
th th
th th
Basics topics (see "Patient information: Sepsis in newborn babies (The Basics)")
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Although the incidence of sepsis in term and late preterm infants is low, the potential for serious adverse
outcomes, including death, is of such great consequence that caregivers should have a low threshold for
evaluation and treatment for possible sepsis. (See 'Introduction' above.)
Supportive care for symptomatic infants is delivered in an intensive care setting to ensure adequate
oxygenation, perfusion, and maintenance of normal fluid and electrolyte balance, especially in severely
affected patients. (See 'Supportive care' above.)
Indications for empiric antibiotic therapy include any of the following:
Ill-appearance (see "Approach to the septic-appearing infant")•
Concerning symptoms, including temperature instability, or respiratory, cardiocirculatory, or neurologic
symptoms (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants",
section on 'Clinical manifestations')
•
Cerebrospinal fluid (CSF) pleocytosis (white blood cell [WBC] cell count of >20 to 30 cells/microL)
(table 2) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on
'Interpretation of CSF')
•
Confirmed or suspected maternal chorioamnionitis (see "Clinical features, evaluation, and diagnosis of
sepsis in term and late preterm infants", section on 'Maternal risk factors' )
•
Positive blood, urine, or CSF culture (see "Clinical features, evaluation, and diagnosis of sepsis in term
and late preterm infants", section on 'Blood culture')
•
We recommend suspected neonatal sepsis be treated initially with empiric antibiotic therapy (table 3) that
provides broad coverage for the most likely pathogens (group B Streptococcus [GBS] and gram-negative
enteric organisms, including Escherichia coli [E. coli ]) (table 4) (Grade 1B).
The empiric regimen for early-onset sepsis without an apparent focus consists of ampicillin and
gentamicin. (See 'Early-onset sepsis' above.)
•
Empiric antibiotic regimens for late-onset sepsis without an apparent focus are as follows (see 'Late-
onset sepsis' above):
•
For neonates admitted from the community, we suggest ampicillin and gentamicin.-
For infants who continue to be hospitalized from birth, we suggest vancomycin and gentamicin.-
Empiric antibiotic regimens for suspected neonatal sepsis (early- or late-onset) with certain special
circumstances are as follows (see 'Special circumstances' above):
•
If there is concern of meningitis, we suggest adding cefotaxime to the regimen. (See "Bacterial
meningitis in the neonate: Treatment and outcome", section on 'Empirical therapy' .)
-
If there is concern for pneumonia, we suggest a regimen of ampicillin and cefotaxime or
vancomycin and cefotaxime.
-
If there is a focus of infection involving the soft tissues, skin, joints, or bones (in which case S.
aureus is a likely pathogen), we suggest substituting vancomycin or, in toxic-appearing infants,
vancomycin plus nafcillin for ampicillin.
-
If intravascular catheter-related infection is a concern, we suggest vancomycin and gentamicin.-
If an intestinal source for sepsis is suspected, we suggest adding clindamycin, or other suitable
antibiotic such as metronidazole.
-
Antibiotic therapy is altered based upon isolation of the causative agent and its antimicrobial susceptibility
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REFERENCES
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12. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of ampicillin and cefotaxime, compared withampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonataldeath. Pediatrics 2006; 117:67.
pattern. (See 'Pathogen-specific therapy' above.)
In infants with culture-proven sepsis, the usual course of therapy is 10 days. Longer treatment is warranted if
a specific focus of infection is identified (eg, meningitis, osteomyelitis, or septic arthritis). (See 'Culture-
proven sepsis' above.)
In well-appearing infants with negative cultures after 48 hours, empiric antibiotic therapy should be
discontinued as sepsis is unlikely in these infants. (See 'Infection unlikely' above.)
Most infants with culture-proven sepsis improve clinically within 24 to 48 hours after appropriate antibiotic
treatment is started. The response to antibiotic therapy is assessed by a repeat blood culture 24 to 48 hours
after initiation of antibiotic therapy. Failure to sterilize the bloodstream suggests either that the
antimicrobial(s) chosen are not active against the infecting pathogen or that there is an unrecognized focus of
infection. (See 'Response to therapy' above.)
The mortality of neonatal sepsis in term infants is less than 10 percent. (See 'Outcome' above.)
The primary intervention to prevent neonatal sepsis is the use of intrapartum antibiotic prophylaxis in mothers
with documented GBS colonization, a previous birth of an infant with GBS disease, or GBS bacteriuria during
the current pregnancy. (See "Neonatal group B streptococcal disease: Prevention".)
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13. American Academy of Pediatrics. Escherichia coli and other Gram-negative bacilli (septicemia andmeningitis in neonates). In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed,Kimberlin DW (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.340.
14. Gulian JM, Dalmasso C, Gonard V. Interaction of beta-lactam antibiotics on bilirubin-albumin complex:comparison by three methods, total bilirubin, unbound bilirubin and erythrocyte-bound bilirubin.Chemotherapy 1990; 36:91.
15. Martin E, Fanconi S, Kälin P, et al. Ceftriaxone--bilirubin-albumin interactions in the neonate: an in vivostudy. Eur J Pediatr 1993; 152:530.
16. Fortunov RM, Hulten KG, Hammerman WA, et al. Community-acquired Staphylococcus aureus infections interm and near-term previously healthy neonates. Pediatrics 2006; 118:874.
17. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the Fetus and Newborn Infant,7th ed, Remington JS, et al (Eds), WB Saunders, Philadelphia 2010. p.222.
18. Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am 2004;51:939.
19. Polin RA, Watterberg K, Benitz W, Eichenwald E. The conundrum of early-onset sepsis. Pediatrics 2014;133:1122.
20. Cohen-Wolkowiez M, Benjamin DK Jr, Capparelli E. Immunotherapy in neonatal sepsis: advances intreatment and prophylaxis. Curr Opin Pediatr 2009; 21:177.
21. INIS Collaborative Group, Brocklehurst P, Farrell B, et al. Treatment of neonatal sepsis with intravenous
immune globulin. N Engl J Med 2011; 365:1201.22. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane
Database Syst Rev 2015; 3:CD001239.
23. Pammi M, Brocklehurst P. Granulocyte transfusions for neonates with confirmed or suspected sepsis andneutropenia. Cochrane Database Syst Rev 2011; :CD003956.
24. Schibler KR, Osborne KA, Leung LY, et al. A randomized, placebo-controlled trial of granulocyte colony-stimulating factor administration to newborn infants with neutropenia and clinical signs of early-onset sepsis.Pediatrics 1998; 102:6.
25. Carr R, Modi N, Doré C. G-CSF and GM-CSF for treating or preventing neonatal infections. CochraneDatabase Syst Rev 2003; :CD003066.
26. Pammi M, Haque KN. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates.
Cochrane Database Syst Rev 2015; 3:CD004205.
27. Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates.Cochrane Database Syst Rev 2011; :CD007138.
28. Weston EJ, Pondo T, Lewis MM, et al. The burden of invasive early-onset neonatal sepsis in the UnitedStates, 2005-2008. Pediatr Infect Dis J 2011; 30:937.
29. Payne NR, Burke BA, Day DL. Correlation of clinical and pathologic findings in early onset neonatal group Bstreptococcal infection with disease severity and prediction of outcome. Pediatr Infect Dis 1998; 7:836.
30. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis workups in infants >/=2000 grams at birth: Apopulation-based study. Pediatrics 2000; 106:256.
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GRAPHICS
Differential diagnosis of neonatal sepsis
Diagnosis Distinguishing
features Diagnostic tests
Other systemic neonatal infections
Viral infections:
Herpes simplex virus Mucocutaneous vesicles, CSF
pleocytosis, elevated CSF
protein, thrombocytopenia,
hepatitis
Viral culture; HSV PCR
Enteroviruses Fulminant systemic disease,
myocarditis, hepatitis,
encephalitis
Viral culture; EV PCR
Parechovirus Encephalitis/meningitis, rash
on palms and soles
HPeV PCR (available through
CDC)
Cytomegalovirus Thrombocytopenia,
periventricular intracranial
calcifications, microcephaly,
sensorineural hearing loss,
chorioretinitis
Viral culture; CMV PCR
Influenza viruses Respiratory symptoms,
rhinorrhea, gastrointestinal
symptoms
Viral culture; influenza-specific
antigen detection or
immunofluorescence assay
Respiratory syncytial
virus
Respiratory symptoms,
rhinorrhea, cough, apnea,
pneumonia
Viral culture; RSV-specific
antigen detection or
immunofluorescence assay
Spirochetal infections –
Syphilis
Skeletal abnormalities
(osteochondritis and
periostitis), pseudoparalysis,
persistent rhinitis,
maculopapular rash
(particularly on palms and soles
or in diaper area)
RPR or VDRL
Parasitic infections:Congenital malaria Anemia, splenomegaly,
jaundice
Detection of parasitemia on
blood smear
Toxoplasmosis Intracranial calcifications
(diffuse), hydrocephalus,
chorioretinitis, mononuclear
CSF pleocytosis, elevated CSF
protein
T. gondii serology
Fungal infection –
Candidiasis
Persistent hyperglycemia,
thrombocytopenia, multiorgan
Isolation of Candida in blood,
urine or CSF culture
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failure
Non-infectious causes of temperature instability in neonates
Altered environmental
temperature
Transient; no other systemic symptoms; resolves with simple
nonpharmacologic measures
Dehydration Clinical history of poor feeding or fluid losses (eg, vomiting and/or
diarrhea)
Neonatal abstinence
syndrome
History of maternal drug use;
sweating, sneezing, nasal
stuffiness, and yawning
Positive drug screening tests
CNS insult (eg, anoxia or
hemorrhage)
History of perinatal asphyxia;
focal neurologic findings or
seizures
Abnormal neuroimaging
studies
Hypothyroidism Hypoton ia, leth argy,
hypothermia, large fontanels
Abnormal T4 or TSH level on
newborn screen
Congenital adrenal
hyperplasia
Ambiguous genitalia (females),
adrenal insufficiency and salt-wasting (hyponatremia,
hyperkalemia, dehydration)
Abnormal 17a-
hydroxyprogesterone level onnewborn screen
Non-infectious causes of respiratory and cardiocirculatory symptoms in neonates
Transient tachypnea of the
newborn
Onset of symptoms within two
hours after delivery; symptoms
usually resolve within 24 hours
CXR findings include increased
lung volumes, mild
cardiomegaly, prominent
vascular markings, fluid in the
interlobar fissures, and pleural
effusions
Respiratory distress
syndrome
Most common in preterm
infants; rare in term infants;
onset of symptoms within first
few hours after delivery,
progressively worsens over first
48 hours of life
CXR findings include low lung
volume and diffuse
reticulogranular ground glass
appearance with air
bronchograms
Meconium aspiration History of meconium-stained
amniotic fluid; respiratory
distress occurs immediately
after birth
Initial CXR may show streaky,
linear densities; as the disease
progresses, the lungs may
appear hyperinflated with
diffuse patchy densities
Pneumothorax Asymmetric chest rise,
decreased breath sounds on
affected side; hypotension (in
cases of tension
pneumothorax)
CXR will usually detect
symptomatic pneumothoraces
Congenital anomalies
(including tracheal-
esophageal fistula, choanal
atresia, and diaphragmatic
Often occur with other
congenital anomalies including
VACTERL and CHARGE
associations; choanal atresia is
CDH is often diagnosed by
routine antenatal ultrasound
screening; postnatal CXR
shows herniation of abdominal
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hernia) characterized by noisy labored
breathing while feeding
contents into hemithorax; TEF
is diagnosed with upper
gastrointestinal series and/or
bronchoscopy
Neonatal abstinence
syndrome
History of maternal drug use;
sweating, sneezing, nasal
stuffiness, and yawning
Positive drug screening tests
Cardiac arrhythmias (eg,
supraventricular
tachycardia)
Abrupt onset and termination
of rapid heart rate
Abnormal ECG
Congenital heart disease Infants with ductal-dependent
lesions may initially lack
symptoms then develop
cyanosis and rapid clinical
deterioration as the PDA closes
in the first few days of life
Abnormal hyperoxia test;
abnormal echocardiography
Non-infectious causes of neurologic symptoms in neonates
Hypoglycemia Common in infants who are
large for gestational age and/or
infants of diabetic mothers
Abnormal blood glucose level
Hypercalcemia Increased n euromuscular
irritability and seizures;
associated with prematurity,
maternal diabetes, and
perinatal asphyxia
Abnormal serum calcium level
Hypermagnesemia Generalized hypotonia,
respiratory depression and
apnea; typically results from
maternal treatment with
magnesium sulfate
Abnormal serum magnesium
level
CNS insult (eg, anoxia or
hemorrhage)
History of perinatal asphyxia;
focal neurologic findings or
seizures
Abnormal neuroimaging
studies
Congenital CNS
malformations (eg,
hydrocephalus)
Abnormal head circumference Abnormal neuroimaging
studies
Neonatal abstinence
syndrome
History of maternal drug use;
sweating, sneezing, nasal
stuffiness, and yawning
Positive drug screening tests
Inborn errors of metabolism Otherwise unexplained acid-
base disorders,
hyperammonemia,
hypoglycemia, hematologic
abnormalities, liver
dysfunction, and renal disease
Positive newborn screen for
inborn errors of metabolism
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Pyridoxine deficiency Refractory seizures Abnormal plasma pyridoxal-5-
phophate level
HSV: herpes simplex virus; PCR: polymerase chain reaction; CSF: cerebral spinal fluid; HPeV: human
parechovirus; EV: enterovirus; CMV: cytomegalovirus; RSV: respiratory syncytial virus; RPR: rapid
plasma reagin; VDRL: venereal disease research laboratory; CNS: central nervous system; T4: thyroxine;
TSH: thyrotropin; CXR: chest radiograph; TEF: tracheoesophageal fistula; CDH: congenital diaphragmatic
hernia; VACTERL: malformations of the vertebrae, anus, cardiac structures, trachea, esophagus, renal
system, and limbs; CHARGE: coloboma of the iris or choroid, heart defect, atresia of the choanae,retarded growth and development, genitourinary abnormalities, and ear defects; ECG: electrocardiogram;
PDA: patent ductus arteriosus.
Adapted from: Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the fetus and
newborn infant, 7th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010.
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Characteristics of cerebrospinal fluid in term and preterm neonates
without bacterial meningitis
Age
Mean
WBC/mm
(range or
90thpercentile)
ANC/mm
or percent
PMNs
(range)
Mean
protein
(mg/dL)
(range or±SD)
Mean
glucose
(mg/dL)
(range or±SD)
Term neonates evaluated in the nursery setting
0 to 24 hours
(n = 135)*
5 (0 to 90) 3/mm (0 to 70) 63 (32 to 240) 51 (32 to 78)
0 to 10 days
(n = 87)
8.2 (0 to 32) 61.3 percent 90 (20 to 170) 52 (34 to 119)
0 to 32 days
(n = 24)
11 (1 to 38) 21 percen t (0 t o
100)
NR NR
Term neonates evaluated in the emergency department setting
0 to 7 days
(n = 17)
15.3 (1 to 130) 4.4/mm (0 to
65)
80.8 (±30.8) 45.9 (±7.5)
0 to 7 days
(n = 118)
8.6 (90
percentile: 26)
NR 106.4 (90
percentile: 153)
NR
1 to 28 days
(n = 297)
6.1 (0 to 18) NR 75.4 (15.8 to
131)
45.3 (30 to 61)
0 to 30 days
(n = 108)
7.3 (0 to 130) 0.8/mm (0 to
65)
64.2 (±24.2) 51.2 (±12.9)
8 to 14 days
(n = 101)
3.9 (90
percentile: 9)
NR 77.6 (90
percentile: 103)
NR
8 to 14 days
(n = 33)
5 .4 (0 to 18) 0 .1/mm (0 to
1)
69 (±22.6) 54.3 (±17)
15 to 22 days
(n = 107)
4.9 (90
percentile: 9)
NR 71 (90
percentile: 106)
NR
15 to 21 days
(n = 25)
7 .7 (0 to 62) 0 .2/mm (0 to
2)
59.8 (±23.4) 46.8 (±8.8)
22 to 28 days(n = 141)
4.5 (90percentile: 9)
NR 68.7 (90percentile: 85)
NR
22 to 30 days
(n = 33)
4 .8 (0 to 18) 0 .1/mm (0 to
1)
54.1 (±16.2) 54.1 (±16.2)
Preterm or low birth weight neonates
0 to 28 days
(n = 30 )
9 (0 to 29) 57.2 percent 115 (65 to 150) 50 (24 to 63)
0 to 32 days
(n = 22 )
7 (0 to 28) 1 6 percen t (0 to
100)
NR NR
33
[1]
3
¶[2]
¶[3]
Δ
[4]
3
[5]
th th
[6]
[4]
◊ 3
[5]
th th
[4]
3
[5]
th th
[4]
3
[5]th th
[4]
3
§ ¶[2]
¥ ¶[3]
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Very low birth weight neonates
<1000 g
0 to 7 days
(n = 6)
3 (1 to 8) 11 percent (0 to
50)
162 (115 to 222) 70 (41 to 89)
8 to 28
days
(n = 17)
4 (0 to 14) 8 percent (0 to
66)
159 (95 to 370) 68 (33 to 217)
29 to 84
days
(n = 15)
4 (0 to 11) 2 percent (0 to
36)
137 (76 to 269) 49 (29 to 90)
1000 to 1500 g
0 to 7 days
(n = 8)
4 (1 to 10) 4 percent (0 to
28)
136 (85 to 176) 74 (50 to 96)
8 to 28
days
(n = 14)
7 (0 to 44) 1 0 percen t (0 to
60)
137 (54 to 227) 59 (39 to 109)
29 to 84
days
(n = 11)
8 (0 to 23) 1 1 percen t (0 to
48)
122 (45 to 187) 47 (31 to 76)
WBC: white blood cell count; ANC: absolute neutrophil count; PMNs: polymorphonuclear leukocytes; SD:
standard deviation; NR: not reported; CSF: cerebrospinal fluid.
* CSF obtained from term neonates without any obvious pathology.
¶ CSF obtained from hospitalized neonates at high risk for infection (eg, unexplained jaundice, prolonged
rupture of membranes, maternal fever, etc); infection excluded by sterile cultures (CSF, blood, urine) and
lack of clinical evidence of bacterial or viral infection.
Δ CSF obtained in the emergency department during evaluation for possible infection; infection was
excluded by sterile cultures (CSF, blood, urine, and negative polymerase chain reaction for enterovirus).
◊ Only two infants had CSF WBC >30/mm : one <7 days of age with 130 WBC/mm , and one 15 t o 21
days of age with 62 WBC/mm .
§ Includes 29 preterm infants and 1 infant who was 2190 g at 40 weeks' gestation.
¥ Includes all infants with birth weight <2500 g.
References:
1. Naidoo BT. The cerebrospinal fluid in the healthy n ewborn infant. S Afr Med J 1968; 42:933.
2. Sarff LD, Lynn H, Platt MD, et al. Cerebrospinal fluid evaluation in n eonates: Comparison of high
risk infants with and without meningitis. J Pediatr 1976; 88:473.
3. Pappu L. CSF cytology in the neonate. Am J Dis Child 1982; 136:297.
4. Ahmed A. Cerebrospinal fluid values in the term neonate. Pediatr Infect Dis J 1996; 15:298.
5. Chadwick SL, Wilson JW, Levin JE, Martin JM. Cerebrospinal fluid characteristics of infant s who
present to the emergency department with fever: establishing normal values by week of age.
Pediatr Infect Dis J 2011; 30:e63.
6. Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr
2011; 158:130.
7. Rodriguez AF, Kaplan SL, Mason EO. Cerebrospinal fluid values in the very low birth weight infant.
J Pediatr 1990; 116:971.
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Suggested antimicrobial regimens in the management of neonatal
sepsis in term and late preterm infants
Antibiotic regimen
Empiric therapy
Early onset (<7 days) Ampicillin AND gentamicin
Late onset (≥7 days): Admitted from the
community
Ampicillin AND gentamicin
Late onset (≥7 days): Hospitalized since birth Gentamicin AND vancomycin
Special circumstances:
Su spected men in gitis Am picillin , gen tam icin , AND cefotaxime
Suspected pneumonia Ampicillin AND gentamicin
Alternatives:
Ampicillin AND cefotaxime, OR
Vancomycin AND cefotaxime, OR
Vancomycin AND gentamicin
Suspected infection of soft tissues, skin,
joints, or bones (S. aureus is a likely
pathogen)
Vancomycin or vancomycin AND nafcillin
Suspected intravascular catheter-related
infection
Vancomycin AND gentamicin
Suspected infection due to organisms
found in the gastrointestinal tract (eg,
anaerobic bacteria)
Ampicillin, gentamicin, AND clindamycin
Alternatives:
Ampicillin, gentamicin, AND metronidazole
OR
Piperacillin-tazobactam AND gentamicin
Pathogen-specific therapy
Group B Streptococcus Penicillin G
Escherichia coli : Ampicillin-sensitive Ampicillin
Escherichia coli : Ampicillin-resistant Cefotaxime
Alternative:
Meropenem
Multidrug-resistant gram-negative bacilli
(including ESBL-producing organisms)
Meropenem
Listeria monocytogenes Ampicillin AND gentamicin
Methicillin-susceptible S. aureus (MSSA) Nafcillin OR cefazolin
Methicillin-resistant S. aureus (MRSA) Vancomycin
Coagulase-negative staphylococci Vancomycin
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ESBL: extended-spectrum beta-lactamase.
References:
1. Edwards MS, Baker CJ. Bacterial infections in the neonate. In: Principles and Practice of Pediatric
Infectious Diseases, 4th ed, Long SS, Pickering LK, Prober CG (Eds), Elsevier Saunders,
Philadelphia 2012. p.538.
2. Nizet V, Klein JO. Bacterial sepsis and menin gitis. In: Infectious diseases of the Fetu s and
Newborn Infant, 7th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010. p.222.
3. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American Academy of
Pediatrics, 2015. p.745.
4. American Academy of Pediatrics. Escherichia coli and other Gram-negative bacilli (septicemia and
meningitis in neonates). In: Red Book: 2015 Report of the Committee on Infectious Diseases,
30th ed, Kimberlin DW (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.340.
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Common bacterial agents causing neonatal sepsis in term infants
Bacterial species
Frequency of
isolation
Early-
onset Late-onset
Group B Streptococcus +++ +++
Escherichia coli +++ ++
Klebsiella spp. + +
Enterobacter spp. + +
Listeria monocytogenes + +
Other enteric gram-negatives + +
Non-enteric gram-negatives* + +
Viridans streptococci + +
Staphylococcus aureus + +++
Citrobacter spp. 0 +
Salmonella spp. 0 +
Coagulase-negative staphylococci 0 +
Enterococcus spp. 0 +
+++: commonly associated; ++: frequently associated; +: occasionally associated; 0: rarely
associated.
* Includes nontypable Hemophilus influenzae and Neisseria meningitidis.
Adapted from: E dwards MS, Baker CJ. Bacterial infections in the neonate. In: Principles and Practice of
Pediatric Infectious Disease, 4th ed, Long SS, Pickering LK, Prober CG. Elsevier Saunders, Philadelphia
2012.
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Intravenous treatment of early-onset group B streptococcal
infections
Site(s) of infection Empirical therapy Definitive
therapy*
Duration
of
therapy
Bacteremia/sepsis/pneumonia Ampicillin 150 mg/kg every 12
hours
Penicillin G:
50,000 to
100,000
units/kg per day
divided every 12
hours
10 days
PLUS
Gentamicin 4 mg/kg every 24
hours for infants born at ≥35
weeks gestation; 3 mg/kg every
24 hours for infants born at
<35 weeks gestation
Meningitis Ampicillin 100 to 150 mg/kg
every 8 hours
Penicillin G:
250,000 to450,000
units/kg per day
divided every 8
hours
14 to 21
days
PLUS
Gentamicin 4 mg/kg every 24
hours for infants born at ≥35
weeks gestation; 3 mg/kg every
24 hours for infants born at
<35 weeks gestation
GBS: Group B streptococcus; CSF: cerebrospinal fluid.
* Definitive therapy should not be started until GBS is identified by culture; clinical improvement is
evident; and for meningitis, CSF is sterile at 24 to 48 hours of therapy.¶ 14 days is sufficient for uncomplicated cases of GBS meningitis.
References:
1. Medications. In: Guidelines for Acute Care of the Neonate, 22nd Ed, Adams JM, Fernandes CJ
(Eds), Baylor College of Medicine, Houston, TX 2014. p.89.
2. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2015 Report of
the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American Academy of
Pediatrics, 2015. p.745.
3. American Academy of Pediatrics. Tables of antibacterial drug dosages, Table 4.2. In: Red Book:
2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American
Academy of Pediatrics, Elk Grove Village, IL 2015. p.882.4. Rao SC, Srinivasjois R, Hagen R, et al. One dose per day compared to multiple doses per day of
gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev
2011 Nov 9(11).
Graphic 71720 Version 8.0
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Intravenous treatment of late-onset group B streptococcal infections
in neonates and young infants
Site(s) of
infection
Empirical
therapy*
Definitive
therapy
Duration of
therapy
Bacteremia without a
focus
Ampicillin, nafcillin, or
vancomycin
PLUS
Gentamicin or
cefotaxime
Penicillin G
75,000 to 150,000
units/kg per day
divided every 8 hours
10 days
Meningitis Ampicillin and/or
vancomycin
PLUS
Gentamicin or
cefotaxime
Penicillin G
450,000 to 500,000
units/kg per day
divided every 6 hours
14 to 21 days
Cellulitis/adenitis Nafcillin or vancomycin
PLUS
Gentamicin or
cefotaxime
Penicillin G
75,000 to 150,000
units/kg per day
divided every 8 hours
10 to 14 days
Septic arthritis Nafcillin or vancomycin
PLUS
Cefotaxime
Penicillin G
75,000 to 150,000
units/kg per day
divided every 8 hours
14 to 21 days
Osteomyelitis Nafcillin or vancomycin
PLUS
Cefotaxime
Penicillin G
75,000 to 150,000
units/kg per day
divided every 8 hours
21 to 28 days
Urinary tract infection Ampicillin, nafcillin, or
vancomycin
PLUS
Gentamicin or
cefotaxime
Penicillin G
75,000 to 150,000
units/kg per day
divided every 8 hours
10 days
The antibiotic doses listed above are for use in neonates and young infants age >1 week andbody weight ≥1 kg with normal renal function. For additional dosing detail, refer to the
Lexicomp pediatric and neonatal drug information monographs included within UpToDate.
GBS: group B streptococcus; CSF: cerebrospinal fluid.
* Selection will depend on age and presumed source of infection (maternal, hospital, or community).
¶ Definitive therapy should be started once GBS is identified by culture; clinical improvement is evident;
and for meningitis, CSF is sterile at 24 to 48 hours of therapy.
References:
1. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2015 Report of
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17/9/2015 M anagem ent and outcome of sepsis in ter m and l ate pr eter m i nfants
http://www.uptodate.com/contents/management-and-outcome-of-sepsis- in-term-and-late-preterm -i nfants?topicKey=PEDS%2F5046&elapsedTimeMs=0&so… 2
the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American Academy of
Pediatrics, 2015. p.745.
2. American Academy of Pediatrics. Tables of antibacterial drug dosages, Table 4.2. In: Red Book:
2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American
Academy of Pediatrics, Elk Grove Village, IL 2015. p.882.
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17/9/2015 M anagem ent and outcome of sepsis in ter m and l ate pr eter m i nfants
Disclosures: Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group BStreptococcus]. Consultant/Advisory Boards: Novartis Vaccines [Group B Streptococcus]. Leonard E
Weisman, MD Consultant/Advisory Boards: Glaxo-Smith Kline [Malaria vaccine]; NIAID [Staphylococcus
aureus (Mupirocin)]. Patent Holder: Baylor College of Medicine [Ureaplasma
diagnosis/vaccines/antibodies, process for preparing biological samples]. Equity Ownership/StockOptions: Vax-Immune [Ureaplasma diagnosis, vaccines and antibodies]. Sheldon L Kaplan, MD
Grant/Research/Clinical Trial Support: Pfizer [vaccine (PCV13)]; Forest Lab [antibiotic (Ceftaroline)];
Optimer [antibiotic (fidaxomicin)]. Consultant/Advisory Boards: Pfizer [vaccine (PCV13)]. Carrie Armsby,
MD, MPH Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to beprovided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy
Disclosures