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Management and outcome of sepsis in term and late preterm infants

Author: Morven S Edwards, MD

Section Editors: Leonard E Weisman, MD, Sheldon L Kaplan, MD

Deputy Editor: Carrie Armsby, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2017. | This topic last updated: Jan 21, 2016.

INTRODUCTION — Sepsis is an important cause of morbidity and mortality among newborn infants.Although the incidence of sepsis in term and late preterm infants is low, the potential for serious adverseoutcomes, including death, is of such great consequence that caregivers should have a low threshold forevaluation and treatment for possible sepsis in neonates. The approach discussed below is consistent withguidelines 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. Theepidemiology, clinical features, diagnosis, and evaluation of sepsis in term and late preterm infants, neonatalsepsis in preterm infants, the management of wellappearing infants at risk for group B streptococcalinfection, and the evaluation of febrile or illappearing newborns are discussed separately:

TERMINOLOGY — The following terms will be used throughout this discussion on neonatal sepsis:

Neonatal sepsis is classified according to the infant's age at the onset of symptoms:

®

®

(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 (<34 weeks gestation)".)(See "Treatment and prevention of bacterial sepsis in the preterm infant (<34 weeks gestation)".)(See "Management of the infant whose mother has received group B streptococcal chemoprophylaxis".)(See "Febrile infant (younger than 90 days of age): Management", section on 'Neonates (28 days of ageand younger)'.)

(See "Approach to the illappearing infant (younger than 90 days of age)".)

Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested by systemicsigns of infection and isolation of a bacterial pathogen from the blood stream [3]. A consensus definitionfor neonatal sepsis is lacking [4]. (See "Clinical features, evaluation, and diagnosis of sepsis in term andlate preterm infants", section on 'Diagnosis'.)

Term infants are those born at a gestational age of 37 weeks or greater.

Late preterm infants (also called nearterm infants) are those born between 34 and 36 completedweeks of gestation [5]. (See "Late preterm infants".)

Preterm infants are those born at less than 34 weeks of gestation [5].

Earlyonset sepsis is defined as the onset of symptoms before 7 days of age, although some expertslimit the definition to infections occurring within the first 72 hours of life [6].

Lateonset sepsis is defined as the onset of symptoms at ≥7 days of age [6]. Similarly to earlyonsetsepsis, there is variability in its definition, ranging from an onset at >72 hours of life to ≥7 days of age[6,7].



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:

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,

evaluation, and management 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

culturebased 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 cultureproven or culturenegative clinical sepsis. Clinical signs suggesting

meningitis 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).

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")

Illappearance (see "Approach to the illappearing infant (younger than 90 days of age)")

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')



Earlyonset sepsis — The recommended empiric regimen for suspected earlyonset sepsis in a term orlate preterm infant is ampicillin 150 mg/kg per dose intravenously (IV) every 12 hours and gentamicin 4 mg/kgper dose IV every 24 hours [7,8]. We generally obtain baseline renal function tests (ie, blood urea nitrogenand creatinine levels) at the initiation of treatment with gentamicin. Serum gentamicin levels should beobtained in infants receiving a full course of antibiotics, but are not required if a treatment course of only 48hours is anticipated and renal function is normal [3,7].

The combination of ampicillin and gentamicin is effective in treating most common pathogens that causeearlyonset sepsis, including group B Streptococcus (GBS), Listeria, Enterococcus, and most isolates ofEscherichia 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 thecombination of penicillin and gentamicin [10]. In a 10year review from a single center, 90 percent of earlyonset sepsis pathogens in term and late preterm infants were susceptible to ampicillin and/or gentamicin [11].Among six infants with earlyonset S. aureus bacteremia that was not susceptible to ampicillin andgentamicin, there were no complications before or after antibiotic therapy was adjusted based upon antibioticsusceptibility.

Ampicillin and gentamicin are preferred over ampicillin and a thirdgeneration cephalosporin (eg, cefotaxime)based upon the following:

The addition of a thirdgeneration cephalosporin to the regimen of ampicillin and gentamicin is warranted forinfants with suspected meningitis and critically ill neonates with risk factors associated with ampicillinresistantinfections (ie, prolonged rupture of membranes and/or prolonged antenatal maternal ampicillin treatment).

Lateonset sepsis — The choice of empiric therapy for lateonset sepsis depends upon whether the infantis admitted from the community, and thus is at lower risk for infection caused by a multidrugresistantpathogen, or is hospitalized since birth and thus at a higher risk.

Admitted from the community — Neonates admitted from the community are at lower risk forinfection caused by a multidrugresistant pathogen than are infants who remain hospitalized since birth. Thecombination of ampicillin and gentamicin or ampicillin and cefotaxime are regimens for empiric treatment ofsepsis without an apparent focus of infection in this setting (table 3) [6].

Ampicillin and gentamicin is generally the preferred regimen; however, local antibiotic resistance patternsmust be considered. The dosing for ampicillin is 75 mg/kg per dose intravenously (IV) every six hours; thedosing of gentamicin is 4 mg/kg per dose IV every 24 hours [7,8]. We generally obtain baseline renal functiontests (ie, blood urea nitrogen and creatinine levels) at the initiation of treatment with gentamicin. Serum

The regimen of ampicillin and a thirdgeneration cephalosporin is not more effective than the combinationof ampicillin and gentamicin [12].

The emergence of cephalosporinresistant gramnegative 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 Listeriamonocytogenes. Cephalosporins are not active against L. monocytogenes.

In a large cohort study, infants who received ampicillin plus cefotaxime had a 1.5fold increase inmortality compared with those treated with ampicillin plus gentamicin (4.2 versus 1.9 percent, adjustedodds ratio 1.5, 95% CI 1.41.7) [12].

Ceftriaxone is highly bound to albumin and appears to displace bilirubin [14,15]. Although displacementof free bilirubin by ceftriaxone has not been reported, avoidance of ceftriaxone in neonates at risk foracute bilirubin encephalopathy is recommended [1]. (See "Clinical manifestations of unconjugatedhyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.)



gentamicin levels should be obtained in infants receiving a full course of antibiotics, but are not required if atreatment 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 lateonset bacteremia weresusceptible to the combination of amoxicillin and gentamicin [10]. The addition of a thirdgenerationcephalosporin to an ampicillin and gentamicin regimen is warranted for neonates with suspected meningitis.(See 'Special circumstances' below.)

Hospitalized since birth — Infants who continue to be hospitalized since birth are at higher risk formultidrugresistant organisms, and therefore vancomycin is substituted for ampicillin (table 3). For terminfants >7 days of life, the dosing of vancomycin is dependent on serum creatinine (Scr) [16]:

Alternative weightdirected neonatal dosing recommendations for vancomycin in are also available (refer toLexicomp pediatric drug information).

Special circumstances — Alternative regimens based upon specific clinical circumstances include thefollowing (table 3):

Cultureproven sepsis — In neonates with cultureproven sepsis, the usual course of therapy is 10 days[1,3,13,18,19]. 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 thesusceptibility profile of the pathogen isolated.

Pathogenspecific therapy — Guidelines for the treatment of the most common causative organisms ofneonatal sepsis are (table 3):

Scr <0.7 mg/dL: 15 mg/kg/dose IV every 12 hoursScr 0.7 to 0.9 mg/dL: 20 mg/kg/dose IV every 24 hoursScr 1 to 1.2 mg/dL: 15 mg/kg/dose IV every 24 hoursScr 1.3 to 1.6 mg/dL: 10 mg/kg/dose IV every 24 hoursScr >1.6 mg/dL: 15 mg/kg/dose IV every 48 hours

Suspected meningitis – In neonates with lateonset sepsis, cefotaxime should be included in the regimenif lumbar puncture suggests meningitis (eg, CSF pleocytosis). Cefotaxime should also be added to theempiric regimen for earlyonset meningitis if the CSF Gram stain reveals gramnegative bacilli.Cefotaxime provides extended spectrum for enteric gramnegative rods and has optimal activity in theCSF against pneumococci. Treatment of bacterial meningitis in neonates is discussed in detailseparately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiricaltherapy'.)

Suspected pneumonia − Empiric regimens for treatment of infants with a pulmonary focus of infectioninclude ampicillin and gentamicin, ampicillin and cefotaxime, vancomycin and cefotaxime, or vancomycinand gentamicin. Treatment of pneumonia in neonates is discussed in detail separately. (See "Neonatalpneumonia", section on 'Treatment'.)

If there is a focus of infection involving the soft tissues, skin, joints, or bones (in which case S. aureus is alikely pathogen), vancomycin should be substituted for ampicillin [17]. In a toxicappearing infant, nafcillinshould also be added.

If intravascular catheterrelated infection is a concern, treatment should be initiated with vancomycin andgentamicin to provide empiric coverage for coagulasenegative staphylococci, S. aureus, and gramnegative bacteria.

If infection is thought to arise from the gastrointestinal tract (eg, anaerobic bacteria), clindamycin oranother suitable agent, such as metronidazole, should be added to the therapeutic regimen to improvecoverage for these pathogens.



Group B streptococcus — The drug of choice for GBS is penicillin. Thus, when GBS is identified, andresolution of bacteremia is documented by a repeat blood culture and, in infants with meningitis, the CSF issterile, we recommend discontinuing gentamicin and continuing therapy with penicillin G alone (table 5AB).(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 haveimproved clinically and in whom meningitis has been excluded, ampicillin monotherapy is administered for a10day course.

For patients with ampicillinresistant E. coli, the choice of definitive therapy is based upon the susceptibilityprofile. Cefotaxime is often employed if the isolate is susceptible.

Other gramnegative bacilli — Nonmeningeal infections caused by E. coli, Klebsiella, Proteus,Salmonella, or Shigella should be treated with a single agent, based upon the antimicrobial susceptibilityprofile.

Antimicrobial treatment for infections caused by Enterobacter, Serratia, or Pseudomonas should be selectedbased upon the susceptibility profile of the organism.

Infections caused by multidrugresistant gramnegative bacilli, including those caused by extendedspectrumbetalactamaseproducing organisms, or those with hyperproduction of betalactamases, should be treatedwith 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 Listeriainfection. 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 'Antibioticregimens'.)

Staphylococcus species — Directed therapy for infection caused by staphylococci is determined bythe sensitivity of the isolate to specific antibiotic agents:

Probable but unproven sepsis — In infants with a negative blood culture but a clinical status that remainsconcerning 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:

S. aureus – Vancomycin or, in a toxicappearing infant, vancomycin plus nafcillin should be employed forS. aureus infection until the susceptibility profile is available. The regimen then should be adjustedaccording to the susceptibility profile:

Methicillinsusceptible S. aureus (MSSA) – Treatment of MSSA infection should be completed withnafcillin. Cefazolin is an alternative for treatment of most MSSA infections outside the centralnervous system (CNS) and not involving endocarditis. (See "Staphylococcus aureus bacteremia inchildren: Management and outcome".)

•

Methicillinresistant S. aureus (MRSA) – Treatment should be completed with vancomycin. (See"Methicillinresistant Staphylococcus aureus in children: Treatment of invasive infections", section on'Treatment of neonates'.)

•

Coagulasenegative staphylococci – Coagulasenegative staphylococcal infections require treatment withvancomycin.

If meningitis has been excluded, the ampicillin regimen can be changed to 75 mg/kg every 12 hours.



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 [1,20].

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 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 conclusivelyimprove outcomes [18,19,21]:

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 earlyonset GBS invasive neonatal infection, it has not had

a similar impact on the rate of lateonset 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 multiinterventional program including effective

maternal 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 [12,29]. 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 sepsisdefinition (lower mortality rates tend to be reported if infants with culturenegative clinical sepsis are included

compared with cases of cultureproven 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 earlyonset disease and 1 to 2 percent for lateonset 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 [30]. (See "Group B streptococcal infection in

neonates and young infants", section on 'Outcome'.)

The risk of mortality is particularly high in neonates with earlyonset sepsis caused by E. coli. Estimatedmortality rates for term neonates with E. coli sepsis are 6 to 10 percent [9,29,31].

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".)

Intravenous immunoglobulin (IVIG) infusions [22,23]

Granulocyte transfusions [24]

Granulocyte and granulocytemacrophage colonystimulating factor (GCSF and GMCSF) [25,26]

Pentoxifylline [27]

Lactoferrin [28]



SOCIETY GUIDELINE LINKS — Links to society and governmentsponsored guidelines from selected

countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in

neonates".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"

and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6

grade reading level, and they answer the four or five key questions a patient might have about a given

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read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more

detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want

indepth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email

these topics to your patients. (You can also locate patient education articles on a variety of subjects by

searching on "patient info" and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

th th

th th

Basics topics (see "Patient education: Sepsis in newborn babies (The Basics)")

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:

Illappearance (see "Approach to the illappearing infant (younger than 90 days of age)")•

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 gramnegativeenteric organisms, including Escherichia coli [E. coli]) (table 4) (Grade 1B).

The empiric regimen for earlyonset sepsis without an apparent focus consists of ampicillin and

gentamicin. (See 'Earlyonset sepsis' above.)

•

Empiric antibiotic regimens for lateonset sepsis without an apparent focus are as follows (see

'Lateonset sepsis' above):

•

For neonates admitted from the community, we suggest ampicillin and gentamicin.



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Topic 5046 Version 27.0

For infants who continue to be hospitalized from birth, we suggest vancomycin and gentamicin.

Empiric antibiotic regimens for suspected neonatal sepsis (early or lateonset) with certain special

circumstances are as follows (see 'Special circumstances' above):

•

If there is concern of lateonset 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 toxicappearing infants,vancomycin plus nafcillin for ampicillin.

If intravascular catheterrelated 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 pattern. (See 'Pathogenspecific therapy' above.)

In infants with cultureproven 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 'Cultureproven sepsis' above.)

In wellappearing 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 cultureproven 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".)



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; influenzaspecific

antigen detection or

immunofluorescence assay

Respiratory syncytial virus Respiratory symptoms, rhinorrhea,

cough, apnea, pneumonia

Viral culture; RSVspecific 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 failure

Isolation of Candida in blood, urine

or CSF culture

Noninfectious 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 Hypotonia, lethargy, 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 17ahydroxyprogesterone

level on newborn screen

Noninfectious causes of respiratory and cardiocirculatory symptoms in neonates



Transient tachypnea of thenewborn

Onset of symptoms within two hoursafter delivery; symptoms usuallyresolve within 24 hours

CXR findings include increased lungvolumes, mild cardiomegaly,prominent vascular markings, fluid inthe interlobar fissures, and pleuraleffusions

Respiratory distress syndrome Most common in preterm infants;rare in term infants; onset ofsymptoms within first few hoursafter delivery, progressively worsensover first 48 hours of life

CXR findings include low lung volumeand diffuse reticulogranular groundglass appearance with airbronchograms

Meconium aspiration History of meconiumstainedamniotic fluid; respiratory distressoccurs immediately after birth

Initial CXR may show streaky, lineardensities; as the disease progresses,the lungs may appear hyperinflatedwith diffuse patchy densities

Pneumothorax Asymmetric chest rise, decreasedbreath sounds on affected side;hypotension (in cases of tensionpneumothorax)

CXR will usually detect symptomaticpneumothoraces

Congenital anomalies (includingtrachealesophageal fistula,choanal atresia, anddiaphragmatic hernia)

Often occur with other congenitalanomalies including VACTERL andCHARGE associations; choanalatresia is characterized by noisylabored breathing while feeding

CDH is often diagnosed by routineantenatal ultrasound screening;postnatal CXR shows herniation ofabdominal contents into hemithorax;TEF is diagnosed with uppergastrointestinal series and/orbronchoscopy

Neonatal abstinence syndrome History of maternal drug use;sweating, sneezing, nasal stuffiness,and yawning


Cardiac arrhythmias (eg,supraventricular tachycardia)

Abrupt onset and termination ofrapid heart rate

Abnormal ECG

Congenital heart disease Infants with ductaldependentlesions may initially lack symptomsthen develop cyanosis and rapidclinical deterioration as the PDAcloses in the first few days of life

Abnormal hyperoxia test; abnormalechocardiography

Noninfectious causes of neurologic symptoms in neonates

Hypoglycemia Common in infants who are large forgestational age and/or infants ofdiabetic mothers

Abnormal blood glucose level

Hypercalcemia Increased neuromuscular irritabilityand seizures; associated withprematurity, maternal diabetes, andperinatal asphyxia

Abnormal serum calcium level

Hypermagnesemia Generalized hypotonia, respiratorydepression and apnea; typicallyresults from maternal treatment withmagnesium sulfate

Abnormal serum magnesium level

CNS insult (eg, anoxia orhemorrhage)

History of perinatal asphyxia; focalneurologic 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


Inborn errors of metabolism Otherwise unexplained acidbasedisorders, hyperammonemia,hypoglycemia, hematologic

Positive newborn screen for inbornerrors of metabolism



abnormalities, liver dysfunction, and

renal disease

Pyridoxine deficiency Refractory seizures Abnormal plasma pyridoxal5

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.

Graphic 100409 Version 1.0



Characteristics of cerebrospinal fluid in term and preterm neonates withoutbacterial meningitis

Age

MeanWBC/mm

(range or 90thpercentile)

ANC/mm orpercent 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 percent (0 to100)

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 (90percentile: 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)



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)


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)



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) 16 percent (0 to100)

NR NR

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)


29 to 84 days (n = 15)


1000 to 1500 g

0 to 7 days (n = 8)


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]

[7]



8 to 28 days

(n = 14)


29 to 84 days

(n = 11)


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 to 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 newborn infant. S Afr Med J 1968; 42:933.2. Sarff LD, Lynn H, Platt MD, et al. Cerebrospinal fluid evaluation in neonates: Comparison of high risk infants withand 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 infants who present to theemergency 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.


3 3

3



Suggested antimicrobial regimens in the management of neonatal sepsis in termand 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:

Suspected meningitis early onset Ampicillin AND gentamicin*

Suspected meningitis late onset, admitted fromthe community

Ampicillin, gentamicin, AND cefotaxime

Suspected meningitis late onset, hospitalizedsince birth

Gentamicin, vancomycin, AND cefotaxime

Suspected pneumonia Ampicillin AND gentamicin

Alternatives:Ampicillin AND cefotaxime, ORVancomycin AND cefotaxime, ORVancomycin AND gentamicin

Suspected infection of soft tissues, skin, joints, orbones (S. aureus is a likely pathogen)

Vancomycin or vancomycin AND nafcillin

Suspected intravascular catheterrelated infection Vancomycin AND gentamicin

Suspected infection due to organisms found in thegastrointestinal tract (eg, anaerobic bacteria)

Ampicillin, gentamicin, AND clindamycin

Alternatives:Ampicillin, gentamicin, AND metronidazole ORPiperacillintazobactam AND gentamicin

Pathogenspecific therapy

Group B Streptococcus Penicillin G

Escherichia coli: Ampicillinsensitive Ampicillin

Escherichia coli: Ampicillinresistant Cefotaxime

Alternative:Meropenem

Multidrugresistant gramnegative bacilli (includingESBLproducing organisms)

Meropenem

Listeria monocytogenes Ampicillin AND gentamicin

Methicillinsusceptible S. aureus (MSSA) Nafcillin OR cefazolin

Methicillinresistant S. aureus (MRSA) Vancomycin

Coagulasenegative staphylococci Vancomycin

ESBL: extendedspectrum betalactamase. * Cefotaxime should be added to the empiric regimen for suspected earlyonset meningitis if the CSF Gram stain revealsgramnegative bacilli.

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 meningitis. In: Infectious diseases of the Fetus 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 Gramnegative 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.




Common bacterial agents causing neonatal sepsis in term infants

Bacterial speciesFrequency of isolation

Earlyonset Lateonset

Group B Streptococcus +++ +++

Escherichia coli +++ ++

Klebsiella spp. + +

Enterobacter spp. + +

Listeria monocytogenes + +

Other enteric gramnegatives + +

Nonenteric gramnegatives* + +

Viridans streptococci + +

Staphylococcus aureus + +++

Citrobacter spp. 0 +

Salmonella spp. 0 +

Coagulasenegative staphylococci 0 +

Enterococcus spp. 0 +

+++: commonly associated; ++: frequently associated; +: occasionally associated; 0: rarely associated.

* Includes nontypable Hemophilus influenzae and Neisseria meningitidis.

Adapted from: Edwards 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.




Intravenous treatment of earlyonset group B streptococcal infections

Site(s) of infection Empirical therapyDefinitivetherapy*

Durationof

therapy

Bacteremia/sepsis/pneumonia Ampicillin 150 mg/kg every 12 hours Penicillin G: 50,000 to100,000 units/kg perday divided every 12hours

10 days

PLUS

Gentamicin 4 mg/kg every 24 hours forinfants born at ≥35 weeks gestation; 3mg/kg every 24 hours for infants born at<35 weeks gestation

Meningitis Ampicillin 100 to 150 mg/kg every 8 hours Penicillin G: 250,000to 450,000 units/kgper day divided every8 hours

14 to 21daysPLUS

Gentamicin 4 mg/kg every 24 hours forinfants born at ≥35 weeks gestation; 3mg/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 formeningitis, 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 Collegeof Medicine, Houston, TX 2014. p.89.

2. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2015 Report of the Committee onInfectious 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 theCommittee 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 fortreatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2011 Nov 9(11).


¶



Intravenous treatment of lateonset group B streptococcal infections in neonatesand 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


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


Penicillin G

75,000 to 150,000 units/kg


hours

10 to 14 days

Septic arthritis Nafcillin or vancomycin

PLUS

Cefotaxime

Penicillin G

75,000 to 150,000 units/kg


hours

14 to 21 days

Osteomyelitis Nafcillin or vancomycin

PLUS

Cefotaxime

Penicillin G

75,000 to 150,000 units/kg


hours

21 to 28 days

Urinary tract infection Ampicillin, nafcillin, or

vancomycin

PLUS


Penicillin G

75,000 to 150,000 units/kg


hours

10 days

The antibiotic doses listed above are for use in neonates and young infants age >1 week and body weight ≥1 kgwith normal renal function. For additional dosing detail, refer to the Lexicomp pediatric and neonatal druginformation 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 the Committee onInfectious 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 theCommittee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American Academy of Pediatrics, Elk Grove Village,IL 2015. p.882.


¶



Contributor DisclosuresMorven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B

Streptococcus]. Leonard E Weisman, MD Grant/Research/Clinical Trial Support: Vax-Immune [Ureaplasmadiagnosis, vaccines, antibodies, other medical diagnostics and pre-analytical devices]. Consultant/AdvisoryBoards: Glaxo-Smith Kline [Malaria vaccine]; NIAID [Staphylococcus aureus (Mupirocin)]. Patent Holder:Baylor College of Medicine [Ureaplasma diagnosis, vaccines, antibodies, process for preparing biologicalsamples]. Equity Ownership/Stock Options: Vax-Immune [Ureaplasma diagnosis, vaccines, antibodies, othermedical diagnostics and pre-analytical devices]. Equity Ownership/Stock Options (Spouse): Vax-Immune[Ureaplasma diagnosis, vaccines, antibodies, other medical diagnostics and pre-analyticaldevices]. Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [S. pneumoniae (PCV13,Linezolid)]; Cubist [S. aureus (Tedizolid)]; Forest Lab [Osteomyelitis (Ceftaroline)]. Consultant/AdvisoryBoards: Pfizer [S. pneumoniae (PCV13, Linezolid); S. aureus (vaccine development)]; Theravance [S. aureus(Telavancin)]. Carrie Armsby, MD, MPH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these areaddressed 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 mustconform to UpToDate standards of evidence.

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