Sepsis in the Newborn

Educational Objectives

The goal of this program is to improve the diagnosis and management of neonatal sepsis. After hearing and assimilating this program, the clinician will be better able to:

1. Determine the most likely etiology for early onset sepsis in an infant of a given birth weight and presentation.
2. List perinatal risk factors and intrapartum prophylaxis recommendations for group B Streptococcus.
3. Manage exposure to chorioamnionitis during labor and delivery.

Summary

Early-onset sepsis (EOS): positive bacterial culture of blood or cerebrospinal fluid (CSF) at <72 hr of life or <7 days of life with group B Streptococcus (GBS); many studies include criterion of antibiotic treatment for ≥5 days or death at <5 days of age while on antibiotic therapy

Group B Streptococcus: since late 1960s, most common pathogen for EOS (previously Gram-negative organisms); in 1996, Centers for Disease Control and Prevention (CDC) outlined screening and intrapartum prophylaxis based on risk factors; universal screening recommended in 2002; early onset GBS dramatically reduced; no difference in late-onset (≥7 days to 3 mo) or very late GBS (≥3 mo); transmission — 66% in utero (usually ascending after rupture of membranes [ROM]), with signs of sepsis at delivery or shortly thereafter; signs of sepsis include lethargy, grunting, retractions, and apnea; intrapartum colonization and infection occur in ≈33%, presenting at 12 to 24 hr; exposure — 50% of infants colonized if prophylaxis not given; 1% develop early onset infection; early onset — median time of presentation ≈1 hr; incidence 0.3 to 0.4/1000 (reduced from 2-3/1000); sepsis most common (65%), followed by pneumonia; meningitis seen in ≈5%; mortality 3% to 10% (much higher in preterm infants); even with adequate therapy, recurrence rate ≈1% (because of poor immunoglobulin G [IgG] immunity and persistent colonization)

Perinatal risk factors for early onset GBS: preterm delivery (risk increases 7-fold if weight <2500 g); ROM >18 hr; unexplained maternal fever (chorioamnionitis [CA]); GBS bacteriuria (heavy colonization); previous GBS-infected infant (≈20-fold); early and late infections occur when mother lacks IgG or preterm infant does not receive full complement (at ≈33 wk, levels similar in mother and fetus; active transport yields higher levels in newborn born at term); vaccination aims to increase transplacental transport of serotype-specific IgG

Guidelines for GBS prophylaxis (CDC, 2010): universal vaginal and rectal screening culture at 35 to 37 wk, unless mother has GBS bacteriuria or previous infant with GBS disease; intrapartum prophylaxis given unless planned cesarean performed in absence of labor or ROM; if status unknown, prophylaxis based on risk factors; early onset GBS — 25% to 33% have no risk factors; risk factor-based management more likely; prophylaxis — penicillin or ampicillin; cefazolin for patients allergic to penicillin; vancomycin for high risk; only use clindamycin if susceptibility known; polymerase chain reaction (PCR) more sensitive than culture, but clinician must instruct laboratory to perform susceptibility testing; efficacy of vancomycin unknown

Etiology of EOS: Stoll et al (2011) evaluated infants >400 g for positive culture ≤72 hr; rate of bacterial sepsis 0.98 per 1000; vast majority of infants evaluated for sepsis did not have proven infection; rate of GBS 0.4/1000; rate of Escherichia coli 3/1000; E coli most common in infants <1500 g; GBS and E coli most common among infants weighing 1501 to 2500 g; GBS most common among infants >2500 g; GBS caused 43% of infections (Gram-negative organisms accounted for 37%); nontype B Haemophilus, Enterococcus, Streptococcus viridans, Staphylococcus aureus, Listeria, and other Gram-positive organisms noted

Listeria monocytogenes: aerobic, motile, Gram-positive bacillus; primarily food borne (unpasteurized milk, soft cheese, undercooked poultry, unwashed raw vegetables); in pregnant women, may result in amnionitis (classic finding brown staining of amniotic fluid), spontaneous abortion, and preterm delivery; causes EOS, late-onset sepsis (LOS), pneumonia, vesiculopustular rash (granulomatosis infantisepticum), and meningitis; treatment — ampicillin, initially with aminoglycoside; discontinue once cultures sterile

Citrobacter species: may cause cerebral abscess in child who appears well; C koseri principal species isolated from CSF, but sepsis seen without positive CSF; pathogenesis seemingly related to cerebral vasculitis with infarction and invasion of necrotic tissue; need for magnetic resonance imaging (MRI) controversial unless C koseri isolated from CSF (speaker recommends MRI for every neonate with bacterial meningitis)

Genital Mycoplasma: cervicovaginal Ureaplasma present in ≈80% of pregnant women, with Mycoplasma hominis in 40% to 50%; transmission to newborn common; in preterm infants, Ureaplasma (endotracheal aspirate, throat culture) associated with bronchopulmonary dysplasia (BPD); either may cause meningitis (abnormal CSF, negative culture)

Stoll et al: GBS not resistant to penicillin, but 20% resistant to clindamycin; 78% of E coli resistant to ampicillin, 4% resistant to gentamycin, and 3% resistant to third-generation cephalosporins; perform lumbar puncture (LP) if sepsis suspected at birth (especially if neonate born preterm); ampicillin and gentamycin ineffective for Gram-negative meningitis; fatality rate — ≈16%; inversely related to gestational age (GA); ≈9% for GBS and 33% for E coli (similar when adjusted for GA)

Neonatal management: CDC guidelines for GBS — signs of neonatal sepsis warrant full diagnostic evaluation with complete blood count (CBC), blood culture, chest x-ray if clinically indicated, and LP; preferred treatment ampicillin and gentamycin; LP — controversial; 40% to 50% of preterm infants <1000 g with positive CSF have negative blood culture; perform if infection strongly suspected

Antimicrobial therapy: 1 additional day of therapy in preterm infant associated with poorer outcome (eg, LOS, necrotizing enterocolitis [NEC], mortality); GBS — if infant asymptomatic with positive blood culture, limit therapy to 24 to 36 hr; 99% of positive blood cultures convert ≤24 hr (most ≤16 hr); bacteremia — treat for 7 days (guidelines specify 10 days for GBS; speaker disagrees); sepsis — 7 to 10 days; meningitis — 10 to 14 days (3 wk for Gram-negative organism); pneumonia — 7 days; culture-negative (presumed) sepsis — 5 days; Engle et al — asymptomatic infants with suspected pneumonia but sterile blood cultures at 48 hr randomized to 4 vs 7 days of ampicillin-gentamicin; no significant difference between groups in effectiveness of treatment (all infants included in the study improved)

Chorioamnionitis: documented in 33% to 56% of infants with positive culture; criteria — poorly defined; unexplained temperature ≥38°C; diagnosed in case of maternal or fetal tachycardia, uterine tenderness, foul-smelling or purulent amniotic fluid, or leukocytosis; maternal fever risk factor for positive neonatal blood culture; Stoll et al found 13% of newborns with maternal CA had no signs or symptoms ≤6 hr; treating all infants with maternal intrapartum fever (recommended by CDC) results in 60 to 1400 well-appearing newborns treated for every positive culture; “triple I” — intrauterine inflammation, infection, or both; status confirmed with pathologic diagnosis of placenta and positive amniotic fluid culture; with fever prior to delivery at ≥34 wk, observe well-appearing infant; re-evaluate every 4 to 6 hr

Recommendations from CDC: blood culture at birth; CBC and differential at 6 to 12 hr; empiric antibiotic therapy (36-48 hr of ampicillin-gentamicin); study of exposed newborns (≥2100 g, ≥35 wk) found sterile culture in most; no infant with abnormal leukocyte (WBC) count readmitted for sepsis ≤2 wk; WBC abnormalities had suboptimal specificity and sensitivity but good negative predictive value; CDC amendment (Polin et al, 2014) — blood culture at birth; WBC count, C-reactive protein (CRP), or both at 6 to 12 hr; use broad-spectrum drugs; if culture positive, treat >48 hr; if sterile, discontinue (48-72 hr); speaker feels WBC and CRP have no effect on management (favors 24 to 36 hr of therapy)

Limitations of antibiotic therapy: prolonged therapy associated with NEC, LOS, candidiasis, BPD, severe retinopathy of prematurity, poorer neurodevelopmental outcomes, and death; therapy associated with colonization by multidrug-resistant organism, delayed breastfeeding, recurrent wheezing by 12 yr of age, and change in intestinal microbiome; potential for hearing loss and renal dysfunction; EOS calculator — identifies infants unlikely to have positive blood culture based on estimated GA, duration of ROM, colonization by GBS, timing and type of antibiotics, degree of maternal temperature, and symptoms in infant; newer recommendations (Benitz et al) — provide empiric therapy for symptomatic infants; may monitor respiratory signs suggestive of transition unless signs worsen or persist >6 hr; in treated infants, serial normal CBC, CRP, and procalcitonin predict absence of bacterial infection; improve prescribing — use antimicrobial “time-out”; do not prescribe at night; prescribe for 24 hr, then reassess

Culture-negative sepsis: possibly explained by maternal antibiotic therapy; Herpes simplex — acquired transplacentally or as ascending infection with prolonged ROM in 5%; infants present at 24 to 48 hr with disseminated infection (rash without vesicles, lethargy, elevated liver function tests, coagulopathy, thrombocytopenia); consider viral infection with neonatal fever <72 hr; adenovirus — high mortality; pneumonia and fever at 24 to 48 hr of age; enterovirus — crosses placenta and infects during delivery; sepsis-like syndrome (hepatitis, myocarditis, meningoencephalitis); no specific therapy (intravenous IG used)

Prevention of infection: hand hygiene; policies for control of infection in nursery; vaccination of mothers and siblings; colostrum and breast milk contain lactoferrin (reduces LOS in infants <1400 g); use of probiotics to decrease risk for LOS in preterm infants has yielded conflicting results; small study found lower levels of vitamin D in infants who develop sepsis

Readings

Benitz WE et al: Reappraisal of guidelines for management of neonates with suspect early-onset sepsis. J Pediatr 2015 Apr;166(4):1070-4; Engle WD et al: Neonatal pneumonia: comparison of 4 vs 7 days of antibiotic therapy in term and near-term infants. J Perinatol 2000 Oct-Nov;20(7):421-6; Garges HP et al: Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters? Pediatrics 2006 Apr;117(4):1094-100; Hornick CP et al: Use of the complete blood count in early-onset neonatal sepsis. Pediatr Infect Dis J 2012 Aug;31(8):799-802; Lechowicz M et al: Multiple brain abscesses caused by Citrobacter koseri in a preterm neonate — case report. Pol J Radiol 2017 Dec 15;82:837-41; Madjunkov M et al: Listeriosis during pregnancy. Arch Gynecol Obstet 2017 Aug;296(2):143-52; Polin RA et al: The conundrum of early-onset sepsis. Pediatrics 2014 Jun;133(6):1122-3; Puopolo KM et al: Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics 2011 Nov;128(5): e1155-63. doi: 10.1542/peds.2010-3464; Shane AL et al: Neonatal sepsis. Lancet 2017 Oct 14;390(10104):1770-80; Sobouti B et al: Colonization of Mycoplasma hominis and Ureaplasma urealyticum in pregnancy women and their transmission to offspring. Iran J Microbiol 2014 Aug;6(4):219-24; Stoll BJ et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics 2011 May;127(5):817-26; Verani JR et al; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC): Prevention of perinatal group B streptococcal disease — revised guidelines from CDC, 2010. MMWR Recomm Rep 2010 Nov 19;59(RR-10):1-36; Wortham JM et al; Eunice Kennedy Shriver NICHD Neonatal Research Network: Chorioamnionitis and culture-confirmed, early-onset neonatal infections. Pediatrics 2016 Jan;137(1): doi: 10.1542/peds.2015-2323.

Additional Resources
CDC guideline for group B Streptococcus: www.cdc.gov/groupbstrep
Early-onset sepsis calculator: https://neonatalsepsiscalculator.kaiserpermanente.org/

Disclosures

For this program, the following has been disclosed: Dr. Sanchez is on advisory panels for AstraZeneca and Sanofi Pasteur and receives grant/research support from MedImmune. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Sanchez was recorded at The Colin J. Condron, MD, Care of the Sick Child conference, presented by Orlando Health and the Arnold Palmer Hospital for Children, and held March 8-10, 2018, in Lake Buena Vista, CA. For information about upcoming CME conferences from Orlando Health, please visit www.orlandohealth.com. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PD644001

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.