1. Neonatal Sepsis Abbey Rupe, MD 7.24.2012

2. 2012 AAP Clinical Report: – Management of Neonates with Suspected or Proven Early-Onset Bacterial Sepsis (May 2012)

3. Epidemiology Overall incidence: 1-5/1000 live births Term infants: 1-2/1000 live births

4. Definitions Neonatal sepsis – Infant 28 days of life or younger – Systemic signs of infection – And/or isolation of bacterial pathogen from bloodstream Early-onset GBS disease – Birth to 6 days of age – (some sources: birth to 72 hours) Late-onset GBS disease Symptom onset at >72 hours or ≥ 7 days of age

5. Transmission Early-onset – Vertical transmission Ascending contaminated amniotic fluid – after ROM or via occult tears in placenta During vaginal delivery from bacteria colonizing or infecting mother’s lower genital tract

6. Transmission Late-onset sepsis – Vertical transmission  neonatal colonization  later infection OR – Horizontal transmission via direct contact w/ care providers or environmental sources Disruption of intact skin or mucosa increases risk of late-onset sepsis

7. Risk factors Early-onset sepsis Major risk factors: – Preterm birth – Maternal colonization w/ GBS – ROM > 18 hours – Maternal chorioamnionitis Other: – Ethnicity (black women higher rate of GBS colonization – Low SES – Male gender – Low Apgar scores

8. Chorioamnionitis Risk factors: – Low parity – Spontaneous labor – Longer length of labor and membrane rupture – Multiple digital vaginal exams (esp w/ ruptured membranes) – Meconium-stained amniotic fluid – Internal fetal or uterine monitoring – Presence of genital tract microorganisms

9. Chorioamnionitis Definition: – Maternal fever (100.4 or higher), plus 2 of the following: Maternal leukocytosis (>15,000) Maternal tachycardia (>100 bpm) Fetal tachycardia (>160 bpm) Uterine tenderness Foul odor of amniotic fluid

10. Infectious agents Early-onset: – GBS – E. coli GBS and E. coli account for 2/3rds GBS most-common cause in term newborns E. coli most-common cause in preterm newborns – Other: Klebsiella, Enterobacter, Listeria

11. Infectious agents Late-onset: – GBS – E. coli – S. aureus (MSSA and MRSA) Increasing in incidence Typically associated with skin, bone, or joint infections – Other: Klebsiella, Enterobacter, Listeria

12. GBS 2002: CDC recommendation of universal, culture-based screening with intrapartum antibiotic prophylaxis (IAP) for GBS + women – 80% decrease in early-onset GBS infection – No change in late-onset disease Guidelines updated in 2010

13. GBS—indications for IAP Mother GBS+ within preceding 5 weeks GBS status unknown and ≥ 1 risk factor present: – < 37 WGA – ROM ≥ 18 hours – Maternal temp of ≥100.4 GBS bacteriuria during current pregnancy Hx of previous infant with GBS disease

14. IAP Penicillin—drug of choice – Ampicillin is acceptable alternative PCN-allergic women at low-risk of anaphylaxis (no hx of anaphylaxis, angioedema, respiratory distress, or urticaria after PCN or cephalosportin administration) – Cefazolin PCN-allergic women at high-risk of anaphylaxis – Clindamycin (if tested and susceptible) – Vancomycin

15. IAP “Adequate IAP” – PCN, Ampicillin, or cefazolin – First dose administered at least 4 hours prior to delivery All three reach high intra-amniotic concentrations within 3 hours of administration – “All other antibiotics, doses, or durations are considered inadequate for the purposes of neonatal management”

16. Clinical manifestations Fetal/delivery room distress – Fetal tachycardia – Meconium-stained amniotic fluid 2-fold increase for sepsis in infants who did not receive IAP – Low Apgar One case-control study: infants with 5-minute Apgar of ≤6 had a 36-fold higher likelihood of sepsis compared to those with Apgar of 7 or higher

17. Clinical manifestations Fever (> 50%) Respiratory distress Poor feeding Vomiting Jaundice Hepatomegaly Lethargy Other: cyanosis, hypothermia, irritability, apnea, abdominal distention, diarrhea

18. Differential Diagnosis Other infections – HSV, CMV, syphilis Pulm: – TTN, RDS CV: – Cyanotic congenital heart disease Endo: – Inborn errors of metabolism

19. Evaluation Blood culture – x1 – Need at least 1 ml – Sensitivity to detect bacteremia approx 90% – Common pathogens: 97% positive by 24 hours 99% positive by 36 hours

20. Evaluation CBC with diff – WBC: Preferable to obtain at 6-12 hours of age – More likely to be abnormal than if obtained at birth I/T ratio: – Poor predictive accuracy, but very high negative predictive accuracy (99%) – Platelet count often low in infected infants Nonspecific, low sensitivity

21. Evaluation Acute-Phase Reactants – CRP Increases within 6-8 hrs of infections episode and peaks at 24 hours Sensitivity improves if first determined at 6-12 hours of age If obtain 2 normal values (first between 8-24 hours of age, second 24 hours later), negative predictive accuracy of 99.7% – Could use to stop abx; data insufficient on how elevated (>1.0) CRP values should affect duration of abx therapy

22. Evaluation Acute-Phase Reactants: – Procalcitonin Levels increase within 2 hours of infectious episode, peak at 12 hours, and normalize within 2-3 days (adult studies) Slightly more sensitive than CRP, but less specific Not routinely available in hospital labs

23. Evaluation Lumbar puncture – When???? Controversial High-risk, healthy-appearing infant, likelihood of meningitis is “extremely low” Infant with clinical signs attributable to a noninfectious condition (such as RDS), likelihood of meningitis low Among bacteremic infants: incidence of meningitis as high as 23%

24. Evaluation LP: – Perform in : Infant w/ positive blood culture Infant whose clinical course or lab data strongly suggest bacterial sepsis Infants who initially worsen with antimicrobial therapy – Threshold to tap gets lower as # of risk factors goes up – Critically ill or likely to have cardiovascular and/or respiratory compromise during the procedure, can defer until more stable (but don’t delay abx)

25. Evaluation LP – Send CSF for: Gram stain Culture Cell count with diff Protein Glucose other

26. Evaluation Urine culture – Not recommended in infant with suspected early- onset sepsis UTIs in neonates are due to seeding of kidney during episode of bacteremia (not ascending infection, as in older infants) – Include in workup of any infant with suspected late-onset sepsis

27. Evaluation CXR – Obtain in infant with respiratory distress

28. Treatment (early-onset) Ampicillin and Gentamicin – Ampicillin: 75-150 mg/kg/day divided q8 – Gentamicin: 4 mg/kg/day div q24 Alternate regimen: Amp + 3 rd gen ceph (cefotaxime) – Not more effective – High risk for emergence of ceph-resistant strains

29. Treatment Duration of abx: – Culture-proven sepsis: 10 days – Meningitis: 14-21 days – Automated blood culture systems ID 97% of pathogens at 24 hours and 99% at 36 hours Can discontinue empiric abx in well-appearing infant after 48 hours – Negative culture, but high clinical suspicion for systemic infection Continue abx until another dx explains the situation OR to complete 10-day course IAP could cause-negative culture

30. Treatment (late-onset) 7-28 day old infant Re-admitted infant – Amp + gent OR amp + cefotaxime Infant hospitalized since birth – Add vanc HSV suspected – “ill-appearance,” mucocutaneous vesicles, seizures, or CSF pleocytosis S. aureus suspected (soft tissue, skin, joint, or bone involvement) Vanc + nafcillin + gent

31. Outcome GBS: overall 5-10% fatality rate – Term infants: Early-onset: 2-3% Late-onset: 1-2 % E. coli: overall mortality rate 4-16% (higher in preterm infants)

32. Neonatal management Infant with signs of sepsis

33. Neonatal management Infant with signs of sepsis – Full diagnostic evaluation Blood culture CBC CXR if indicated LP – Antibiotic therapy

34. Neonatal management Well-appearing term infant mother diagnosed with chorioamnionitis

35. Neonatal management Well-appearing term infant mother diagnosed with chorioamnionitis – “Limited evaluation” Blood culture at birth CBC with diff at birth and/or 6-12 hours of life NO lumbar puncture – Antibiotic therapy

36. Neonatal management Well-appearing term infant mom GBS negative

37. Neonatal management Well-appearing term infant mom GBS negative – Routine clinical care

38. Neonatal management Well-appearing term infant mom GBS + received ampicillin, PCN, or cefazolin ≥4 hours prior to delivery

39. Neonatal management Well-appearing term infant mom GBS + received ampicillin, PCN, or cefazolin ≥4 hours prior to delivery (“Adequate IAP”) – Observation for ≥ 48 hours **If other discharge criteria are met, could discharge at 24 hours IF – Ready access to medical care – Person able to fully comply with instructions for home observation will be present

40. Neonatal management Term, well-appearing infant Mom GBS + Mom PCN-allergic and received Vanc ROM < 18 hours

41. Neonatal management Term, well-appearing infant Mom GBS + Mom PCN-allergic and received Vanc ROM < 18 hours – Observation for ≥48 hours

42. Neonatal management Term, well-appearing infant Mom GBS + Received 1 dose of ampicillin 2 hours before delivery ROM < 18 hours

43. Neonatal management Term, well-appearing infant Mom GBS + Received 1 dose of ampicillin 2 hours before delivery ROM < 18 hours – Observation for ≥48 hours

44. Neonatal management Term, well-appearing infant Mom GBS + Received inadequate IAP ROM ≥18 hours

45. Neonatal management Term, well-appearing infant Mom GBS + Received inadequate IAP ROM ≥18 hours – “Limited evaluation” Blood culture at birth CBC with diff at birth and/or 6-12 hours of life – Observation for ≥48 hours

46. Neonatal management Well appearing near-term infant Mom received inadequate IAP – “Limited evaluation” Blood culture at birth CBC with diff at birth and/or 6-12 hours of life – Observation for ≥48 hours

47. Neonatal management Term newborn Tachypneic, no O 2 requirement Mom GBS+, received appropriate IAP

48. Neonatal management Term newborn Tachypneic, no O 2 requirement Mom GBS+, received appropriate IAP – DDx: TTN, pneumonia, sepsis – If clinically improving over first 6 hours of life, it is “reasonable” to withhold antibiotics and monitor closely If worsens, obtain blood culture, CBC, and start abx