Neonatal Infections

1. Neonatal Infections Catherine M. Bendel, M.D. Associate Professor of Pediatrics Director, Neonatal-Perinatal Medicine Fellowship Program

2. Why are infants, especially premies, more susceptible to infections? What are the clinical manifestations of neonatal infections? Bacterial? HSV? How to prevent infections? Antibiotics - indications, contraindications, cautions, resistance, etc. How to interpret labs? Any precautions with lines? Questions?

3. Objectives • To briefly review neonatal immunology and why neonates are so susceptible to infections • To review the epidemiology, clinical presentation, diagnosis and treatment of the most common bacterial and HSV neonatal infections. • To review modes of infection prevention. • To differentiate between preterm and term infants in all these areas

4. “Prematurity is an infectious disease.” - James Todd, M.D.

5. Why are infants, especially premies, more susceptible to infections?

6. Neonatal Immune System • All neonates relatively immunocompromised • Immature and Ineffective: • Antibodies • Complement • Neutrophils • Skin / mucosal barriers

7. Antibody

8. Antibodies  Infectious agent   Immunity Figure 1.1 Antibodies (anti- foreign bodies) are produced by host while cells on contact with the invading micro-organism which is acting as an antigen (e.g. generates antibodies). The individual may then be immune to further attacks. (Modified From: Roitt, I: Essential Immunology, 4th edition, Blackwell Scientific Publications, 1980)

9. Antibodies  Infectious agent   Immunity x x No contact with infectious agents = no antibody production

10. Maternal Transfer of Antibodies • Antibody transfer increases with GA • Most during 3rd trimester • No guarantee maternal antibodies present to the infecting organism Remington and Klein, Sixth Edition, 2006

11. Complement

14. Neutrophils

15. Neonatal Neutrophils • Immature •  Chemotaxis •  Deformability •  Phagocytosis •  Storage pool • Adults 14-fold > circulating pool • Neonates only 2-fold

16. Manroe et al, J Pediatr, 1979

17. “Normal” VLBW neonates Mouzinho et al, Pediatr 94:76, 1994

18. “Normal” VLBW neonates Mouzinho et al, Pediatr 94:76, 1994

19. Neonatal Barriers to Infection

20. Neonatal Anatomic Barriers • Immature skin and mucosal surfaces • layers • junctions between cells • secretory IgA • Umbilical cord • Breaches - catheters, tape

21. Invasive Fungal Dermatitis in a VLBW infant JL Rowen, Sem Perinatal 27:406-413, 2003

22. Epidemiology

23. Neonatal Sepsis: Incidence • 2/1000 live births with culture proven sepsis • Bacterial / Viral / Fungal • 80% infants develop bacterial sepsis • 20% infants perinatally acquired viral infections • ~ 25% of infected infants have meningitis • Higher rate with preterm birth • 26/1000 preterm infants with BW < 1000g • 8-9/1000 preterm infants with BW 1000-2000g Remington and Klein, Sixth Edition, 2006

24. Early Onset Neonatal Sepsis (EONS) Fulminant, multi-system illness < 5 days old Obstetrical complications Prematurity Perinatal acquisition High mortality, 5-50% Late Onset Neonatal Sepsis (LONS) Sepsis or meningitis 5 days to 3 months old Perinatal or postnatal acquisition Lower mortality, 2-6% Neonatal Bacterial Sepsis:Disease Patterns

25. Neonatal Infections Sepsis Meningitis Pneumonia Otitis Media Diarrheal Disease UTI Osteomyelitis Suppurative Arthritis Conjunctivitis Orbital Cellulitis Cellulitis - - Omphalitis Bacterial / Viral / Fungal

26. Etiologic Agents of Neonatal Sepsis Frequency(%) Group B Streptococci 40  Escherichia coli 17 Streptococcus viridans 7 Staphylococcus aureus 6 Enterococcus spp 6 Coagulase-negative staphylococci 5 Klebsiella pneumoniae 4 Pseudomonas spp 3 Serratia marcescans 2 Others 10 *Schuchat et al, Pediatrics 105: 21-26, 2000

27. Etiologic Agents of Neonatal Meningitis Gram Positive Bacteria; Frequency (%)  Group B Streptococci 53 Listeria monocytogenes 7 Miscellaneous gram-positives 6 Gram Negative Bacteria:  Escherichia coli 19 Klebsiella species 8 Haemophilus influenzae 1 Miscellaneous gram-negatives 8 Anaerobes 3 Feigen & Cherry, Fifth Edition, 2004

28. Incidence of Neonatal Group B Streptoccal Sepsis • 5-35% Pregnant women colonized • 1/100-200 colonized women will have an infant with early onset disease • 1-7/1000 live births in 1993 • 0.44/1000 live births in 1999 Remington and Klein, Sixth Edition, 2006

29. Group B Strep Association formed 1st ACOG & AAP statements CDC draft guidelines published Rate of Early- and Late-onset GBS Disease in the 1990s, U.S. Consensus guidelines Schrag, New Engl J Med 2000 342: 15-20

30. Black White Healthy People 2010 Rate of Early-Onset Disease by Race 1993-1998 Schrag, New Engl J Med 2000 342: 15-20

31. Current Estimates of Annual GBS Early-Onset Disease in the U.S. (2001 provisional, from ABCs/EIP Network) ~4,400 cases prevented per year 1720 cases still occurring annually 70 - 90 deaths Remains leading infectious cause of neonatal morbidity and mortality

32. What do we know about trends in “other pathogens”? • Most studies: stable rates of ‘other’ sepsis • Concerns for increased rates of E. coli, all gram negatives, or amp-R infections • Population-based (multicenter) studies find stable rates of total non-GBS and E. coli • One multicenter study of very LBW infants found a decrease in GBS by 4.2 /1,000, but an increase in E coli rates of 3.6/1,000 (Stoll et al, NEJM, 2002, 347:240-7) • % of E. coli sepsis w/ amp resistance may be increasing • Increases restricted to low birth weight or preterm deliveries

33. Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases, Full-Term Infants, ABCs, Selected Counties CA and GA, 1998-2000 N=22, p=0.52, linear trend Hyde et al, Pediatrics 2002;110(4):690-5.

34. Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases Preterm Infants, ABCs, Selected Counties CA and GA, 1998-2000 N=37, p=0.02, linear trend Hyde et al, Pediatrics 2002;110(4):690-5.

35. Susceptibility of GBS: ABC/EIP Isolates, 1995-2000 • 1280 isolates from MN, GA, NY, OR (1173 invasive, 107 colonizing): • All susceptible to penicillin, ampicillin, cefotaxime and vancomycin • 19% erythromycin resistance • 11% clindamycin resistance

36. Risk Factors for Early Onset Neonatal Sepsis • Primary (significant) • Prematurity or low birth weight • Preterm labor • Premature or prolonged rupture of membranes • Maternal fever / chorioamnionitis • Fetal hypoxia • Traumatic delivery • Secondary • Male • Lower socioeconomic status • African-American race Remington and Klein, Sixth Edition, 2006

37. Factors associated with early-onset GBS disease: multivariable analysis Schrag et al, NEJM 2002, 347:233-9

38. Early Onset Neonatal Sepsis:Risk Factors - Maternal Fever • Maternal fever is a significant risk factor for EONS and may add in the identification of infected but initially asymptomatic infant. • 5.36 = adjusted RR • 25% of asymptomatic infants, with culture positive sepsis, had maternal fever as the ONLY criteria for evaluation. Chen et al, J of Perinatal, 2002, 22:653-657

39. Early Onset Neonatal Sepsis:Presentation and Diagnosis

40. Early Onset Neonatal Sepsis:Signs/Symptoms ?

41. Early Onset Neonatal Sepsis:Signs/Symptoms Strongly suggestive hypoglycemia / hyperglycemia hypotension metabolic acidosis apnea shock DIC hepatosplenomegaly bulging fontanelle seizures petechiae hematochezia respiratory distress

42. Early Onset Neonatal Sepsis:Signs/Symptoms Nonspecific lethargy, irritability temperature instability -- hypothermiaor fever poor feeding cyanosis tachycardia abdominal distention jaundice tachypnea

43. Early Onset Neonatal Sepsis:Signs/Symptoms - Fever • The infant with sepsis may have an elevated, depressed or normal temperature. • Fever is seen in up to 50% of infected infants. • Fever is more common in term infants, while hypothermia is more common in preterm infants • A single elevated temperature reading or fever as an isolated finding is infrequently associated with sepsis. • Persistent fever for greater than 1 hour is more frequently associated with infection. • Fever occurs more frequently with LONS or with viral, rather than bacterial, sepsis. Klein, Sem in Perinat, 5:3-8

44. Early Onset Neonatal Sepsis:Laboratory Evaluation •  Cultures  • Chest Radiograph • Complete Blood Cell Count • Glucose • Bilirubin • Liver Function Tests • Coagulation studies • C-reactive Protein (CRP)

45. Early Onset Neonatal Sepsis:Cultures -- Who and Which? • Blood culture -- indicated in ALL infants with suspected sepsis. Repeat cultures indicated if initial culture positive. • Urine culture -- low yield in EONS • + in 1.6% EONS compared to 7.47% LONS Klein, Sem in Perinat, 5:3-8

46. Early Onset Neonatal Sepsis:Cultures -- Who and Which? • CSF culture -- should always be considered Meningitis frequently accompanies sepsis • 50-85% meningitis cases have + blood culture • Yield reportedly low if respiratory distress is the only major sign of infection • Specific signs & symptoms occur in less than 50% of infants with meningitis • Using “selective criteria” for obtaining CSF may result in missed or delayed diagnosis in up to 37% of infants with meningitis Wiswell et al, Pediatrics, 1995

47. Laboratory Diagnosis of Neonatal Meningitis CSF - - > 32 WBC/mm3 > 60% PMN glucose < 50% - 75% of serum protein > 150 mg/dl organisms on gram stain

48. Early Onset Neonatal Sepsis:Complete Blood Cell Counts • Is the CBC helpful as an indicator of early onset neonatal sepsis? • Thrombocytopenia frequently associated with sepsis • WBC may be high, low or “normal” --timing of the sample important • Persistent low WBC more predictive of sepsis than elevated WBC (ANC < 1200) • I:T quotient unreliable

50. Early Onset Neonatal Sepsis:Complete Blood Cell Counts