1. Neonatal Sepsis and Recent Challenges Mohammad Khasswneh, MD Assistant Professor of Pediatrics JUST

3. introduction Common –20% of VLBW has sepsis –In term 0.1% –Inter-institution difference 11-32% ( NICHD net work ) Serious –mortality is 3-5 times more for infant with sepsis in NICU

4. Classification Early onset sepsis (EOS): –bacteria acquired before and during delivery –5-7/1000 live birth –1.5% of VLBW infants had EOS (intrapartum antibiotics) Late onset sepsis (LOS): –bacteria acquired after delivery (Nosocomial or community) –20% of VLBW infants

5. Who is the septic neonate? Positive blood culture with clinical symptoms of infection –Coagulase-negative Staphylococcus (CoNS) 2 positive blood cultures One positive blood culture and elevated CRP Clinical sepsis” or “probable sepsis

6. Adult and Pediatrics Definitions Systemic Inflammatory response syndrome (SIRS) Sepsis – as SIRS plus infection Severe sepsis: – as sepsis associated with organ dysfunction, hypo perfusion or hypotension, Septic shock –sepsis with arterial hypotension despite fluid resuscitation

7. Blood Culture –One out of five evaluations for sepsis has positive blood culture –80% of the time, empiric antibiotics will be given when no organism is isolated from culture

8. Blood culture In a 1999, autopsy study of ELBW infants infection was primary cause of death by pathologists in (56 of 111) sepsis was not diagnosed prior to death for 61% of these 56 neonates

9. False negative Blood Culture Maternal antibiotics Small blood sample in a prospective study of nearly 300 blood cultures drawn from critically ill neonates, 55% of culture vials contained less than 0.5 ml of blood Bacteria load, timing of sampling

10. Diagnosis

11. Clinical Signs according to WHO Integrated Management of Childhood illness Respiratory rate >60 breaths/min Retraction, flaring, Grunting Crepitation Cyanosis

12. Clinical Sings according to WHO Integrated Management of Childhood illness Temperature >37.7°C (or feels hot) or <35.5°C (or feels cold) Convulsions,Lethargic or unconscious Reduced movements and activity) Not able to feed (sustain suck) Bulging fontanels

13. Other signs in NICU abnormal heart rate characteristics Reduced digital capillary refill time metabolic acidosis Increase in weight

14. Clinical signs of sepsis in VLBW infants NICHD network study Apnea in 55% gastrointestinal problems (46%), increased need for oxygen or ventilatory support 36% lethargy/hypotonia 23% Hypotension 5% The positive predictive value 14 to 20%.

15. New Diagnostic Methods CRP Interleukin 6,8 IgM Polymerase chain reaction (PCR) DNA microarray technology Immunoassay

16. CRP Best discriminatory value for predicting septicemia Expressed by all gestational age sensitivity 48 to 63%

17. Serial CRP elevated CRP on day 1 and/or day 2, identify most case of sepsis – sensitivity (90.2%)

18. Serial CRP When CRP is normal on days 1 and 2,neonatal sepsis can be confidently excluded and antibiotic therapy ceased –negative predictive value (97.7%).

19. CRP Sensitivity of serial CRP testing is lower for bacteremia due to gram- positive than to gram- negative bacteria

20. CRP Help in timing of discontinuation of antibiotics when CRP normalize Further studies is needed

21. Polymerase Chain Reaction (PCR) PCR: under investigation for bacterial and fungal infection –amplification of 16S rRNA, –a gene universally present in bacteria but absent in humans – Results in 9 h of sample acquisition

22. PCR –Sensitivity 96% –Specificity 99.4% –positive predictive value 88.9% –negative predictive value 99.8%

23. Microbiology in Developing Country Gram negative organisms –Klebsiella, Escherichia coli, –Pseudomonas, and Salmonella. Gram positive less common – Staphylococcus Aureus – Coagulase negative staphylococci (CONS) – Streptococcus pneumoniae, and Streptococcus pyogenes

24. Microbiology In Developing Country Group B streptococcus (GBS) is rare Maternal recto-vaginal Carriage rates for GBS is similar to that in developed country

25. Meningitis developing country 1st week mainly Gram negative. Older than 1 week: – Streptococcus pneumonia, 50% of all bacterial meningitis occurring between 7 and 90 days of age –Fatality rate of 53%.

26. Microbiology in Developed Country EOS –GBS and E coli –Recently decrease in Gram positive organisms (GBS) and increase in Gram negative organisms LOS: –Coagulase Negative Staph (CON), – GBS –Staph Aureus.

27. New trends incidence of GBS sepsis decreased from 5.9 to 1.7 per 1,000 the incidence of sepsis from E. coli increased from 3.2 to 6.8 per 1,000 between 1991-1993 and 1998-2000

28. Case Fatality EOS: more severe and case fatality rate is higher( all-causes mortality was 37%) LOS: less sever (CoNS) 18%.

29. Mortality Per Organisms percentages/ LBW infants Gram-negative 257cases (36%) –E coli 53 cases (34%) –Klebsiella 62 cases (22%) –Pseudomonas 43 cases (74%) –Enterobacter 41 cases (26%) –Serratia 39 cases (35%) fungal 151cases (31%)

30. Mortality Rate by Organisms in low birth weight infants Gram-positive 905 case 101 deaths (11.2%) –CoNS. 606 cases (9.1%) –S aureus 99 cases (17.2%) –GBS 32 cases (21.9%) –All other streptococci 65 cases (10.8%)

31. Sepsis Risk Factors Prematurity Birth weight –Term 0.1% –1,000 -1,500 g 10% – <1,000 g 35% –<750 g. 50% Delay enteral feeding and Prolonged TPN

32. Frequent Blood Drawing??

33. Group B streptococcus (GBS) Maternal colonization 15 to 40% 50% of infants acquire surface colonization at delivery 1% of colonized full-term infants develop EONS

34. GBS In 1996, GBS guidelines Incidence declined from 5.9-1.7 per 1,000 in 1992 and 1999 respectively Emergence of penicillin resistance among GBS ( Japan )

35. GBS Guideline the incidence of infections with gram-negative bacteria increased antibiotic resistance among gram-negative pathogens has increased

36. Coagulase-Negative Staphylococci commonest cause of nosocomial bacteremia – ventriculoperitoneal shunt infection –Endocarditis with umbilical lines S. epidermidis, S. haemolyticus, S. hominis, S. saprophyticus,

37. Coagulase-Negative Staphylococci Sepsis with CoNS is often indolent nonspecific symptoms

38. Coagulase-negative staphylococci a positive blood culture for CoNS may represent either contamination –26 cases, in only 16 cases were cultures from two sites positive, and the other 10 cases were considered to represent contamination

39. Coagulase-negative staphylococci Studies have shown that initial therapy of suspected LONS with nafcillin or oxacillin and an aminoglycoside,rather than vancomycin did not change outcome (decrease resistance )

40. Staphylococcus aureus Less commonly seen S. aureus strains remained sensitive to extended- spectrum penicillins (oxacillin or nafcillin)

41. Gram Negative bacteria Klebsiella pneumoniae in our area E. coli in united states Increase in incidence Multiresistance Invasion of CNS, Citrobacter koseri

42. Gram Negative P. aeruginosa –conjunctivitis –systemic disease high mortality Haemophilus influenzae. –Non typeable –Fulminant, simulating RDS. –Mortality 90%

43. Antibiotics Resistance Induced by antibiotic pressure (over use) Broad-spectrum cephalosporin induce chromosomal ESBLs in gram-negative bacilli

44. Antibiotics Resistance Ampicillin and Amikacin for empiric treatment of EONS Oxacillin and amikacin for empiric treatment of LONS reduce colonization with resistant gram- negative bacilli from 32 to 11%

45. Practical points LP should be done in evaluation of sepsis even with negative blood culture Urine culture is not part of work up for EOS Vesicoureteral reflux was present in 14% of VLBW infants with UTI.

46. Conclusions Gram negative organism is becoming more common worldwide GBS is not common in our area Multi-resistance organism mandate different approaches for N. sepsis treatment

47. Conclusions CRP can help in early discontinuation of antibiotics New Diagnostic Technology will play role in both –Early diagnosis and treatment –Restrict antibiotics over use