Neonatal sepsis

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1. Neonatal Sepsis Prof. Dr. Saad S Al Ani Senior Pediatric Consultant Head of Pediatric Department Khorfakkan Hospital Sharjah ,UAE [email protected]

2. Neonatal Sepsis Diagnosis is clinical and based on culture results 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 2 Neonatal sepsis is an invasive infection, usually bacterial, occurring during the neonatal period Signs are multiple, nonspecific

3. Neonatal Sepsis The highest rates occur in Low-birth-weight (LBW) infants Infants with depressed function at birth as manifested by a low Apgar score Infants with maternal perinatal risk factors Males 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 3 Neonatal sepsis occurs in 0.5 to 8.0/1000 births.

4. Neonatal Sepsis Categories of neonatal sepsis Neonatal sepsis may be categorized as: Early onset (day of life 0-3) Late onset (day of life 4 or later ) 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 4

5. Neonatal Sepsis Early-onset neonatal sepsis Early-onset sepsis is associated with acquisition of microorganisms from the mother . Infection can occur via hematogenous , transplacental spread from an infected mother or, more commonly, via ascending infection from the cervix . 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 5

6. Neonatal Sepsis Early-onset sepsis is 10 to 20 times more likely to occur in premature , very low birthweight infants 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 6

7. Neonatal Sepsis The microorganisms most commonly associated with early-onset infection include the following     : 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 7   Klinger G, Levy I, Sirota L, et al, for the Israel Neonatal Network. Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants.  Am J Obstet Gynecol . 2009 Jul. 201 (1):38.e1-6.  Group B Streptococcus (GBS) Escherichia coli Coagulase-negative Staphylococcus Haemophilus influenzae Listeria monocytogenes

8. Neonatal Sepsis With early-onset sepsis 85% present within 24 hours (median age of onset 6 hours ) 5% present at 24-48 hours Smaller percentage present within 48-72 hours . Onset is most rapid in premature neonates . 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 8

9. Neonatal Sepsis Late-onset neonatal sepsis Late-onset sepsis occurs at 4-90 days of life and is acquired from the environment . 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 9

10. Neonatal Sepsis Organisms that have been implicated in late-onset sepsis include the following : 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 10 Coagulase-negative Staphylococcus Pseudomonas Serratia Staphylococcus aureus Enterobacter Acinetobacter E coli Candida Anaerobes Klebsiella GBS Many additional less-common organisms

11. Neonatal Sepsis In early-onset sepsis : Pneumonia is more common 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 11 In late-onset sepsis Meningitis and Bacteremia are more common

12. Neonatal Sepsis Pathophysiology Currently, GBS and   E coli   continue to be the most commonly identified microorganisms associated with neonatal infection 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 12

13. Neonatal Sepsis In neonatal sepsis additional organisms that have been identified include: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 13 Coagulase-negative Staphylococcus epidermidis H influenzae L monocytogenes, Enterobacter aerogenes, Chlamydia pneumoniae species of Bacteroides  and Clostridium

14. Neonatal Sepsis Early onset: Risk factors M aternal perinatal and obstetric factors that increase risk : Premature rupture of membranes ( PROM ) occurring ≥ 18 h before birth Maternal chorioamnionitis Colonization with GBS Preterm delivery 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 14

15. Neonatal Sepsis Hematogenous and transplacental dissemination of maternal infection occurs in the transmission of certain: viral (e.g.,  rubella, cytomegalovirus ) protozoal (e.g.,  Toxoplasma gondii ) treponemal (e.g.,  Treponema pallidum) pathogens 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 15

16. Neonatal Sepsis Late onset : risk factors The most important risk factor in late-onset sepsis is  preterm delivery . Others include: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 16 Prolonged use of intravascular catheters Exposure to antibiotics (which selects resistant bacterial strains) Associated illnesses Prolonged hospitalization Contaminated equipment or IV or enteral solutions

17. Neonatal Sepsis Symptoms and Signs 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 17 Early signs of neonatal sepsis are frequently nonspecific and subtle and do not distinguish among organisms Common early signs include: Diminished spontaneous activity Apnea Less vigorous sucking Bradycardia Anorexia Temperature instability (hypothermia or hyperthermia)

18. Neonatal Sepsis Fever is present in only 10 to 15% but, when sustained (e.g.  > 1 h), generally indicates infection 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 18 Other symptoms and signs include: Respiratory distress Vomiting Neurologic findings (e.g., seizures, jitteriness) Diarrhea Jaundice Abdominal distention

19. Neonatal Sepsis Diagnosis 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 19 High index of suspicion Blood, CSF, and sometimes urine culture

20. Neonatal Sepsis Neonates with clinical signs of sepsis   Should have : 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 20 CBC, Differential with smear Urine culture (not necessary for evaluation of early-onset sepsis) Blood culture lumbar puncture (LP), if clinically feasible, As soon as possible.

21. Neonatal Sepsis Neonates with clinical signs of sepsis   (Cont.) Neonates with respiratory symptoms require chest x-ray . Diagnosis is confirmed by isolation of a pathogen in culture. Other tests may have abnormal results but are not necessarily diagnostic. Infants should be given broad-spectrum   empiric antimicrobial therapy 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 21

22. Neonatal Sepsis Other tests for infection and inflammation 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 22 Acute-phase reactants Quantitative C-reactive protein . -The sensitivity is higher if measured after 6 to 8 h of life . - Two normal values obtained between 8 h and 24 h after birth and then 24 h later have a negative predictive value of 99.7%. Procalcitonin - Appears more sensitive than C-reactive protein, it is less specific Pontrelli G, De Crescenzo F, Buzzetti R, et al : Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: A meta-analysis.  BMC Infect Dis  17(1):302, 2017.

23. Neonatal Sepsis Prognosis 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 23 The fatality rate is 2 to 4 times higher in LBW infants than in full-term infants The overall mortality rate of: - Early-onset sepsis is 3 to 40 % (that of early-onset GBS infection is 2 to 10%) - Late-onset sepsis is 2 to 20% ( that of late-onset GBS is about 2 %)

24. Neonatal Sepsis Treatment 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 24 Antibiotic therapy Supportive therapy

25. Neonatal Sepsis Treatment (Cont.) 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 25 Because sepsis may manifest with nonspecific clinical signs and its effects may be devastating , rapid empiric antibiotic therapy is recommended

26. Neonatal Sepsis Treatment (Cont.) 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 26 Drugs are later adjusted according to sensitivities and the site of infection . If no source of infection is identified clinically, the infant appears well , and cultures are negative , antibiotics can be stopped after 48 h ( up to 72 h in small preterm infants).

27. Neonatal Sepsis 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 27 Treatment (Cont.) General supportive measures, including respiratory and hemodynamic management , are combined with antibiotic treatment .

28. Antimicrobials Early-onset sepsis , initial therapy should include   ampicillin   plus an aminoglycoside Cefotaxime may be added to or substituted for the aminoglycoside if meningitis caused by a gram-negative organism is suspected Antibiotics may be changed as soon as an organism is identified . 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 28

29. Antimicrobials (Cont.) late-onset sepsis should also receive therapy with ampicillin plus gentamicin or ampicillin plus cefotaxime If gram-negative meningitis is suspected , ampicillin, cefotaxime, and an aminoglycoside may be used 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 29

30. Antimicrobials (Cont.) In late-onset hospital-acquired sepsis : Initial therapy should include Vancomycin ( active against methicillin-resistant S. aureus ) plus an Aminoglycoside . If P. aeruginosa is prevalent in the nursery, Ceftazidime , Cefepime , or Piperacillin/ Tazobactam may be used in addition to, or instead of, an aminoglycoside depending on local susceptibilities. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 30

31. Antimicrobials (Cont.) For neonates previously treated with a full 7- to 14-day aminoglycoside course who need retreatment, a different aminoglycoside or a 3rd-generation cephalosporin should be considered . 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 31

32. Antimicrobials (Cont.) If coagulase-negative staphylococci are suspected (e.g., an indwelling catheter has been in place for > 72 h) or are isolated from blood or other normally sterile fluid and considered a pathogen: Initial therapy for late-onset sepsis should include  vancomycin . I f the organism is sensitive to nafcillin , cefazolin   should replace vancomycin. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 32

33. Other treatment ??? Exchange transfusions Fresh frozen plasma Granulocyte transfusions Recombinant colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF ]) IV  immune globulin  11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 33

34. Prevention Neonates who appear well may be at risk of group B streptococcus infection If there is: Neither chorioamnionitis Nor indication for group B streptococcus prophylaxis NO testing OR treatment is indicated . 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 34

35. Prevention (Cont.) If  chorioamnionitis is present or strongly suspected: -   Preterm and term neonates should: *have a blood culture at birth and *begin   empiric broad-spectrum antibiotic therapy. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 35

36. Prevention (Cont.) - Testing should also include: * WBC count and differential * C-reactive protein at 6 to 12 h of life . - Further management depends on the clinical course and results of the laboratory tests. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 36

37. Prevention (Cont.) If   maternal group B streptococcus prophylaxis was indicated and given appropriately   (i.e., penicillin, ampicillin , or cefazolin given IV for ≥ 4 h ): - Infants should be: * Observed in the hospital for 48 h * Testing and treatment are done only if symptoms develop. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 37

38. Prevention (Cont.) If   adequate group B streptococcus prophylaxis was not given: -   Infants are observed in the hospital for 48 h without antimicrobial therapy. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 38

39. Prevention (Cont.) - If membranes ruptured ≥ 18 h before birth or gestational age is < 37 wk.: *blood culture, CBC with differential, and perhaps a C- reactive protein level is recommended at birth and/or at 6 to 12 h of life. - The clinical course and results of the laboratory evaluation guide management. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 39

40. Neonatal Sepsis Summary: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 40 1.Neonatal sepsis can be early onset (≤ 3 days of birth) or late onset (after 3 days).

41. Neonatal Sepsis Summary: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 41 2.Early-onset sepsis usually results from organisms acquired intrapartum , and symptoms appear within 6 h of birth .

42. Neonatal Sepsis Summary: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 42 3.Late-onset sepsis is usually acquired from the environment and is more likely in preterm infants , particularly those with prolonged hospitalization , use of IV catheters , or both.

43. Neonatal Sepsis Summary: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 43 4.Early signs are frequently nonspecific and subtle, and fever is present in only 10 to 15% of neonates .

44. Neonatal Sepsis Summary: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 44 5.Do blood and CSF cultures and, for late-onset sepsis, also do urine culture

45. Neonatal Sepsis Summary: 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 45 6.Treat early-onset sepsis initially with ampicillin plus gentamicin ( and/or cefotaxime if gram-negative meningitis is suspected ), narrowed to organism-specific drugs as soon as possible.

46. References van den Hoogen A, Gerards LJ, Verboon-Maciolek MA, Fleer A, Krediet TG. Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents.  Neonatology . 2010. 97 (1): 22-8 Berardi A, Rossi C, Spada C, et al, for the GBS Prevention Working Group of Emilia-Romagna. Strategies for preventing early-onset sepsis and for managing neonates at-risk: wide variability across six Western countries. J Matern Fetal Neonatal Med. 2019 Sep. 32 (18): 3102-8 https://www.msdmanuals.com/professional/pediatrics/infections-in-neonates/neonatal-sepsis https :// emedicine.medscape.com/article/978352 Escobar GJ, Puopolo KM, Wi S, et al: Stratification of risk of early-onset sepsis in newborns ≥ 34 weeks' gestation. Pediatrics 133(1):30–36, 2014 . Pontrelli G, De Crescenzo F, Buzzetti R, et al: Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: A meta-analysis. BMC Infect Dis 17(1):302, 2017 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 46

47. 11/23/2019 Neonatal Sepsis Prof. Dr. Saad S Al Ani 47 Good Job, Pal!