2018 AAP and 2021 NICE Guidelines for Neonatal Sepsis PPT.pptx

Journal report on the AAP and NICE guidelines on Early Onset Neonatal Sepsis

1. JOURNAL REPORT 2018 AAP Guidelines on the Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis Reporter : Lindsey Beatrice T. Lim Date : October 21, 2022

2. 2012 2018 ≥ 35 0/7 weeks 2018 ≤ 34 6/7 weeks Polin (2012) Puopolo, Benitz , Zaoutis (2018) Puopolo, Benitz , Zaoutis (2018)

3. NICE Guideline (NG195) One guideline for preterm and term infants up to 28 days of age – early and late onset sepsis included

4. Background Definition of EOS : Blood or CSF culture obtained within 72 hours from birth with growth of a pathogenic bacterial species Epidemiology : US : 0.8 in 1000 births (overall); 0.5 in 1000 births (term); 1 in 1000 births (late preterm); 6 in 1000 (<34 wks ), 29 in 1000 (<29 wks ), 32 in 1000 (22-24 wks ) Decreasing incidence in term infants due to use of intrapartum antibiotics, but unclear role in preterm infants Asia : 7.1-38 in 1000 births Philippines : 4-9 in 1000 births

5. Morbidity and Mortality Rates 95% of preterm infants with EOS require intensive care for respiratory distress and/or cardiovascular support 75% of deaths from EOS are among the VLBW Mortality rates by AOG ≥37 weeks: 1.6% 25-28 weeks: 30% 22-24 weeks: 50% Mortality rates by weight ≥1500: 3.5% <1500: 35%

6. Source: WHO and Maternal and Child Epidemiology Estimation Group (MCEE) interim estimates produced in September 2019, applying cause fractions for the year 2017 to UN IGME estimates for the year 2018 Philippines — Causes of Neonatal Mortality, 2015

7. Background Use of antibiotics among neonates is more widespread than the incidence of EOS Burden of administering short course antibiotics is low Adverse effects of antibiotics not immediate and dramatic Avoidance of consequences of starting antibiotics too late especially among well-appearing infants but with risk factors Hazards of antibiotic misuse : Bacterial resistance to antibiotics Altered microbiome of patients – gut and respiratory tract Development of allergic disorders In preterms : increased mortality from NEC, mortality in general, and BPD Hence need for approaches to target neonates at risk and avoid needless antibiotic therapy.

8. Critically Important Decisions Assess newborn’s risk for EOS Determine next steps to take at particular levels of risk (work-up, starting antibiotics) When or if antibiotics should be discontinued

9. Epidemiology , microbiology , and pathogenesis of EOS differ between TERM and PRETERM infants with VLBW Gestational age is the strongest predictor of EOS 2018 ≥ 35 0/7 weeks 2012 2018 ≤ 34 6/7 weeks Categorization for treatment is different

10. PATHOGENESIS OF EOS TERM PRETERM Begins in utero Ascending colonization and infection of the uterine compartment w/ maternal GI/ GU flora  colonization and invasive infection of fetus, or fetal aspiration of infected amniotic fluid May develop near term before onset of labor (rare) acquired through placenta/hematogenous route Infection ⇋ PROM/Preterm labor In 25% of cases, IAI causes preterm labor due to microbial-induced maternal inflammation Bacterial isolates: Vaginal flora (ascending infection): ureaplasma urealyticum , E. coli, GBS Oral flora (transplacental) Listeria (transplacental) Another possible pathogenesis: Immune-mediated rejection of fetal/ placental compartment from maternal extrauterine infection

11. RISK FACTORS: TERM & LATE PRETERM Independent Variables Gestational age Maternal intraamniotic infection Duration of rupture of membranes (ROM) Maternal GBS colonization Appropriate intrapartum antibiotic therapy Newborn clinical condition Race Twin gestation Fetal tachycardia Meconium stained amniotic fluid Dependent Variables

12. Difficult to identify independent variables Gestational age Birth weight PROM Preterm onset of labor Maternal age and race Maternal intrapartum fever Mode of delivery Administration of intrapartum antibiotics RISK FACTORS: PRETERM

13. CHORIOAMNIONITIS / INTRAAMNIOTIC INFECTION (IAI) Most infants with EOS are born to mothers with this diagnosis, but specificity is poor Review of 400,000 infants: 450 newborns exposed to clinical chorioamnionitis will be treated with antibiotics per 1 case of confirmed EOS Argument against clinical chorioamnionitis as indicator for risk of EOS In preterms : NNT 6-40 infants/case of EOS NNT 1:200-380 in 22-28 weeks via CS without clinical/confirmed chorioamnionitis

14. Criteria for CONFIRMED Diagnosis (+) Amniotic fluid gram stain and/or culture OR Placental histopathology Maternal intrapartum fever (1x ≥39.0C, Temp 38.0-38.9C > 30 mins) + Maternal leukocytosis Purulent cervical drainage Fetal tachycardia Criteria for SUSPECTED Diagnosis CHORIOAMNIONITIS / INTRAAMNIOTIC INFECTION (IAI) ACOG suggests intrapartum antibiotic therapy when IAI is diagnosed IAI is suspected Otherwise unexplained maternal fever during labor

15. NICE Guideline (NG195) on IAI Offer antibiotics during labor to women who Are in preterm labor Colonized with GBS in present pregnancy Colonized with GBS in past pregnancy without a negative test for GBS (rectovaginal culture or PCR) Had a previous baby with invasive GBS infection Clinical diagnosis of chorioamnionitis Give first antibiotics on onset of labor or when chorioamnionitis is suspected For mothers at 34-37 weeks + prolonged prelabor ROM + GBS colonization/ bacteuria /infection  offer labor induction or CS

16. RISK STRATIFICATION

17. Risk Stratification in ≥ 35 weeks Approaches : Categorical Multivariate (sepsis calculator) Clinical All with merits and limitations but all reasonable for use Develop institutional approaches suited to local resources and structures, and monitor its efficacy

18. CATEGORICAL RISK FACTOR ASSESSMENT Limitations : No clear definition of an ill-appearing newborn, maternal chorioamnionitis Inconsistent consideration of intrapartum antibiotics Absence of guidance on normal/abnormal lab results Any newborn who is ill-appearing Clinically diagnosed chorioamnionitis GBS (+) with inadequate IAP + ROM > 18 hours or birth < 37 weeks GBS (+) with inadequate IAP but no other risk factors (ROM < 18 hours, ≥ 37 weeks) Laboratory testing + Empiric antibiotics Laboratory testing only Observe ≥ 48 hours in hospital

19. MULTIVARIATE RISK ASSESSMENT SEPSIS CALCULATOR https:// publications.aap.org /pediatrics/article/128/5/e1155/30935/Estimating-the-Probability-of-Neonatal-Early-Onset Predictive model made by Puopolo et al. in 2011 Case control 1993-2007 in 14 California and Massachusetts Cohort of 608, 014 infants Prospective validation: Request for blood culture decreased by 66% Empiric antibiotic administration decreased by 48% No significant difference for readmissions compared to categorical risk assessment method

20. MULTIVARIATE RISK ASSESSMENT Kaiser Permanente Northern California Experience https:// neonatalsepsiscalculator.kaiserpermanente.org / InfectionProbabilityCalculator.aspx Used for all deliveries 34-43 weeks AOG Clinical presentations are validated with data from the first 12 hours after delivery, but used up to 24 hours of life 85% are detected <12 hours On laboratory tests CRP used to stop antibiotics; not used to rule in sepsis WBC and differentials may be used as basis to start antibiotics for equivocal patients Use of maternal antipyretics may alter risk results May use temperature of mother up to 1 hour post delivery

21. MULTIVARIATE RISK ASSESSMENT SEPSIS CALCULATOR https:// neonatalsepsiscalculator.kaiserpermanente.org / InfectionProbabilityCalculator.aspx

22. ≥ 38C or <36.4C

23. EXAMPLE

24. MULTIVARIATE RISK ASSESSMENT SEPSIS CALCULATOR https:// publications.aap.org /pediatrics/article/128/5/e1155/30935/Estimating-the-Probability-of-Neonatal-Early-Onset Advantages : Bases on individual infant’s risk rather than placing infants in categories Includes only objective data Few well-appearing infants treated empirically Concerns : Requires increased clinical surveillance especially on the first 12 hours of life Changes in protocol are allowed but requires validation

25. ASSESSMENT BASED ON CLINICAL CONDITION Regardless of presence of risk factors, ill-appearing infants are either treated empirically or worked up. Monitor patients every 4-6 hours until 48 hours of life Basis : 60-70% decreased risk of EOS in late preterm and term infants with good clinical condition at birth Single center study in Italy 7,628 infants: categorical risk assessment 7,611 infants: clinical condition Result: Significant decrease in request for laboratories, empiric antibiotic treatment. 2 infants in the clinical condition group were eventually treated.

26. ASSESSMENT BASED ON CLINICAL CONDITION Advantage: Significant reduction in the use of antibiotics Disadvantages : Need to establish processes for universal, serial, structured, and documented examinations Need for development of clear criteria for additional evaluation and empirical antibiotic administration Frequent examinations may increase cost of well newborn care

27. Risk Stratification in ≤ 34 6/7 weeks Approaches for term may not be used in preterm due to the complicated pathogenesis of EOS in this population Circumstances of preterm birth may provide the best current approach to EOS management for preterm infants

28. Obstetric indications for preterm birth Preeclampsia Non-infectious medical illness Placental insufficiency Birth by CS Absence of labor, attempts to induce labor, or any ROM prior to delivery PRETERM INFANTS AT LOW RISK FOR EOS CRITERIA APPROACHES No lab evaluation, no antibiotics Blood culture + clinical monitoring, no antibiotics CAVEATS Reasonable to start empiric antibiotics if patient did not improve after initial stabilization or if with severe systemic instability If with labor or attempts to induce labor, or ROM, treat as high risk, or work-up and start antibiotics if with cardiorespiratory instability

29. Cervical incompetence Preterm labor Chorioamnionitis and intraamniotic infection Acute otherwise unexplained onset of non-reassuring fetal status ***Consider IAI as cause of above conditions PRETERM INFANTS AT HIGH RISK FOR EOS CRITERIA APPROACHES Do blood culture and start antibiotics Consider obtaining CSF culture prior starting antibiotics

30. NICE Guideline (NG195) Before birth: Identify risk factors for EOS and continue to monitor throughout labor Risk factors for and clinical indicators of possible early-onset neonatal infection

31. NICE Guideline (NG195) Assessing and managing the risk of early-onset neonatal infection after birth: Check for risk factors of EOS Check for clinical indicators of EOS Perform immediate clinical assessment Review the maternal and neonatal history VS and PE Risk factors for and clinical indicators of possible early-onset neonatal infection Red flags : Apnea, seizures, need for resuscitation, need for mech vent, signs of shock Other clinical indicators: Altered behavior or responsiveness, altered muscle tone, feeding difficulties, feeding intolerance, abnormal HR, respiratory distress, hypoxia, PPHTN, jaundice in the first 24HOL, neonatal encephalopathy, temp abnormality (<36C, >38 C) unexplained by environmental factors, unexplained hematologic abnormalities, hypo/hyperglycemia, metabolic acidosis

32. NICE Guideline (NG195) GBS status of mom known only after birth (within 72 hours) Check for risk factors of EOS Check for clinical indicators of EOS Risk factors for and clinical indicators of possible early-onset neonatal infection Red flags : Apnea, seizures, need for resuscitation, need for mech vent, signs of shock Other clinical indicators: Altered behavior or responsiveness, altered muscle tone, feeding difficulties, feeding intolerance, abnormal HR, respiratory distress, hypoxia, PPHTN, jaundice in the first 24HOL, neonatal encephalopathy, temp abnormality (<36C, >38 C) unexplained by environmental factors, unexplained hematologic abnormalities, hypo/hyperglycemia, metabolic acidosis

33. Red flags : Apnea, seizures, need for resuscitation, need for mech vent, signs of shock Other clinical indicators: Altered behavior or responsiveness, altered muscle tone, feeding difficulties, feeding intolerance, abnormal HR, respiratory distress, hypoxia, PPHTN, jaundice in the first 24HOL, neonatal encephalopathy, temp abnormality (<36C, >38 C) unexplained by environmental factors, unexplained hematologic abnormalities, hypo/hyperglycemia, metabolic acidosis ANY red flag or ≥2 clinical indicators Work up + start antibiotics No red flag 1 risk factor 1 clinical indicator Use clinical judgment re antibiotics & 12 hour monitoring No red flag/clinical indicators No risk factors Routine newborn care NICE Guidelines also allow the use of the sepsis calculator but only as part of a prospective audit.

34. LABORATORY TESTING Blood culture | CSF culture | WBC and differential | Inflammatory Markers

35. BLOOD CULTURE Newborn surface cultures and gastric aspirate: not helpful Urine culture not indicated in < 72 hours Studies report no effect of intrapartum antibiotics on positivity At least 1mL volume Considerations : 2 separate culture bottles and compare growth Consider use of 1 aerobic + 1 anaerobic - More beneficial in preterm infants due to possibility of B fragilis infection (16% of isolates among VLBW)

36. Ideally performed with blood culture before antibiotic therapy in infants at highest risk for EOS (w/ critical illness) 1-2 cases in 100,000 births When to do: Blood CS (-): Use clinical judgement to decide Blood CS (+): Do CSF culture Balance with other factors such as contraindications to do procedure or delay in initiation of antibiotics CSF CULTURE TERM PRETERM 2012 GUIDELINE Decision to do LP still controversial Blood CS negative in 38% of patients with meningitis If blood CS positive, risk of meningitis is 23% Do lumbar puncture if (+) blood CS Clinical/lab parameters suggestive of bacterial sepsis Infants who initially worsen with antibiotics Incidence of meningitis 0.7/1000 births 22-28 weeks In the study, no meningitis among lower risk preterms No actual recommendations made Balance the physiologic stability, risk of EOS, and potential harms of prolonged antibiotic therapy when deciding if LP should be done in preterm infants who are critically ill

37. WBC COUNT / I/T RATIO / ANC Many factors affecting WBC and differential count Gestational age Gender Mode of delivery Fetal bone marrow suppression secondary to maternal preeclampsia, placental insufficiency, prolonged exposure to inflammatory signals Decreasing incidence of EOS also decreases utility of WBC Extreme values more helpful WBC <5, I/T >0.3, ANC <2000/ uL : highest likelihood ratio but low sensitivity WBC > 20 and platelet count not associated with EOS In preterm infants LR >3 associated with WBC <1, ANC < 1000, I/T > 0.25 ; WBC >50 , Platelet <50 had modest relationship (LR 2.2-2.3)

38. OTHER INFLAMMATORY MARKERS CRP and Procal increase in cases of asphyxia, infection, pneumothorax Procalcitonin rises in the first 24-36 hours of life Single values: No use Serial monitoring: (i.e. normal in the first 48 hours) associated with absence of EOS But do not prolong antibiotic therapy if serially elevated without site-specific infection Should not be requested on a well-appearing infant

39. NICE Guideline (NG195) Blood culture CRP (baseline) Lumbar puncture if safe to do so if Strong clinical suspicion of early-onset neonatal infection Clinical symptoms or signs suggesting meningitis Do not: Routinely perform urinalysis and culture Perform skin swab microscopy or culture Investigations before starting antibiotics For site-specific infections: Purulent eye discharge : consider chlamydia or gonococcus  swab immediately and start antibiotics as appropriate Umbilical infection : Do blood CS, swab umbilical stump for microscopy and culture, start antibiotics (IV oxacillin + gentamicin) If not gram negative, stop gentamicin

40. TREATMENT

41. TREATMENT TERM & LATE PRETERM PRETERM Ampicillin and gentamicin GBS: 40-45% E. Coli: 10-15% [7% resistant to both] Others: Viridians group strep and enterococci; 5% gram (-), 3-4% S. aureus, 1-2% Listeria Not suggested to use broader spectrum antibiotics If critically ill, consider use of broader spectrum antibiotics Ampicillin and gentamicin E. Coli: 50% [1-2% resistant] GBS: 20% Fungal: < 1% Not suggested to use broader spectrum antibiotics B. fragilis isolated in 15% of preterm with VLBW if anaerobic CS is routinely done Since 1-2% of E. coli isolates are resistant and B fragilis is not sensitive to ampi-genta , may use broader spectrum antibiotics to avoid gram negative sepsis among the VLBW Base on local antibiotic resistance data

42. NICE Guideline (NG195) IV benzylpenicillin 25mg/kg Q8-12 + gentamicin 5mg/kg Q36 May give shorter intervals of antibiotics if baby is very ill For gentamicin, may give shorter intervals if with gram negative growth Recommend gentamicin trough level monitoring Reassess and consider change of antibiotic if: No improvement in baby’s condition Based on culture results Expert IDS advice including local surveillance data If with evidence of gram negative sepsis, add cefotaxime. Once confirmed, discontinue benzylpenicillin Antibiotics for suspected early-onset infection

43. AAP: FOLLOW UP CARE If EOS is confirmed by blood culture, do lumbar puncture if not already done Do serial blood cultures until negative Shift antibiotic to narrowest spectrum possible Duration should be guided by expert references or by culture sterility Consider IDS referral in complicated cases (e.g. meningitis, atypical or resistant growth) If critically ill + term , may continue broad spectrum antibiotics even if blood culture is negative Patients with cardiorespiratory instability + preterm/VLBW may not necessarily need prolonged empiric antibiotic administration Discontinue antibiotics once culture negative for 36-48 hours , unless with evidence of site-specific infection Continuing antibiotics based on lab abnormalities is rarely justified.

44. NICE Guideline (NG195) Investigations during antibiotic treatment for early onset neonatal infection Consider use of CRP 18-24 hours after presentation Consider lumbar puncture if (+) blood culture (except if CONS) Does not respond satisfactorily to antibiotic treatment Strong clinical suspicion for infection Clinical signs or symptoms suggesting meningitis Duration of antibiotic treatment

45. NICE Guideline (NG195) Decisions 36 hours after starting antibiotics Consider stopping antibiotics if Blood culture negative Initial clinical suspicion of infection was not strong Baby’s clinical condition is reassuring Level and trends of CRP are reassuring Consider establishing hospital systems to provide blood culture results 36 hours after starting antibiotics Duration of antibiotic treatment

46. NICE Guideline (NG195) 7 days: (+) blood culture or (-) blood culture but sepsis has been strongly suspected >7 days : Baby not yet fully recovered Depending on pathogen on blood culture If continuing antibiotics > 36 hours despite negative cultures, review continuing need of antibiotics based on level of initial clinical suspicion for infection & baby’s clinical progress & level and trend of CRP Treatment Duration (without Meningitis)

47. Prevention Strategies Appropriate administration of maternal intrapartum antibiotic prophylaxis Administration of antibiotics in cases of suspected or confirmed intraamniotic infection

48. In summary, the guidelines emphasize: Epidemiology and pathogenesis of EOS among term and preterm infants differ, which affects the way risk for EOS is categorized Importance of appropriately given intrapartum antibiotic prophylaxis All risk categorization methods have been effective in reducing antibiotic usage among well-appearing neonates, but all have advantages and concerns Laboratory parameters cannot rule in sepsis Discontinue antibiotics when blood cultures are negative for 36-48 hours Each center should develop their own guidelines, and should do surveillance of its efficacy continuously

49. Thank you.