Neonatal sepsis

Neonatal Sepsis Now and the Next DISSAJEE LUMBIGANON, MD.

Case A baby boy born at 36 weeks gestation to a 37 year-old mother with unknown GBS who presented with PROM 19 hours prior to delivery. APGARS were 8 and 9. The mother received 1 dose of ampicillin 3 hours prior to delivery The baby is well with normal physical exam. What is the management in this patient?

Definition: Neonatal sepsis Clinical syndrome in infants < 28 days old, manifested by systemic signs of infection and isolation of a bacterial pathogen from the bloodstream (Edwards MS, 2004) No consensus of definition of sepsis Classification (NICHD, VON definition) Early neonatal sepsis (<72 hour) versus Late neonatal sepsis (>72 hour)

Causes of Deaths Among Children Under 5 Years, 2015 Neonatal sepsis 7% Global Health Observatory (GHO) data, WHO, 2015

Epidemiology: Neonatal sepsis Global: 1-5/1,000 live births USA: 0.98/1,000 (396,586 NICHD infants: 2006-2009) Rates of EO Infections per 1000 LBs According to Birth Weigh (Stoll, Hansen et al. 2011)

Epidemiology: GBS sepsis  Improvement in prenatal and neonatal care, intrapartum antibiotic prophylaxis - > reduction of early onset GBS sepsis Late-onset GBS infection rates have remained relatively stable in the same interval Rate of GBS sepsis Year 2000 (per 1,000 LB) Year 2015 (per 1,000 LB) Early-onset 0.6 0.21 Late-onset 0.4 0.32 Centers for Disease Control and Prevention's (CDC) Active Bacterial Core Surveillance Report, 2000, 2015

Pathogen associated with EOS and EOM Pathogen EOS (%) EOM5 (%) Gram positive 62 50 43 19 GBS 5 13 Viridans group streptococci 2 6 S aureus 3 6 Enterococci 2 - Group A streptococci <1 - CONS 6 6 Other gram positive 37 50 Gram negative 29 44 E.Coli 3 - Haemophili 5 6 Other gram negative <1 - Candida albicans Adapted from Stoll, Hansen et al. 2011

Pathogen associated with late neonatal sepsis Pathogen EOS (%) CONS 48 Staphylococcus aureus 8 Candida albicans 6 E.Coli 5 Klebsiella 4 Candida parapsilosis 4 Enterococcus species 3 Pseudomonas 3 GBS 2 Other bacteria 15 Other fungi 2

Pathophysiology

Early Neonatal Sepsis Late Neonatal Sepsis Usually absent Intrapartum Often present complication Horizontal, Vertical After 72 hours Transmission Vertical Focal infection Onset Within 72 hours, usually first hour Meningitis and UTI are common 90% within 24 hours of life Extreme prematurity (36%) Clinical manifestation Multisystem involvement Indwelling central catheter Asymptomatic bacteremia, generalized sepsis, On ET tube pneumonia and/or meningitis Dependence of TPN H-2 blockers usage Risk factors Maternal characteristics PPI usage Maternal GBS colonization Maternal fever 5% Maternal chorioamnionitis PROM > 18 hours Inadequate intrapartum antibiotics Infant characteristics Preterm Low birth weight infants Case fatality rate 5-20%

Clinical manifestation Clinical manifestations range from subtle symptoms to profound septic shock Temperature instability (primarily fever) Irritability Lethargy Respiratory symptoms (eg, tachypnea, grunting, hypoxia) Poor feeding Tachycardia Poor perfusion and hypotension

Management: neonatal Sepsis Guidelines  2010: CDC, American Academy of Family Physicians, AAP, American Academy of Nurse and Midwives, ACOG, American Society of Microbiology  Prevention of perinatal group B streptococcal disease: revised guidelines from the CDC 2010  36 pages 2011: COID, COFN  Agreement with the 2010 GBS guidelines in Pediatrics 2012: COFN  Management of neonates with suspected or proven early onset neonatal sepsis COID: Committee of Infectious Disease, COFN: Committee of Fetus and Newborn Brady and Polin, 2013

Verani, McGee et al., 2010

Verani, McGee et al., 2010

Verani, McGee et al., 2010

Verani, McGee et al., 2010



Evaluation of asymptomatic preterm infants (<37 weeks) with sepsis risk factors Polin, 2012

Evaluation of asymptomatic term infants (>37 weeks) with sepsis risk factors Polin, 2012

Evaluation of asymptomatic term infants (>37 weeks) with sepsis risk factors Polin, 2012

Challenges in management of neonatal sepsis Identify neonates with a high likelihood of sepsis promptly and initiating antimicrobial therapy Distinguishing “high risk” healthy-appearing infants or infants with clinical signs who do not require treatment Discontinuing antimicrobial therapy once sepsis is deemed unlikely.

Management: 1. Infant with signs 2. Well infant 3.Well infants and symptoms of with maternal with high risk neonatal sepsis chorioamnionitis for sepsis Full diagnostic Blood culture at evaluation ASAP birth CBC +/- CRP at 6-12 hours Broad spectrum Broad spectrum antibiotics antibiotics

Well infants: comparing between 2 guidelines Well infants + Term > 37 Observe for > 48 hours adequate maternal weeks: IAP > 4 hour ROM > 18 hr (ampicillin, Preterm < 37 weeks Observe for > 48 hours (ACOG) penicillin or Limited W/U + broad spectrum antibiotics (COFN) cefazolin) ROM < 18 hr: Observe for > 48 hours

Well infants: comparing between 2 guidelines Well infants + Term > 37 ROM < 18 hr sepsis risk weeks -Observe for 48 hr, 24 hours if other criteria are met factors (ACOG, COFN) [Inadequate Preterm < 37 weeks ROM > 18 hr maternal IAP] -H/C, CBC +/- CRP at 6-12 hr) + observe for 48 hr (ACOG) -CBC +/- CRP at 6-12 hr (COFN) Regardless of ROM -H/C, CBC +/- CRP at 6-12 hr) + observe for 48 hr (ACOG) - Limited W/U + broad spectrum antibiotics (COFN)

Adapted from Stoll, Hansen et al. 2011

Inadequate IAP Adapted from Stoll, Hansen et al. 2011

Back to the case Management of this preterm infant?  Asymptomatic Unknown GBS PROM 19 hours Inadequate intrapartum antibiotics prophylaxis ACOG: Blood culture, CBC +/- CRP, observe for 48 hours COFN: Blood culture (birth), CBC +/- CRP at 6-12 hours, broad spectrum antibiotics

Management: well infants Observation ACOG 48 hours COFN: 24 hour discharge in term infants with sepsis risk factors who Has normal lab, remain well, good compliance Limited evaluation Limited evaluation + broad spectrum antibiotics

Investigation Goal: identifying infants with low probability of sepsis, NOT at identifying infants likely to be infected CBC  IT ratio has best sensitivity Acute phase protein (CRP, procalcitonin) Blood culture  At least 1 ml (to be able to detect low level bacteremia (< 4 CFU/ml)  From peripheral vein or UAC (shortly after inserted), High contamination if draw from an UVC Culture of superficial body sites, gastric aspirates and urine culture -> of no value in EOS Lumbar puncture

CBC & CRP: why at 6-12 hours? 245/67,623 (3.6/1,000) term and late preterm infants had positive blood culture (Newman, Puopolo et al. 2010)

Benitz 2010

CRP versus procalcitonin? Rising after infection C-reactive protein Procalcitonin Appliciability 8-24 hr 2-12 hr -Good negative predictive -Better sensitivity but less value specificity than CRP -Serial sample Benitz 2010

Benitz 2010

Benitz 2010

When to perform a lumbar puncture  LP Recommended  Infants with clinical course or labs strongly suggestive of bacterial sepsis and can tolerate the procedure  Bacteremic infants (23 % have meningitis)  Infants who worsen despite antibiotic therapy LP not recommended  High-risk healthy appearing infant  Clinical signs suggestive of non-infectious condition

Management Empirical therapy >> EOS ◦ Ampicillin + aminoglycoside ◦ 7 days for pneumonia ◦ 7-10 days for bacteremia without a focus, 10-14 days in preterm ◦ 14 days for GBS and uncomplicated meningitis ◦ Gram negative meningitis 21 days or 2 weeks after first negative blood culture (whichever is longer) ◦ Consider a third cephalosporin (cefotaxime) for meningitis

Management Empirical therapy >> LOS ◦ Vancomycin + aminoglycoside ◦ Duration depent on pathogen and site ◦ Vancomycin may be considered based on local epidemiology and clinical presentation. ◦ Aminoglycoside based regimen preferred to cephalosporin given reduced risk of resistance. ◦ Consider cephalosporin if meningitis suspected. >> carbapenem ◦ Consider amphotericin if fungal etiologies. ◦ Consider discontinuation of therapy if pathogen not isolated.

Prevention Primary Secondary prevention Prenatal care Intrapartum antibiotics prophylaxis  Education of sepsis risk factors Universal GBS screening Tertiary prevention Exclusive maternal milk feeding  Prompt antibiotic therapy Proper infection controls  Hand hygiene  Central line care  Appropriate use of antibiotics  Limited use of H2 blockers, PPIs

Neonatal sepsis: What’s coming next? Prevention  Universal GBS screening  GBS vaccine  Future study  Lactoferrin prophylaxis  Probiotics Investigation  Cytokines  Flow cytometry to identify immature granulocytes 62  Molecular technique Treatment  Pentaglobulin

References Shane AL, Sanchez PJ, Stoll BJ. Neonatal sepsis. Lancet (London, England). 2017. Edwards MS, B. C. (2004). Krugman's Infectious Diseases of Children Stoll, B. J., N. I. Hansen, P. J. Sanchez, R. G. Faix, B. B. Poindexter, K. P. Van Meurs, M. J. Bizzarro, R. N. Goldberg, I. D. Frantz, 3rd, E. C. Hale, S. Shankaran, K. Kennedy, W. A. Carlo, K. L. Watterberg, E. F. Bell, M. C. Walsh, K. Schibler, A. R. Laptook, A. L. Shane, S. J. Schrag, A. Das and R. D. Higgins (2011). \"Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues.\" Pediatrics 127(5): 817-826. Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2010;59(Rr-10):1-36. Baker CJ, Byington CL, Polin RA. Policy statement-Recommendations for the prevention of perinatal group B streptococcal (GBS) disease. Pediatrics. 2011;128(3):611-6. Polin RA. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012;129(5):1006-15. Brady MT, Polin RA. Prevention and management of infants with suspected or proven neonatal sepsis. Pediatrics. 2013;132(1):166-8.

References Newman, T. B., K. M. Puopolo, S. Wi, D. Draper and G. J. Escobar (2010). \"Interpreting complete blood counts soon after birth in newborns at risk for sepsis.\" Pediatrics 126(5): 903-909. Benitz, W. E. (2010). \"Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis.\" Clin Perinatol 37(2): 421-438.