Neonatal SepsisNow and the NextDISSAJEE LUMBIGANON, MD.

CaseA 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)

Global Health Observatory (GHO) data, WHO, 2015

Causes of Deaths Among Children Under 5 Years, 2015

Neonatal sepsis 7%

Epidemiology: Neonatal sepsisGlobal: 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

Centers for Disease Control and Prevention's (CDC) Active Bacterial Core Surveillance Report, 2000, 2015

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

Pathogen associated with EOS and EOMPathogen EOS (%) EOM5 (%)

Gram positive 62 50

GBS 43 19

Viridans group streptococci 5 13

S aureus 2 6

Enterococci 3 6

Group A streptococci 2 -

CONS <1 -

Other gram positive 6 6

Gram negative 37 50

E.Coli 29 44

Haemophili 3 -

Other gram negative 5 6

Candida albicans <1 -

Adapted from Stoll, Hansen et al. 2011

Pathogen associated with late neonatal sepsisPathogen 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

Intrapartumcomplication

Often present Usually absent

Transmission Vertical Horizontal, Vertical

Onset Within 72 hours, usually first hour90% within 24 hours of life

After 72 hours

Clinical manifestation Multisystem involvementAsymptomatic bacteremia, generalized sepsis, pneumonia and/or meningitis

Focal infectionMeningitis and UTI are common

Risk factors Maternal characteristicsMaternal GBS colonizationMaternal feverMaternal chorioamnionitisPROM > 18 hoursInadequate intrapartum antibiotics

Infant characteristicsPretermLow birth weight infants

Extreme prematurity (36%) Indwelling central catheterOn ET tubeDependence of TPNH-2 blockers usagePPI usage

Case fatality rate 5-20% 5%

Clinical manifestationClinical 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

Brady and Polin, 2013COID: Committee of Infectious Disease, COFN: Committee of Fetus and Newborn

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

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

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 and symptoms of neonatal sepsis

2. Well infant with maternal

chorioamnionitis

3.Well infants with high risk

for sepsis

Full diagnostic evaluation ASAP

Blood culture at birth

CBC +/- CRP at 6-12 hours

Broad spectrum antibiotics

Broad spectrum antibiotics

Well infants: comparing between 2 guidelines

Well infants + adequate maternal IAP > 4 hour (ampicillin, penicillin or cefazolin)

Term > 37 weeks: Observe for > 48 hours

Preterm < 37 weeks

ROM > 18 hr

Observe for > 48 hours (ACOG)

Limited W/U + broad spectrum antibiotics (COFN)

ROM < 18 hr: Observe for > 48 hours

Well infants: comparing between 2 guidelines

Well infants + sepsis risk

factors [Inadequate

maternal IAP]

Term > 37 weeks

ROM < 18 hr

-Observe for 48 hr, 24 hours if other criteria are met (ACOG, COFN)

ROM > 18 hr

-H/C, CBC +/- CRP at 6-12 hr) + observe for 48 hr (ACOG)

-CBC +/- CRP at 6-12 hr (COFN)

Preterm < 37 weeks

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 caseManagement 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 infantsObservationACOG 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

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

Goal: identifying infants with low probability of sepsis, NOT at identifying infants likely to be infected

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?C-reactive protein Procalcitonin

Rising after infection 8-24 hr 2-12 hr

Appliciability -Good negative predictive value-Serial sample

-Better sensitivity but less specificity than CRP

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 recommendedHigh-risk healthy appearing infant

Clinical signs suggestive of non-infectious condition

ManagementEmpirical 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

ManagementEmpirical 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.

PreventionPrimary Prenatal care Education of sepsis risk factors

Universal GBS screening

Exclusive maternal milk feeding

Proper infection controls Hand hygiene

Central line care

Appropriate use of antibiotics

Limited use of H2 blockers, PPIs

Secondary prevention Intrapartum antibiotics

prophylaxis

Tertiary preventionPrompt antibiotic therapy

Neonatal sepsis: What’s coming next? PreventionUniversal GBS screening

GBS vaccine

Future study Lactoferrin prophylaxis

Probiotics

Investigation Cytokines

Flow cytometry to identify immature granulocytes 62

Molecular technique

Treatment Pentaglobulin

ReferencesShane 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." Pediatrics127(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.

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.

References