11/9/2012. Group B Streptococcal Infections: Consensus and Controversies. Prevention of Early-Onset GBS Disease in the USA.

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Group B Streptococcal Infections: Consensus and Controversies Carol J. Baker, M.D.

current disease burden and outcome from early- and late-onset GBS infant infections Employ optimal management strategies for early- and late-onset GBS infections Implement appropriate management of

5 0 1st guidelines (AAP) CDC, AAP, ACOG consensus guidelines Choice of culture screen or risk based IAP 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Year * Schrag S et al.

1 Group B Streptococcal Infections: Consensus and Controversies Carol J. Baker, M.D. Professor of Pediatrics, Molecular Virology and Microbiology Executive Director, Center for Vaccine Awareness and Research at TCH Texas Children s Hospital November 15, 2012 Objectives Comprehend the current disease burden and outcome from early- and late-onset GBS infant infections Employ optimal management strategies for early- and late-onset GBS infections Implement appropriate management of neonates born to maternal candidates for IAP to prevent early-onset GBS sepsis live births Cases per 1000 Prevention of Early-Onset GBS Disease in the USA st guidelines (AAP) CDC, AAP, ACOG consensus guidelines Choice of culture screen or risk based IAP Year * Schrag S et al. New Engl J Med 2000 Healthy People 2000 Goal Early-Onset GBS Disease: Revised CDC Guidelines GBS Disease Burden in the US Universal Screening 0 live births Cases/ Year Source: CDC Active Bacterial Core Surveillance Healthy People 2010 Goal 0 live births Cases/ Year Source: Active Bacterial Core Surveillance of CDC No Impact Late Onset Disease 1

Infant GBS Invasive Disease Burden in the US National estimate of invasive GBS disease 2010* Early-onset cases: 1,040

8-5%% * Active Bacterial Core Surveillance (ABC s) report emerging infections program network group B Streptococcus, 2010.

Percent of cases with meningitis* Early-onset cases: 7% = 74 Late-onset cases: 27% = 270 Total GBS meningitis burden in the

Bacterial Meningitis in the United States: 1998-2007* The incidence of meningitis changed by -30% (95% CI, -33 to -29) from

3 % in 2006-2007) did not change significantly Despite significant declines in incidence of pediatric bacterial meningitis,

2 Infant GBS Invasive Disease Burden in the US National estimate of invasive GBS disease 2010* Early-onset cases: 1,040 Late-onset cases: 1,030 Estimated mortality (2010) Early-onset disease: 3-7% Late-onset disease: 2.8-5%% * Active Bacterial Core Surveillance (ABC s) report emerging infections program network group B Streptococcus, Infant GBS Invasive Disease Burden in the US Statistics are people with their tears wiped dry. Percent of cases with meningitis* Early-onset cases: 7% = 74 Late-onset cases: 27% = 270 Total GBS meningitis burden in the USA: ~350 cases/year Dr. Jules Richmond Former Surgeon General * Phares CR et al. JAMA 2008;299: Bacterial Meningitis in the United States: * The incidence of meningitis changed by -30% (95% CI, -33 to -29) from 2.00 to 1.38 cases per 100,000 population The case fatality rate (15.7% in and 14.3 % in ) did not change significantly Despite significant declines in incidence of pediatric bacterial meningitis, the incidence in infants <2 months of age did not decrease The major causative organism in this vulnerable age group remains GBS *Thigpen MC et al. N Engl J Med 2011;364: Thigpen MC et al. N Engl J Med 2011;364:

Flow Chart for Late Outcomes of GBS Meningitis 37 children not evaluated on site: 23 lost to follow-up 7 normal by report 7 delayed by report 22 (51%) are functioning normally Libster R et al

died d at 6 months to 3 yrs of age 8 (19%) have severe long-term sequelae Features Predicting Adverse Outcomes Late Death and Any Delay (n = 21) Severely Impaired vs. (n = 13) vs.

3 Flow Chart for Late Outcomes of GBS Meningitis 37 children not evaluated on site: 23 lost to follow-up 7 normal by report 7 delayed by report 22 (51%) are functioning normally Libster R et al Pediatrics 2012;130:e8 90 infants with GBS meningitis 85 survivors of GBS meningitis 43 evaluated at 3-12 years of age 13 (30%) mildto-moderate sequelae 5 died during the acute illness 5 children died d at 6 months to 3 yrs of age 8 (19%) have severe long-term sequelae Features Predicting Adverse Outcomes Late Death and Any Delay (n = 21) Severely Impaired vs. (n = 13) vs. Normal (n = 22) Normal (n = 22) Admission Features Lethargy 6.1 ( )* 13 (1.8- ) + Respiratory distress 18(0559) 1.8 ( ) 12 ( ) 110 Coma/semicoma 2.1 ( ) 6 (1.2-29) Seizures 3 ( ) 7.5 ( ) Bulging fontanel 4.5 ( ) 10 (1.1-92) Laboratory Tests at Admission CSF protein >300 mg/dl 2.9 ( ) 9.9 ( ) CSF glucose <20 mg/dl 1.8 ( ) 6.5 ( ) * Odds ratio (95% confidence interval) + Exact logistic regression; estimated odds ratio Features Predicting Adverse Outcomes Late Death/ Normal Severe Impairment Outcome (n = 13) (n= 22) Hospital Course NICU or PICU 13 (100)* 13/20 (65) Ventilatory support 10/11 (91) 4/19 (21) + Pressor support 11 (85) 3/21 (14) + Discharge Features Abnormal neurologic exam 10 (77) 1/21 (5) + Failed hearing screen 5/11 (45) 0/16 (0) + Abnormal brain imaging 11/12 (92) 7/15 (47) * Number of children (%); + P <0.01; P <0.05 Features Predicting Adverse Outcomes Late Death and Any Delay (n = 21) Severely Impaired vs. (n = 13) vs. Normal (n = 22) Normal (n = 22) Hospital Course Ventilatory support 4.9* ( ) 37.5 ( ) Pressor support 6.5 ( ) 33 ( ) Discharge Features Abnormal neurological examination 15.4 ( ) 70 ( ) Failed hearing screening 7.4 (0.96- ) 14.7 (1.7- ) End of therapy abnormal 4.1 ( ) 12.6 ( ) image First and end therapy 4.8 ( ) 7.3 ( ) abnormal image * Odds ratio Outcomes for 21 Impaired Survivors Severe (n = 8) Mild-to-Moderate (n = 13) Developmental delay (8) Developmental delay (11) + Hydrocephalus (2) Grade retention ti (3) Cortical vision impairment (4) Persistent seizures (3) ++ Bilateral deafness (4) Hydrocephalus VP shunt (1) Cerebral palsy / spasticity (5) Loss of digits (1) Persistent seizures (4) + * Some children had multiple sequelae 3

Objectives Comprehend current disease burden and outcome from early- and late-onset GBS infant infections Employ optimal management of GBS earlyand late-onset infections in infants Implement

requiring intubation. He was born to a 34-year-old G2,P0-1, Ab1 woman with a UTI at 24 weeks. She was GBS negative at 35 weeks and serologies were unremarkable. He was transferred to the NICU.

4 Objectives Comprehend current disease burden and outcome from early- and late-onset GBS infant infections Employ optimal management of GBS earlyand late-onset infections in infants Implement appropriate management of neonates born to maternal candidates for IAP to prevent early-onset GBS sepsis Case Scenario A 10-hour-old 39 weeks gestation male had onset of tachypnea followed by apnea requiring intubation. He was born to a 34-year-old G2,P0-1, Ab1 woman with a UTI at 24 weeks. She was GBS negative at 35 weeks and serologies were unremarkable. He was transferred to the NICU. Ampicillin and gentamicin were given. The WBC was 8.7 and platelets were 115K. Blood culture grew GBS. LP was performed on DOL2. The CSF had 2800 WBC (84% polys), glucose was 20, protein was 388, and gram stain revealed a few gram positive cocci in pairs. Case Scenario The infant required dopamine for 30 hours, the chest radiograph excluded pneumonia, but eye deviation and jerking movement of his right arm were noted. Anticonvulsants controlled what the EEG documented were seizures. Would you perform another LP? Would you perform neuroimaging? The infant was extubated on DOL 5. On DOL 12, a hearing screen was normal. How long would you treat this infant? With what antimicrobial agent (s)? What is the prognosis? Repeat Lumbar Punctures? At hours to document sterility and assess complications End of therapy (optional) Determine baseline CSF values Assess intracranial complications Role of neuroimaging: Enhanced CT or MRI; late (2-3 weeks) not early Early Cranial Imaging 30 of 43 children evaluated in follow-up (70%) had imaging within first 72 hours of admission (CT scan with [63%] or without [23%] enhancement) Early MRI (Hospital Day 5)) More infants sustaining impairment had early imaging than those with normal outcome (90% vs 50%; P <0.01) Abnormal findings were noted in 70% of studies but did not predict outcome Extra-axial fluid collections (23%) Ischemia or infarct (30%) Thrombus or hemorrhage (17%) 5 of 9 children with normal early imaging had impairment at follow-up Libster R, et al Pediatrics 4

End-of-Therapy MRI (Hospital Day 21) End-of-Therapy Cranial Imaging 32 of 43 children (74%) had imaging at a mean of 16 (range 7-63) days, usually enhanced CT (59%) or MRI (28%) More infants

often noted in children with impairment than those with a normal outcome (61% vs. 21%, P = 0.

5 End-of-Therapy MRI (Hospital Day 21) End-of-Therapy Cranial Imaging 32 of 43 children (74%) had imaging at a mean of 16 (range 7-63) days, usually enhanced CT (59%) or MRI (28%) More infants sustaining impairment had late imaging than those with a normal outcome Abnormalities were noted in most (72%) studies Imaging findings of infarction, encephalomalacia or hydrocephalus were more often noted in children with impairment than those with a normal outcome (61% vs. 21%, P = 0.04) Drug (s) for Treatment of GBS* Empirical therapy Ampicillin and gentamicin IV until blood and CSF are sterile (~3-4 days Ampicillin should be 300 mg/kg/day if meningitis not excluded Definitive therapy Penicillin G IV 450, ,000 units per kg per day if meningitis Others: ampicillin, cefotaxime (not ceftriaxone in neonates) * Early or late-onset disease. Red Book 2012, page 682. Route: Duration: Duration and Routine of Administration Sepsis: Meningitis: Osteoarthritis: Ventriculitis: Endocarditis: IV or IM (never oral) Depends on site of infection 10 days days days 28 days 4-6 weeks GBS Infections in Multiples Uncommon Clinical Issues Multiple gestation is not an independent risk factor for GBS infection If one infant from a multiple gestation has GBS infection, risk for disease in the other is substantial As many as 40% of apparently well twins may develop GBS infection Second twin ill in 4 of 11 sets Two of 3 triplets had early-onset disease Edwards M et al. JAMA 1981;245: Moylett E et al. Clin Infect Dis 2000;30:

6 Management Interval between onset: Hours to days Assessment: other multiples should be checked for illness at time of sibling s presentation Outcome: can differ between twins Consideration should be given to empirical evaluation and treatment of sibling(s) of affected multiples Breast Milk Transmission Attributed as a cause of late-onset and recurrent disease and disease in second of twins GBS has been cultured from breast or breast milk Clinical mastitis can be present Direct contact with breast not required Edwards M et al. JAMA 1981;245: Moylett E et al. Clin Infect Dis 2000;30: Kotiw M et al. Pediatr & Devp Pathol 2003;6: Godambe S et al. Pediatr Infect Dis J 2005;24: Mechanism of Breast Milk Transmission Concept of circular transmission GBS colonizes infant s oropharynx Mammary ducts become infected during breast feeding; microbial concentration increases Infant infected or re-infected during feeding Management: continue breast feeding Rench M et al. Obstet Gynecol 1989;73: Godambe S et al. Pediatr Infect Dis J 2005;24: Recurrent GBS Infections Incidence estimated ~ 1-5% Early- and late-onset disease Second or third episode can be more severe (e.g., bacteremia then meningitis) Typically same organism (persistent colonization / re-exposure) within the infant s household) Management Objectives Immune evaluation? No Evaluation for occult focus? No Comprehend current disease burden and outcome from early- and late-onset GBS infant infections Assessment of colonization status? t No De-colonization? Good idea not possible Susceptibility testing of GBS? Maybe Longer duration of therapy? No Employ optimal management of GBS earlyand late-onset infections in infants Implement appropriate management of neonates born to maternal candidates for IAP to prevent early-onset GBS sepsis 6

7 Summary: 2011 AAP Policy* Signs of neonatal sepsis? Full diagnostic evaluation Antibiotic therapy Major strategies remain the same Universal screening and IAP for GBS-colonized women Maternal chorioamnionitis? Limited evaluation Antibiotic therapy Key changes Refined recommendations for obstetric providers GBS prevention among preterm deliveries IAP choices for penicillin-allergic (EMPHASIS on cefazolin) Revised neonatal algorithm Broaden scope to all newborn infants Increase clarity Decrease unnecessary diagnostic tests and empirical antimicrobial agents for low-risk newborn infants * Endorsed by COFN and COID and published in Pediatrics in 2011 IAP indicated for GBS prophylaxis? Mother received 4 hours of penicillin, ampicillin or cefazolin IV? 37 weeks AND ROM <18 hours? Either <37 weeks OR ROM 18 hours? Routine clinical care Observation for 48 hours Observation for 48 hours Limited evaluation Observation for 48 hours Algorithm Footnotes Full diagnostic evaluation: includes CBC with differential, platelets, blood culture, chest radiograph (if respiratory abnormalities are present), and LP (if infant stable enough to tolerate the procedure) Maternal chorioamnionitis: consultation with obstetrician to determine the level of clinical suspicion. Chorioamnionitis is a clinical diagnosis (some signs are nonspecific) Algorithm Footnotes Limited evaluation: Includes blood culture (at birth) and CBC with differential platelets. Some experts recommend a CBC with differential and platelets at 6-12 hours of age Routine clinical i l care: If signs of sepsis develop, a full diagnostic evaluation should be done and antibiotic therapy initiated Observation 48 hours: If 37 weeks gestation, observation may occur at home after 24 hours if there is a knowledgeable observer and ready access to medical care COFN Clinical Report 2012 Different Recommendations* Duration of ROM not considered and adequate IAP: no change in infant management Well-appearing preterm infants: antibiotics only if maternal chorioamnionitis, but not if IAP was indicated and inadequate Well-appearing term infants: ROM duration is only important if IAP is indicated and inadequate Well-appearing term infants: with inadequate IAP and ROM >18 hours, blood culture recommended Timing of CBC: flexible timing, at birth or 6-12 hours Limited Evaluation, Blood culture & Observation Inadequate IAP and PROM 18 hrs *GBS colonized woman CDC/COID/COFN COFN 2012 Inadequate IAP* or PROM 18 hrs Limited evaluation Blood culture Antibiotics * Polin R, et al. Management of Neonates with Suspected or Proven Early- Onset Sepsis. Pediatrics 2012;129:

Healthy: Risk Factors Other Than Chorioamnionitis and >37 Weeks Gestation Summary Inadequate IAP* CDC/COID/COFN Observe Early- and late-onset GBS disease

Evaluation (includes blood culture) Limited Evaluation (no blood culture) or Observation Management includes appropriate antibiotic, antibiotic dosage,

8 Healthy: Risk Factors Other Than Chorioamnionitis and >37 Weeks Gestation Summary Inadequate IAP* CDC/COID/COFN Observe Early- and late-onset GBS disease burden remains considerable Inadequate IAP* and ROM 18 hrs *GBS colonized woman COFN 2012 CDC/COID/COFN COFN 2012 Limited Evaluation or Observation Limited Evaluation (includes blood culture) Limited Evaluation (no blood culture) or Observation Management includes appropriate antibiotic, antibiotic dosage, duration, knowledge of complications and prognosis For now, stay with the CDC and 2011 AAP policy for management of neonate born to woman with GBS infection risk Thank you 8

Fever in neonates (age 0 to 28 days)

Fever in neonates (age 0 to 28 days) INCLUSION CRITERIA Infant 28 days of life Temperature 38 C (100.4 F) by any route/parental report EXCLUSION CRITERIA Infants with RSV Febrile Infant 28 days old Ill