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Neonatal Meningitis

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Dr Ifeanyichukwu Okike's presentation at Meningitis Research Foundation's 2014 Meningitis Symposium http://www.meningitis.org/symposium2014

Dr Ifeanyichukwu Okike's presentation at Meningitis Research Foundation's 2014 Meningitis Symposium http://www.meningitis.org/symposium2014

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  • 1. Bacterial meningitis in infants <90 days of age: burden of disease & assessment of healthcare deliveryDr Ifeanyichukwu O Okike & Prof Paul T Heath St George’s, University of London MRF Symposium, Bristol
  • 2. “It was a living nightmare watching our baby so ill and fighting for his life” Parent of a baby with GBS meningitis Courtesy of MRF &
  • 3. The rate in <3month-olds is >70 x that of adults All p values <0.0001 bacterial meningitis in E+W, 2004- 2011 (PHE, LabBase2) Age group % of total population No of cases (%) Incidence (95% CI) (/ 100,000 population) Incidence Rate Ratio < 3months 0.3 978 (16) 72.19 (67.74-76.86) 136 (118- 155) 3-11 months 0.9 755 (12) 18.58 (17.27-19.95) 35 (30-40) 1-4 years 4.7 522 (8) 2.54 (2.33-2.77) 4.8 (4.1-5.5) 5-14 years 11.6 270 (4) 0.53 (0.47-0.60) Reference 15-44 years 41.0 1538 (25) 0.86 (0.82-0.91) 1.6 (1.4-1.8) 45-64 years 25.3 1331 (22) 1.21 (1.14-1.27) 2.3 (2.0-2.6) ≥65 years 16.2 752 (12) 1.07 (0.99-1.15) 2.0 (1.7-2.3) Okike et al Lancet Infectious diseases: 2014;14(4): 301 - 307
  • 4. Location Period / 1000 LB Fatality (%) Sequelae Leeds 1947-1960 0.5 NW Thames 1969-1973 0.26 Nottingham 1980-1989 0.37 25 Oxford region 1984-1991 0.25 26 E+W 1985-1987 0.22 25 50% E+W 1996-1997 0.21 10 51% E+W* 2010-2011 0.21 11 Lancet. 1976;1:701 Arch Dis Child 1991;66:603-7 Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9 * Okike et al (accepted CID 2014) Neonatal meningitis surveillance studies in E+W (≤28 days of age) E+W= England & Wales
  • 5. Bacteria 1985-87 (0.22/1000) 1996-97 (0.21/1000) 2010-11* (0.21/1000) GBS 38% 48% 60% E. coli 25% 18% 14% S. pneumoniae 6% 6% 6% L. monocytogen es 7% 5% 3% N. meningitidis 4% 4% 2% Other Gram neg 12% 8% 8% Aetiology of neonatal (0-28 days of age) current vs historical for England & Wales Arch Dis Child 1991;66:603-7 . Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9 * Okike et al (accepted CID 2014)
  • 6. Bacteria All 1st month 2nd month 3rd month Group B strep 50 58 47 24 E. coli 13 15 12 11 S. pneumoniae 9 6 7 29 N. meningitidis 8 2 15 24 in infants <3 months of life in the UK No case of Listeria meningitis after 29 days of ageOkike et al accepted CID 2014
  • 7. Identified bacteria: by route of admission & gestation at birth 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Home (term) Home (preterm) In-patient (term) In-patient (preterm) Percentageofcases Route of admission and maturity at birth N. meningitidis Other G negative E. coli Other G positive L. monocytogenes Non pyogenic streptococci S. pneumoniae Group B strep 47% E0 = 5 (29%) LO= 12 (71%)
  • 8. Comparison of aetiology with other international studie GBS: 86.1% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% <2mo Percentageoftotalcases GBS: 78.1% USA 2003-07 UK & ROI 2010-11Cases < 2 months of age Thigpen et al. N Engl J Med 2011; 364:2016-2025 Okike et al accepted CID 2014
  • 9. 0% 10% 20% 30% 40% 50% 60% 70% 80% Percentageofcases Presenting features All 0-28 d >28 d Non-specific Specific Presenting features (n=329)Combination of features Percentage of cases Fever and irritability 41% Fever and lethargy 33% Fever, lethargy and poor feeding 29% Fever, irritability and poor perfusion 19% Fever and convulsion 11% Convulsion and bulging fontanelle 7% Convulsion, bulging fontanelle and neck stiffness 1%
  • 10. Presenting features: GBS vs. others 0% 10% 20% 30% 40% 50% 60% 70% 80% Percentageoftotalcases Presenting features GBS Other bacteria Non specific Specific p=0.001
  • 11. (%) Presenting features Baumgartner N=24, USA 2-6 weeks Riordan N=42, Merseyside <3months Okike et al N=329, UK &RoI <3months Neck stiffness 17 13 3 Seizures 17 35 24 Full fontanelle 13 45 20 Fever 79 70 53 Rash Poor feeding 50 76 67 Lethargic 25 33 63 Irritable 79 70 63 Baumgartner Am J Dis Child 1983 Riordan Postgrad Med Journal 1995 p=0.05Riordan: GBS & NM (65%)
  • 12. Role of LP in making a diagnosis [X2, p=0.001] Timing of LP No bacteria in the CSF (%) Pre antibiotics 27 (21) Post antibiotics 103 (79) • LP was done in 315/329 (96%) • Post antibiotics 197/307 (64%) - in-patient vs. home admissions: 84% vs. 52%, p<0.0001 Okike et al (accepted CID 2014)
  • 13. Combination All: N (%) Home admission: N (%) In patient: N (%) Amoxicillin/ Ampicillin and Cephalosporin 84 (26) 76 (38) 7 (6) Cephalosporin only 64 (20) 47 (24) 17 (14) Benzyl penicillin and Gentamicin/ Amikacin 64 (20) 20 (10) 44 (37) Benzyl penicillin and Cephalosporin and Gentamicin 19 (6) 12 (6) 7 (6) Cephalosporin and Gentamicin 15 (5) 11 (6) 4 (3) Amoxicillin/ Ampicillin and Cephalosporin and Gentamicin 13 (4) 11 (6) 2 (2) Benzyl penicillin and Cephalosporin 11 (3) 7 (4) 4 (3) Amoxicillin and Gentamicin 11 (3) 6 (3) 5 (4) Flucloxacillin and Gentamicin 8 (2) 0 (0) 7 (6) Cefotaxime and Flucloxacillin 6 (2) 3 (2) 3 (3) Benzyl penicillin only 3 (1) 3 (2) 0 (0) Tazocin and Vancomycin 3 (1) 0 (0) 3 (3) Other* 21 (7) 3 (2) 16 (13) TOTAL 322 (100) 199 (100) 119 (100) Empiric Antibiotics used 70% of ≤ 28day-olds received a Penicillin 50% of >1month-olds received a Penicillin Only 38% of home admissions used empiric antibiotics as per NICE: Amoxicillin & Cefotaxime.
  • 14. Our study Vs. Empiric antibiotic therapy: Audit of UK & Ireland Unit policies *Journal of Antimicrobial Chemotherapy (2008) 61, 743–745. ** BPSU study 2010-2011 Antibiotic Audit 2006*, n(%): 202 units Okike et al** in-patient, n(%): 119 cases Include a cephalosporin 96 (45) 48 (40) Cephalosporin monotherapy 25 (12) 17 (14) Does not include a Penicillin 39 (19) 49 (41) Cephalosporin + a penicillin + + Aminoglycosides 11 (5) 9 (8) If we assume current- inpatient represent NNUs
  • 15. Empiric antibiotic coverage Cases in-patient (93) Amox + CTX: Presumed coverage: 82/93 (88%) TERM: 40 Unknown: 1/40 (Prevotella) Presumed coverage: 39/40 (98%) PRETERM: 53 Unknown: 10/53 (GNB + CONS)* Presumed coverage: 43/53 (81%) Cases admitted from home ≤ 28 days: 95 Susceptibility known: 64/95 (67%) - Amox + CTX: 63/64 (98%) Susceptibility not known: 31/95 [BUT 29 expected to be susceptible & 2 not known (GNB, Pasteurella)] Presumed coverage: 92/95 (98%) > 28 day: 71 Susceptibility known: 39/71 (55%) - CTX: 39/39 (100%) Susceptibility not known: 32/71
  • 16. Organism Total Died (%) *Complication in survivors (%) None detected 65 2 (3) 5 (8) Group B strep 135 7 (5) 28 (22) E. coli 35 3 (9) 7 (22) S. pneumoniae 26 5 (19) 11 (52) N. meningitidis 20 0 (0) 5 (25) L. monocytogenes 9 0 (0) 2 (22) Non-pyogenic streptococci 7 1 (14) 2 (33) Other Gram positive 11 2 (18) 1 (11) Other Gram negative 19 5 (26) 4 (29) Overall Outcome Overall CFR 25/329 = 7.6% [95% CI: 5.2-11.0], 7-day: 5.8% & 28- day: 7.3% Death or any serious complication 90/329 = 27% [95% CI: 23-33] *seizures 26 (9%), motor disorder/abnormal neurology 24 (8%), hydrocephalus 15 (5%), abnormal hearing 8 (3%), severe skin/musculoskeletal defect 5 (2%), other 2 (1%) [drainage
  • 17. Variable OR (95% CI) p value Prematurity (<28 weeks) 4.8 (1.7- 13.1) 0.003 Temperature instability on admission 2.1 (1.1- 4.2) 0.03 Convulsions on admission 4.5 (2.3 - 8.8) <0.000 1 Coma on admission 10.4 (2.1- 0.004 Independent risk factors for death / any serious complication Features present at the time of admission Multivariate logistic regression analysis of risk of death or developing a serious complication.
  • 18. Variable OR (95% CI) p value Prematurity (<28 weeks) 4.6 (1.8- 11.6) 0.001 Temperature instability on admission 3.0 (1.5- 5.8) 0.001 Convulsions on admission 4.8 (2.4 - 9.4) <0.000 1 Coma on admission 19.7 (3.9- <0.001 Independent risk factors for death / any serious complication Multivariate logistic regression analysis of risk of death or developing a serious
  • 19. Summary: Burden of disease Incidence: BM in E+W unchanged in 3 decades (≤28d) Clinical: Mainly non-specific, ~1 in 2 did not have fever Causal bacteria: GBS & E. coli leading causes Empiric antibiotics: wide variation used, consensus? Neonates from home & term IP: Amox + CTX, Home & term IP >1 mo: CTX IP & preterm: consider meropenem Outcome: Death/ acute complication : 27% of cases
  • 20. ARE THERE OPPORTUNITIES IN EARLY HEALTHCARE DELIVERY TO IMPROVE THE OUTCOME?
  • 21. Bacterial meningitis in infants <90 days: assessment of healthcare delivery Objectives • To describe the early presenting features • To review pre hospital management • To review in-hospital & discharge management • To determine the long-term neurodevelopmental outcome of infants <90 Preliminary data
  • 22. Methodology (between Sept 2010- July 2013) Participant Identification centres (PICS) 95 NHS Trusts in England, 7 health boards in Wales Parental Pack (Study information, Consent form, parental questionnaire for onset to progression) Hospital review of case management (Research Fellow visits hospital to review case management) Expert panel review of case management (PID, Neonatologist, General Paediatrician, trainee) Inclusion: Significant bacterial pathogen from CSF or from blood culture & csf pleocytosis (≥20 cells : m3 for babies 0-28d old & ≥10cells/ mm3 for babies 29-89d) Exclusion criteria: Intraventricular shunt device, spina bifida Ethics Cambs 2 REC: Ref: 10/H0308/64 Public Health England Support charities (parents) Paediatricians (PICs)
  • 23. Recruitment 322 packs sent to Paediatricians 271 packs eligible to be sent to parents 227 packs confirmed to have been sent to parents 103 Consented to take part 97 Eligible for analysis 51 packs not sent to parents (not cases or not appropriate to send) 44 packs were not confirmed as sent 124 did not return consent form 45% recruitment rate 94% eligible for analysis Viral: 4 No organism: 2
  • 24. 13 (13%) Median age: 14 days (IQR: 3-25) Admitted from home: 66 (68%) Recruited =103, included cases=97* *1 case from Wales 26 (27%) 18 (19%) 39 (41%)
  • 25. Cases admitted from home Category Value Male 34 (52%) Age in days: median (IQR) 17 (11-34) Prematurity (<37 weeks), n=66 8 (12%)
  • 26. Cases already on NNU at diagnosis Category Value Male 18 (58%) Age in days: median (IQR) 1 (0-7) Prematurity (<37 weeks) 15 (48%) Risk factors for EO neonatal infection including red flags 9 (29%)
  • 27. Summary THERE APPEAR TO BE SIGNIFICANT OPPORTUNITIES TO IMPROVE EARLY HEALTHCARE DELIVERY! - Pre hospital management inappropriate in 41% of cases - Delay in antibiotics >1 hour in 73% (home) & 82% (IP) - Inappropriate empiric antibiotics: 52% (home) & 61% (IP) - 38% of home admissions discharged at age < 2years - 16% of IP cases discharged at age < 2 years (NB. follow up of 1980s & 90s survivors showed sequelae in 50%) - Quality of clinical practice needs improvement BMJ 2001;323:1-5; Eur J Pediatr 2005;164:730–4
  • 28. Next steps… Towards better outcomes for bacterial meningitis  Prevention - GBS vaccines (ClinicalTrials.gov, number NCT01193920) - Pneumococcal conjugate vaccines (herd immunity: PCV 13) - Hygiene strategies during pregnancy (listeria) - Improving infection prevention & control practices in NNUs  Improve early management - Education of parents (Orange book ,Your Guide, update Baby watch)
  • 29. Message from a parent
  • 30. Thank you Collection from visit to St Mary’s Hospital Isle of Wight
  • 31. AMR & HCAI Prof. Alan Johnson Katherine Henderson Ruth Blackburn Dr. Berit Muller-Pebody MRL Manchester Prof. Ray Borrow Dr. Claire Cameron Dr. Alison Smith-Palmer Dr. Eisin McDonald Chief Investigator Prof Paul T Heath Dr Nelly Ninis (London) Dr. Mark Anthony (Oxford) Dr. Laura Jones (Edinburgh) Prof Mary Cafferkey (Ireland) Dr. Katy Sinka (Scotland) Dr. Robert Cunney (HSE Ireland) Helen Friend Richard Lynn All Paediatricians in the UK & the RoI Support Charities: Meningitis UK/ Meningitis Trust and Group B Strep Support St George’s Vaccine Institute staff Others Dr Eva Galiza Dr. S Ladhani UK & ROI Paediatricians and PIC contacts (HCD) Acknowledgements Funding meningitis@sgul.ac. uk Families & infants affected