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Okike for web
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  • important role for non-culture methods of detection (PCR) – 62 cases with preRx: +ve culture 29%, +ve PCR 58% (J infect Chemother 2009; 15:92-8)
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    • 1. Bacterial meningitis in babies, establishing standards of care to improve the outcome. Dr Ifeanyichukwu Okike Clinical Research Fellow Child Health & Vaccine Institute St. George`s, University of London. MRF Meningitis Symposium, Bristol 16 June 2011
    • 2. Neonatal bactertial meningitis <ul><li>What is the burden of disease? </li></ul><ul><ul><li>How many cases? </li></ul></ul><ul><ul><li>How often is it fatal? </li></ul></ul><ul><ul><li>Long term complications? </li></ul></ul><ul><ul><li>(Cost to the family and to society?) </li></ul></ul><ul><li>What are the causes? </li></ul><ul><li>How is it diagnosed? </li></ul><ul><li>How is it managed? </li></ul><ul><li>Results from Neomen (BPSU arm of study) </li></ul>
    • 3. Bacterial meningitis Image from Encyclopedia of health
    • 4. Incidence of neonatal bacterial meningitis ~ 250 cases / year in the UK
    • 5. Bacterial causes of meningitis in neonates (1996-97) <ul><li>Group B Streptococcus (48%) </li></ul><ul><li>E. coli (18%) </li></ul><ul><li>Other Gram- negatives (8%) </li></ul><ul><li>Streptococcus pneumoniae (6%) </li></ul><ul><li>Listeria monocytogenes (5%) </li></ul><ul><li>In 2010-11 ? </li></ul>
    • 6. Mortality <ul><li>E+W 1985-7: </li></ul><ul><ul><li>GBS 27/112 = 22% overall 25% </li></ul></ul><ul><ul><li>E coli 18/72 = 25% </li></ul></ul><ul><ul><li>(Arch Dis Child 1991;66:603-7) </li></ul></ul><ul><li>E+W 1996-7: </li></ul><ul><ul><li>GBS 8/69 = 12% overall 10% </li></ul></ul><ul><ul><li>E coli 4/26 = 15% </li></ul></ul><ul><ul><ul><li>(Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9) </li></ul></ul></ul><ul><li>UK 2000-1: </li></ul><ul><ul><li>GBS 16/109 = 12% </li></ul></ul><ul><ul><li>( Lancet 2004;363:292-4) </li></ul></ul>
    • 7. Disability at 5 years of age BMJ 2001;323:1-5; Eur J Pediatr 2005;164:730–4 1985-7 n = 274 1996-7 n = 166 severe 7% 5% moderate 18% 18% mild 24% 26% none 50% 51%
    • 8. Long term consequences of meningitis in very premature babies <ul><li>Babies born at less than 1500 grams </li></ul><ul><li>Study looked at neurological outcome of babies with infection compared to those babies without infection </li></ul><ul><li>Results showed that having any infection increases the risk of poor neurological outcome - but especially if it was meningitis </li></ul>JAMA 2004;292:2357-2365
    • 9. What are the signs &amp; symptoms? <ul><li>Non-specific and subtle (esp. premature infants) </li></ul><ul><li>Not possible to distinguish sepsis and meningitis </li></ul><ul><li>Most babies (&gt;50%) have fever / low temperature, lethargy, vomiting, breathing problems, fits (40%), irritability (32%), bulging fontanelle (28%) (n = 255)*. </li></ul><ul><li>No information available on the timing of onset of signs. Classical clinical features often appear late and their appearance may predict a worse outcome. </li></ul><ul><ul><li>e.g. low level of consciousness at hospital admission is a predictor of poor outcome </li></ul></ul>*Infectious Diseases of the Fetus and Newborn Infant. 6 ed. Philadelphia:, Elsevier Saunders; 2006. 247-95.
    • 10. How is it diagnosed? <ul><li>Too difficult to diagnose based simply on clinical signs. </li></ul><ul><li>A lumbar puncture is the only reliable tool. </li></ul><ul><li>Should a lumbar puncture be done when ever any infection is suspected? ……….but how often are LPs performed? </li></ul><ul><ul><li>ASGNI: 1992-02: 3966 infants with sepsis; LP in 51%. </li></ul></ul><ul><ul><li>( Arch Dis Child Fetal Neonatal Ed 2005;90:F324–F327) </li></ul></ul>
    • 11. How is it diagnosed? <ul><li>Only do an LP if blood culture is +ve? </li></ul><ul><ul><li>BUT meningitis occurs with -ve BC! </li></ul></ul><ul><ul><li>1/3 of babies with meningitis have negative blood culture </li></ul></ul><ul><ul><ul><li>6/39 (Visser et al) </li></ul></ul></ul><ul><ul><ul><li>12/43 (Wiswell et al) </li></ul></ul></ul><ul><ul><ul><li>35/92 (Garges et al) </li></ul></ul></ul><ul><ul><ul><li>9/27 (Vergnano et al) </li></ul></ul></ul>
    • 12. Neonatal meningitis: how is it diagnosed? <ul><li>Other issues: </li></ul><ul><li>LP should not be done if there is shock / respiratory distress / signs of raised intracranial pressure…..but done later when the baby has improved </li></ul><ul><li>Does this prevent a diagnosis being made? </li></ul><ul><li>pretreatment with antibiotics does not prevent diagnosis of meningitis (but may prevent identification of which bacteria) </li></ul><ul><ul><li>those who received antibiotics 12 -72 h pre LP had significantly ↑ glucose and ↓ protein vs. those who did not receive them or received them &lt; 4h but no influence on CSF WBC </li></ul></ul><ul><ul><li>(Pediatrics 2008;122:726–730) </li></ul></ul>
    • 13. How should it be treated if it is suspected? <ul><li>Needs an antibiotic that: </li></ul><ul><li>Cover the most likely bacteria </li></ul><ul><li>Has excellent penetration into the cerebrospinal fluid </li></ul>Based on 143 cases where a bacteria was isolated from CSF. Holt et al (2001) Organism % Group B Streptococcus 48 Escherichia coli 18 S. pneumoniae 6 Listeria monocytogenes 5 Neisseria meningitidis 4 H. influenzae &lt;1 Other Gram +ve 12 (1 S aureus, 2 S epi) Other Gram -ve 8 (6 on NNU)
    • 14. Empiric antibiotic therapy <ul><li>In the community (NICE guidelines)* </li></ul><ul><li>(NB. 50% of cases &lt; 3 months of age admitted from home) </li></ul><ul><ul><li>amoxycillin + cefotaxime </li></ul></ul><ul><li>In the neonatal unit* </li></ul><ul><ul><li>cefotaxime + amoxycillin + aminoglycoside; consider vancomycin </li></ul></ul><ul><li>But </li></ul><ul><ul><li>We need to watch antibiotic resistance rates as they are rising….. </li></ul></ul>
    • 15. Note of concern: Neonatal infections in Asia <ul><li>Recent study </li></ul><ul><li>Gram negative bacteria are developing increasing resistance to antibiotics </li></ul><ul><li>1/3 of isolates of gram negative bacteria were resistant to the main antibiotics we use in meningitis. </li></ul><ul><li>50% are resistant to at least one of the two. </li></ul>
    • 16. Neonatal meningitis: Empiric antibiotic therapy: Listeria <ul><li>Infection with Listeria is rare; ~ 5% of cases </li></ul><ul><li>Most cases are &lt;7 days of age, in premature infants and are related to maternal infection. </li></ul><ul><li>Nearly all pregnancy-associated cases present in the first month of life. </li></ul><ul><li>BUT: </li></ul><ul><li>Optimal therapy for this infection requires a penicillin…..and sometimes this is forgotten </li></ul>
    • 17. Neonatal meningitis: Empiric antibiotic therapy: what are UK Neonatologist currently doing? <ul><li>45% use a cephalosporin </li></ul><ul><li>19% do not include any penicillin </li></ul><ul><li>5% (11) used a triple combination </li></ul><ul><ul><li>(cephalosporin + a penicillin + aminoglycoside) </li></ul></ul>Journal of Antimicrobial Chemotherapy (2008) 61, 743–745
    • 18. Which antibiotic is best? how long should antibiotics be given for? <ul><li>No good studies found comparing antibiotics currently used to treat meningitis in infants younger than 3 months. </li></ul><ul><li>No good studies found that evaluated the optimal duration of antibiotic treatment in infants younger than 3 months. </li></ul><ul><li>NICE Meningitis Guidelines 2010 </li></ul>
    • 19. Neonatal meningitis: what about new antibiotics? <ul><li>Meropenem? </li></ul><ul><li>European multicenter network of Meropenem in neonatal sepsis and meningitis (NeoMero) </li></ul><ul><ul><li>evaluate its pharmacokinetics and safety in bacterial meningitis ( how it gets to the area of the body with infection and the safety in babies ) </li></ul></ul>
    • 20. Adjunctive therapy <ul><li>Steroids </li></ul><ul><li>- works well in adults and children for meningitis by certain bacteria </li></ul><ul><li>- no good study to support this in neonates. </li></ul><ul><li>Glycerol </li></ul><ul><li>- evidence that it works in children is emerging but no studies in neonates. </li></ul>
    • 21. Neonatal meningitis: what about better early management? Factors that predict poor outcome <ul><li>On admission: </li></ul><ul><li>Low blood pressure </li></ul><ul><li>Need for medication to support blood pressure </li></ul><ul><li>Seizures </li></ul><ul><li>Coma </li></ul><ul><li>Perhaps more aggressive management of these factors might improve the outcome? </li></ul>
    • 22. Improving the outcome from neonatal infection <ul><li>There is good evidence in adults and children </li></ul><ul><li>BUT </li></ul><ul><li>There are no high-quality studies assessing initial fluid therapy in neonates with meningitis (NICE meningitis 2010). </li></ul><ul><li>Delayed reversal of shock = worse outcome; </li></ul><ul><li>every hour of failure to reverse shock = doubling of risk of death </li></ul><ul><ul><li>(Pediatrics 2003;112:793-9) </li></ul></ul>
    • 23. Neonatal meningitis how can we do better? <ul><li>Better management? </li></ul><ul><ul><li>Earlier recognition of symptoms/signs? </li></ul></ul><ul><ul><li>Earlier use of appropriate antibiotics? </li></ul></ul><ul><ul><li>New antibiotics? </li></ul></ul><ul><ul><li>Better fluid therapy and supportive care? </li></ul></ul><ul><ul><li>New adjunctive therapy? </li></ul></ul>
    • 24. How can we do better? <ul><li>Prevention: </li></ul><ul><li>- antibiotics in labour (GBS) </li></ul><ul><li>- vaccination (pneumococcal, meningoccocal B*) </li></ul><ul><li>- vaccination** (GBS) </li></ul><ul><li>- Avoidance of certain food in pregnancy ( listeria ) </li></ul><ul><li>* Submitted to EMEA for approval </li></ul><ul><li>** Currently no licensed vaccine </li></ul>
    • 25. Bacterial meningitis in babies &lt;90 days of age: defining the current burden of disease and identifying opportunities for improving the outcome. (NeoMen) <ul><li>2 studies: </li></ul><ul><li>British Paediatric Surveillance Unit (BPSU) </li></ul><ul><ul><li>(13 months) (burden of disease) number of cases, causes, short term outcomes in UK and ROI- from July 2010 (Cambridgeshire 2 REC ref: 10/H0308/45) </li></ul></ul><ul><li>Healthcare delivery study (18 months)- England </li></ul><ul><ul><li>- To identify opportunities for improving the outcome through detailed analysis of early case management relative to an evidence based optimal standard </li></ul></ul><ul><ul><li>- from Sept 2010. </li></ul></ul><ul><ul><li>(Cambridgeshire 2 REC ref: 10/H0308/64) </li></ul></ul>
    • 26. Methodology Other Sources Health Protection Agency Meningitis Support Charities Parents
    • 27. RESULTS
    • 28. Summary <ul><li>Mortality has decreased but morbidity has not changed…..both are still unacceptable. </li></ul><ul><li>There are a number of possible areas for improvement. </li></ul><ul><li>NeoMen hopes to address and identify some of these areas. </li></ul>
    • 29. Acknowledgements <ul><li>Chief Investigator and Supervisor: Dr Paul T Heath </li></ul><ul><li>BPSU- Helen Friend and Richard Lyn </li></ul><ul><li>Health Protection Agency London </li></ul><ul><li>Dr Alan Johnson, Katherine Henderson, Ruth Blackburn, Berritt Muler-Peabody </li></ul><ul><li>Other Paediatricians/ Neonatologists </li></ul><ul><li>Dr Nelly Ninis (London) </li></ul><ul><li>Dr Mark Anthony (Oxford) </li></ul><ul><li>Dr Laura Jones (Edinburgh) </li></ul><ul><li>Health Protection Scotland </li></ul><ul><li>Dr Katy Sinka, Dr Claire Cameron </li></ul><ul><li>Irish National Meningitis Reference Centre: </li></ul><ul><li>Dr Mary Cafferkey </li></ul><ul><li>Funding - Meningitis Research Foundation </li></ul><ul><li>Support Charities: </li></ul><ul><li>Meningitis UK, Meningitis Trust and Group B Strep Support </li></ul><ul><li>All Paediatrician in the UK and Ireland who report cases regularly to the BPSU </li></ul><ul><li>St George’s vaccine Institute staff </li></ul>
    • 30. A BIG THANK YOU!

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