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

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