Bacterial meningitis in infants <90 days of

age: burden of disease & assessment of

healthcare deliveryDr Ifeanyichukwu O Okike & Prof Paul T HeathSt George’s, University of LondonMRF Symposium, Bristol11 June 2014.

“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 & GBSS

The rate in <3month-olds is >70 x that of adults

All p values <0.0001

Laboratory-confirmed cases of 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

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

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. monocytogenes

7% 5% 3%

N. meningitidis

4% 4% 2%

Other Gram neg

12% 8% 8%

Other Gram pos

5% 12% 7%

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)

Bacteria All 1st mont

h

2nd mont

h

3rd mont

hGroup B

strep50 58 47 24

E. coli 13 15 12 11

S. pneumoni

ae

9 6 7 29

N. meningitid

is

8 2 15 24

L. monocyto

genes

4 5 0 0

Identified bacteria by month of life (%)in infants <3 months of life in the UK

No case of Listeria meningitis after 29 days of ageOkike et al accepted CID 2014

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)

Perc

enta

ge o

f cas

es

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%)

Comparison of aetiology with other international studies

GBS:86.1%

<2mo0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Perc

en

tag

e o

f to

tal

cases 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

Poor f

eedin

g

Irrita

bility

Leth

argy

Fever

Poor p

erfu

sion

Respir

ator

y dis

tress

Vomitin

g

Apnoe

a

Temp

insta

bility

Jaun

dice

Convu

lsion

Bulging

font

anell

e

Comat

ose

Neck

stiff

ness

0%

10%

20%

30%

40%

50%

60%

70%

80%

All0-28 d>28 d

Presenting features

Pe

rce

nta

ge

of

ca

se

s

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%

Presenting features: GBS vs. others

Poor feeding

Lethargy

Irrita

bility

Respira

tory distress

Fever

Poor perfu

sion

Temperature insta

bility

Apnoea

Vomiting

Convulsion

Bulging fontanelle

Comatose

Neck sti

ffness0%

10%

20%

30%

40%

50%

60%

70%

80%

GBSOther bacteria

Presenting features

Perc

enta

ge o

f tot

al c

ases

Non specific Specific

p=0.001

Clinical features compared (%)

Presenting features

BaumgartnerN=24, USA2-6 weeks

RiordanN=42, Merseyside<3months

Okike et alN=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 63Baumgartner Am J Dis Child 1983 Riordan Postgrad Med Journal 1995 p=0.05

Riordan: GBS & NM (65%)

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)

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 Gentamicin13 (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 Penicillin50% of >1month-olds received a Penicillin

Only 38% of home admissions used empiric antibiotics as per NICE: Amoxicillin & Cefotaxime.

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 +

+ Aminoglycoside

s

11 (5) 9 (8)

If we assume current- inpatient represent NNUs

Empiric antibiotic coverage

Cases in-patient (93)Amox + CTX:Presumed coverage: 82/93 (88%)

TERM: 40Unknown: 1/40 (Prevotella)Presumed coverage: 39/40 (98%)PRETERM: 53Unknown: 10/53 (GNB + CONS)*Presumed coverage: 43/53 (81%)

* All babies ≤ 33 weeks

Cases admitted from home≤ 28 days: 95Susceptibility 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: 71Susceptibility known: 39/71 (55%)- CTX: 39/39 (100%)Susceptibility not known: 32/71[BUT 28 expected to be susceptible & 4 not / known (CONS 2, GNB, LM)Presumed covered: 67/71 (94%)

Organism TotalDied (%)

*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 OutcomeOverall 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 cerebral abscess 1, diabetes insipidus 1].

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)

<0.00

01

Coma on admission 10.4 (2.1-

52.0)

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.

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)

<0.00

01

Coma on admission 19.7 (3.9-

98.7)

<0.00

1

S. pneumoniae 6.6 (2.3-

19.3)

<0.00

01

Independent risk factors for death / any serious complication

Multivariate logistic regression analysis of risk of death or developing a serious complication.

Summary: Burden of diseaseIncidence: 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 causesEmpiric antibiotics: wide variation used, consensus?Neonates from home & term IP: Amox + CTX, Home & term IP >1 mo: CTXIP & preterm: consider meropenemOutcome: Death/ acute complication : 27% of cases-Risk of death or any serious complication (poor outcome)

presence of coma on admission (20-fold ⬆). S. pneumoniae meningitis (7-fold ⬆), convulsion (5-fold )⬆

ARE THERE OPPORTUNITIES IN EARLY HEALTHCARE DELIVERY TO IMPROVE THE OUTCOME?

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 days of age with meningitis

Preliminary data

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 EnglandSupport charities (parents)Paediatricians (PICs)

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 rate94% eligible for analysis

Viral: 4No organism: 2

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%)

Cases admitted from home

Category Value

Male 34 (52%)

Age in days: median (IQR) 17 (11-34)

Prematurity (<37 weeks), n=66 8 (12%)

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%)

SummaryTHERE 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

Next steps…Towards better outcomes for bacterial meningitisPrevention - GBS vaccines (ClinicalTrials.gov, number NCT01193920) - Pneumococcal conjugate vaccines (herd immunity: PCV 13) - Hygiene strategies during pregnancy (listeria) - Improving infection prevention & control practices in NNUsImprove early management- Education of parents (Orange book ,Your Guide,

update Baby watch)- Education of healthcare workers RCPCH “how to manage bacterial meningitis package” Guideline development: specific for this age group Collaboration with MRF for e-learning package

Message from a parent

Thank you

Collection from visit to St Mary’s Hospital Isle of Wight

AMR & HCAIProf. Alan JohnsonKatherine HendersonRuth BlackburnDr. Berit Muller-Pebody

MRL ManchesterProf. Ray Borrow

Dr. Claire Cameron Dr. Alison Smith-Palmer Dr. Eisin McDonald

Chief InvestigatorProf 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 LynnAll Paediatriciansin the UK & the RoI

Support Charities: Meningitis UK/ Meningitis Trustand Group B Strep SupportSt George’s Vaccine

Institute staffOthersDr Eva GalizaDr. S LadhaniHenry Gowen & Dr G Borgulya

UK & ROI Paediatricians and PIC contacts (HCD)

Acknowledgement

s

Fundingmeningitis@sgul.ac.uk

Families & infants affected