welcome to our infection catalyst event eve… · continuous veno venous haemofiltration (cvvh)...
TRANSCRIPT
Welcome to our Infection Catalyst Event
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Introductions and welcome
Prof John Goodacre, NWC AHSN Prof Nigel Cunliffe, University of Liverpool
Follow us on Twitter @NWCAHSN @LiverpoolUni
Networking
Healthcare / NHS
Industry
Academia
Thank you to all our exhibitors:
5D Health Protection Group Ltd
Mr Archie Veale Patient representative
Staphylococcus Aureus Panton-Valentine Leukocidin+
Septicaemia
Continuous Veno Venous
Haemofiltration
(CVVH)
Tracheostomy
Extracorporeal Membrane
Oxygenation (ECMO)
Alter-G Anti-Gravity Treadmill
Wheelchair Basketball
What could have been done? • “…although urine and blood
samples were taken I was sent home with some strong painkillers”
• “Two major tell tail signs of the early stages of an infection”
• “An opportunity was definitely missed”
• Glucose in my urine • High blood sugar
levels • Bloody sputum
Enter subtitle here (24pt, Arial Regular)
Enter date: 25.06.13
RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn
A NATIONAL APPROACH FOR SEPSIS
IN IRELAND
- LESSONS FROM THE FIRST YEAR
Dr. Fidelma Fitzpatrick
Chair, National Sepsis Steering Group
Senior Lecturer, Royal College of Surgeons in Ireland &
Consultant Microbiologist, Beaumont Hospital, Dublin, Ireland
@ffitzP
BACKGROUND – HEALTHCARE IN THE
REPUBLIC OF IRELAND
Source: hse.ie
• External regulator
(HIQA)
• 5 HSE divisions
1. Acute hospitals
2. Social Care
3. Mental Health
4. Primary Care
5. Health & Wellbeing
SEPSIS IN IRELAND
OUTLINE
1. The National Sepsis Steering Group
2. National Guidelines
3. The first year
a. Speaking a common language
b. Establishing the burden
c. The importance of the first hour
d. Making it easier to diagnose sepsis
e. Making tools readily available
4. Where do we go next?
1. THE NATIONAL SEPSIS STEERING GROUP
• Established July 2013
• Multidisciplinary (33 people!)
– Patient Representation
– Hospital, pre-hospital and primary care
– National Clinical Programmes
– Junior doctor
– Hospital manager
– External expert: Prof Kevin Rooney
• Sepsis lead appointed mid 2014: Dr. Vida Hamilton
2. NATIONAL GUIDELINES
3. THE FIRST YEAR
- GUIDELINES ARE ONLY THE
STARTING POINT
IMPLEMENTING THE 2005 IRISH NATIONAL MRSA GUIDELINES
• Education
– (hand hygiene , antibiotic stewardship)
• Governance
• Infrastructure
• Bed occupancy
• Laboratory resources
• Infection control specialist staffing
Challenges of Implementing National Guidelines for the Control and Prevention of Methicillin‐Resistant Staphylococcus aureus Colonization or Infection
in Acute Care Hospitals in the Republic of Ireland ICHE 30, No. 3 (March 2009), pp. 277-281
IMPLEMENTING IRISH STROKE GUIDELINES
‘The introduction of stroke clinical guidelines at a national
level is not sufficient to improve health care quality’
Donnellan C, et al. Implementing clinical guidelines in stroke: A qualitative study of perceived facilitators and
barriers. Health Policy (2013), http://dx.doi.org/10.1016/j.healthpol.2013.04.002
THE CHALLENGES
GUIDELINE
Lots of attention
DISSEMINATION
Usually published – sometimes education
IMPLEMENTATION
LESS ATTENTION++
Qual Health Care 1993; 2(4);243-8 Qual Health Care 1994; 3(1);45-52 The Psychiatrist (2004) 28: 8-11
Guideline implementation
Behaviour
Knowledge
Attitudes
JAMA. 1999;282(15):1458-1465. doi:10.1001/jama.282.15.1458
“If I read and memorized two medical journal articles
every night,
by the end of a year
I’d be 400 years behind.”
http://e-patients.net/archives/2013/08/400-years-behind-updated-bigtime.html
FROM THE START
• Dissemination
• Care pathway for every patient diagnosed with sepsis in
Ireland
• Recognition, Resuscitation, Referral
• Tools, Education, audit
• First things first…..
A. SPEAKING A COMMON
LANGUAGE
He
looks
‘septic’
He has
septicaemia He is
‘septic’
He has no
obvious
source of
sepsis’
He must have
sepsis as he
has gone off
Bone et al. Chest, 1992, 101:1644
COMMON DEFINITIONS
SIRS
•Infectious & non infectious causes
•Clinical response arising from a non specific insult
Sepsis
•SIRS plus
•Presumed or confirmed infection
Severe Sepsis
•Sepsis plus
•Sepsis-induced organ dysfunction or tissue hypoperfusion
Septic Shock
•Sepsis-induced hypo-perfusion or hypotension persisting despite 30 mls/kg fluid resuscitation
INFECTION
• A pathological process caused by invasion of normally
sterile tissue or fluid or body cavity by pathogenic or
potentially pathogenic micro-organisms.
• Causes by bacteria, viruses, fungi, parasites
• Infection can be present without being microbiologically
confirmed.
Source: National Sepsis Guidelines -
http://www.hse.ie/eng/about/Who/clinical/natclinprog/sepsis/summary%20sepsis%20management.pdf
SIRS - SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME
• Clinical response to nonspecific insult
– Characterised by abnormal vital signs
• SIRS can be caused by infectious + non infectious causes
• Infection
• Ischaemia
• Haemorrhage,
• Inflammation (e.g. pancreatitis)
• Trauma
• Burns
SIRS (MODIFIED)
• Temperature > 38°C or < 36°C
• Heart rate > 90 beats/min
• Respiratory rate > 20 breaths/min
• WCC > 12 or < 4
• Blood glucose > 7.7 mmol/l in non-diabetic
• Altered mental status
SEPSIS
• Sepsis is the systemic response to infection
• The clinical syndrome defined by both
– Infection + the systemic inflammatory response
syndrome (SIRS).
Sepsis = SIRS + infection
Source: National Sepsis Guidelines -
http://www.hse.ie/eng/about/Who/clinical/natclinprog/sepsis/summary%20sepsis%20management.pdf
COMMON INFECTIVE SOURCES OF SEPSIS
SEVERE SEPSIS
• Severe sepsis refers to sepsis complicated by organ
dysfunction
SEPTIC SHOCK
• Severe sepsis
PLUS
• persistent hypotension and perfusion abnormalities
DESPITE
• adequate fluid resuscitation
SPEAKING A COMMON
LANGUAGE
He has
SEPSIS
B. ESTABLISHING THE BURDEN
“IN GOD WE TRUST-
ALL OTHERS BRING DATA.”
W. E. DEMING
ESTABLISHING THE BURDEN – SEPSIS IS
COMMON AND KILLS
International estimates
• Sepsis: 300 per 100,000 per annum
• Acute myocardial infarction: 208 per 100,000 per annum
• Mortality: 20 - 55%
Breast cancer
THE BURDEN IN IRELAND – HIPE DATA
• 60% all in-hospital deaths has a code of ‘sepsis’ or
‘infection’ diagnosis
– But cant infer causality
• 2013: Sepsis:
– Cases = 8,770
– Bed days = 220,288
2013 2012 2011
In-hospital mortality* 28.8%
31.3% 32.4%
Source: Dr. Vida Hamilton, National Sepsis Lead
* Critical care area
THE REALITY OF SEPSIS
2013 Without With
ALOS Sepsis 5.59 26
ALOS Infection 5.59 10
ALOS Maternity 2.61 5.47
ALOS Paediatrics
3.08 22.19
Source: Dr. Vida Hamilton, National Sepsis Lead
AGE STANDARDISED HOSPITAL DISCHARGE
RATE FOR MEDICAL SEPTIC SHOCK
2005 - 2012
SEPSIS 2013
National Average
Sepsis cases
- as % of all cases
- as % of all bed days
1.44
6.8
Sepsis + Infection
- as % of all cases
- as % of all bed days
20.22
42.3
Source: Dr. Vida Hamilton, National Sepsis Lead
COSTS
Sepsis consumes 30% of the UK critical care budget
• £20,000 per patient
• £2.5 billion annually
• Chronic health burden for survivors
Iwashyna et al: Long-term cognitive impairment & functional disability among survivors of severe sepsis.
JAMA, 2010.
16.8
3.8
6.2
7.1
0 5 10 15 20
Moderate-severe
Mild
Before sepsis After sepsis
COSTS - COGNITIVE IMPAIRMENT
C. ESTABLISHING SEPSIS AS A
TIME DEPENDENT EMERGENCY
• 90% of cases with poor outcome in
the Australian sepsis database,
inadequate recognition was found to
be the most common feature
0%
100%
Time (Hours)
1 3 6
Adapted from: Kumar A, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the
critical determinant of survival in human septic shock. Crit Care Med 2006; 34(6):1589–96
EARLY APPROPRIATE ANTIBIOTICS SAVES
LIVES
D. MAKING IT EASIER TO
DIAGNOSE SEPSIS
SEPSIS
IT CAN BE DIFFICULT ESPECIALLY EARLY ON!
“…as the physicians say it happens in hectic fever,
that in the beginning of the malady it is easy to
cure but difficult to detect, but in the course of
time, not having been either detected or treated in
the beginning, it becomes easy to detect but
difficult to cure”.
Niccolo Machiavelli, The Prince, 1513
• Not all patients have classic SIRS
• Some groups at special risk
– e.g. neutropenia, haemodialysis, diabetes mellitus, alcoholism, lung
disease, patients with invasive devices
Laupland et al Crit Care Med 2004
• Elderly patients (age > 65 years)
• Decreased inflammatory response
• Often not febrile
• More likely to be delirious
• Falls may be only evidence of sepsis-induced delirium
• More likely to develop septic shock and multiple organ dysfunction
syndrome
DIAGNOSING SEPSIS CAN BE DIFFICULT
IMPROVING SURVIVAL
• Early Recognition
• Appropriate intervention – Resuscitation
• Appropriate Referral - critical care expertise
SEPSIS SCREENING
• Early Recognition
• 2% of all ED referrals are due to sepsis
• NSW audit of NEWS: sepsis is the cause of 30% of
triggered reviews
• UK: NEWS > 5; 52% sepsis
ED VS IN-PATIENT
ED
• Community acquired
• Less co-morbidities
• Generalised training
• Mortality 20%
Ward
• Hospital acquired
• Co-morbidities
• Second – Hit
• Specialist training
• Mortality ??? Higher
ONCE SEPSIS RECOGNISED –
THE IMPORTANCE OF 6 IN 60
SEPSIS 6 IN 1ST HOUR
3 to give 3 to take
1. O2 (94-98% or 88-92%) 1. Blood cultures & other
appropriate cultures
2. IV antibiotics 2. FBC, Lactate
3. IV fluids 3. Assess urinary output
MANAGEMENT OF SEPSIS IN ADULT IN-
PATIENT
ANTIBIOTICS - START SMART
• 9-fold increase in mortality with inappropriate antibiotics
• Independent risk factors
– COPD
– Immunocompromised
– Chronic dialysis
COMPLIANCE WITH SEPSIS 6
• Reduces the relative risk of death by 46.6%
• 1 additional life saved for every 5 care episodes
• Mortality reduced from 44% to 20%
• Daniels et al, Emergency medicine journal 2011
COMPLIANCE WITH SEPSIS 6
IS THAT IT?
• Sepsis 6 is the minimum intervention
• Sepsis is a continuum
• Source control
• Seasonal and other outbreaks, recent travel, patient at
risk of antibiotic resistant organisms
E. MAKING TOOLS READILY
AVAILABLE
www.hse.ie/sepsis
BARRIERS TO IMPLEMENTATION
• Lack of awareness, Lack of agreement
• Lack of self-efficacy
– Perception – Reality gap, Education, Audit
• Lack of outcome expectancy
– Audit
• Inertia of previous practice
– Lactate, Audit, Discussion forums, Bottom-up/ Top-down
EXTERNAL BARRIERS
• Guideline related
– Lack of maternity guidelines
– Poor specificity of SIRS criteria
• Patient related
– Late presentation, co-morbidities
• Environment related
– Lack of resources
OVERCOMING BARRIERS
• Education
• Audit
– HIPE, KPI, ward-based audit
• Resourcing
SO WHERE TO NEXT THIS YEAR?
• Educational tools
– App / E learning / Educational video
• Hospital visits by sepsis lead
• Patient education and awareness
• Sepsis summit July 2015
• Better data
– New HIPE codes
• Monitor progress
– Compliance i.e. form present in chart aim is to attain 95%
compliance by 2018
– Mortality from sepsis
– Mortality from severe sepsis
– Incidence of sepsis per 100,000 population.
IN SUMMARY
• Sepsis is a Medical Emergency
• Awareness, Screening, Recognition
and Prompt Treatment is the Key to
Reliable Rescue
ACKNOWLEDGEMENTS
• Dr. Vida Hamilton, National Sepsis Lead, Ireland
• Dr. Ron Daniels
• UK Sepsis Trust
• Prof. Kevin Rooney
HTTPS://WWW.YOUTUBE.COM/WATCH?V=ECD
PQ74DXFM
Improving the diagnosis of sepsis using
point -of-care tests
Enitan D Carrol
Chair in Paediatric Infection
Infection Catalyst Event 29 April 2015
Background
• Estimated 18 million cases worldwide annually. Developing world, > 6 million neonates and children die/yr
• In UK, 36 –64,000 deaths per year attributed to severe sepsis, cost to the NHS/year ~ £2.3 billion
• Mortality 28-50%
• Incidence rising: ageing population, antibiotic resistance, survival from cancer, new treatments
• Delays in diagnosis: symptoms and signs non-specific, deterioration rapid, inadequate diagnostic tools
• Sepsis is a medical emergency
Neutrophil Gelatinase Associated Lipocalin (NGAL)
Resistin
Procalcitonin
PROMPT SEPSIS: Partnership for Rapid On-Site
Microfluidic POC Test for Sepsis
July 2012- October 2014
Conjugate release pad
Nitrocellulose membrane
Absorbent pad
Conjugated particles (immobilised)
(T3) Control Line (C)
Multiplex Sandwich Assay Schematic
Target capture antibody (anti-PCT)
Control capture antibodies (Anti-mouse + goat IgG)
Anti-PCT + RES + NGAL gold nanoparticle conjugate
Sandwich LFD format
Biomarker in the sample: No biomarker in the sample:
Test Lines (T2) (T1)
Target capture antibody (anti-RES)
Target capture antibody (anti-NGAL)
Y
Sample well Viewing window
anti-RES pAb and anti-biotin pAb conjugated to 40nm gold detector
particles anti-RES pAb
Biotin-BSA
Y
T C
Y
anti-PCT pAb and anti-biotin pAb conjugated to 40nm gold detector
particles anti-PCT pAb
Biotin-BSA
Y
Y
anti-NGAL pAb and anti-biotin pAb
conjugated to 40nm gold detector particles anti-NGAL
pAbBiotin-
BSA
Y
A
B
C
D
E
Gold conjugate pad
NC membrane Wick pad
Y
Sample well Viewing window
anti-RES pAb and anti-biotin pAb conjugated to 40nm gold detector
particles anti-RES pAb
Biotin-BSA
Y
T C
Y
anti-PCT pAb and anti-biotin pAb conjugated to 40nm gold detector
particles anti-PCT pAb
Biotin-BSA
Y
Y
anti-NGAL pAb and anti-biotin pAb
conjugated to 40nm gold detector particles anti-NGAL
pAbBiotin-
BSA
Y
A
B
C
D
E
Gold conjugate pad
NC membrane Wick pad
The POC system developed incorporates 3 simplex lateral flow assays utilising gold nanoparticle technology to detect (a) NGAL, (b) PCT and (C) RES. (d) vertical plan view of assay strip and (e) vertical plan view of housed assay.
R² = 0.680
0
100
200
300
400
500
600
0 100 200 300 400 500 600
Exp
ecte
d N
GA
L C
on
cen
trat
ion
(ng/
ml)
Actual NGAL Concentration (ng/ml)
NGAL
R² = 0.800
0
100
200
300
400
500
600
700
800
0 100 200 300 400 500 600
Exp
ecte
d R
ES C
on
cen
trat
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(ng/
ml)
Actual RES Concentration (ng/ml)
RES
R² = 0.912
0
100
200
300
400
0 100 200 300 400 500 600
Exp
ecte
d P
CT
Co
nce
ntr
atio
n (n
g/m
l)
Actual PCT Concentration (ng/ml)
PCT
A B
C
R² = 0.680
0
100
200
300
400
500
600
0 100 200 300 400 500 600
Exp
ecte
d N
GA
L C
on
cen
trat
ion
(ng/
ml)
Actual NGAL Concentration (ng/ml)
NGAL
R² = 0.800
0
100
200
300
400
500
600
700
800
0 100 200 300 400 500 600
Exp
ecte
d R
ES C
on
cen
trat
ion
(ng/
ml)
Actual RES Concentration (ng/ml)
RES
R² = 0.912
0
100
200
300
400
0 100 200 300 400 500 600
Exp
ecte
d P
CT
Co
nce
ntr
atio
n (n
g/m
l)
Actual PCT Concentration (ng/ml)
PCT
A B
C
Actual vs. expected concentration of (a) NGAL, (b) PCT and (c) RES in spiked human plasma samples.
• Lack of correlation with measured biomarkers on clinical
samples
• Cross reactivity of antibodies, unable to multiplex
• Biomarkers did not offer sufficient discrimination of sepsis
• Search for alternative bio-recognition molecules
• Electrochemical POC test
• Peptide aptamers (Affimers) on gold electrode
Limitations of LFD approach to POC diagnostic
The picture above, adapted from - S Jenko et al.
(2003) J Mol Biol 326: 875-885 shows a co-crystal
between Stefin A and its natural partner, cathepsin H.
• Affimers are small, single domain proteins based on the
human protease inhibitor Stefin A.
• Stefin A, which uses three surfaces to interact with its
target, has been engineered to remove any reactivity of its
basic core with human targets and improve the stability of
the new protein which is called the Affimer “scaffold”.
• The scaffold displays two loops and the amino terminus, a
similar interaction surface to the variable region of an
antibody.
• The Affimer’s ability to recognise and bind a specific target
is endowed by the amino acid sequences of these binding
surfaces.
What is an Affimer?
Johnson A, Analytical Chemistry 2012
Affimers present surfaces of low initial steric bulk and charge
transfer resistance and are highly responsive to target binding
Antibody on a PEGylated gold electrode
Affimer on a PEGylated gold electrode
Antigen
C
D
Reporter
molecule
Point-of-care diagnostic for sepsis
Qualitative Reading
Quantitative Reading
108
Communication device
Telehealth facilities Clinical decision
Stuart Carter Professor of Veterinary Pathology
Making a vaccine:
working with industry
2005 - Venture capitalists: • Develop new vaccines? • Not a chance – no profit 2015 – Biotech companies: • Anti-microbial drug resistance • Post-genomic era • Very interested….
Science and Finance
Digital Dermatitis Research at
Liverpool Veterinary School
Digital Dermatitis:
a preventable infectious lameness
caused by novel bacterial infections
School of VETERINARY SCIENCE
Liverpool & Leahurst
The problem: Bovine Digital Dermatitis
An emerging disease of cattle, sheep and goats which causes severe lameness. Major cost to cattle industries.
Only Liverpool Vet School can routinely isolate and grow the causative bacteria
Can we make an effective vaccine to
prevent disease?
Genome sequences
Modelling of surface proteins
Select antigens
Design recombinant
vaccine
Bacterial cocktail
Vaccine trial
From our isolates?
From the genomes?
Currently funded by big pharma (Zoetis - ex-Pfizer) to make a vaccine for digital
dermatitis by reverse vaccinology approaches.
Looking for more partners…
University researchers working with Industry
Opportunities for both • Very good value for company as research infrastructure and expertise is
immediately available • Funding stream for academics • Scale up benefits eg testing and production • Access to pool of researchers and funders. • Access to UK Research Council support for joint projects
• Eg BBSRC gives 50% costs for LINK award and 90% for IPA Disadvantages • Can be quick or slow progress
• Success not guaranteed as research is involved • Academic requirements eg rapid publishing • IP ownership • Patent issues
Major opportunity overall for both parties
That’s all folks……
That’s quite
enough.
Get orf!
That’s all folks……
A blood test for improving diagnosis of central
nervous system infection? or
“Do you wear a pink shirt?” Dr Michael Griffiths
Senior Clinical Lecturer / Paediatric Neurologist Brain Infections Group
Institute of Infection Global Health University of Liverpool
29/4/15
Scan shows inflamed lining of brain
Improving diagnosis of central nervous system infection?
Rationale Currently limited predictive tests for central nervous system (CNS) infection Pathogen culture from CSF can be insensitive (if low bacterial load / selective growth conditions ) Indirect pathogen detection (i.e. PCR) Can give false negative - particularly if not sure what the pathogen looking for. Doesn’t discriminate between acute / past infection Other CSF parameters (glucose, protein) limited sensitivity / specificity Blood biomarkers for CNS infection offer: • Quick / easy to take blood • Encourage need to undertake Lumbar Puncture – help expediate this procedure • Improved patient management - earlier decision on antimicrobial / antiviral treatment
Team doing lumbar puncture in Indonesia to rule out infection
Principle Different CNS diseases generate different human host responses Differences in the human host response (cell state) correlate with differences in gene expression These differences can be identified by examining patterns of transcript abundance in patient’s leukocytes Aim Identify diagnostic markers that discriminate between shunt infection and malfunction.
“Do you wear a pink shirt?”
Whole-blood gene-expression can distinguish between different meningitis patients
Bacterial Meningitis
n=17
Meningism n=23
Viral Meningitis
n=21
Transcripts highly abundant in Bact. Men.
Transcripts highly abundant in Viral. Men.
Whole-blood gene expression patterns of patients from our Meningitis NW study (n=61) with proven Bacterial meningitis compared to patients with Meningism (CSF wcc <4cells/ul;) or patients with proven Viral meningitis.
Increased
Decreased
Griffiths McGill Gosia et al.
Bacterial Other
Test+ 17 9
Test- 0 35
Sens. 100% (17/17) Spec. 79.5% (35/44)
Bacterial Meningitis
n=17
Meningism n=23
Viral Meningitis
n=21
Array data Genes selected by PAM
Ratio > 1.18 predict BM
BM:VM ratio (based on 4 genes) correctly predicted sample class in 29/30 (97%) patients
Array data can be reduced to a subset of 4 genes that detect bacterial meningitis (n=30 [duplicate samples])
This point represents a ratio of >1.18. It gives 100% sensitivity and 95% specificity for identifying samples from patients in the BM group
Same subset of 4 genes detect bacterial meningitis (n=13) from meningism or viral meningitis (controls; n=88; independent samples)
This point represents a ratio of >1.18. It gives 84% sensitivity and 74% specificity for identifying samples from patients in the BM group
Ratio (based on 4 genes) correctly predicted sample class in 76/101 (75%) patients Markers tested in sample set with
real life prevalence of BM (approx 10%)
FTD ceo
Generated meta-data training set 180 samples - 71 bacterial meningitis - 109 other from 5 array experiments (2 in-house – 3 GEO) 80,000 potential markers
Tested the array data (n=180 samples) Using a variety of classification algorithms Selected marker sets with AUC >0.8 190 + markers
Generated meta-data training set 180 samples - 71 bacterial meningitis - 109 other from 5 array experiments (2 in-house – 3 GEO) 80,000 potential markers
Tested the array data (n=180 samples) Using a variety of classification algorithms Selected marker sets with AUC >0.8
Tested marker combinations in array data (n=180 samples) Selected marker comb. with sens. >80% spec. >80% Best – identified markers 100% sens 85% spec.
Tested markers in overlapping PCR samples (n=30) + compared to array data for these samples (n=30 ) Selected marker comb. Sens >80% Spec >80% (Sig & diff. between classes) 30+ markers [Some not performing as predicted]
Tested markers independent samples (n=102) via PCR Ongoing 16 markers [so far]
6 marker combinations (9 markers) gives 90.9% sensitivity and 74.7% specificity for identifying samples from patients in the Bacterial Meningitis group (Accuracy 76% [78/102] - AUC 0.81).
10 marker combinations (12 markers) gives 100% sensitivity and 71.8% specificity for identifying samples from patients in the BM group (Accuracy 75% [61/81] - AUC 0.86).
Non-Bacterial Final Diag. (n=45)
Abx No-Abx Proportion on Abx
Clinical
27 18
0.60
Gene score
14 31
0.31
Using the score could significantly reduce Antibiotic prescribing p=0.011
Biomarkers can also help rationalise treatment of brain infections
Next steps for Bacterial Meningitis Biomarkers
Further collaborative agreement between UoL and FTD. Agreement involves UoL providing knowledge on markers, marker combinations and provide sample sets to test assays. FTD provide knowledge/expertise on PCR primer selection and assay (including multiplex) development. Business Gateway has reviewed the intellectual property of the marker combination and secured permission from University of Liverpool to file a patent application. As bacterial meningitis is relatively rare in the UK we will aim to continue the UK Meningitis study to collecting further sets of blood samples on which to test the assays
Further steps in host diagnostics New tests to help detect CNS infection
- NIHR HTA – BASICS – ‘Baculoseal Against Silver Impregnated Catheter Study ‘ follow-on diagnostic study.
- WHO Searo – National Nepalese encephalitis aetiology study
Examine broader infection sets - Collect / examine samples for discriminating between viral and bacterial infection.
Any questions?
Contact: Mike Griffiths [email protected]
Thanks Gosia Wnek
Ryan Keh Fiona McGill Graeme Hickey Ajit Rayamajhi Alison Hardy Conor Mallucci Bill Carman Tom Solomon
Novel models for testing new therapeutic agents
Professor Craig Winstanley Professor of Bacteriology
Prof. Aras Kadioglu Dr Jo Fothergill
My research interests
use of genomics and molecular techniques to study the evolution, population behaviour, transmission and pathogenicity of Gram-negative pathogens, including Campylobacter, and Escherichia coli, but with a particular focus on Pseudomonas aeruginosa lung infections
Pseudomonas aeruginosa – an opportunistic pathogen
endocarditis
respiratory
infections bacteraemia
CNS
infections ear
infections
eye
infections
urinary tract
infections GI tract
infections
bone & joint
infections
wound /
burns
infections
Large genome – adaptable & metabolically versatile
Intrinsic resistance to antibiotics
Efflux pumps (eg. MexAB-OprM)
Beta-lactamases (eg. AmpC)
Low permeability (eg. OprD porin)
Hypermutators
Resistance can also be acquired
General properties of P. aeruginosa
Chronic pulmonary infection
Tissue damage &
Inflammatory exacerbations
Hospitalisation and IV
therapy
Impaired mucociliary
clearance
Cystic Fibrosis
Serosal side
Lumen
• cftr mutations
• Carrier rate = 1 in 25
• 1 in 2500 live births in UK
P. aeruginosa in the Cystic Fibrosis lung
Switch to mucoidy =
chronic debilitating
pulmonary infection
Barrier against
phagocytic cells and
effective opsonisation -
antibodies are denied
access to antigens large numbers of
neutrophils are
attracted, leading to
immune system-
mediated tissue
damage
biofilm forms a barrier to
antimicrobial agents
INFLAMMATORY
EXACERBATIONS
Hospitalisation
& IV therapy
Artificial sputum
medium (ASM) biofilm
model
CF sputum
Mucin, lipids, DNA, amino
acids
P. aeruginosa grown in ASM
Grows in a biofilm typical of CF
Phenotypic diversificiation
LESB58 in ASM
for 7 days
ASM
Resembles CF sputum
Use of Artificial Sputum Medium to Test Antibiotic Efficacy Against P. aeruginosa
Kirchner et al. J. Vis. Exp. 2012 64:e3857
Nature Comm 5:4780
Natural inhalation murine model for studying adaptation and testing new therapeutic agents
0 1 2 3 5 7 14 21 28 DAYS
LESB65
• Suggests that long term persistence in the nasopharynx allowed reseeding of the lower respiratory compartment.
• Biofilm-associated genes are expressed. • Bacteria show signs of adaptation
Naso
Naso Lung
Lung
Rechallenge Experiments
Evolved isolates clearly outperformed the original LESB65 isolate in vivo.
Model can be used for at least 28 days
“evolved” isolates “evolved” isolate
NASOPHARYNX LUNG
original isolate original isolate
Toxin sequestration therapy for treatment of severe bacterial respiratory
infection and sepsis
Aras Kadioglu
Department of Clinical Infection, Microbiology & Immunology
Streptococcus pneumoniae (pneumococcus)
Over 1 million deaths per year mainly in infants, elderly and
immunocompromised
Kills more children under 5yrs old, than measles, malaria and HIV-
AIDS combined
Most common cause of bacterial respiratory infection in the UK;
main cause of community-acquired pneumonia (~70%)
Novel treatments against invasive pneumococcal disease
[1] Target the immune system –
P4 peptide immunotherapy - MRC DPFS funded
[2] Target major bacterial virulence factor –
Liposome Toxin sequestration therapy
Pneumolysin
• Protein toxin produced by
all clinical isolates.
• Lytic toxin, able to bind to
and lyse all cells that have
cholesterol in their
membranes.
• Highly pro-inflammatory at
sub-lytic concentrations
• High levels correlate with
poor patient outcome
Bacterial Pore-Forming Toxins
Cholesterol Dependent Cytolysins (CDC) - Toxins from 24 different Gram-positive
bacterial species – food poisoning, gas gangrene, necrosis, meningitis, pneumonia
Clostridium perfringens Perfringolysin
Streptococcus pneumoniae Pneumolysin
Streptococcus pyogenes Streptolysin
Streptococcus suis Suilysin
Listeria monocytogenes Listeriolysin
Bacillus cereus Cereolysin
Staphylococcus aureus Alpha hemolysin
Liposomes
• Artificial lipid vesicles composed of naturally occurring
lipids.
• Can be loaded with artificially high cholesterol concentrations.
Our question: Could bacterial toxins bind to cholesterol enriched liposomes instead
of host cells?
Could liposomes act as decoys during infection?
Liposomes are effective against a wide range of bacterial toxins
Streptolysin O Tetanolysin Pneumolysin Phospholipase C α-hemolysin
S. pyogenes C. tetani S. pneumoniae C. perfringens S. aureus
Lysis of human epithelial and endothelial cells by pneumolysin is prevented by
liposome treatment
Epithelial cells - transfected with a cytoplasmic
yellow-fluorescent protein, lose their cytoplasm
after permeabilization by PLY (200 ng) in the
absence of liposomes.
In contrast, when Ch:Sm liposomes (100 μg) were added, the
loss of the cytoplasm (cell lysis) was prevented
liposomes prevented lysis of HUVEC endothelial cells by PLY
(200 ng)
Liposome treatment against pneumococcal pneumonia
Control : 40% survival
+ Liposomes: 80% survival
Control : 0% survival
+ 6h liposome treatment : 70% survival
+ 10h liposome treatment: 50% survival
+ 16h liposome treatment: No difference
Liposome treatment against pneumococcal sepsis
Adjunct therapy with liposomes against bacterial sepsis
Control : 0% survival
Antibiotic alone: 40% survival
Antibiotic + liposome treatment at 10hrs : 80% survival
Advantages of Liposome Therapy
• Non-toxic and already used for drug and vaccine delivery
• Inexpensive, stable and easy to administer
• Broad spectrum liposomes effective against all bacterial toxins tested
• Targeting bacterial toxins unlikely to lead to drug resistance
• Protects major targets of bacterial toxins. i.e. host immune cells, epithelial &
endothelial cells
• Reduces toxin driven inflammation – a key factor in bacterial sepsis
Laura Bricio-Moreno
Suzy Gore
Dan Neill
Hesham Malak
Ecological assessment of the direct and indirect effects of routine rotavirus vaccination in Merseyside, UK
Nigel A Cunliffe Professor of Medical Microbiology
Institute of Infection and Global Health
Estimated incidence of infectious intestinal disease in children <5 years in England
• Hospital episodes1 ~ 41,000 episodes per year (Primary diag - ICD10 A00-A09)
• GP consultations2 – ~85 per 1,000 person-years - highest rate of any age group
– Equivalent to ~270,000 GP consultations per year
• NHS direct/NHS24 consultations in England2 – ~113 per 1,000 person-years <1 year olds –highest rate
– ~32 per 1,000 person-years 1-4 year olds
– Equivalent to ~150, 000 community consultations per year
• Community cases in the England2 – ~1079 per 1,000 person-years <1 year olds –highest rate
– ~713 per 1,000 person-years 1-4 year olds
– Equivalent to upto 10 million cases in England
1. HSCIC. Hospital episode statistics. Admitted patient care, England–2012–13: diagnosis. Health and Social Care Information Centre, 2014. 2. 2. Tam C, et al. Gut 2012;61:69-77 / https://www.food.gov.uk/science/research/foodborneillness/b14programme/b14projlist/b18021
Global surveillance shows that 40% of diarrhoeal hospitalizations are due to rotavirus
Rotavirus is the most common cause of severe, dehydrating diarrhoea among children < 5 yrs worldwide
Each year it causes:
•111 million diarrhoea cases
•25 million outpatient visits
•2 million hospitalizations
•450,000 deaths
Current rotavirus vaccines
Rotarix®
GlaxoSmithKline
RotaTeq®
Merck & Co
Indication
For the active immunisation of infants aged ≥6 weeks against RVGE
Composition
Live attenuated monovalent human rotavirus
strain
G1P[8]
Live attenuated pentavalent bovine (WC3)-
human reassortant strains
G1P[5]; G2P[5]; G3P[5]; G4P[5]; G6P[8]
Form Orally administered in liquid formulation
Administration
Two doses
First dose from 6 weeks of age
Minimum of 4 weeks between doses
Schedule should be completed by 24
weeks of age
Three doses
First dose between 6 and 12 weeks of age
Minimum of 4 weeks between doses
Schedule should be completed by 26
weeks of age
Information based on summary of product characteristics RVGE = rotavirus gastroenteritis
USA: Laboratory Reports
Lopman et al;Curr Opin Virol. 2012 Aug;2(4):434-42
Rotavirus vaccine has been introduced in the UK!
Aims
• To use routine health data sources to estimate the direct and indirect effects (herd) of vaccination on a range of outcome indicators and the relationship of such effects to vaccine coverage and socio-demographic indicators.
• Identify key areas that require improved data collection tools to maximise the usefulness of this surveillance approach.
• To produce a learning resource and template for ecological vaccine effectiveness studies in the UK
Study design
Design Ecological study – before and after approach
Location Merseyside ~1.4 million pop ~ 80,000<5 years
Population All ages, not just vaccine eligible age
Data Routine health surveillance and clinical data
Case definition
Differs for each dataset / outcome measures – clinical, laboratory confirmation and syndromic
Study period >= 3 years pre-vaccine and 1-3 years post
Data set Case definition
Nosocomial and community acquired
Nosocomial—laboratory-confirmed rotavirus case. Gastroenteritis symptoms beginning >2 days after admission Community acquired—laboratory-confirmed rotavirus case. Gastroenteritis symptoms <3 days of admission
Hospital admissions Rotavirus case—inpatient FCE with a primary or subsidiary diagnosis ICD10 A08.0 AGE case—inpatient FCE with a primary or subsidiary diagnosis ICD10 A08–A09
ED attendances Attendance with a primary or secondary diagnosis code Z:III Gastrointestinal conditions––other
GP consultations
GP consultations (Read codes): diarrhoea and vomiting (19G); diarrhoea symptom NOS (19F6), viral gastroenteritis (A07y0), diarrhoea (19F2); gastroenteritis—presumed infectious origin (A0812), diarrhoea of presumed infectious origin (A083); infantile viral gastroenteritis (A07y1); infectious gastroenteritis (A0803); enteritis due to rotavirus (A0762); and infectious diarrhoea (A082).
Community consultations (Walk-in Centres)
Variable coding system for diagnosis. Patient consultation field will be queried using the following key words: diarrhoea, vomiting, GI and gastroenteritis. A Soundex script will be used to allow for spelling inaccuracies
Laboratory detections Detection of rotavirus in a faecal specimen by a standard assay Detection of other AGE causative organisms
Case definitions by health data set
Outcomes
• Change in trends of gastroenteritis indicators and rotavirus diarrhoea rates during the first three years post vaccine introduction.
• Relative impact on various services (i.e. GP consultations, A&E attendances, hospital admission, walk-in centres and telephone consultation).
• Measure of direct (those vaccinated) and indirect (not vaccinated) impact on overall gastroenteritis.
• Assessment of the effect of deprivation on vaccination uptake and incidence of gastroenteritis.
Alder Hey Rotavirus Lab Data
• (+) laboratory detections 07-2004 to 04/2014
Acknowledgements
Dan Hungerford, Miren Iturriza-Gomara, Jon Read, Neil French
Roberto Vivancos
HIV / Hepatitis Drug Interactions
Saye Khoo
Institute of Translational Medicine
The Problem ….. • Global burden of HIV (37M), HCV (170M) and hepatitis B.
• Notwithstanding success, HIV & HCV therapy carry liability for harm from drug-drug interactions (DDI)
• Global surveys (US, EU, SSA) suggest 1 in 4 treated patients have clinically significant DDIs, yet clinicians able to identify only a third
• Patient population is ageing, with multiple co-morbidities, and liver/renal dysfunction – multiple medications from multiple sources
• 5.2% of HIV hospital admissions receiving contraindicated medicines
• Available resources provide inadequate coverage
Gallagher et al CID 2008;47:e36
Our Solution ….. • Online and smartphone/tablet prescribing support.
• a clinically useful, reliable, comprehensive, up-to-date, evidence-based resource, freely available to healthcare workers, patients and researchers
• Covers all known data, predicts unknown, advises management
• Data synthesis - HIV (>11,000 DDI-pairs) and HCV (>5,000 DDI-pairs) from wide range of sources – updated weekly
• ‘Traffic lights’ recommendations, paired with GRADE-based evidence evaluation
• Supported by Pharma, British HIV Association, European AIDS Clinical Society, Elton John AIDS Foundation, Glasgow HIV Conference, NIHR
• Governance (International Editorial Board) and patient involvement
• Covers WHO Essential Medicines List
A Brief History
1998 1st HIV Charts launched
1999 We went ‘Digital’
2002 Partnership with KP360
2006 Website redeveloped to current form
2009 Editorial Board – ‘internationalised’ stakeholders
2013 Electronic prescribing in Kampala
2011 Hepatitis website launched 1st App launched – iOS and Android
HIV iCharts
Hep iCharts
What should ‘success’ look like ? • Acknowledged to be the ‘Premier’ DDI resource - resource for Treatment Guidelines in > 16 countries/territories - UK Standards & BHIVA Guidelines require every GP letter to carry URL - partnered with major specialist societies in Europe and USA
• Web metrics (Google analytics) - Unique users/y – 105,000 (HIV) and 35,500 (Hep)- rising year-on-year - multiple territories - App downloads: >55,000 (HIV); >13,000 (Hep)
• External funding - Pharma funding (£1.3M in past 5 years) - Buy in from Specialist societies and charities
What could we have done better ? • Fundraise, especially from charities • Define ownership and controls right from inception code, content management, URL, publisher • Horizon scan NHS Apps, MHRA and EDD
What would we do with a million dollars ? • Modernise website – declutter, mobile-optimised, user experience • Equip for 21st century prescribing – electronic prescribing • Patient-friendly/ 3rd party Apps / translations • Personalise – exploit in-silico tools • Expand – other infections, cancer • Restructure for research
HIV Drug Monitoring
• Patient responses and drug exposures variable • Adherence is a major problem • Vulnerable groups and risky situations
• Drug monitoring for individualised therapy • Incorporated into Guidelines 2003 • Spun out in 2006 (now incorporated into Lab21)
• GCP lab (4 triple quad LC/MS systems) • HIV/HCV/TB drugs • Plasma, tissues, fluids, cells • Dried blood/plasma/breast milk spots
http://www.liv.ac.uk/translational-medicine/research/bioanalytical-facility/about/
LC- MS/MS
Chromatography
Q & As
Lunch, networking and booked 1:1s
HASHTAG FOR THE EVENT #InfectionCatalyst
Company elevator pitches
HASHTAG FOR THE EVENT #InfectionCatalyst
IMPLEMENTING BEST
PRACTICE IN THE
NHS
Martin Kiernan, Visiting Clinical Fellow, UWL
Rise of S. aureus bacteraemia England 1991-2003
181
Slide adapted from Susan Hopkins, HPA/PHE
MRSA
MSSA
C. diff Annual Cases (England) Data source: Health Protection Agency
182
0
10000
20000
30000
40000
50000
60000
2001 2002 2003 2004 2005 2006
182
Getting engagement 183
Staff have to believe that they can make a difference
and can prevent infection
Tricky
We do not implement the organisations IPC programme
How C. difficile get so bad?
OK, there were some changes
Healthcare practice
Patient risk profile, Age
Increase in Community CdI
Effect of new strains (027/NAP1) that demonstrated that
Infection Control was not working
The authors of a 2009 report stated
‘it is the failure to implement the guidelines described in 1994
that has contributed to the recent rise’
184
184
185
Quarterly C. difficile England >2y: 2004-2014
0
2000
4000
6000
8000
10000
12000
14000
16000
18000 Surveillance
Problems in detection of CDI?
Testing and sampling protocols vary significantly
Lab interpretation of what you see in front of them does
not always reflect what the nurse sees in front of them..
186
People are plotting against us
What about a type 7 stool on a incontinence pad?
Scrape up a lump? – tested? – not ‘shape of the container’
No ¼ of a container
187
Specimen testing 188
Do we get specimens from every diarrhoeal
patient?
Experience says not
E-reader to all staff to ask them to write the Bristol
Stool Chart score 5-7 on the form
Compliance <100%, but it had an impact
Impact of Specimen e-reader M
ay-1
3
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May
-13
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3
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-13
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-14
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-15
Specim
ens p
er
month
Period
Monthly Faecal Specimens from inpatients 2013-15
Isolation - Let’s play Trumps.. 190
You have competing priorities, so who gets the side room?
Isola
tion
MDR GNB
Carbapenem-resistant Enterobacteriaceae
Carbapenem-resistant A. baumannii
ESBL Klebsiella sp
Carbapenemase-producing P. aeruginosa
ESBL E coli and other Enterobacteriaceae
AmpC Enterobacteriaceae
CDI
MRSA
Norovirus
Influenza
TB
Etc, etc.. 191
192
Quarterly MRSA Bacteraemia England: 2001-14
0
500
1000
1500
2000
2500
Surveillance
What does this mean
England has gone from 434 HAI cases/month (Jan 2006) to 15 in November 2014; a 96.7% reduction
Annual totals still falling by 8.4% per month
How did the NHS do this?
Good practice (and a big stick)
In my organisation, no cases for 2.5 years – until recently
1 missed screen in a haematology patient – parotitis treated with the wrong antibiotics
1 osteomyelitis – treatment failure that was missed
193
You have a problem and you are going to
fix it
We have a problem, how will you fix it?
We have a problem, how do we fix it?
Do we have a problem? How should
we fix it?
Solution
194
Southport ITU
2010 - IC Team feel that Central Catheter-related
Bloodstream Infections are too high
Clinicians do not…
But have no idea what their rate is
Data collected
Rate of infection 10.97/1000 device days
Ah…. I asked them to write why this was down on a
post-it note
195
Receiving Bad News: Five stages of grief
Kübler-Ross
Denial
Anger
Bargaining
Depression
Acceptance
CR and CA-BSI in ITU 2009-14 Rate/1000 device days
10.97
3.58
1.48 2.22
1.35 1.17
0
2
4
6
8
10
12
2009 2010 2011 2012 2013 2014
Antibiotic prescribing
Standard for stop/review dates and indications was
80%
Wards were audited
Multiple clinical teams per ward with outlying patients
No ownership from clinicians
Ward Managers felt the pressure
We never hit the standard
198
Audit of prescribing Stop/review dates by hospital ward
199
Target 80%
Actual 77%
Antibiotic prescribing
We did two things
We increased the standard from 80% to 90%
Possibly a lower standard did not demonstrate a true desire
for high quality prescribing
We changed method to audit by clinician teams not
wards
200
Antibiotic Prescribing Getting Personal - Stop/Review Dates 2012-14
201
IPC Programme
We need to find a way of better ways of engaging with
those who will deliver the programme
I had the worst job title in the world; I controlled nothing
What motivates people?
What are their desires….. or fears..
202
Motivators
204
Advance pre pre-op 2% CHG reduces incidence of SSI in knee
arthroplasty Zyweil et al. International Orthopedics 2010 Epub
SSI in Breast Surgery 205
All infected with Staph. aureus
Commonly found in the axilla
Consideration to pre-op washing
It works, however non-compliance an issue
Zyweil et al. International Orthopedics (2010)
Pre-op skin disinfection
Wide variation in skin prep
2% CHG in Alcohol introduced as the only change
Infection rate is 1.0% over the past 12 months
So let’s see if a bundle works 206
Implemented a 9-point bundle
Antiseptic bathing
2% Alcoholic Chlorhexidine
MRSA Screening
Abx prophylaxis
Normothermia
Iodine incise drapes
Supplemental Oxygen
Glucose control
No hair removal or clippers
SSIs pre and post
Baseline (127) Cohort (166)
Superficial SSIs 9% 17%
Deep SSIs 15% 11%
Total SSIs 24% 28%
Compliance with interventions
Baseline Cohort MRSA screening, decontamination
88% 89%
Pre-op wash 63% 63%
App. hair removal Not recorded 100%
App. antibiotic prophylaxis 75% 73%
Skin prep 2% CHG Not used 63%
Normothermia 23% 35%
Iodine incise drapes Not recorded 100%
Supplemental oxygen Not recorded 100%
Glucose for diabetics 98% 95%
What scares me?
MDROs
209
2012
2004-9
Getting research into practice is the
greatest challenge
There are variety of reasons, but one of the primary is
the failure of those developing an intervention to truly
consider how (and if) it could be implemented
We need good qualitative studies to determine the
reasons for non-implementation
210
Coffee / tea and networking
NWC AHSN and the Patient Safety Collaborative
Prof John Goodacre, NWC AHSN
Follow us on Twitter @NWCAHSN @LiverpoolUni
Wrap up, next steps and close
Drinks reception, networking and 1:1s