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Clinical and Interventional Microbiology for the
Prevention of Antimicrobial Resistance
Prof. Dr. Alex W. Friedrich
Prof. Dr. Alex W. Friedrich
Chair and head of department
Medical Microbiology and Infection Prevention
University Medical Center Groningen
Netherlands
SIMPIOS Bergamo
21-5-2018
Affiliated to:
Disclosure of speaker’s interests
(Potential) conflict of interest None
Potentially relevant company relationships in
connection with event
None
Sponsorship or research funding Several National and European Grants
The next 35 minutes…
➢Challenge&Changes
➢Technological change
➢Clinical Microbiology
➢Network-prevention
➢Crossing borders
Specific infectious Diseases
-> Primary disease
Obligatory Pathogens
Natural transmission way
Defined incubation-, carrier time,
Epidemiology (TPP+species)
Public health medicine
Healthcare associated infections
-> Secondary disease
Facultative pathogens (e.g. CRE)
Healthcare generated transmission ways
Colonisation before infection
Infections depening on intervention
Molecular epidemiology
(TPP+species, resistance, subtype)
Network medicine
The role of CM in today’s clinical practice
• In classical infectious disease:80% clin. diagnostics,
obligatory pathogens, CM-diagnostics is just one more lab-result
• In healthcare-associated infections: 50% clin. diagnostics
facultative pathogens, Search for focus/species is relevant due to different
biological properties and natural ab-resistance
• In case of AMR: 90% lab-based diagnostics
changing virulence and resistance pattern (MGE)
Determination on species level is not sufficient (subtyping)
CM conditio sine qua non
Answers to the questions
Clinician
Lab Hygienist
Diagnostic Hygiene
treatment
nurses
technical
registration
Bacteriology
Virology
Molecular
culture
conservativesurgeon
generalist
MDL, …
ID
pharmacist
a) Do you protect me from an infection?
b) Do I have one and if so, which one?
c) What is the optimal therapy?
The “old world”
approach
Costs
Prevention
Quality
Time
Therapy
Diagnostic
value
..to the new way of working
…30 minutes…
➢Challenge&Changes
➢Technological change
➢Clinical Microbiology
➢Network-prevention
➢Crossing borders
Innovations that influence
diagnostics today
• Netwerkgeneeskunde en value-based medicine
• Preventie economisch model: pay for safety
• Disruptive Innovations en barriers for innovation
• Companion diagnostics (as in oncology)
• Personalized /tailor made microbiology
• Zero-cost-diagnostic
Porter M. NEJM 2010
Report of the review of NHS pathology services in England. 2008
Paper-based microfluidics, George Whitesides, TED
Clinical Microbiology needs to be
interventional
• Blood culture diagnostics 16-24h/7h -> organisational change
• Rapid ID and resistance <12h -> molecular tests
• Adaptive screening -> network analysis
• Ad hoc upscaling of diagnostic frequency -> 20% over-capacity
• Tailor-made diagnostics (outbreak-specific targets) -> NGS unique marker
• Molecular typing is identification at suspecies level -> WGS molecular typing
• In-situ immunology
(up-regulation of host-specific immune-response) -> Shot-Gun metagenomics
0
10
20
30
40
50
60
70
80
ST22 ST398 ST9 ST80 ST110 ST1 ST42 ST23 ST54 ST984
Colonisation Infection
Metagenomics: multiple layers of information
-2-
Culture independent detection
by Shot-Gun Metagenomics for diagnostics
Quantification
Molecular Epidemiology
In-silico Surveillance
Co-infections and effect on commensal
environment
Host reaction
Minion, Nanopore technology
Couto et al. 2018 Genome Announce
Moran-Gilead et al. CMI 2018
Lizzararo et al. 2018 (accepted)
Bathoorn et al. 2017
…25 minutes…
➢Challenge&Changes
➢Technological change
➢Clinical Microbiology
➢Network-prevention
➢Crossing borders
CM core competences
Gatekeeping Diagnostics
InfectionControl
Antibioticstewardship
€ = (A+B+C)x(1/t)
A B C
Clinical Microbiology in the Netherlands
Courtesy: NVMM.nl
Clinical Microbiologists
- Gatekeeper for diagnostic specimens
- Managing own laboratory
- Automatic 2days-bundle
- Daily Bedside consult/ Multidisciplinary board
- ---
Training:
Medical Doctor
2 Years Laboratory diagnostic
3 Year Clinical consultant in IP/ABS
Colleagues of Molecular Microbiologists
ID-doctors, IC-practitioners
Multidisciplinary patient-Board at the UMCG
Dia
gnostic
Treatment
Prevention
Vitek results
From 21 to 6:
Proactive antibiotic stewardship
Report to clinic
Microbio-
logical
Diagnostic
Prevention
ABS
Internal
Med
Innovations Imaging/
Nuclear
Medicine
HCAI/AMR-
oriented
Intensivist
HCAI/AMR-
oriented
Fello
w-p
hase
Basic
tra
inin
g
Preparing the common trunk…
HCAI/AMR-
oriented
HCAI/AMR-
oriented
meta
-phase
CM&ID
ABS
Prevention
2y
3y
…18 minutes…
➢Challenge&Changes
➢Technological change
➢Clinical Microbiology
➢Network-prevention
➢Crossing borders
19-1-2017
3 patients colonized with VRE (vanB)
Screening of 250 contacts:
13 pos.: all MLST ST117
Patient had been on German ICU before
Baseline: 0,6%; now: 5%
Outbreak-management team
Crisis management team (selective admission)
Regional outbreak team (transfer, screening)
Contact tracing inhouse/at home
Automatic Flagging of all patients at risk
In total 2950 patients screened
46 colonized patients on 6 wards
1-3-2017: Outbreak under control
My last year’s nightmare
n
Key factors for successful control are
beyond classical infection control
• Epidemiology: Case-definition, Flagging alerts
• Infection control: hygiene/outbreak measures
• ID: reduction of selective pressure
• CM: NGS typing, Upscaling of screening capacity
➢ Additional:
- Epidemiological Bulletin at 16h
- Carrier prediction at day 1: 60 patients
- Network analysis for adaptation of screening
- Outbreak specific rapid-test
- Isolation capacity (MDRO-ward)
- Regional outbreak management
Only NGS revealed that we had two
concomitant outbreaks
• MLST ST 117 / cgMLST CT24
CT24
current
• MLST ST 117 / cgMLST CT71
CT71
Sequencing of isolates
Trimming and de novo assembly
de novo assemblies used: in SeqSphere for typing
in ResFinder (identification of resistance genes)
WGS of VRE(B) outbreak isolates
Comparative genomics generated by WebACT
Analysis looking for target genes using ACT
Verification of identified target genes in database and among UMCG collection
using blast, BRIG, WebACT
Primer design for confirmed targets in CLC Genomics Workbench (qPCR; primers and probes)
Validation in the lab for diagnostic use
Verwachting UM2thi UM3pha UM5YrrC-P UM6-1(3)
17020586533-03 T12-ST117-CT24 outbreak pos pos pos ct24-UMCG
T12-ST117-CT24 non-outbreak pos ct24
17022031231 T137-ST117-CT71 outbreak pos pos pos ct71
Verwachting UM2thi UM3pha UM5YrrC-P UM6-1(3)
17020586533-03 T12-ST117-CT24 outbreak pos pos pos ct24-UMCG
T12-ST117-CT24 non-outbreak pos ct24
17022031231 T137-ST117-CT71 outbreak pos pos pos ct71
Verwachting UM2thi UM3pha UM5YrrC-P UM6-1(3)
17020586533-03 T12-ST117-CT24 outbreak pos pos pos ct24-UMCG
T12-ST117-CT24 non-outbreak pos ct24
17022031231 T137-ST117-CT71 outbreak pos pos pos ct71
Concept: Zhou et al. Nat Scient Rep 2015
Ad hoc development of outbreak-specific
PCR-primers
VRE-B/CT71
VRE-B CT24
Cluster analysis of two
concomitant VRE-outbreaks in the UMCG
Outbreak strain 1
Xnummer = number of ward
VRE-B/CT71
VRE-B/CT24
VRE-B/CT71
Outbreak strain 2
Screening
Screening
VRE-B/CT71
3 dept
3 dept
VRE-B/CT24
VRE-B/CT24
VRE-B/CT24
Regional AMR-Prevention Networks
A. Management: Acute Care Network - CEO‘s of all regional healthcare providers
B. Medical: all regional infection-related healthcare professionals
C. Organisation: Coherent, network, non-gerarchical, collaborative competence (meta-)
A+
A
A+
A+
B
B
A
A+➢ Overal goal = “CRE-free”
➢ Regional organisation
➢ Multidiscipliniary collaboration
➢ Regional training
B+
National Policy (So-Zi/AMR)
• No public reporting
• Reporting on professional website by all CM’s/labs
• Reports are discussed weekly by a professional committee
• Escalation phase 1 to 5
(5: uncontrolled outbreak - > report to Inspectorate)
• We know where outbreaks are at the moment
(adaptive screening policy)
• Peer pressure from (regional) colleagues
• Semi-public has advantageous
• Cross-border collaboration important
The last 8 minutes…
➢Challenge&Changes
➢Technological change
➢Clinical Microbiology
➢Network-prevention
➢Crossing borders
Parameters Euregio-NL Euregio-DE
Acute care hospitals (beds/1000 inhab) 22 (3,3) 69 (6,1)
ICU beds/100.000 inhab. 6,1 29,4
HCW:Patient ratio (on ICU) 1 : 1,2 1 : 3,2
CM (/1000 beds) 37 (3,6) 19 (1,0)
Distance pat:CM 0,5 km (0-23) 149km (30-350)
Blood culture sets/1000 pat. 242(50-350) 145 (180-300)
Bed occupance rate (BOR) in acute care hospitals
-> Impact on hand hygiene
-> Impact on isolation capacity
(2013)
Parameter EUREGIO-NL EUREGIO-DE Ratio
MRSA/100 admissions* 0,11 1,1 1:10
VRE/ 100 admissions 1,3 3,9 1:3
ESBL/100 admissions 6,1 7,7 1:1
CR-MO/100 admissions** 0,03 0,12 1:4
Zhou, X et al. 2017 Frontiers Microbiol
*Jurke et al. (submitted)
Regional Hub&Spoke-Diagnostic
Hub
Spoke
hub
Spoke
Spoke
Spoke
Hub
Regional Hub
- logistic centers
- High-throughput-diagnostic
Regional Spoke-lab
- Gatekeepers
- Appropriate diagnostic
- Diagnostic Stewardship
Academic Hub
- most complex diagnostics
- Research/innovation
- Training (coordination)
Hub&Spoke:Beastall, G. The Modernisation of Pathology and Laboratory Medicine in the UK: Networking into the Future. 2008 Clin Biochem Review. Moynihan, B et al. 2010. Delivering regional thrombolysis via a hub-and-spoke model. 2010 J R Soc Med.
Leer (DE)
Re-Introduction of
Lab-capacity by
Implementing
Diagnostic Stewardship
on the German side
Take home…
➢ Awareness that resistance is threat to medicine
➢ Look at factors beyond the medical ones
➢ Diagnostic stewardship generates answers, no results
➢ Is your diagnostic responsive, rapid, relevant?
➢ Collaborative competence
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