clinical and interventional microbiology for the ... · • netwerkgeneeskunde en value-based...

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…





➢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…





➢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…





➢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









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…





➢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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