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Marc Bonten

UMC Utrecht@MarcBonten

https://reflectionsipc.com

2

Geen (potentiële) belangenverstrengeling

Voor bijeenkomst mogelijke relevante relaties Bedrijfsnamen

• Sponsoring of onderzoeksgeld• Honorarium of andere (financiële) vergoeding• Aandeelhouder• Andere relatie, namelijk…

• Janssen Vaccines• Geen• Geen• Geen•

The Netherlands Not the Netherlands

Antibiotic resistance genes are natural, omnipresent

& ancient

Andersson and Hughes, 2014, Nature Reviews in Microbiology

DNA from 30,000-year old permafrost

sediments from north-western Canada

Resistance against:

tetracycline

β-lactams

vancomycine

Creating a Carbapenamase-Producing bug?

No! It’s selection & transmission & introduction

Antibiotic resistance is a system failure, that can be driven by:

1. Transmission within healthcare settings2. Antibiotic use (=selective pressure)3. Transmission from animals to humans4. Human-human transmission in the community5. Acquisition through environmental sources

Attributable mortality due to antibiotic-resistant Gram-

negative infections• 8 hospitals in the Netherlands

– 1 tertiary center

– 1 year per hospital during 2013-2016

– Weekly screening for 5 Gram-negative infections

Representative sample of Gram-negative infections

Non-infectedcontrol patients

matched 1:1on hospital,

length of stay, age

GN infections: 1,954

Bacteremia: 39%

Urinary tract: 52%

E. coli: 51%

P. aeruginosa: 7%

‘Highly’ R: 12%

Infections withresistant G-

Infections withsensitive G-

Controlpatients

Controlpatients

10.3% 11.2%

6.2% 8.5%

RR

1.2

3 (0

.54

-2.8

0)

RR

1.2

5 (1

.00

-1.5

6)

RR 0.98 (0.54-1.80)

D30 mortality

Attributable mortality due to antibiotic-resistant Gram-

negative infections

Antibiotic resistance is a system failure, that can be driven by:

1. Transmission within healthcare settings2. Antibiotic use (=selective pressure)3. Transmission from animals to humans4. Human-human transmission in the community5. Acquisition through environmental sources

Arias and Murray 2012 Nat Rev Microbiol

Transmission of antibiotic resistant bacteria in healthcare settings

Infection control measures

mentioned1. Air pressure differences to keep germs

from escaping rooms2. Quarantining patients3. Surgical gowns when entering rooms4. Respiratory masks when entering rooms5. Pre-emptive isolation of…6. … high risk patients7. Testing of healthcare workers8. Prudent antibiotic use9. Single-bed rooms10. Unused beds “wrapped as tightly as

sandwiches in plastic foil until being used”

11. Used beds cleaned in “dishwasher”12. Separated elevators for dirty and clean

beds13. Daily fresh uniforms for staff

Infection control measures

not-mentioned14. Number of patients in a ward are titrated upon

the number of available staff 15. New patient admissions can be temporarily

stopped in case of documented transmission.16. The number of infection control staff is based on

the number of beds…17. Infection control staff is supervised by a clinical

microbiologists, ..18. .. and recommendations are usually followed.19. Hospitals are remarkably clean (at least that is

what foreigners say)…20. … and the oldest buildings are about thirty years.21. You can’t admit a patient without notification of

risk factors for AMR in the electronic patient system.

22. … and this list still is not complete.

Epidemiological characteristics of pathogens in ICUs

• Rapid patient turnover

• Different acquisition routes (not ICU-specific)

– Selection / de novo resistance

– Cross-transmission

– Environmental contamination

• Multiple HCW-Patient contacts

• Hardly any Patient-Patient contacts

• Patient-dependency (characteristic of communicable diseases!)

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Prevalence of VRE, Chicago

Prevalence of P. aeruginosa, Maastricht

Mean: 36%

Range: 0-75%

Mean: 35%

Range: 0-87%

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Prevalence of VRE, Chicago

Prevalence of P. aeruginosa, Maastricht

Theoretical framework for resistance transmission

Pathogen-free

InfectiousPathogen-free

Death/discharge

admission

Death/discharge

Infected/iouspatients

HCW

admission

• About 70 hospitals and 50 microbiology labs

– Creating strong peer pressure

• National guidelines reasonably well adopted

– Search & Isolate for MRSA (introduced in the 1990s)

• Later for VRE, ESBL, CRE

– Number of patients admitted based on number of HCWs avaiable

– Ward closure if transmission is not controlled

• Reasonably clean hospitals

• Modern buildings (oldest about 30 years); large proportion is single-bed (6-bed rooms are

exceptional)

• NOT: better hand hygiene or less antibiotic use!

4 reasons why - I think - AMR is controlled in Dutch hospitals

16 mei 2011

ZuiderziekenhuisClara ziekenhuis

Maasstad ziekenhuis

Klebsiella pneumoniae ESBL (CTX-M15)

Beschikbare epicurve juli 2011

0123456789

10

31 36 40 44 49 1 5 9 14 18 23 27 31 36 40 44 49 1 5 9 13 17 22 26 30 35 39 44 48 1 5 9 13 17 22

augseptokt novdec jan feb mrt apr meijunijuliaugseptokt novdec jan febmrtapr meijunijuli augsept okt novdec jan febmrtapr meijuni

Week nummer en maand: 2008-2011

Aan

tal

case

s

ctx-M pos oxa-pos

ctx-M pos oxa-neg

ctx-M pos oxa-discrep

ctx-M neg oxa-pos

2008 2009 2010 2011

Classification of patients, infection prevention measures and screening results

Riskgroup

Definition Screening Isolation Patients (n)

Patients (n tested)

OXA-Ecarrier, n (%)

OXA-Ecarrier

Infection or colonizationwith OXA-48 E

Every 2 months,until 1 year negative

SRGG

63

High risk Shared room with OXA-E carrier

Active tracing SRGG

4722 3394 40 (1.18)

Low risk All hospital admissionsduring outbreak period

On admission CGP

67361 4133 14 (0.34)

Newlyadmitted

No hospital admissionduring outbreak period

CGP

1214 0

Total 8741 117

SR: single room, GG: gowns and gloves, C: cohort, GP: general precautions

• VRE Vancomycin-resistant enterococcus

• MRSA Methicillin-resistant Staphylococcus aureus

• ESBL Extended-spectrum β-lactamase producingEnterobacteriaceae (mostly E. coli)

• CPE Carbapenamase-producing Enterobacteriaceae (mostly K. pneumoniae)

• CPPA Carbapenamase-producing Pseudomonas aeruginosa

Top 5 reasons for outbreak control measures in

Dutch hospitals (for AMR)

Enterococci

• Gram-positive facultative anaerobic cocci

• <1% of intestinal microbiota in healthy humans

• Enterococci are intrinsically resistant to antibiotics of various classes (low-level

aminoglycosides, cephalosporins, clindamycin)

• Well developed mechanisms to acquire novel resistance traits against ampicillin, high-

levels gentamicin, tetracyclines, macrolides, chloramphenicol and vancomycin

• VAN-resistance (vanA/B) is plasmid-based

10 year research on 1 slide

• VRE are mostly E. faecium (instead of E. faecalis)

• There is host specificity of E. faecium

• All human outbreak-related VRE (5 continents) grouped in a specific

genetic clade (clade A1)

• Characterized by ampicillin-resistant, ARE (most others are ampicillin

susceptible)

• Characterized by multiple putative virulence factors (that others lacked)

• In retrospect,

– the 90’s VRE epidemic in the USA was preceded by an increase of ARE

infections (clade A1) by 10 years

– Around 2005, ARE infections (clade A1) started to emerge in Europe

Mechanisms of vancomycin resistance in E. faecium

ARE VRE (vanA or vanB)

You cannot make vancomycin-resistance with

vancomycin!

Mechanisms of vancomycin resistance in E. faecium

ARE VRE (vanA or vanB)

Horizontal Gene Transfer

Natural reservoirs

vanA vanB

LivestockPetsSoilWild birds

Human Clostridia species(Howden et al, mBio 2013)

• 36 Hospitals

• 487 VRE (E. faecium)

• MLST: 30 different STs

• 22 hospitals with > 1 ST

• High-level of diversity

• High prevalent STs:

• ST117 n=126, 20 Hosp

• ST203 n=82, 15 Hosp

• ST18 n=24, 12 Hosp

• ST80 n=33, 6 Hosp

Hospitals with VRE April 2011 – December 2014

Last 10 years: Clonal

spread of ST117 ARE (= VS

E. faecium) and

diversification

Polyclonal endemicity of

ARE

Introduction of vanA and

vanB gene clusters

followed by (limited) clonal

spread of VRE

van

B

van

B

van

B

van

A

van

A

What makes LA-MRSA a public health threat?

• High acquisition rate after animal contact

• High transmission rate through the food chain

• High transmission rate among humans (in community

and/or health care settings)

– High transmission and short duration of carriage

– Low transmission but long duration of carriage

• High virulence

• Few (if any) treatment options

LA-MRSA: after 10 years of research:

• High acquisition rate after animal contact– Van Cleef et al. JCM 2011; 49: 1030-3

• No evidence of transmission through the food chain

• Low transmission rate among humans (in community and/or health care

settings

– Low transmission and short duration of carriage– Van Cleef et al. PLoS One 2010; e9385

– Van Cleef et al. JCM 2011; 49: 1030-3

– Graveland et al. PLoS One 2011; e16830

– Wassenberg et al. CMI 2011; 17: 316-9

– Hetem et al. EID 2013; 19: 1797-1802

• Virulence, not different from other S. aureus

• Multiple treatment options remaining

• 0 of the first 40 reported healthcare-associated MRSA-outbreaks in the

Netherlands were caused by LA-MRSA

Prevalence of ESBL carriage in the Netherlands

1. 9.5% among 337 inhabitants from 8 Long-Term Care Facilities (LTCF)• 4.2% E. coli, 5,2% K. pneumoniae (all in 1 LTCF)Courtesy Linda Verhoef, RIVM, SNIV study

2. 10.9% among 643 inhabitants of 9 LTCFWillemsen et al. Antimicrob Resist Infect Control. 2014;3:26

3. 8.2% among 1,351 patients at hospital admission• 8.6% when admitted from LTCF• 7.9% when admitted from homePlatteel et al. Clin Microbiol Infect. 2015; 21: 141-6

4. 7.7% among 1,871 ICU patients receiving SOD4.4% among 1,928 ICU patients receiving SDDOostdijk et al. JAMA, Oct 2014

5. 5.0% in 4000 randomly selected subjects (open population)ESBLAT study, van der Bunt (submitted)

Acquisition of ESBL carriage in Dutch hospitals

Rectal carriage of ESBL-E

SoM study

14 hospitals

8,400 admissions

R-GNOSIS study

Single hospital

5,450 admissions

Mathematical model

(data R-GNOSIS study)

Prevalence at admission

% [95% CI/CrI]

7.4%

[6.2%-8.7%]

6.4%

[5.2%-7.8%]

7.0%

[6.2%-7.8%]

Prevalence at discharge

% [95% CI /CrI]

9.9%

[8.2%-11.8%]

8.7%

[6.8%-11.0%]

9.3%

[8.6%-10.0%]

Hospital-acquired prevalence at

discharge

% [95%CI/Crl]

2.5%

[1.7%-3.6%]

2.3%

[1.3%-3.6%]

2.3%

[1.7%-2.9%]

Acquisition rate

n/1000 patientdays at risk [95% CI/CrI)

3.2

[2.2-4.5]

2.7

[1.4-4.2]

3.8

[2.9-4.9]

Results: MCMC model

28.5% cross-transmission

71.5% endogenous selection

R= 0.06Kluytmans-van de Bergh, Mens, et al. ICHE 2017

Occurrence of CRE (K. pneumoniae and E. coli),

May 2015

Since 2010 sporadic CPE (K. pneumoniae), usually linked to hospitalization abroad.

3 hospital outbreaks2011: OXA48 in hospital (117 carriers, 20 infected)2013: KPC in LTCF (5 carriers)2015: NDM-1 in hospital (26 carriers)

Since then 3 more outbreaks

National CPE surveillance

172 CPE K. pneumoniae (wgMLST of about 5000 genes)

8 identical (0-5 genes difference) NDM type 1 K. pneumoniae, related to 26 NDM-1 K. pneumoniae isolates fromhospital outbreak December 2015

In 6 labs in different regions betweenDecember 2015 and October 2016

ST873 -> sporadically found before

No identifiable epidemiological linkage

Current status of AMR problem in the Netherlands

1. Accurate information about prevalence of carriage in the most relevant human populations.

2. Attributable mortality and recurrent infections is low, with stilltreatable bacteria.

3. Low human-to-human transmission rates of AMR in hospitals and community.

4. Antibiotic selective pressure in the community is stable and low.

5. Infection control measures for outbreaks still very effective, but cost-benefit considerations seem justified for some pathogens.

How to keep CRE/CPE from becoming endemic:

1. National (mandatory) surveillance for CPE/CRE in clinical microbiology.

2. Sentinel surveillance of CPE/CRE carriage in long-term care facilities, returning travelers and livestock animals.

3. Zero tolerance to not implementing (rigorous) control measures whentransmission of CPE/CRE is documented.

4. Maintaining low antibiotic selective pressure in the community, long-term care facilities and agricultural industry.

https://www.abrzorgnetwerkutrecht.nl/

@MarcBonten

https://reflectionsipc.com