VJarlier 2010

Carbapenem-resistance in Enterobacteriaceae :

bacteriology and infection control view points

(in a country of low prevalence)

Vincent JarlierBacteriology-Hygiene

Pitié-Salpêtrière Hospital, Paris

Central Infection control teamAssistance Publique – Hôpitaux de Paris

VJarlier 2010

1st detection of CARBAPENEMASES in EUROPE

2001

1997

2004

2004

2005

VIM-1

KPC-2KPC-3

Carbapenemasesclass A

Carbapenemases class B, metalloenzymes

G.Arlet, ann biol clin, 2006

VJarlier 2010

1st outbreak in France : winter 2003-summer 2004

VJarlier 2010

Paul Brousse hospital

(Paris) 2004 Klebsiella pneumoniae VIM-1

+ SHV-5

(index case : transfer

from

Athens)

MIC : imipenem 32 mg/l ; gentamicin 8 mg/l

Pip Tic TzAmx

Ctx Amc CazFox

Imp

Atm TccCf

Mox

Fep

Ma

Amk NetTb

Cip Ofx

G

Pi

FosTmp

Cs

K

Sul

Courtesy: N. Kassis-Chikhani

~Therapeutical dead end

VJarlier 2010

Initial control measures From December 2003 to June 2004

–

IR-Kp

carriers isolation in 1 bed rooms

–

Promotion of alcohol-based-hand rubing

–

daily staff training

–

Screening ICU patients at admission and 1/week (rectal swabs, 4 mg/l imipenem

containing agar )

Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

Extended control measures in June 2004 (1)

•

ICU divided in 3 separate sections–

1 for cohorting

IR-Kp

carriers (“IR-Kp ICU”)

–

2 for the IR-Kp-free patients (“IR-Kp free ICU”)•

for expected duration >> 2days and “heavy”

ICU (“”long”)

•

for expected duration ≤2days and “ligth”

ICU (“short”)

•

Acute care divided in two sections :–

1 for IR-Kp-free patients but

transferred from ICU or

patients previously hospitalized in the ward (at risk

to be carrier : ”contact patients”)

–

1 for new

patients (not

at risk : “IR-KP free ACF”)Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

Paul Brousse

hospital (Paris) 2004 Klebsiella pneumoniae VIM-1

+ SHV-5 :

splitting the ward in distinct sectors

Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

•

nurse staff exclusively dedicated to “IR-Kp ICU”

•

nurse staff exclusively dedicated to “IR-Kp free ICU”

Extended control measures in June 2004 (2)

Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

•

Strict limitation of patient transfer

to other wards or other care centers :

•

Screening all contact patients till discharge and after and in case of readmission

•

Limitation of broad spectrum antibiotics•

IR-Kp

carriers informed on their status and

received specific instructions at discharge

Extended control measures in June 2004 (3)

Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

Paul Brousse hospital

(Paris) 2004 Klebsiella pneumoniae VIM-1

+ SHV-5 :

screening : 277 patients (~1,000 swabs)

Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

December January MarchFebruary April May June July August

1

2

3

4

7

8

6

ICU4th

floor

Medecine

unit

3rd

floor

5

First isolation of KP

Rectal swab

Blood

Broncho-pulmonary

Urine

Urine

Rectal swab-Blood-Abdominal

Rectal Swab

Rectal swab

2

No link link

MDR Mesures renforcées

Paul Brousse hospital

2004

Classical MDR measures Reinforced measures

No new case since 2005

Kassis-ChikaniEurosurveillance

2010 in press

VJarlier 2010

Practicing control of emerging MDROs

in France : VRE

Summer 2004-2007

VJarlier 2010

VRE cases per month 39 univ. hosp. Paris area (AP-HP)

2004-2007

0

10

20

30

40

50

08.0

409

.04

10.0

411

.04

12.0

401

.05

02.0

503

.05

04.0

505

.05

06.0

507

.05

08.0

509

.05

10.0

511

.05

12.0

501

.06

02.0

603

.06

04.0

605

.06

06.0

607

.06

08.0

609

.06

10.0

611

.06

12.0

601

.07

02.0

703

.07

04.0

705

.07

06.0

707

.07

08.0

709

.07

10.0

7

Date

Nom

bre

Nouveaux cas Infection

Classical MDRmeasures

Reinforced measures (2006)

Founier 2010 submitted

VJarlier 2010

VRE cases per month observed and predicted by time series analysis

39 univ. Hosp. Paris area (AP-HP) 2004-2007

-10

0

10

20

30

40

50

60

Aug

-04

Oct

-04

Dec

-04

Feb-

05

Apr

-05

Jun-

05

Aug

-05

Oct

-05

Dec

-05

Feb-

06

Apr

-06

Jun-

06

Aug

-06

Oct

-06

Dec

-06

Feb-

07

Apr

-07

Jun-

07

Aug

-07

Oct

-07

Dec

-07

Mon

thly

num

ber o

f VRE

cas

es

Observed casesPredicted values from the segmented regression modelPredicted values (with 95% CI) from the segmented regression model estimated on period 1

Period 1 (Multidrug resistant bacteria guidelines)

Period 2(Enhanced measures)

Founier 2010 submitted

95% CI

Classical MDRmeasures

Reinforced measures (2006)

VJarlier 2010

The 23 VRE outbreaks in 39 univ. hosp. Paris area (AP-HP)

2004-2007

Aug-

04Oc

t-04

Dec-0

4Fe

b-05

Apr-0

5Ju

n-05

Aug-

05Oc

t-05

Dec-0

5Fe

b-06

Apr-0

6Ju

n-06

Aug-

06Oc

t-06

Dec-0

6Fe

b-07

Apr-0

7Ju

n-07

Aug-

07Oc

t-07

Dec-0

7

(894 days - 112 cases)(310 days - 17 cases)

(62 days - 9 cases)(168 days - 4 cases)(60 days - 3 cases)(7 days - 3 cases)

(63 days - 39 cases)(31 days - 6 cases)

(568 days - 68 cases)(782 days - 37 cases)

(25 days - 3 cases)(70 days - 11 cases)

(7 days - 4 cases)(30 days - 5 cases)

(116 days - 5 cases)(29 days - 2 cases)

(109 days - 16 cases)(94 days - 2 cases)(92 days - 6 cases)(32 days - 4 cases)(34 days - 2 cases)

(49 days - 14 cases)(13 days - 8 cases)

(Duration of outbreak - No. of cases)

Start in period 1Start in period 2

*

*

**

**

*

**

*

Classical MDRmeasures

Extendedmeasures (2006)

Founier 2010 submitted

VJarlier 2010

Releasing French national guidelines for emerging

MDROs

control (e.g. Carb-R Enterobacteriaceae):

2006 (new edition 2010)

VJarlier 2010

As soon as identification of the index case

•

Isolate

the patient in a single bedroom •

Alert

hospital administrator and IC team•

Stop transfer

to other units or hospitals of (a) the index case and (b) patients of the same unit (defined as contact patients)

•

Limit admissions

in the unit as much as possible•

Screen contact patients

French MDRO control guidelines 2006, 2010

VJarlier 2010

The two days following the identification

•

Identify other contact patients: including those already transferred to another unit of the hospital at time of detection of the index case.

•

Screen

them•

Re-enforce hand hygiene

(alcohol base hand-rub

solution)•

Clean daily patient environment with disinfectant

•

Identify antibiotics that could be used in case of serious infection with the strain of the index case

French MDRO control guidelines 2006, 2010

VJarlier 2010

During the entire period of the outbreak•

Cohort patients in distinct sections, each with dedicated nursing staff:

-

case patients («

case section")-

contact patients ("contact patient section

")

-

newly admitted patients ("free section

")•

Screen once weekly

all contact patients •

After 3 neg

screenings, contact patients can be transferred in other unit of hospital (continue to isolate and screen)•

Resume screening in contact patients receiving antibiotic.•

Restrict antibiotics use•

Update the list of cases and contact discharged patients, set up an information system allowing to identify them in case of re-admission

French MDRO control guidelines 2006, 2010

VJarlier 2010

Detecting carbapemenase- producing

Enterobacteriaceae at the bench

VJarlier 2010

Detecting carbapemenase- producing

Enterobacteriaceae :

(1)

warning

VJarlier 2010

KPC-2K.pneumoniaePetri dish 1

Courtesy Kassis-Chikani

cefotaxime

Imip

VJarlier 2010

KPC-2K.pneumoniaePetri dish 2

Ertap ImipErtap Imip

Courtesy Kassis-Chikani

VJarlier 2010

Detecting carbapemenase- producing

Enterobacteriaceae :

(2)

phenotypic confirmation

VJarlier 2010

Detecting carbapemenase- producing

Enterobacteriaceae :

(2)

phenotypic confirmation

Metalloenzymes

VJarlier 2010

Extended-spectrum β-lactamase (ESBL) SHV-5

IMP IMPIMP+IMP+EDTAEDTA

IMPIMP

+ EDTA+ EDTA

cefepimcefepimceftazidimeceftazidime

clavulclavul + EDTA+ EDTA

VIM-1 + SHV-5 :Synergy tests for detecting

metallo-carbapemenases and ESBL

Kassis-ChikaniJAC 2006

VIM

VJarlier 2010

Detecting carbapemenase- producing

Enterobacteriaceae :

(2)

phenotypic confirmation

Class A enzymes

VJarlier 2010

Imip-EDTA = neg Imip-Clav = pos

~ 0.5 mg/l

Synergy tests for mclasse

A carbapemenases

:

Example of KPC-2

Courtesy Kassis-Chikani

VJarlier 2010

Céfépime

Cefotax

Clav

KPC-2K.pneumoniae

Synergy C3G –clavulanate

Narrowing the distance betweenC3G and clavulanate disks

Still a doubt

VJarlier 2010

KPC-2K.pneumoniae

Synergy C3G –clavulanate

CéfépimeCefotaxCeftaz

Idem + adding clavulanateon the disks

No more doubt

VJarlier 2010

KPC-2K.pneumoniae

Hodges testimipénème

Hodges

test (~ Gots

test)

E.coli wt

KPC‐2 Kp

VJarlier 2010

KPC-2K.pneumoniae

Hodges testertapénème

Hodges

test (~ Gots

test)

KPC‐2 Kp

E.coli wt

VJarlier 2010

Detecting carbapemenase- producing

Enterobacteriaceae :

(3)

identification of enzyme : molecular tests

required

VJarlier 2010

Controlling further outbreaks of Carb-R Enterobacteriacea

in France : applying the new

guidelines

VJarlier 2010

Early warnings concerning carbapemenase-R

Enterobacteriaceae in French hospitals

(frame: French national system for signaling abnormal nosocomial events)

- 24 events 2004-2010 -

so far all controlled

(but wait and see!!!)Vaux 2010 being submission

VJarlier 2010

Investigations and control measures of a KP-KPC2 outbreak occurring in hospitals A,B and C

Suburb South of Paris, September-December 2009

A : date of admissionD : date of duodenoscopy+ : date of 1st positive specimen Carbonne

Eurosurveillance2010 in press

• 1 source case (from Greece)• 7 secondary cases linked

with duodenoscopy• 5 secondary cases linked

with cross-transmissionthrough care

Total : 13 cases

VJarlier 2010

G

E

CA

D B

Haute-Normandie

Ile-de-France

Centre

Transfer of case

Hospitals where cross-transmission occurred

Hospitals where cases were transferred (no further cross-transmission)

Investigations and control measures of the KP-KPC2 outbreak in hospitals A,B,C and D,E,F,G

September-December 2009

CarbonneEurosurveillance

2010 in press

F

Screened contacts : 341A: 87B: 208C: 25

D: no contactE: no contact

F: 3G: 18

No new case since December 2009

VJarlier 2010

ESBL and Carbapenemases :

break « the infernal

circle »

VJarlier 2010

ESBL E.coli in Europe

VJarlier 2010

EARSS : E.coli resistant

to 3rd gen. cephalosporins (%) in bacteremias

2002 2009

2% 6.5%* ~5% ESBL

VJarlier 2010

% R 3rd gener. Cephalosporins in E.coli Bacteremias

in Europe, EARSS 2006-09

Stability or small increase

VJarlier 2010

ESBL K.pneumoniaein Europe

VJarlier 2010

EARSS : K.pneumoniae resistant

to 3rd generation

cephalosporins in bacteremias

2% 19%

2002 2009

~15% ESBL

VJarlier 2010

% R 3rd gener. Cephalosporins in K.pneumoniaeBacteremias

in Europe, EARSS

2006-09

Stability or small decrease

VJarlier 2010

Relation 3rd Gen Cephalosporin-Resistance E.coli vs. K.pneumoniae

EARSS 2007 : 26 countriesTitre du graphique

y = 0,2768x + 1,8969R2 = 0,4221

0

5

10

15

20

25

30

35

40

45

0 20 40 60 80 100CTXKpneu

CTX

Ecol

i

%_CTXEcoLinéaire (%_CTXEco)

R=0.65

VJarlier 2010

ESBL at national level

VJarlier 2010

ESBL National survey (« RAISIN ») Incidence rate / 1,000 DHs per area

2004-2008 (227 hospitals 3 months/year)

0

0,1

0,2

0,3

0,4

0,5

0,6

2004 2005 2006 2007 2008

NorthParisEastWestS.EastS.WestTOTAL

0.17

0.31

Rate x 2 in 4 years

VJarlier 2010

ESBL national survey

(«

RAISIN

») Incidence rates / 1,000 DHs

per activity

227 French hospitals

(3 months/year) 2003-2007

0

0,2

0,4

0,6

0,8

1

1,2

1,4

2003 2004 2005 2006 2007

Acute

ICU

LCF

TOTAL

ICU

all acute care

VJarlier 2010

Consommation

des Blactamines

à

large spectre

à

l’AP-HP 2003-09

0

2

4

6

8

10

12

14

16

2003 2004 2005 2006 2007 2008 2009

DD

J/1

00

0 J

H

Ceftriaxone Cefotaxime

0

2

4

6

8

10

12

2003 2004 2005 2006 2007 2008 2009

DD

J/1

00

0 J

H

Ceftazidime Tazocilline

0

2

4

6

8

10

12

2003 2004 2005 2006 2007 2008 2009

DD

J/10

00 J

H IMIPENEMEERTAPENEMEMEROPENEMECarbapénèmes

CefotaximeCeftriaxone

PIP-TAZ

Carbapénèmes

Ratio2 – 1 - 1

1/100 JH !!!

VJarlier 2010

Carb-R Enterobacteriaceae

VJarlier 2010

K.pneumoniae IMP-R en GRECE

A. Vatopoulos, eurosurveillance, 2008

VJarlier 2010

K.pneumoniae IMP-R en ISRAEL (Tel Aviv)

Epidémie de souches K. pneumoniae résistantes aux carbapénèmes possédant KPC-2et KPC-3 dans un hôpital à Tel Aviv de 2004 à 2006.12 clones différents et un clone majeur Q avec des profils de sensibilité différents

A.leavitt, AAC, 2007

VJarlier 2010

% R Imipenem in K.pneumoniae Bacteremias, EARSS 2005-08

0

10

20

30

40

50

2005 2006 2007 2008year

% IM

I R a

nd #

cou

ntrie

s w

ith c

ases

Israel

Greece

Cyprus

Italy

Turkey

UK

N countrieswith casesN=6

N=15

VJarlier 2010

The MDROs control programmes in France : starting 1993

VJarlier 2010

MDR program

RegionalUniv. hospitals

Paris area(AP-HP)

1993

VJarlier 2010

MDR program

National

1999

VJarlier 2010

Alcool based

hand rub solution

campaigns

2001-02

VJarlier 2010

MRSA in Europe (% in S.aureus) EARSS 2001-2009

23%

2009

33.2%

2001

24% in 2008

VJarlier 2010

18,4

39,4

0,41

0,90

0,51

1,16

0,0

5,0

10,0

15,0

20,0

25,0

30,0

35,0

40,0

45,0

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008 année

% d

e SA

RM

par

mi l

es S

.aur

eus

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

inci

denc

e po

ur 1

00 a

dmis

ou

100

0 jo

urs

% de SARMincidence pour 100 admissionsincidence pour 1000 JH CS

% MRSA in S.aureus and MRSA incidence in acute care

Univ. hospitals of Paris area (n=39) 1993-2007

% MRSA in S.aureusRate per 100 admissionsRate per 1.000 DHS

Global decrease : 53 %

Jarlier

Arch

Int Med 2010

VJarlier 2010

Classical contact precautions used to control MRSA will not be enough

for

controlling emerging “digestive tract driven”

MDROs

such as ESBL and Carb-R

Enterobacteriaceae• Mobile resistance elements

– spread of strains…– …but also spread of mobile elements

• Bacterial (and mobile elements) excretion – ~1010 per carrier and per day (feces) – ~109 per day and per UTI

• Wastes = feces and urines environment– risk of “back trough food chain”

VJarlier 2010

ESBL in hospital

wastewater (1) Brazil

Letters in Applied Microbiology 2008

VJarlier 2010

ESBL in hospital

wastewater (2) Portugal

J Antimicrob Chemother 2009

VJarlier 2010

Antibiotic

consuption

in Europe – Community

-

ESAC 2002

ESAC Goossens et al., Lancet 2005

VJarlier 2010

HC

us e

in D

DD

/100

0 in

h abi

tant

s/da

y

FI FR HR LU PL BE GR EE SI MT DK SK HU SE NO0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Penicillins J01C

Tetracyclines J01A

Macrolides J01F

Quinolones J01M

Sulfonamides J01E

Others*

CephalosporinsJ01D

Vander Stichele J. Antimicrob. Chemother 2006; 58:159 – 167

Antibiotic

consuption

in Europe – Hospital

-

ESAC 2002

VJarlier 2010

Antibiotic

policy campaigns

in hospitals of Paris area

(AP-HP) 2006-10

VJarlier 2010

Antibiotic

consumption

in the 39 hospitals

of Assistance Publique –

Hôpitaux de Paris

2003-09Source : AGEPS-Direction des finances

Analyse : EOH/DPM

515 514

468 465

452

529

483

400

420

440

460

480

500

520

540

2003 2004 2005 2006 2007 2008 2009

DD

J/10

00 J

H

2005-2009 : - 15% only !!!

VJarlier 2010

Absolute needs today in France•

Apply specific extended measures (quick and strong intervention as soon as 1st case) for controlling emerging MDRs (Carb-R Enterobacteriaceae, VRE…)

•

Set up a global approach to limit (slow down) the spread of ESBL including E.coli (combine community, hospital, farming, environment) : take profit of a still low incidence !!!

•

Drastic restriction of antibiotic use in the community, hospital, animal

VJarlier 2010

Antibiotic stewardship and ESBL-carbapemenase

problem

• Decrease drastically global ATB consumption(e.g. in France by a factor of 2-3 !

• Promote all possible alternatives to 3rd gen. cephalosp., fluoroquinolones and carbapenems

e.g. : betalactams- inhibitors, cephamycins, nitrofuranes, fosfomycine…

• revisit in depth national recommendations (UTIs, abdominal surgery…)

VJarlier 2010

Prevent X trans-mission

Identifycarriers at discharge

Identify risk factors for carriage at entry

Decreaseantibioticpressure

ESBL spread in community (x trans + ATB)

X transmission

in HCFs

Colonization(high contration)

Patients enterring HCFs with ESBL

(low contration)

Environment, water supply, food chain

ATB policy + prevent X transm. (school, family, elderly homes..)

Wastewater treatment

Farming, Food & water

DischargeAdmission

ATB

VJarlier 2010

•

Controlling MDROs

= saving a precious collective treasure : antibiotics

•

concern comparable to saving clean water and forests or preventing planet global warming

•

1st irruption of sustainable development in medicine

VJarlier 2010

VJarlier 2010

Stabilize (at least slow down) ESBL rates and

prevent carbapemenases

spread

•

Hospital•

Community

•

Environment

•

Cross transmission•

ATB policy

•

Food-water supply

Global and integrated approach