Résistance aux antibiotiques:la Résistance aux antibiotiques:la prochaine pandémieprochaine pandémie

Dr Jean CARLETRéanimateur teinté d’infectiologieAncien president du CTIN(National Committee for Prevention of Nosocomial Infections)N’a fait que passer à la HASConsultant pour l’OMS

THERE ARE SOME VERY GOOD THERE ARE SOME VERY GOOD NEWSNEWS

Efficacy of most programs against MRSA ( France, Belgium, Denmark, UK, USA…)

Efficacy of some national campaigns aimed at reducing antibiotic consumption (France, Belgium, Scotland, South Korea, Japan..)

Efficacy against carbapenemases ( Israel, Poland), VRE (France)

Strong international « reaction » to resistance ( ECDC, IDSA, TATFAR…)

Lobbying groups: ACdeBMR, React, AB action, APUA ….Reasearch programs ( Mosar…)Quality indicators

Courtesy: Grundmann et al. (EARSS, Sept 2009) and Harbarth for Sarkoleon

MRSA bacteremia in Europe, 2008

Taux annuels SARM acquis pour 100 patients Taux annuels SARM acquis pour 100 patients admis plus de 24 heures : portage sur tout site admis plus de 24 heures : portage sur tout site et bactériémies et bactériémies

0,940,99

0,73

0,65

0,440,29

0,062

0,073

0,062

0,023

0,015

0,113

0

0,2

0,4

0,6

0,8

1

1,2

1999 2000 2001 2002 2003 2004

0

0,02

0,04

0,06

0,08

0,1

0,12

SARM acquis tout site/100 admisbactériémies à SARM acquises/100 admis

% %

Counts of MRSA bacteraemia Counts of MRSA bacteraemia

Oct 2005 to June 2009Oct 2005 to June 2009

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2

2005 2006 2007 2008 2009

Counts of MRSA bacteraemia

Ye

ar

an

d q

ua

rte

r

* DATA ARE PROVISIONAL NOT FOR WIDER CIRCULATION

BBC World news

Courtesy: A. Pearson and colleagues (HPA, Sept 2009)

MR

SA

BS

I ep

isod

es

29,4

26,2525,15

23,9523,09

6,96

10,06

17,5

18,99

0,130,11

0,230,330,29

0,44

0,650,73

0,99

0

4

8

12

16

20

24

28

32

2000 2001 2002 2003 2004 2005 2006 2007 2008

0

0,2

0,4

0,6

0,8

1

1,2

Consommation de SHA année 2008

Taux de SARM acquis (novembre 2008)

0,5

0,7

0,9

1,1

1,3

1,5

1,7

1,9

2,1

2,3

1 2 3 4 5 6 7 8 9 10 11

0

1

2

3

4

5

6

7

8

QUINOLONES

MRSA per 1000 pat-days

Antibiotic use : specific classes

0

20

40

60

80

100

120

1999 2000 2001 2002 2003 2004 2005

Year

DD

D/1

,000

pat

ient

-day

s

Quinolones 3rdG Cephalosporins Glycopeptides

p = 0.01

p;: 0.03NS.

P. aeruginosa P. aeruginosa : ICU St Joseph hospital: ICU St Joseph hospital

Résistance toCiprofloxacineRésistance toCiprofloxacine

P. aeruginosa P. aeruginosa :ICU St Joseph :ICU St Joseph

Résistance to AmikacineRésistance to Amikacine

0

10

20

30

40

50

60

70

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

%

Années

St JOSEPH E. coli : Résistance (I+R)

Ampicilline

Amox / Clav

Pip / Tazo

Cefotaxime

Gentamicine

Ac. Nalidixique

Ciprofloxacine

TMP

Sulfamide

I

2005-2008 program: Politicians want a 2005-2008 program: Politicians want a public reporting of nosocomial infections public reporting of nosocomial infections rates. Quality Indicators selected rates. Quality Indicators selected

Composite indicator using data from annual mandatory report of Infection Control committees ( started in 2005: ICALIN):1st to be released

Consumption of alcohol based handrub: Nb of liters/1000 hosp days

Surgical site infection (SSI) rate: probably not very controversial topic.The indicator is yes or no, and % of units participating in a given hospital

Meticillin-resistant Staphylococcus aureus (MRSA) rate: Nb of MRSA/1000 hospital days + trends ,,

Antibiotic consumption ICATB: process indicator for AB usage in hospitals

Monthly notifications received at the InVS, Monthly notifications received at the InVS, France, 01/08/2001 to 31/12/2007 (N=5,357)France, 01/08/2001 to 31/12/2007 (N=5,357)

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

août

-01

oct-0

1

déc-

01

févr

-02

avr-0

2

juin

-02

août

-02

oct-0

2

déc-

02

févr

-03

avr-0

3

juin

-03

août

-03

oct-0

3

déc-

03

févr

-04

avr-0

4

juin

-04

août

-04

oct-0

4

déc-

04

févr

-05

avr-0

5

juin

-05

août

-05

oct-0

5

déc-

05

févr

-06

avr-0

6

juin

-06

août

-06

oct-0

6

déc-

06

févr

-07

avr-0

7

juin

-07

août

-07

oct-0

7

déc-

07

Month of notification

Not

ifica

tions

(N)

+20% p.year+20% p.yearMedian delay: 9 days

c. 30% HCF have notified at least once

ABT prescriptions from 2001-02 to 2006-07ABT prescriptions from 2001-02 to 2006-07(Oct-March periods) Guillemot et al PLOS medicine 2009(Oct-March periods) Guillemot et al PLOS medicine 2009

French Campaigns 2002-2007French Campaigns 2002-2007Outpatient antibiotic use in France in prescriptions Outpatient antibiotic use in France in prescriptions per inhabitant – October to Marchper inhabitant – October to March

Sabuncu et al., PloS Medicine; June 2009

Belgian Campaigns 2002-2010 Outpatient antibiotic use in Belgium in packages

per 1,000 inhabitants per day – July – June

Belgian National Belgian National Public CampaignsPublic Campaigns

When: since November 2000, annually during winter season Organised by: BAPCOC (Belgian Antibiotic Policy

Coordination Committee) Budget:

◦ 400,000 EUR/annual campaign Interventions targeting the public:

◦ Ads on TV, radio and newspaper ◦ Information booklets◦ Folders ◦ Posters◦ Internet campaigns: www.antibiotics-info.be

Results Scotland – Results Scotland – Empirical PrescribingEmpirical Prescribing

National compliance 93% and 7/14 NHS boards achieved target

Results Scotland – Results Scotland – Empirical PrescribingEmpirical Prescribing

National compliance 83% and 4/14 NHS boards achieved target 2011 - need to focus on improvement

18 November 2

008

Why is Europe (partially) Why is Europe (partially) successful?successful?

Bottom up Member States initiatives (e.g. rotating European presidencies) resulting in top down political support and commitment at European level (e.g. surveillance programme);

Strong leadership with close link between opinion leaders, policy makers and politicians

European antibiotic awareness day, built on success stories of countries;

Support of AMR research projects by EC, providing evidence for public health interventions

DG Research funded projectsDG Research funded projects

ARPACArMEDPARGRACEMOSARCHAMPInTopSensTheraEDGETEMPOtest

SATURNHAPPY AUDITR-GNOSISEvoTAR………

BAD NEWS, UnfortunatelyBAD NEWS, Unfortunately

Some negative experience

ESBL increases, in humans, animals, water, soil !!!

New mechanims of resistance (NDM-1, Oxa-48)

Extremely high levels of resistance in several countries, very close to us !!

Asia, Africa ??

NO new antibiotic active against Gram negatives in the pipe ( anti ESBL ?)

Poor investement of the industry

No moneyDiagnostic tests

poorly usedEducation poorly

effective.53% of consumers : AB work on viruses

Negative or poorly positive Negative or poorly positive trialstrials

Negative trials in England or the US Recent increase in consumption in FranceRCT in primary medicine Butler BMJ 2012

34 practices vs 34 controls139 clinicians vs 124 controlsSTAR program: practice based seminar,

analysis of practices, outline education,practising consulting skills

Reduction in AB consumption: 4% !Reduction in cost: 830 pounds per practice

0,00

0,05

0,10

0,15

0,20

0,25

0,30

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

année

den

sité

d'in

cid

ence

(10

00jh

)

incidence E.coli BLSEincidence K.pneumoniae BLSEincidence E.cloacae BLSEincidence autres entérobact. BLSE

Vincent Jarlier Sept 2009

Rate of incidence (/1,000DHs) of different species of ESBL enterobacteria

38 Univ. hospitals of Paris area 1996-2008

2002 K.pneumoniae

E.coli

E. cloacae

Assistance publique Paris. Incidence Assistance publique Paris. Incidence of MRSA ( Pink) and ESBL ( green)of MRSA ( Pink) and ESBL ( green)

Community-onset bacteremia Community-onset bacteremia due due to ESBL E coli.to ESBL E coli. Rodriguez-BanoRodriguez-Bano CID 2010CID 2010

95 cases of E coli with ESBL ( 7.3%) From Oct 2004 to Jan 2006 87% were CTX-M Risk factors: contact with healthcare,

urinary cath, previous AB Inappropriate AB correlated with ESBL,

and with mortality

Success with MRSA…..failure with Success with MRSA…..failure with ESBLs….WHY ??ESBLs….WHY ??

Low inoculum for MRSA high with ESBL Skin, nose for MRSA, GUT for ESBL Selection in the gut with antibiotics Transmission in the community ( 6% of

healthy carriers, MH Nicolas-Chanoine ICAAC 2011)

ESBLs in food animals. 90% of the sampled chicken Overdevest EID 2011

ESBLs in water, both used and drinking ( Recent study in India)

Vatopoulos A. Eurosurveiillance 2008

Klebsiella pneumoniae resistant Klebsiella pneumoniae resistant to carbapenems. EARS-net ECDC to carbapenems. EARS-net ECDC 20102010

Pseudomonas aeruginosa resistant to Pseudomonas aeruginosa resistant to carbapenems. EARSS-net ECDC 2010carbapenems. EARSS-net ECDC 2010

Eurobact study Tabah A, Timsit JF Eurobact study Tabah A, Timsit JF 20 most frequent pathogens during 20 most frequent pathogens during bacteremiabacteremia

Current Status Current Status of Antimicrobial Resistance in Asiaof Antimicrobial Resistance in Asia

1st APEC Expert Forum 34

MRSA

Korea

Japan

HK

Taiwan

Sri Lanka

Vietnam

India

Saudi Arabia

Thailand

Philippines

Singapore

Malaysia

China

Indonesia

< 1 %

5-10 %

10-25 %

25-50 %

> 50 %

1-5 %

unknown

Resistance %

Korea >50%

Japan >50%

China >50%

Hong Kong 25-50%

Taiwan >50%

Philippines 25-50%

Thailand 25-50%

Vietnam >50%

Malaysia 10-25%

Singapore 25-50%

Indonesia 10-25%

India 25-50%

Sri Lanka >50%

Saudi Arabia 25-50%

(49/377)

(270/574)

(93/97)

(654/147)

(147/705)

(82/345) (46/93)

(122/316)

Distribution of MRSA by Distribution of MRSA by CountryCountry2004-6, CA-MRSA and HA-MRSA, 2004-6, CA-MRSA and HA-MRSA, Asia

%

No. of isolates

(CA-SA,HA-SA)

CA-MRSA

ESBL-producing E. coli

Korea

Japan

HK

Taiwan

Sri Lanka

Vietnam

India

Saudi Arabia

Thailand

Philippines

Singapore

Malaysia

China

Indonesia

1st APEC Expert Forum

< 1 %

5-10 %

10-25 %

25-50 %

> 50 %

1-5 %

unknown

Resistance %

Korea 10-25%

Japan 10-25%

China >50%

Hong Kong 25-50%

Taiwan 10-25%

Philippines 10-25%

Thailand 25-50%

Vietnam >50%

Malaysia 10-25%

Singapore 25-50%

Indonesia 25-50%

India >50%

Sri Lanka ?

Saudi Arabia 25-50%

Carbapenem R Enterobacteriaceae

Korea

Japan

HK

Taiwan

Sri Lanka

Vietnam

India

Saudi Arabia

Thailand

Philippines

Singapore

Malaysia

China*

Indonesia

1st APEC Expert Forum

< 1 %

5-10 %

10-25 %

25-50 %

> 50 %

1-5 %

unknown

Resistance

rate

Korea <1%

Japan 5-10%

China 1-5%

Hong Kong <1%

Taiwan 1-5%

Philippines 1-5%

Thailand <1%

Vietnam <1%

Malaysia

Singapore 1-5%

Indonesia 1-5%

India 5-10%

Sri Lanka

Saudi Arabia <1%

MDR A. baumannii

Korea

Japan

HK

Taiwan

Sri Lanka

Vietnam

India

Saudi Arabia

Thailand

Philippines

Singapore

Malaysia

China*

Indonesia

1st APEC Expert Forum

< 1 %

5-10 %

10-25 %

25-50 %

> 50 %

1-5 %

unknown

Resistance rate

Korea 10-25%

Japan <1%

China 25-50%

Hong Kong

25-50%

Taiwan 25-50%

Philippines

10-25%

Thailand >50%

Vietnam >50%

Singapore >50%

Indonesia 5-10%

India 25-50%

Saudi Arabia

10-25%

Total outpatient antibiotic use (J01), 32 Total outpatient antibiotic use (J01), 32 countries, 2009countries, 2009

41

* Cyprus, Lithuania: total use, including the hospital sector.** Spain: reimbursement data, does not include over-the-counter sales without prescription.

10.2 DID

38.6 DID

28.7%66.0%

Median=19.0 DID

25.5%

0.2%

Grave et al., J Antimicrobial Chemotherapy, 2010, 65, 2037-2040.

Criticised for not taking into account

• Differences in dosing between the various substances

• All animals species at risk of being treated (e.g. horses, sheep and goat)

• Biomass animals transported to other countries for fattening or slaughter

10 fold differences

Pre ESVAC data. Published sales data retrieved from national reports for 2007 (Germany 2005) and normalized for biomass at risk

Can we stop ESBL outbreak ?Can we stop ESBL outbreak ? ESBL is now endemic: difficult task Infection control in hospitals: upgraded

standard precautions or isolation Screening of at risk patients: difficult Hygiene in the community: change some

habits to prevent fecal transmission: kids Treat hospital and animal farms effluents

to kill MDRO, and to neutralize antibiotics Stop treating animals with AB as groth

factors Decrease AB usage in therapy, and

prophylaxis of animals

Containement of a country-wide Containement of a country-wide outbreak of carbapenem-resistant K outbreak of carbapenem-resistant K pneumoniae Schwaber CID 2011pneumoniae Schwaber CID 2011

2007 national program by ministry healthGuidelines, with detection of carriers

( screening), and dedicated staffingRessources for an extensive audit of IC

practicesFeed back to hospital directorsDuration:One yearOutcome: nosocomial cases of CRE

Schwaber MJ et al Foll….Schwaber MJ et al Foll….

Before march 2007: 1275 cases in 27 hospitals ( 175/Million inhabitants)

Mortality before: 55.5 % per 100.000 patients days

Intervention led to a sharp decrease in the Nb of cases ( 11.7/ 100.000 Pts days)

Correlation between the number of cases and compliance to the guidelines (P:.02)

Beau travail, exportablePeu différent des mesures pour VRE

One hospital’s experience –moving from single room contact to cohorting and dedicated staff

0

2

4

6

8

10

12

14

16

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

TIME (weeks)

NO. OF CASES

Implementation of guidelines

LAG TIME

Incidence of KPC-producing Klebsiella spp.

P=0.01

Schechner V, unpublished

Focusing on carbapenemases ???Focusing on carbapenemases ???

Looks more easy Screening, isolation, destruction of the

bug in the gut ….but ESBL outbreak will induce a

dramatic increase in carbapenem usage, and the incidence of carbapenemases will uncrease quickly

A global program against both MRSA, VRE, ESBL and carbap is mandatory, but it is a lot of energy

Cost of antibiotic resistanceCost of antibiotic resistance

25.000 deaths in Europe per year ( ECDC)MRSA USA: 90.000 infections. 19.000

deaths.1.5 billion euros in Europe ??20 billion USD in the States ??

Ready for a world without Ready for a world without antibiotics ?? The Pensières antibiotics ?? The Pensières antibiotic resistance call to actionantibiotic resistance call to action

Organized by Biomerrieux2 days meeting of 70 international expertsVery active meeting, an disposal of 33

posters from 33 countriesQuestionnaire on the privilaged actions for

reducing resistancePublication: Special issue of Antimicrobial

resistance and Infection control February 2012

Actions directed toward Health Actions directed toward Health autoritiesautorities

Reserve the most important classes of antibiotics for humans 66%

Stop over-the-counter sales of AB 51%Make the proposal to WHO to develop a

chart to be signed by all ministries of health worlwide ( including access to Ab, Infection control, and vaccines 51%

Change the re-imbursement system, rewarding the appropriate usage of Ab, for HCP and pharma companies 36%

Message to the Health care Message to the Health care communitycommunity

Establish standardized, timely, universal surveillance of Ab resistance and consumption 82% of the 70 participants

Educate on AB stewardship and AB resistance, using modern tools 75%

Develop culturally sensitive awaireness campaigns for HCP 49%

Provide public with indicators of HAI 36%Avoid usage of quinolones 15% only

Messages to the general Messages to the general publicpublic

Develop culturally sensitive awaireness campaigns targetted to general pub 75%

Develop sanitation and hygiene education 72%

Include consumers among stakeholders for AB resistance control, including the food chain 51%

Balance cost and benefit of antibioic free food 15…only

Messages to the industry Messages to the industry ( pharma, food, diagnostics( pharma, food, diagnosticsfarming/bio-industry)farming/bio-industry)

Develop bedside and rapid testing to better guide AB treatment decisions 63%

Banish the use of antibioics as groth promoters in animal food 60%

Develop new antibiotics 57%Develop alternatives to antibiotics 46%

V. Jarlier 28.6.2011

ATB stewardship

ATB stewardship + Infection control

Infection control

Survey (ATB, HAI)

PRONALIN POST/STOP Panafrican initiatives

MDR-TB control MDRO

surveyATB stewardship R

ATB stewardship

C

ATB stewardship + Infection

control MRSA

Infection control

MRSA

ATB stewardship + Infection control

C MRSA

Infection control

ATB stewardship + Infection control MRSA, VRE

Infection control MRSA

Infection control CRE

HAI survey

Survey MDRO in

environment MDRO survey

International action

Notification of threats WHO

MDRO survey Gulf corp. council

countries

MDRO survey

ATB stewardship C

ATB, HAI surveys Panamerican HO

ALCIS

MDRO survey

ATB stewardship R P.aeruginosa

ATB stewardship

C

Infection control MRSA

C: ATB consumption ; R: resistance

Infection control CRE

World Alliance Against World Alliance Against Multiple-Drug-Resistant Multiple-Drug-Resistant Organisms (WAAMDRO)Organisms (WAAMDRO)

Created on april 7th 2011 ( Lancet Paper) International ( initially french) 345 participants Supported by 50 societies/ prof bodies Multi-professionnal ( MDs, veterinaries,

pharmacists, environnement specialists, deputees)

Multi-disciplinary Active participation of consumers ( Lien, Ciss,

Patients for patient safety WHO)

OBJECTIVESOBJECTIVES

The main objective is the ACTIVE PROTECTION of antibiotics

The bacterial world must be respected (peace with microbes SB Levy)

Antibiotics: « special » drugs, with specific modalities of prescription

Antibiotic referent Different ABs in humans and animals ABs must belong to the UNESCO

mondial patrimony

Quelles modalités de prescription Quelles modalités de prescription Pour la villePour la ville

Ordonnance spécifique, type carnet à souche pour toxiques: NON

Diagnostic présumé indiqué sur l’ordonnance. Pb confidentialité ?

Durée de traitementRé-évaluation systématique à J 2/3( coup de

fil, e-mail, consultation si sévèreQuantités exactes délivrées par le

pharmacien ( déconditionnement)Travail en réseau ville/hôpital

Modalités de prescription à Modalités de prescription à l’hôpitall’hôpital

Rôle du référent bien identifié. Décret ++Diagnostic présumé mentionné sur

l’ordonnance, et dans le dossierDurée présumée de traitement indiquéeListe d’antibiotiques protégés, ne pouvant

être prescris que par un spécialiste/référentPremières doses ( 48 h) libresRé-évaluation systématique à J2/3Travail en réseau ville/hôpital

OBJECTIVES Fol..OBJECTIVES Fol..

Develop antibiotic stewardship programs worldwide

Access to Abs to developping countries Upgrade infection control ( HRAS) Develop rapid diagnostic testing. DO NOT treat non bacterial infections Vaccination programs Accelerate the developpement of new

compounds Anti-virulence agents, non AB agents

ACTIONSACTIONS

Participation to meetings ( french parliament, academy of medicine)

Contacts with HAS, AFSSAPS, DGS,ANSES Papers, citations The Barcelona declaration Involvement of consumers ( garance Upham) International action, in cooperation with

React, Antibiotic action, APUA… Contacs with WHO

Le Point 12 janvier 2006