Antimicrobial treatments with a

minimum risk of resistance

- and Critical Important Antimicrobials

Jenny Dahl Knudsen Senior Hospital Physician, M.D., D.M.Sc.

Department of Clinical microbiology

Copenhagen University Hospital

Hvidovre Hospital

Jenny.dahl.knudsen@hvh.regionh.dk

Antimicrobial agents, statements

Antimicrobials are drugs that provide causal treatments against infectious diseases

Antimicrobials are developed for short-time treatments

Effect on the whole body and its microbiota, not only the infective microorganisms

In the ideal world

The antimicrobial therapy only harms/kills

the invasive microorganisms

Antimicrobial therapy is only used when a

patient will gain from it

Antimicrobial therapy is only given for the

time necessary to cure the patient

Antimicrobial resistance is not a seen

CIA critical important antimicrobials

Antimicrobials that are second or third line

choices for treatments, - or used for critically ill

patients (septic shock, necrotizing fasciitis, etc) – Fluoroquinolones

– Cephalosporins

– Carbapenems

– ..

– Piperacillin-tazobactam

– Linezolid

– Vancomycin

– Colistin/polymycin

The world is not ideal!

• Due to increasing resistance, the CIA’s become first-line drugs

• Only unfavourable drugs are left

• Sometimes there is no treatment possible

• With resistance, there is increasing morbidity, mortality, and need for resources

Cephalosporin resistant E. coli in Europe

% o

f is

ola

tes

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

0

10

20

30

Austria Latvia

Lituania

Luxenburg

Malta

The Netherlands

Norway

Poland

Portugal

Romania

Slovakia

Sweden

United

Kingdom

Spain

Slovenia

Belgium

Bulgaria

Cyprus

Czech Republic

Denmark

Estonia

Finland

France

Greece

Hungaria

Iceland

Ireland

Italy

Germany

Fluoroquinolone resistant E. coli in Europe

% iso

late

s

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

0

10

20

30

40

50

LatviaLituaniaLuxenburgMaltaThe NetherlandsNorwayPolandPortugalRomaniaSlovakiaSweden

United Kingdom

SpainSlovenia

AustriaBelgiumBulgariaCyprusCzech RepublicDenmarkEstoniaFinlandFrance

GreeceHungariaIcelandIrelandItaly

Germany

MRSA in Europe

% M

RS

A

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

0

20

40

60

80

Latvia

Lituania

Luxenburg

Malta

The Netherlands

Norway

Poland

Portugal

Romania

Slovakia

Sweden

United Kingdom

Spain

Slovenia

Austria

Belgium

Bulgaria

Cyprus

Czech Republic

Denmark

Estonia

Finland

France

Greece

Hungaria

Iceland

Ireland

Italy

GermanyBlo

od

-culture

isola

tes

, E

AR

S d

ata

MRSA in Europelow

% o

f is

ola

tes

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

0

1

2

3

4

Denmark

Finland

Iceland

The Netherlands

Norway

Sweden

MRSA in Europemedium

% o

f is

ola

tes

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

0

10

20

30

40

Czech Republic

Bulgaria

France

Latvia

Poland

Slovenia

Austria

Estonia

Lituania

Luxenburg

Slovakia

Germany

MRSA in Europehigh

% o

f is

ola

tes

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

0

20

40

60

80

Hungaria

Malta

Portugal

Cyprus

Ireland

Romania

United Kingdom

Belgium

Greece

Spain

Italy

Impact of consumption

Community use is 10 x the hospital use, and

therefore an enormous impact on resistance

Consumptions of antimicrobials in the

European countries are very different

Rates of resistance in the European countries

are very different

Resistance and consumption are related

Adriaenssens N et al. JAC 2011

Total outpatient consumption in 2009

Adriaenssens N et al. JAC 2011

Number of treatments in 2009

Adriaenssens N et al. JAC 2011

Versporten A et al. JAC 2011

cephalosporins

quinolones

CIA!

Hospital consumption

Nursing home usage

Amtimicrobials in nursing homes

Latour K, et al, Pharmacoepidemiology and Drug Safety, 2012

Prophylaxis

Empiric

Documented

SSI

RTI

UTI

Bacteremia

Other

Antimicrobial usage Indication

Problems in hospitals right now

Gram positive resistance • Vancomycin resistant Enterococci

• MRSA, Methicillin resistant Staphylococcus aureus

• Penicillin-resistant Pneumococci

• …

Gram negative resistance • Fluoroquinolone resistant Enterobacteriaceae (E. coli, etc)

• ESBL/AmpC producing Enterobacteriaceae

• Carbapenem resistant Enterobacteriaceae

• Carpapenem resistant Pseudomonas

• Multiresistant Acinetobacter spp.

• …

Risk factors for acquiring (multi)-

resistant microbe

• Prior admittance to a hospital

• Prior antimicrobial therapy – especially fluoroquinolones and

cephalosporins

• Surgery and transplantations

• Artificial nutrition, high age, diabetes, alcoholisms, other co-morbidities

• Travels to Asia

Schwaber: CID 2011, JAC 2007, AAC 2006; Cassier: CMI 2011;

Rodrigues-Banõ: CID 2010; Demirdag: J Infect Dev Ctries 2010.

Eurosurveillance, Volume 17, Issue 7, 16 February 2012

Table of Contents

Isolation of NDM-1-producing Klebsiella pnemoniae in Ireland, July 2011 by H McDermott, D Morris, E McArdle, G O'Mahony, S Kelly, M Cormican, R Cunney

NDM-1 producing Acinetobacter baumannii isolated from a patient repatriated to the

Czech Republic from Egypt, July 2011 by J Hrabák, M Štolbová, V Študentová, M Fridrichová, E Chudáčková, H Zemlickova

Microbiological and molecular characteristics of carbapenemase-producing Klebsiella

pneumoniae endemic in a tertiary Greek hospital during 2004-2010 by A Zagorianou, E Sianou, E Iosifidis, V Dimou, E Protonotariou, S Miyakis, E Roilides, D Sofianou

Emergence and outbreak of carbapenemase-producing KPC-3 Klebsiella pneumoniae in

Spain, September 2009 to February 2010: control measures by A Robustillo Rodela, C Díaz-Agero Pérez, T Sanchez Sagrado, P Ruiz-Garbajosa, MJ Pita López, V Monge

(Some of the contents)

http://www.eurosurveillance.org/images/dynamic/ES/V14N01/V14N01.pdfhttp://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20087http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20087http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20087http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20087http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20087http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20085http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20085http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20085http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20085http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20085http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20088http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20088http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20088http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20088http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20088http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20088http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20086http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20086http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20086http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20086http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20086http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20086

A local story

ESBL-project / General focus on

Bispebjerg Hospital antimicrobials ESBL-steering committee

Janne Elsborg,

Steen Werner Hansen,

Annette Søndergaard,

Stig Ejdrup Andersen,

Jenny Dahl Knudsen

ESBL-coordinationsgroup Marie Stangerup,

Jeannette Havstreym,

Dorrit Langsted Olsen,

Annette Søndergaard,

Karin Brems,

Mette Christensen,

Vibeke Thygesen,

Thomas Graeser Kramp,

Charlotte Kjærgaard

Stig Ejdrup Andersen,

Jenny Dahl Knudsen

Department of Clinical

Microbiology, Hvidovre Hospital,

All doctors

Hospital Quality council

Quality group

January 2008 Chloric cleaning

Incidente patienter med ESBL-producerende K. pneumoniae

Bispebjerg Hospital januar-marts 2008

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januar februar marts

An

tal

ptt

Incidente patienter med ESBL-producerende K. pneumoniae

Bispebjerg Hospital april-juni 2008

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april maj juni

An

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ptt

Incidente patienter med ESBL-producerende K. pneumoniae

Bispebjerg Hospital juli-september 2008

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An

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ptt

Incidente patienter med ESBL-producerende K. pneumoniae

Bispebjerg Hospital oktober-december 2008

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oktober november december

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Afd I

Afd L

Afd K

Afd M

Afd Y

AMA

Afd S

Afd N

Afd H

Afd Z

Afd E

Afd D

Afd G

Incidente patienter med ESBL-producerende E. coli

Bispebjerg Hospital januar-marts 2008

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Incidente patienter med ESBL-producerende E. coli

Bispebjerg Hospital april-juni 2008

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Incidente patienter med ESBL-producerende E. coli

Bispebjerg Hospital juli-september 2008

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Incidente patienter med ESBL-producerende E. coli

Bispebjerg Hospital oktober-december 2008

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Afd K

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Afd Z

Afd E

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The intervention over time

Procent resistente bakterierBispebjerg Hospital

2000 2001 2002 2003 2004 2005 2006 2007 2008

0

5

10

15

20

25

30

35

40

% a

f is

ola

ter

Procent resistente bakterierHvidovre Hospital

2000 2001 2002 2003 2004 2005 2006 2007 2008

0

5

10

15

20

25

30

35

40

% a

f is

ola

ter

Procent resistente bakterierAmager Hospital

2000 2001 2002 2003 2004 2005 2006 2007 2008

0

5

10

15

20

25

30

35

40

% a

f is

ola

ter

Procent resistente bakterierFrederiksberg Hospital

2000 2001 2002 2003 2004 2005 2006 2007 2008

0

5

10

15

20

25

30

35

40

% a

f is

ola

ter

Resistens overvågning, Klinisk mikrobiologisk afdeling, Hvidovre Hospital.

Pneumokokker-Penici l l in IPneumokokker-Penici l l in RMethici l l in Resistent S. aureusEnterobacteriaceae-Gentamicin REnterobacteriacea-Ciprofloxacin RE. coli-Cefuroxim RKlebsiel le spc.-Cefuroxim RPseudomonas-Gentamicin RPseudomonas-Ciprofloxacin R

JDK 27.08.09

Produkt Døgn dosering Pris pr. døgn Antal beh.døgn i 2008 Pris i alt, 2008 Cefuroxim Ertapenem 1g x 1 Pip+tazo 4g x 4

Cefuroxim break-seal 1500 mg x 3 kr 123,64 3595 kr 444.485,80

Cefuroxim "Farma Plus", pulver t. inj. 1500 mg x 3 kr 30,00 507 kr 15.210,00

Cefuroxim break-seal 750 mg x 3 kr 96,06 817 kr 78.481,02

Cefuroxim "Farma Plus" pulver t. inj. 750 mg x 3 kr 15,72 84 kr 1.320,48

Ceftriaxon 1g x 2 kr 17,90 0 kr 0,00

Ceftriaxon 2g x 2 kr 27,61 0 kr 0,00

Ertapenem, i.v. 1g x 1 kr 372,00

Pip+tazo "Stragen", i.v. 4g x 3 kr 141,71

Behandlingsregime Cefur til Erta Cefur til Pip+tazo Ceftriaxon til Erta Ceftriaxon til Pip+tazo

Difference, kr. pr. år kr 1.321.618,70 kr 169.477,83

Difference, kr. pr. 6 mdr. kr 660.809,35 kr 84.738,92

Note:

Break-seal er inkl. 100 ml NaCl og overføringskanyle, der skal ikke manipuleres yderligere med produktet inden indgift.

Ertapenem, i.v. , eksklusiv NaCl og overføringskanyle, og skal tilberedes af sygeplejersker.

Tazocin, i.v., eksklusiv NaCl og overføringskanyle, og skal tilberedes af sygeplejersker.

Afdeling M, total 2008

Konvertering til

kr 539.497,30 kr 1.861.116,00 kr 708.975,13

Summer 2008

January 2010

January 2009

Project strategy

Project plan

Prevalence studies

Carrier studies

Teaching of all doctors

and head nurses

Guidelines rewritten

2009

Intervention project

Start January 18,

2010

Pamphlet: new guidelines for

antimicrobial therapy

Pip-tazo in break-seal

Numerous groups working

App. June 2010:

•Yellow MRSA/ESBL-stickers for

patients charts

•Yellow triangles for beds

•Pamphlet for patients and

relatives about ESBL’s

•When ordering investigations (X-

rays, blood sampling, training,

biochemistry, etc,) electronic

marks for patients in isolations

precaution

Daily visit of infection control nurses to department with patients

in isolation precautions

Project prolonged

Photo: Marie Stangerup & Anne-Mette Mud

Guidelines in principal

Empiric regimes were in principal as narrow spectred as possible, and change from empiric to final therapy was encouraged

Change from cephalosporins to penicillins (The former used cefuroxim (1.5 g x 3, i.v.) was replaced with piperacillin-

tazobactam (4 g x 3, i.v.), for penicillin-allergic patients ertapenem or meropenem)

Avoid fluoroquinolones when possible (Macrolides for Mycoplasma, Legionella, Chlamydiaphila)

All surgical prophylaxes were unchanged cephalosporins (one dose/one day (ortopedic patients))

Cefuroxime

0

50

100

150

200

250

300

350

400

1-08

4-08

7-08

10-0

81-

094-

097-

09

10-0

91-

104-

107-

10

10-1

01-

114-

117-

11

10-1

1

Month

DD

D/1

000 O

BD

BBH

FH

Graphs from Stig Ejdrup Andersen

Ciprofloxacin

0

50

100

150

200

250

300

350

1-08

4-08

7-08

10-0

81-

094-

097-

09

10-0

91-

104-

107-

10

10-1

01-

114-

117-

11

10-1

1

Month

DD

D/1

000 O

BD

BBH

FH

Cefuroxime:

Stable 75% reduction

Ciprofloxacin:

Only 25% reduction

ESBL/AmpC rates

ESBL/AmpC incidences

ESBL/AmpC carriers

Need for isolation precautions

(= resourses)

Number of isolation precuations per month

2009-2010-2011

Nu

mb

er

tota

lly

Nu

mb

er E

SB

L/A

mp

C

jan

09 feb

mar ap

rm

ajju

n julau

gse

pok

tno

vde

c

jan

10 feb

mar ap

rm

ajju

n julau

gse

pok

tno

vde

c

jan

11 feb

mar ap

rm

ajju

n

0

200

400

600

800

0

100

200

300

totallyESBL/AmpC

Procent resistente bakterierBispebjerg Hospital

0

5

10

15

20

25

30

35

40

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

% a

f is

ola

ter

2011

Procent resistente bakterierHvidovre Hospital

0

5

10

15

20

25

30

35

40

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

% a

f is

ola

ter

2011

Procent resistente bakterierAmager Hospital

0

5

10

15

20

25

30

35

40

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

% a

f is

ola

ter

2011

Procent resistente bakterierFrederiksberg Hospital

0

5

10

15

20

25

30

35

40

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

% a

f is

ola

ter

2011

Pneumokokker-Penicillin I

Pneumokokker-Penicillin R

Methicillin Resistent S. aureus

Enterobacteriaceae-Gentamicin R

Enterobacteriacea-Ciprofloxacin R

E. coli-Cefuroxim R

Klebsielle spc.-Cefuroxim R

Pseudomonas-Gentamicin R

Pseudomonas-Ciprofloxacin R

Rate of resistance

October country prevalenceKlebsiella pneumoniae

% E

SB

L

2007 2009 20110

10

20

30

40K.p. fra blood culture CPH

K.p. urine hospitals CPH

K.p. urine out-patients CPH

K.p. fra blood culture DK

K.p. urine hospitals DK

K.p. urine out-patients DK

October country prevalenceEscherichia coli

%E

SB

L

2007 2009 20110

5

10

15

20E.c. fra blood culture CPH

E.c. urine hospitals CPH

E.c. urine out-patients CPH

E.c. fra blood culture DK

E.c. urine hospitals DK

E.c. urine out-patients DK

Similar experience from Sweden

Tängden T el al. JAC 2011

ESBL-producing

Klebsiella pneumoniae

Is there anything to do?

Yes we can

- We can stop facilitate spreading resistance

- We can be aware if resistance occurs

- We can reverse the trends in epidemiology

If we don’t do anything

- More cases with untreatable infections

- Treatment expenses increase

- More use of the more expensive drugs

- More isolation precautions needed

Prudent use of antimicrobials • Empiric coverage due to local resistance rates

• Use diagnostic tests

• All prescription of antimicrobials should be time limited (stop/evaluation date)

• The reason for the prescription should be given

• Change to narrow spectred when possible

• Avoid fluoroquinolones unless proven needed by diagnostics or the patient status

• Choose penicillins when possible

Organization

1. Surveillance of resistance,

2. Infection control and

3. Antimicrobial guidelines should be combined in one organisation !!

For hospitals:

- With close connection to the hospital managements

For general practices:

- Governmental, economic reimbursements

Clinical microbiologists, infectious disease specialists, epidemiologists, etc.

Effects of antimicrobials

The good: kill/inhibit the microorganisms

The bad: the side effect for the patients – Minor: rash, nausea, headache, etc.

– Major: liver-failure, agranulocytosis, etc

The ugly: the ecological effect – The patients treated, - super-infections!

– In nature (hospitals, institutions, home, etc)

Antimicrobial agents, statements

• If used against a resistant organism

you only see the bad and ugly

effects

• If used for too long, you will see

more bad and ugly effects

• If used too broad-spectred you will

see more bad and ugly effects

There is nothing

as pure nature

Cool party !

Borrowed from WulffMorgenthaler