Winfried V. KernAbteilung InfektiologieUniversitätsklinikum Freiburg

«Antibiotic Stewardship»programmes & antibiotic resistance

www.if-freiburg.de

� Definition� Healthcare quality & patient safety aspects� Research aspects

Agenda

…ongoing effort by a healthcare institution to optimize antimicrobial use among hospitalized patients to ...

- improve patient outcomes- ensure cost-effective therapy, and - reduce adverse sequelae of antimicrobial use (including antimicrobial resistance).

MacDougall & Polk CMR 2005

What is „Antibiotic Stewardship“?

…ongoing effort by a healthcare institution to optimize antimicrobial use among hospitalized patients to ...

- improve patient outcomes- ensure cost-effective therapy, and - reduce adverse sequelae of antimicrobial use (including antimicrobial resistance).

MacDougall & Polk CMR 2005

What is „Antibiotic Stewardship“?

system

Dennis Maki 1998

“The development of new antibiotics without having mechanisms to ensure their appropriate use is much like supplying your alcoholic patients with a finer brandy.“

… assumptions

� prescribing is (often) suboptimal

… assumptions

� prescribing is (often) suboptimal (and often too excessive)

… assumptions

� prescribing is (often) suboptimal (and often too excessive) and induces resistance

… assumptions

� prescribing is (often) suboptimal (and often too excessive) and reduces resistance

� “optimized” (and/or reduced) prescribing improves outcomes and can minimize or even reverse antimicrobial resistance

Bratzler et al Arch Surg 2005

Ansari et al CID 2009

*20 hospitals, 11,571 patients, 30% with antibiotics

… European data (ESAC-PPS 2006*)

ESAC investigators 2011

*50 hospitals, 28 countries

… European data (ESAC-PPS 2008*)

Zarb et al Eurosurv 2012

*66 hospitals, 23 countries

… European data (ESAC-PPS 2010*)

… surgical prophylaxis exceeded one day in 61% of cases

• 9% n=776 Turkey 2009• 11% n=107 France 2003• 15% n=104 France 2009• 20% n=1079 UK 2007• 20% n=2306 Israel 2001• 22-27% n=539 Switzerland 2007• 24% n=166 Spain 2003• 29% n=493 Croatia, 2005• 17-37%, n=1270 Switzerland 2010• 30% n=129 USA 2003• 31% n=177 Italy 2008• 35% n=105 France 2003• 36% n=281 Turkey 2003• 37% n=938 Netherlands 2007• 43% n=189 Spain 2003• 44% n=378 Turkey 2005• 47% n=223 Turkey 2005• 47% n=173 Switzerland 2004• 54% n=156 Turkey 2000• 64% n=438 Croatia 2007• 66% n=122 France 2007

Burden of hospital-wide „inadequate“ antibiotic prescriptions

… assumptions

� prescribing is (often) suboptimal (and often too excessive) and induces resistance

This is where a large graphic or chart can go.

Antibiotikaverbrauch (definierte Tagesdosen [DDD]/1000 Tage)

403020100

% P

enic

illin

-nic

htem

pfin

dlic

he

Pne

umok

okke

n

60

50

40

30

20

10

0

USA

UK

Sweden

Spain

Portugal

NorwayNetherlands

LuxemburgItaly

Ireland

Iceland

Greece

Germany

France

FinlandDenmark

Canada

BelgiumAustria

Australia

Alb

rich

et a

l. E

mer

g In

fect

Dis

2004

Taiwan

70%

75%

80%

85%

90%

95%

100%

1994 1995 1996 1997 1998

Gra

m-n

egat

ive

baci

lliP

erce

nt im

ipen

em-s

usce

ptib

le

0

10

20

30

40

50

60Im

ipenemD

DD

per 1000 pt days

Group -level dataGroup -level data

Clin Infect Dis 2001; 33: 1462-68

0.10

0.20

0 20 40 60 800.00

0.30

Days in hospital

No imipenem

Imipenem

Individual-level dataP

roba

bilit

y of

res

ista

nce

Adjusted hazard ratio: 5.7 (95% CI, 3.7 - 8.7)

Clin Infect Dis 2001; 33: 1462-68

Limitations

� to consider

� the limited evidence provided by purelyobservational (vs interventional studies)

� individual-level or group-level analysis(ecological bias)

0

1

2

3

4

5

6

7

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

% F

Q R

esis

tanc

e

0

10

20

30

40

50

60

70

80

90

100

DD

D/1

000

patie

nt-d

ays

E. coli (r = 0.79; p = 0.002)

FQR-EC and FQ Use

Lautenbach, SHEA, 2002

0

1

2

3

4

5

6

7

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

% F

Q R

esis

tanc

e

0

2000

4000

6000

8000

10000

12000

DJI

A

E. coli (r=.96; p<.001)

FQR-EC and the Dow Jones Index

Courtesy: Y. Carmeli

… assumptions

� prescribing is (often) suboptimal (and often too excessive) and reduces resistance

� “optimized” (and/or reduced) prescribing improves outcomes and can minimize or even reverse antimicrobial resistance

� local guidelines, audit/education with feedback� “improvement in antimicrobial prescription

included among the annual objectives linked to economic incentives in every department”

CMI 2013

Interventions –Endpoint: prescribing quality

Cisneros et al CMI 2013

Cisneros et al CMI 2013

Cisneros et al CMI 2013

Cisneros et al CMI 2013

Limitations

� consider endpoints

�prescribing density

�prescribing quality

�cost (from which perspective)

�patient outcomes

vs

� „microbial“ endpoints)

Bean et al. JAC 2005

Drug resistance in E. coli „without“ apparent selection pressure

Limitations

� to consider

�design of interventional studies

�experimental (e.g. cluster-randomized) vs quasi-experimental (e.g. controlled before/after)

�analysis (e.g. time-series analysis, adverseevents)

Change: DDD/100 P

t test +0.54 0.2

Slope -0.266 <0.001

Ansari et al JAC 2003Courtesy: Peter Davey, Dundee (UK)

Intervention to Reduce Use of A le rt Antibiotics

0

2

4

6

8

10

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48Months

DD

D/1

00 b

ed-d

ays

Kim et al JAC 2008

Baseline Intervention Postintervention

Limitations

� sustainability often not described

�which component is the most critical ? (and needs most investment)

Limitations

�background epidemiology may bedifferent

� confounding: cultural environment & prevalent „prescribing etiquette“� risk forlimited transferability/generalizability ??

�be aware of potentially adverse effects !!

… assumptions & strategies

� what is “optimized” and/or “reduced” ? �no use by indication�shorter treatment�PK/PD-optimized treatment (dosing)�use (or switch to) the “ecologically” (“collateral

damage”) best-performing drugs

e.g. Bronchitis

e.g. Uncomplicated UTI

https://www.escmid.org/escmid_library/online_lecture_library/material/?mid=25322

� double-blind trial � n=253 women (18-70 years old)� diclofenac vs norfloxacin for 3 days (with

fosfomycin 3 g as rescue treatment)� resolution of symptoms (day 3):

� 50% vs 77% (risk difference 27%, 95%CI 15-38%)� 61% of patients in the diclofenac group ever

consumed antibiotics

https://www.escmid.org/escmid_library/online_lecture_library/material/?mid=25322

� double-blind trial � n=253 women (18-70 years old)� diclofenac vs norfloxacin for 3 days (with

fosfomycin 3 g as rescue treatment)� resolution of symptoms (day 3):

� 50% vs 77% (risk difference 27%, 95%CI 15-38%)� 61% of patients in the diclofenac group ever

consumed antibiotics

https://www.escmid.org/escmid_library/online_lecture_library/material/?mid=25322

… assumptions & strategies

� what is “optimized” and/or “reduced” ? �no use by indication�shorter treatment�PK/PD-optimized treatment (dosing)�use (or switch to) the “ecologically” (“collateral

damage”) best-performing drugs

… assumptions & strategies

� what is “optimized” and/or “reduced” ? �no use by indication�shorter treatment�PK/PD-optimized treatment (dosing)�use (or switch to) the “ecologically” (“collateral

damage”) best-performing drugs

Malhotra-Kumar et al. Lancet 2007; 369:482-490

Macrolide

resistanceam

ongoral streptococci

• Plazebokontrollierte Studie mit Amoxicillin (3x1g, n=37) oder Plazebo(n=38) über 1 Woche

• Rachenspülungen untersucht bis Tag 28 auf Streptokokken mit verminderter Empfindlichkeit auf Penicillin und Amoxicillin

• Ergebnisse:

�� Malhotra-Kumar et al ; K-1579

Makrolide verändern nachhaltig die Mundhöhlenflora –Amoxicillin auch ??

… assumptions & strategies

� what is “optimized” and/or “reduced” ? �no use by indication�shorter treatment�PK/PD-optimized treatment (dosing)�use (or switch to) the “ecologically” (“collateral

damage”) best-performing drugs

� Some milestone studies, e.g. the „3F“ (French Fluoroquinolone Free-Study):multicenter trial showing substantial MRSA reductionfollowing a 90% fluoroquinolone reduction(Charbonneau et al CID 2006) (!!)

Fluoroquinolone studies

� Recently many more „3C“ and „3C+“ studies3C: ↓Ceph + ↓Cipro/other FQs = ↓C. difficile

3C+: ↓Ceph + ↓Cipro/other FQs = ↓C. difficile ± ESBL ± MRSA

Ceph + Fluorquinolone studies

Talpaert et al JAC 2011

Talpaert et al JAC 2011

Talpaert et al JAC 2011

[109]Dancer et al IJAA 2013

Summary

� „Stewardship“ is important but complex

�Best evidence so far regarding impact on C.difficile infection

�Very limited evidence for impact on MDR gram-negatives

�Many more interventional studies(hospital and outpatient setting) areneeded