kern - antibiotic stewardship programmes & antibiotic...
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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