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1 Modelling the impact of antibiotic use on antibiotic-resistant Escherichia coli using population-based data from a large hospital and its surrounding community N. Vernaz*, B. Huttner, D. Muscionico, J. Salomon, P. Bonnabry, J.M López-Lozano, J. Schrenzel, S. Harbarth (Geneva, CH; Alicante, ES) Efficacy and efficiency of a restrictive antibiotic policy on MRSA in the intensive care unit N. Vernaz*, R. Aschbacher, B. Moser, S. Harbarth, P. Mian, P. Bonnabry, L. Pagani (Geneva, CH; Bolzano, IT) Challenge of time series models Reinforce the evidence Real-world questions Real-world data Methodological

Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

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Page 1: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

1

Modelling the impact of antibiotic use on antibiotic-resistant Escherichia coli using

population-based data from a large hospital and its surrounding community

N. Vernaz*, B. Huttner,

D. Muscionico, J. Salomon, P. Bonnabry,

J.M López-Lozano, J. Schrenzel, S. Harbarth

(Geneva, CH; Alicante, ES)

Efficacy and efficiency of a restrictive antibiotic policyon MRSA in the intensive care unit

N. Vernaz*, R. Aschbacher, B. Moser, S. Harbarth, P. Mian, P. Bonnabry, L. Pagani (Geneva, CH; Bolzano, IT)

Challenge of time series models

• Reinforce the evidence

• Real-world questions

• Real-world data

• Methodological

Page 2: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

2

Transfer function modelOutcomes of interest:

Incidence of non-duplicate clinical isolates

MRSA E. coli resistant to- ciprofloxacin- cefepime (ESBL)

Explanatory variables: antibiotic usage - interventions

antibiotic usage in ICU antibiotic usage- surrounding community

Restriction antibiotic policy (0,1) - HUG (2’000 beds)

ARIMA

Efficacy and efficiency of a restrictive antibiotic policy

1) November 2003: withdrawing ampicillin/sulbactam prophylaxis2) Mai 2004: targeting vancomycin therapy whenever indicated

on MRSA in the intensive care unit

Intervention model Tranfer function model

Study period: January 2002 to December 2007

Page 3: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

3

MRSA model identification

0

2

4

6

8

10

2002 2003 2004 2005 2006 2007

MRSA

MRSA = 2.55 + 0.32 MRSA(t-2) + εt

Restrictive antibiotic policyefficacy

0

10

20

30

40

50

60

70

80

2002

M04

2002

M07

2002

M10

2003

M01

2003

M04

2003

M07

2003

M10

2004

M01

2004

M04

2004

M07

2004

M10

2005

M01

2005

M04

2005

M07

2005

M10

2006

M01

2006

M04

2006

M07

2006

M10

2007

M01

2007

M04

2007

M07

2007

M10

DD

D

vancomycineintervention

ampi-sulbactam, R2 = 66%

Vancomycin, R2 = 39%vancomycin = 34.9 - 23.5 y + 0.255 AR(3) + εt

0 < Mai 2004

1 ≥ Mai 2004

0

100

200

300

400

500

600

2002

M02

2002

M06

2002

M10

2003

M02

2003

M06

2003

M10

2004

M02

2004

M06

2004

M10

2005

M02

2005

M06

2005

M10

2006

M02

2006

M06

2006

M10

2007

M02

2007

M06

2007

M10

DDD

ampi-sulfaintervention

ampi-sulbactam = 301 – 167 y

- 0.267 AR(1) – 0.379 MA(7) + εt

0 < November 2003

1 ≥ November 2003y

y

Page 4: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

4

Transfer function on MRSA incidence: efficiency

Variable lag Coefficient Std. Error t-Statistic Prob. month

intercept 1.628 0.673 2.420 0.019ceftriaxone 2 0.021 0.008 2.531 0.014ceftriaxone 3 0.023 0.008 2.990 0.004levofloxacine 0 0.012 0.004 2.785 0.007avr.03 -1.613 0.688 -2.346 0.022AR 2 0.316 0.125 2.523 0.014MA 3 0.291 0.137 2.133 0.037

Useful tool for policy maker• Modelling antibiotic usage and resistance is a useful tool

for antimicrobial stewardship

– to drive a more appropriate empirical and targeted antimicrobialtherapy

– to control and prevent the misuse of antimicrobials

– to increase the level of evidence

• Time series analysis is a useful tool even at a ICU level

Page 5: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

5

Questions?

Modeling the impact of antibiotic use on antibiotic-resistant Escherichia coli using

population-based data from a large hospital and its surrounding community

outside de Box plot: 18% at Geneva surrounding community

excess usage of fluoroquinolones can be associated with the development of resistance

ESF EMRC EXPLORATORY WORKSHOP Antwerp, Belgium, 7-9 September 2005. Antibiotic Prescribing Quality Indicators.

DDD (J01MA) x 100DDD (J01)

Antibiotic prescribing quality indicator: outpatient fluoroquinolone use in 2003

Page 6: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

6

Settings & Methods

• Incidence of non-duplicate clinical isolates of E. coli resistant to• ciprofloxacin; of community origin (= CA -Cipro-R)• ciprofloxacin; of hospital origin (= HA -Cipro-R)• cefepime (= surrogate of ESBL)

• Antibiotic usage:• Geneva surrounding community: 450’000 inhabitants• HUG: 2’000 beds

• Defined Daily Dose (DDD) normalised • per 100 patients-days

• per 1’000 inhabitants

• Exclude Paediatric, Psychiatry, Rehabilitation wards• Study period: Jan. 2000 to Dec. 2007

Non-duplicate, resistant E. coli isolates

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

01 20

00

6 20

00

11 20

00

4 20

01

9 20

01

2 20

02

7 20

02

12 20

02

5 20

03

10 20

03

3 20

04

8 20

04

01 20

05

6 20

05

11 20

05

4 20

06

9 20

06

2 20

07

7 20

07

12 20

07

Inci

denc

e pe

r 100

pat

ient

day

s

R_E.Coli_ciprofloxacineR_E.Coli_cotrimoxazoleESBL

Page 7: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

7

Total antibiotic usage surrounding community

0

2

4

6

8

10

12

14

16

18

janv

.00

juin.

00

nov.0

0

avr.0

1

sept.0

1

févr.

02

juil.0

2

déc.0

2

mai.0

3

oct.0

3

mars.

04

août.

04

janv

.05

juin.

05

nov.0

5

avr.0

6

sept.0

6

févr.

07

juil.0

7

déc.0

7

DD

D p

er 1

'000

inha

bita

nts

trimethoprim-sulfamethoxazoleIII gen. cephalosporinsII gen cephalosporinsmacrolidesfluoroquinolonesamoxicillinamoxicillin/clavunate

Average antimicrobial use: 14.22 (8.6-19.77) DDD/1’000 inhabitants

Outpatient FQ usage Fluroquinolones consumption

0.000.200.400.600.801.001.201.401.601.802.00

janv

.00

juil.

00

janv

.01

juil.

01

janv

.02

juil.

02

janv

.03

juil.

03

janv

.04

juil.

04

janv

.05

juil.

05

janv

.06

jui

l.06

janv

.07

juil.

07

DI D

OfloxacineCiprofloxacineNorfloxacineLoméfloxacineFléroxacineLévofloxacineMoxifloxacine

Page 8: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

8

Antibiotic usage Geneva Univ. Hospitals

0

10

20

30

40

50

60

01

2000

6 2

000

11

2000

4 2

001

9 2

001

2 2

002

7 2

002

12

2002

5 2

003

10

2003

3 2

004

8 2

004

01

2005

6 2

005

11

2005

4 2

006

9 2

006

2 2

007

7 2

007

12

2007

DDD

per 1

00 p

atie

nt d

ays

glycopeptidestrimethoprim-sulfamethoxazolemacrolidescarbapenemsfluoroquinolonescefepimeIII gen cephalosporinsII gen cephalosporinscefazolineamoxicillinamoxicillin/clavulanate

Average antimicrobial use: 54.99 (45.63-62.17) DDD/100 patients-days

ESBL transformation

.00

.01

.02

.03

.04

.05

I II III IV I II III IV I II III IV I II III IV I II III IV I II III IV

2002 2003 2004 2005 2006 2007

-.03

-.02

-.01

.00

.01

.02

.03

I II III IV I II III IV I II III IV I II III IV I II III IV I II III IV

2002 2003 2004 2005 2006 2007

Null Hypothesis: R_ESBL has a unit root Exogenous: None Lag Length: 4 (Automatic - based on SIC, maxlag=11)

t-Statistic Prob.*

Augmented Dickey-Fuller test statistic 0.373541 0.7894 Test critical values: 1% level -2.599934

5% level -1.945745 10% level -1.613633

*MacKinnon (1996) one-sided p-values.

Null Hypothesis: D(R_ESBL) has a unit root Exogenous: None Lag Length: 3 (Automatic - based on SIC, maxlag=11)

t-Statistic Prob.*

Augmented Dickey-Fuller test statistic -7.865141 0.0000 Test critical values: 1% level -2.599934

5% level -1.945745 10% level -1.613633

*MacKinnon (1996) one-sided p-values.

t*: 0.37 > -1.94 non stationary t* -7.89 < -1.94 stationary

ESBL Yt- Yt-1: D_ESBL

Page 9: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

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Transfer function model for E. coli resistant to cefepime (ESBL)

Variable Lag

(months)

Parameter (SE) t-Statistic P-value

d - ceftriaxone HUG 0 0.0041 (0.0017) 2.4047 0.0195

d - ciprofloxacin HUG 1 0.0043 (0.0013) 3.2126 0.0022

5 0.0045 (0.0014) 3.2045 0.0022

d - cefepime HUG 3 0.0034 (0.0016) 2.1502 0.0358

d - piperacilline/tazobactam HUG 3 0.0099 (0.0042) 2.3073 0.0247

d - ciprofloxacin GE 4 0.0247 (0.0080) 3.0809 0.0032

Autoregressive term 1 -0.5877 (0.01084) -5.4236 0.0000

Transfer function model on ESBL incidence explains 51% of ESBL variation over time

Cipro-R- CA, R2 = 0.52 Cipro-R-HA, R2=0.18

Variable Lag

(months)

Parameter

(SE)

t-

Statistic

P-value Lag

(months)

Parameter

(SE)

t-

Statistic

P-value

Constant -3.54(0.24) -14.76 0.0000 -3.34 (0.01) -42.86 0.0000

log ciprofloxacin GE 0 1.31(0.49) 2.68 0.0089

1 1.01(0.49) 2.08 0.0406 1 0.82 (0.30) 2.76 0.0069

log moxifloxacin GE 4 0.44(0.16) 2.72 0.0081

Autoregressive term 1 0.31(0.11) 2.89 0.0050 1 0.24 (0.10) 2.43 0.0170

Moving average term 8 0.36(0.11) 3.24 0.0017

Transfer function model on E. coliresistant to

ciprofloxacin, community origin ciprofloxacin, hospital origin

Page 10: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

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Conclusion• Added value of time series analysis:

to better understand the interaction between community and hospital antibiotic prescribing

• Temporal relationship between:outpatient fluoroquinolone use and incidence of– CA- Cipro-R- E Coli– HA- Cipro-R- E Coli– ESBL

• Support efforts to reduce prescriptions of fluoroquinolones

Useful tool for policy maker:hierarchy of evidence

Colleagues or members of the multidisciplinary team

Views of colleagues / peersVI

Evidence based local procedures and care pathways

Opinions from respected authorities, based on clinical evidence, descriptive studies or reports from committees

V

Articles published in peer-reviewed journals

Evidence from well designed non-experimentalstudies from more than one centre or research group

IV

Articles published in peer-reviewed journals

Evidence from well designed trials without randomization: cohort study, time-series or matched case control studies

III

Articles published in peer-reviewed journals

Evidence from at least one properly designed RCT of appropriate size

II

Meta-AnalysisThe Cochrane Collaboration

Strong evidence from at least ONE systematic review of well designed RCT

I

ExampleDescriptionLevel

Page 11: Efficacy and efficiency of a restrictive antibiotic …antibiotic usage - interventions antibiotic usage in ICU antibiotic usage - surrounding community Restriction antibiotic policy

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“Remember that all models are wrong;

the practicalquestion is

how wrong do they have to be to not be useful”

G. Box, N. Draper