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YEHUDA CARMELI_ISAR2014

Antibiotic Stewardship

in Era of MDR

Yehuda Carmeli, M.D., M.P.H.

Division of Epidemiology, & The National Center for Antibiotic Resistance and Infection Control Tel Aviv Medical Center, Israel

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Correlation between antibiotic use and resistance

Copyright: YEHUDA CARMELI 2014 Correlation between antibiotic use and resistance Albrich WC. EID 2004

Albrich WC. EID 2004

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Copyright: YEHUDA CARMELI 2014 Cochrane Review 2013

Cochrane Review 2013

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Copyright: YEHUDA CARMELI 2014 Davey P. Cochrane Review 2013

Davey P. Cochrane Review 2013

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Antibiotic Stewardship in an era of

MDR resistance

Adequate and responsible antibiotic use

In era of high ESBL prevalence

How to assure adequate coverage for ESBLs

Improve patient outcomes

Reduce total antibiotic use

How not to overuse the carbapenem group

How to reduce carbapenem selection pressure from

P. aeruginosa and Acinetobacter baumannii

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Copyright: YEHUDA CARMELI 2014 CID 2007 • Primary goal is to optimize clinical outcomes • Essential

CID 2007

Primary goal is to optimize clinical outcomes

Essential part of patients safety Improve appropriate therapy

Prevent toxicity, adverse events, and emergence of

resistance

A multidisciplinary antimicrobial stewardship team

Infectious disease physician, clinical pharmacist with infectious

diseases training, clinical microbiologist, information system specialist, infection control professional hospital epidemiologist

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Antimicrobial stewardship programs

Optimize antimicrobial use to achieve

The best clinical outcomes

Minimizing adverse events

Limiting selective pressures that drive the emergence

of resistance

Coordinated interventions to improve the appropriate use of antimicrobial agents by:

Promoting the selection of the optimal antimicrobial

drug regimen including

Dosing

Duration

Route of administration

Policy Statement SHEA, IDSA, PIDS. Infect Control Hosp Epidemiol 2012; 33: 322-327

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Stewardship program activity

Guidelines incorporating local microbiology

and resistant patterns can improve antimicrobial utilization

Guidelines implementation can be facilitated

through providing education and feedback on

antimicrobial use and outcomes

Elimination of redundant combination therapy can more effectively target the causative

pathogens, resulting in decreased AB exposure

and substantial cost savings.

CID 2007; 44: 159-77

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Other measures in Stewardship

Minimize antibiotic use

Need to be performed with caution against the risk

of delay in therapy

De-escalate using diagnostics

IV to oral switch (?)

Important if reduces IV use or allow early discharge

Otherwise, primarily cost saving and carries the risk

of treatment failure and increased resistance

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Resistance & Patients Outcomes

Resistance is associated with 2 fold increase in mortality, morbidity and cost as compared to infection

with a susceptible strain

Resistance leads to delay in adequate therapy

mismatch between treatment and susceptibility

Delay in adequate therapy results is severe adverse outcomes

Resistance may lead to use of clinically less-effective agents

Resistance - fitness cost and virulence

Acar J. CID 1997 Cosgrove S, Carmeli Y. CID 2003 Giske C. AAC 2008

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Adequacy of therapy in GNR sepsis

Underlying P-value disease Mortality with appropriate therapy Mortality without appropriate therapy Rapidly 84%
Underlying
P-value
disease
Mortality with
appropriate therapy
Mortality without
appropriate therapy
Rapidly
84%
85%
NS
fatal
(80-86%)
(71-100%)
Ultimatel
y fatal
42%
67%
<0.001
(39-45%)
(63-72%)
Non-fatal
10%
29%
<0.001
(0-13%)
(23-31%)
Total
28%
49%
<0.001
(22-32%)
(47-51%)

Bochud P-Y et al. Intensive Care Med 2001;27:S33-S48.

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Effect of adequacy of empiric

therapy on mortality

Alvarez-Lerma,1996

Rello, 1997

Kollef, 1999

Kollef, 1998

Ibrahim, 2000

Luna, 1997

Harbarth, 2003

0% 20% 40% 60% 80% 100 %
0%
20%
40%
60%
80%
100 %

Mortality

Initial adequate

therapy

Initial inadequate therapy

YEHUDA CARMELI_ISAR2014

Time to appropriate therapy in ICU

and survival

Risk of mortality increase by 12%

for each hour of delay in effective therapy

increase by 12% for each hour of delay in effective therapy Kumar: Crit Care Med, Volume
increase by 12% for each hour of delay in effective therapy Kumar: Crit Care Med, Volume

Kumar: Crit Care Med, Volume 34(6).June 2006.1589-1596

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Consequences of need to escalate

therapy

Copyright: YEHUDA CARMELI 2014 Consequences of need to escalate therapy Kollef M. Chest 2006

Kollef M. Chest 2006

Delay in Rx

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Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40

Mortality pOR=1.85

non-ESBL ESBL

non-ESBL

non-ESBL ESBL

ESBL

Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40
Delay in Rx Copyright: YEHUDA CARMELI 2014 Mortality pOR=1.85 non-ESBL ESBL 0 10 20 30 40

0

10

20

30

40

50

60

JAC 2007

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Spread in the community

No. of cases of ESBL-EC/UHABSIs per

9 7.87 8 6.93 7 6 5.57 6 5 4.53 3.83 4 2.94 3 2
9
7.87
8
6.93
7
6
5.57
6
5
4.53
3.83
4
2.94
3
2
1
0
2003
2004
2005
2006
2007
2008
2009
10, 000 admissions

Year

Karfunkel D. EJCID 2013

ESBLs in hospital and community E. coli

(<48 vs. ≥ 48 hours in hospital) 2001 2002 2003 2004 2005 2006 2007 2008
(<48 vs. ≥ 48 hours in hospital)
2001
2002
2003
2004
2005
2006
2007
2008
E. coli >=48 hours
E. coli <48 hours
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10
15
20
0
5

BSAC Bacteraemia 2001-2008

2014

YEHUDA CARMELICopyright:

2014 YEHUDA CARMELICopyright: 340 ESBL isolates were reported: 87% E. coli Type varied by region Ben-Ami
2014 YEHUDA CARMELICopyright: 340 ESBL isolates were reported: 87% E. coli Type varied by region Ben-Ami

340 ESBL isolates were reported:

87% E. coli

Type varied

by region

Ben-Ami R. CID 2009.

YEHUDA CARMELI_ISAR2014

Risk factors for infection with ESBL-producing

Enterobacteriaceae in non-hospitalized patients -

metasynthesis

Significant risk factors

(multivariate analysis):

Recent antibiotic use

Residence in a long-term care

facility

Recent hospitalization

– Age ≥ 65 years

Male sex

Recent hospitalization – Age ≥ 65 years – Male sex 65% of 339 patients had no

65% of 339 patients had no recent health care

contact Area under the ROC curve: 0.70

Ben Ami R. CID 2009

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Clinical guidelines improves

appropriateness of therapy

Standard Rx Guidelines
Standard Rx
Guidelines

Ibrahim EH. Crit Care Med 2001

YEHUDA CARMELI_ISAR2014

Mortality among 97 patients with

adequate empiric therapy

Mortality (%)

60

50

40

30

20

10

0

50

50
50
50
50
50
50
50
25 12 3
25 12 3
25 12 3
25 12 3
25 12 3

25

12

3

25 12 3

FQ (16)

Amino (20)

Bla/bli (33)

Carbapenem

(28)

Antimicrobial treatment

Tumbarello M. AAC 2007

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YEHUDA CARMELI_ISAR2014 JAC 2012
YEHUDA CARMELI_ISAR2014 JAC 2012
YEHUDA CARMELI_ISAR2014 JAC 2012

JAC 2012

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Mortality with ESBL bacteremia:

quinolone susceptible isolates

Tumbarello 07

Paterson

Endiamini

susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem
susceptible isolates Tumbarello 07 Paterson Endiamini 0 10 20 30 40 50 60 70 80 Imipenem

0

10

20

30

40

50

60

70

80

ImipenemQuinolones

QuinolonesImipenem

Endiamini A. CID 2004 Paterson DL. CID 2004

Tumbarello M. AAC 2007

YEHUDA CARMELI_ISAR2014

PK/PD Markers for Clinical Efficacy C max (peak) AUC 24 MIC Half-life AUC Time above
PK/PD Markers for Clinical Efficacy
C max (peak)
AUC 24
MIC
Half-life
AUC
Time above MIC
C min (trough)
Time
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Reprinted with permission from Schentag JJ et al. Clin Infect Dis 2001; 32 (Suppl. 1): S39-S46.

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Failure rate in clinical trials depend on PK/PD parameters

YEHUDA CARMELI 2014 Failure rate in clinical trials depend on PK/PD parameters Preston SL. JAMA 1998;

Preston SL. JAMA 1998; Jacobs MR. CMI 2001

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Ciprofloxacin MICs of ESBL producers

susceptible to ciprofloxacin by CLSI

 

N

ESBL

MIC 50

MIC 90

E. coli

55

-

<0.03

0.03

 

41

+

0.03

0.75

Klebsiella

35

-

0.06

0.12

pneumoniae

 

142

+

0.125

0.75

PK/PD breakpoint for ciprofloxacin 400mg bid is 0.25 *

ESBL data from Edmiston CE, JAC 2005 ESBL+, Israeli ESBL Study * Frei C, JAC 2008

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Copyright: YEHUDA CARMELI 2014 Low MIC <=2 AAC 2013
Low MIC <=2
Low MIC <=2

AAC 2013

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%

175

150

125

100

75

50

25

0

imipenem Cephalosporins ESBL Imp-R-PA
imipenem Cephalosporins ESBL Imp-R-PA
imipenem Cephalosporins ESBL Imp-R-PA
imipenem Cephalosporins ESBL Imp-R-PA
imipenem Cephalosporins ESBL Imp-R-PA

imipenemCephalosporins ESBL Imp-R-PA

Cephalosporinsimipenem ESBL Imp-R-PA

ESBLimipenem Cephalosporins Imp-R-PA

Imp-R-PAimipenem Cephalosporins ESBL

1995

Year

1996

Adapted from Rahal JJ. JAMA 1998

YEHUDA CARMELI_ISAR2014

Correlation between group 2 carbapenem and

imipenem-resistant P. aeruginosa

group 2 carbapenem and imipenem-resistant P. aeruginosa Lapper PM. AAC 2002 Carmeli Y. DMID 2010 Group

Lapper PM. AAC 2002 Carmeli Y. DMID 2010

Group 2 carbapenem 0 20 40 60 80 carb2 95% CI predicted imprpa Group 1
Group 2 carbapenem
0
20
40
60
80
carb2
95% CI
predicted imprpa
Group 1 carbapenem
0
20
40
60
erta
95% CI
predicted imprpa
-2
0
2
4
6
1
2
3
4
5
6
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JAC 2011

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Risk stratification

(A) Contact with the healthcare system

(1) no contact

(2) contact with healthcare (e.g. recent admission, nursing home, dialysis) without invasive procedures

(3) long hospitalization and/or invasive procedures

(B) Antibiotic treatment

(1) no treatment

(2) recent treatment

(C) Patient characteristics

(1) young, few comorbid conditions

(2) old or multiple comorbidities

(3) cystic fibrosis, structural lung disease, advanced AIDS, neutropenia, other severe immunodeficiency

YEHUDA CARMELI_ISAR2014 Time to effective Rx: 30 vs 20 hours, p=0.21 CID 2013
YEHUDA CARMELI_ISAR2014 Time to effective Rx: 30 vs 20 hours, p=0.21 CID 2013

YEHUDA CARMELI_ISAR2014

Time to effective Rx:

30 vs 20 hours, p=0.21

CID 2013

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Copyright: YEHUDA CARMELI 2014 Infect Control Hosp Epidemiol 2013 (Feb) ; 34: 109-116
Copyright: YEHUDA CARMELI 2014 Infect Control Hosp Epidemiol 2013 (Feb) ; 34: 109-116
Copyright: YEHUDA CARMELI 2014 Infect Control Hosp Epidemiol 2013 (Feb) ; 34: 109-116

Infect Control Hosp Epidemiol 2013 (Feb) ; 34: 109-116

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Side effects are minimized by stewardship programs

Copyright: YEHUDA CARMELI 2014 Side effects are minimized by stewardship programs Septimus EJ. CID 2011

Septimus EJ. CID 2011

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Copyright: YEHUDA CARMELI 2014 Chastre J. JAMA 2008

Chastre J. JAMA 2008

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Critical Infections- Infections in

which delay in treatment will result in severe adverse outcomes

Pathogen

Host

Treatment

Syndrome

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Antibiotic treatment

Tailored to the local epidemiology and

microbiology

The specific patient characteristics

Taking into account PK/PD parameters

The specific syndrome

Duration of therapy

Must be coupled with targeted infection

control program

Carbapenem Resistant Klebsiella

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Effect of nationwide infection control

intervention

Copyright: YEHUDA CARMELI 2014 Effect of nationwide infection control intervention Schwaber M. CID 2011

Schwaber M. CID 2011

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Mandatory ID approval of OPAT as part of antibiotic stewardship

OPAT is used to discharge patients early or

even avoid hospitalization

cost saving, reduces hospital associated complications

improves patients satisfaction

Overusing OPAT may be costly

56 patients were denied OPAT: antibiotic stopped or switch to oral

saving $ 215,000 ($ 3847 per patient)

One treatment failure, required IV antibiotics

Conant MM. JAC 2014