DR Carmeli - ISAR - 03 07 2014

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

Copyright: YEHUDA CARMELI 2014
Cochrane Review 2013

Davey P. Cochrane Review 2013

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
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
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
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
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
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
Adequacy of therapy in GNR
sepsis
Underlying Mortality with Mortality without P-value
disease appropriate therapy appropriate therapy
Rapidly 84% 85% NS

fatal (80-86%) (71-100%)
Ultimatel 42% 67% <0.001
y fatal (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.

Effect of adequacy of empiric
therapy on mortality
Alvarez-Lerma,1996 Initial adequate
therapy
Rello, 1997
Initial inadequate
Kollef, 1999 therapy
Kollef, 1998
Ibrahim, 2000
Luna, 1997
Harbarth, 2003
0% 20% 40% 60% 80% 100 %

Mortality
Time to appropriate therapy in ICU

and survival
Risk of mortality increase by 12%
for each hour of delay in effective therapy
Kumar: Crit Care Med, Volume 34(6).June 2006.1589-1596

Consequences of need to escalate
therapy
Kollef M. Chest 2006

non-ESBL ESBL
Delay in Rx 0 10 20 30 40 50 60
Mortality pOR=1.85
JAC 2007
Spread in the community
9
No. of cases of ESBL-EC/UHABSIs per
7.87
8
6.93
7
10, 000 admissions
6
6 5.57
5 4.53
3.83
4
2.94
3
0
2003 2004 2005 2006 2007 2008 2009
Year
Karfunkel D. EJCID 2013

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

340 ESBL
isolates were
reported:
87% E. coli
Type varied
by region
Ben-Ami R.
CID 2009.
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
65% of 339 patients had no recent health care

contact
– Area under the ROC curve: 0.70 Ben Ami R. CID 2009
Clinical guidelines improves
appropriateness of therapy
Standard Rx Guidelines
Ibrahim EH. Crit Care Med 2001
Mortality among 97 patients with
adequate empiric therapy
60
50
50
Mortality (%)
40
30 25
20 12
10 3
0
FQ (16) Amino (20) Bla/bli (33) Carbapenem
(28)
Antimicrobial treatment
Tumbarello M. AAC 2007

JAC 2012
Mortality with ESBL bacteremia:
quinolone susceptible isolates
Tumbarello 07
Imipenem
Quinolones
Paterson
Endiamini
0 10 20 30 40 50 60 70 80
Endiamini A. CID 2004

Paterson DL. CID 2004
Tumbarello M. AAC 2007
PK/PD Markers for Clinical Efficacy

Cmax (peak)
AUC24
MIC
Half-life
AUC
Time above MIC

Cmin (trough)
Time
Reprinted with permission from Schentag JJ et al. Clin
Infect Dis 2001; 32 (Suppl. 1): S39-S46.
Failure rate in clinical trials depend
on PK/PD parameters
Preston SL. JAMA 1998; Jacobs MR. CMI 2001

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 ESBL – data from Edmiston CE, JAC 2005
400mg bid is 0.25 * ESBL+, Israeli ESBL Study
* Frei C, JAC 2008
Low MIC <=2
AAC 2013
175
150
125
100
%
75
50
imipenem
Cephalosporins
25 ESBL
Imp-R-PA
0
1995 1996
Year
Adapted from Rahal JJ. JAMA 1998
Correlation between group 2 carbapenem and

imipenem-resistant P. aeruginosa
6
Group 2 carbapenem
5
4
3
2
1
0 20 40 60 80
carb2
95% CI predicted imprpa
6
Group 1 carbapenem
4
2
0
Lapper PM. AAC 2002

-2
0 20 40 60
erta
Carmeli Y. DMID 2010 95% CI predicted imprpa
JAC 2011
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
Time to effective Rx:
30 vs 20 hours, p=0.21
YEHUDA CARMELI_ISAR2014 CID 2013

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

Side effects are minimized by
stewardship programs
Septimus EJ. CID 2011

Chastre J. JAMA 2008

Critical Infections- Infections in
which delay in treatment will result

in severe adverse outcomes
Host
Pathogen Syndrome
Treatment
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
Effect of nationwide infection control
intervention
Schwaber M. CID 2011

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

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YEHUDA CARMELI_ISAR2014

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

Albrich WC. EID 2004

Cochrane Review 2013

Davey P. Cochrane Review 2013

• Adequate and responsible antibiotic use

• Primary goal is to optimize clinical outcomes

• Optimize antimicrobial use to achieve

Policy Statement SHEA, IDSA, PIDS. Infect Control

Stewardship program activity

Other measures in Stewardship

• Resistance is associated with 2 fold increase in

Acar J. CID 1997

Rapidly 84% 85% NS

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

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

Time to appropriate therapy in ICU

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

Kollef M. Chest 2006

Karfunkel D. EJCID 2013

2001 2002 2003 2004 2005 2006 2007 2008

E. coli >=48 hours E. coli <48 hours

BSAC Bacteraemia 2001-2008

Significant risk factors

– Recent antibiotic use

65% of 339 patients had no recent health care

Tumbarello M. AAC 2007

quinolone susceptible isolates

Endiamini A. CID 2004

PK/PD Markers for Clinical Efficacy

Time above MIC

Preston SL. JAMA 1998; Jacobs MR. CMI 2001

susceptible to ciprofloxacin by CLSI

E. coli 55 - <0.03 0.03

Klebsiella 35 - 0.06 0.12

Low MIC <=2

Correlation between group 2 carbapenem and

95% CI predicted imprpa

Lapper PM. AAC 2002

• (A) Contact with the healthcare system

YEHUDA CARMELI_ISAR2014 CID 2013

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

Septimus EJ. CID 2011

Chastre J. JAMA 2008

which delay in treatment will result

• Tailored to the local epidemiology and

Schwaber M. CID 2011

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