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De-escalation of antibiotic therapy
Jeroen Schouten, MD PhD
intensivist, Nijmegen (Neth)
Istanbul, Oct 7th 2016
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Increase MDR pathogens
Severely ill patient with infection
No new antibiotics in pipeline
Link antibiotic use and development
of resistance
De-escalation: concept
Rapid, adequate therapy
Narrow spectrum, reduce AB use
Broad Spectrum empirical R/
De-escalation
figure: Liesbeth de Bus
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De-escalation: concept
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De-escalation: concept
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Authors conclusions (2012)
• “We did not include any study”
• There is no adequate evidence that de-escalation of antimicrobial agents is effective and safe in patients with sepsis, severe sepsis and septic shock
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Narrow the spectrum
Stop if infection is
unlikely
Reduce the amount
of antibiotics
‘Switching’
Stop ‘safety’ antibiotics
(MRSA)
Therapy aimed at ‘causative
pathogen’
De-escalation: definitions
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Hit hard with appropriate antibiotic(s) administered adequately - early, IV,
high dose, PK/PD
De-escalate when possible: change to NARROWER SPECTRUM
The de-escalation paradigm
This is not exactly right!
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Elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams
E. Weiss, J.-R. Zahar, P. Lesprit, E. Ruppe, M. Leone, J. Chastre, J.-C. Lucet,
C. Paugam-Burtz, C. Brun-Buisson, J.-F. Timsit on behalf of the
‘De-escalation’ Study Group
• It is not just about the spectrum! but also on the impact
on bystander microbiota and on colonisation resistance:
both have to be considered (84% agreement)
• potential ecological effects = not only spectrum but also
route, PK/PD, and in vivo inactivation
CMI 2015
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Elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams
E. Weiss, J.-R. Zahar, P. Lesprit, E. Ruppe, M. Leone, J. Chastre, J.-C. Lucet,
C. Paugam-Burtz, C. Brun-Buisson, J.-F. Timsit on behalf of the
‘De-escalation’ Study Group
• no consensus was reached on the delay within which DE
should be performed and on whether or not the
shortening of antibiotic therapy duration should be
included in DE definition
• work also underlines the difficulties of reaching a
consensus on the relative ecological impact of each
individual drug and on the timing of DE
CMI 2015
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Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
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A.J. Cremers , T. Sprong, J. Schouten, J. Meis, G. Ferwerda, JAC 2014
De-escalation in pneumococcal bacteremia
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E. Schuts; M. Hulscher; BJ. Kullberg; J. Prins Lancet Inf Dis 2016
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Goal
•Which are the definitions used for de-escalation in the literature?
•What is the effect of de-escalation on outcomes of care in ICU patients?
A. Tabah, J.F. Timsit, J. Schouten, J. Dewaele, CID 2016
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430 MEDLINE
CITATIONS
121 duplicates removed
603 records screened for content & incl.crit.
559 of records excluded
410 unrelated
11 other language
107 not experimental or cohort (reviews or editorials)
32 congress abstracts
46 of full-text articles assessed for adjusted
EPOC criteria
13 studies included in the review
34 excluded
3 congress abstracts
14 unrelated
10 not enough data to compare
7 not an ICU cohort
293 EMBASE
CITATIONS
1 Cochrane
CITATION
2 records added from references
1 rec added from MEDLINE update
A. Tabah, J.F. Timsit, J. Schouten, J. Dewaele CID 2016
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What evidence exists to support antimicrobial de-escalation in the intensive care unit?
A systematic review
Results: 14 studies
•two randomised clinical trials (unblinded) Cochrane Risk of Bias tool
•12 cohort studies Newcastle–Ottawa Quality Assessment Scale
A. Tabah, J.F. Timsit, J. Schouten, J. Dewaele CID 2016
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What evidence exists to support antimicrobial de-escalation in the intensive care unit?
A systematic review
Which definitions are used for de-escalation in the literature?
• Always described as “narrowing” or “streamlining” therapy, considerable variability
• Ranking “broadness of spectrum” in 4/14 studies
• Concept of the “pivotal” antibiotic (Leone)
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What evidence exists to support antimicrobial de-escalation in the intensive care unit?
A systematic review
Outcomes after de-escalation:
• Lower or improving severity scores associated with DE (p=0.04 to <0.001)
• Pooled effect of DE on mortality protective (RR 0.68, 95% CI 0.52-0.88)
• Limited quality of cohort studies
•Adjustment and multivariable analysis on the effect of DE on outcome only in 4 /12 cohort studies
•Two studies accounted for severity of illness at the moment where DE was considered
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What evidence exists to support antimicrobial de-escalation in the intensive care unit?
A systematic review
Secondary outcomes after de-escalation:
•Non-inferiority length of stay in DE group
•More superinfections and longer AB use in DE
•No (measurable) effect on ecology
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RCT de-escalation in ICU
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• Multicenter (9) ICU study in France
•Radomised: continue vs. de-escalate
•Unblinded
•120 patients
•Primary outcome: LOS (non-inferiority de-escalation)
•Secundary outcomes: 90 day M; AB free days; superinfections; Clostridium difficile infections
De-escalation: Leone et al. 2014
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• Inclusion severe sepis / septic shock
•Randomisation as soon as positive cultures available
•Adequate empirical therapy acc. guidelines
•Definition de-escalation:
• Change”Pivotal antibiotic” to AB with narrowest possible spectrum
• Stop combination therapy (quinolone, amino-glycoside or macrolide) at day 3
• Stop Vancomycin if no rationale for MRSA
De-escalation: Leone et al. 2014
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•Definition continue:
• Continue”Pivotal antibiotic”
• Stop combination therapy (quinolone, amino-glycoside or macrolide) between day 3 and 5
• Stop Vancomycin if no rationale for MRSA
• Therapy duration acc. to international guidelines
De-escalation: Leone et al. 2014
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p = 0.35
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De-escalation: Leone et al. 2014
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De-escalation: Leone et al. 2014
antibiotic days
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De-escalation: Leone et al. 2014
Number of secondary infections
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Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
?
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Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
? ?
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Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
? ? ?
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L.De Bus, W. Denys, J. Decruyenaere, P. Depuydt Intensive Care Medicine 2016
• Retrospective study comparing de-escalation vs. escalation vs. continuation for betalactam use
• Outcomes:
✴Duration of antibiotic course, Antibiotic consumption
✴Cumulative incidence of MDR resistant pathogens to the initial betalactam antibiotic using systematically collected surveillance cultures (!)
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L.De Bus, W. Denys, J. Decruyenaere, P. Depuydt Intensive Care Medicine 2016
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L.De Bus, W. Denys, J. Decruyenaere, P. Depuydt Intensive Care Medicine 2016
No confirmation of expected favorable effect of de-escalation on selection of antimicrobial resistance
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L.De Bus, W. Denys, J. Decruyenaere, P. Depuydt Intensive Care Medicine 2016
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Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
? ? ?
?
![Page 36: De-escalation of antibiotic therapy · •Definition de-escalation: •hange”Pivotal antibiotic” to A with narrowest possible spectrum •Stop combination therapy (quinolone,](https://reader034.vdocuments.mx/reader034/viewer/2022042802/5f40da730e7f902e8837767f/html5/thumbnails/36.jpg)
Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
? ? ?
? ?
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Reduce selection of
MDR bacteria
Reduce time to recovery
LOS, mortality
Reduce colonisation with
MDR bacteria
Reduce costs
Reduce infection with MDR bacteria
Reduce Antibiotic use
(DDD)
De-escalation: goals?
? ? ?
? ? ?
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Increase MDR
Severely ill patient in ICU
Cost reduction
Link antibiotic use and development
of resistance
De-escalation: future ?
Rapid, adequate therapy
Narrow spectrum, reduced AB
Broad Spectrum empirical R/
Narrow Spectrum
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Increase MDR
Severely ill patient in ICU
Cost reduction
Link antibiotic use and development
of resistance
De-escalation: future
Rapid, adequate therapy
Narrow spectrum, reduced AB
Broad Spectrum empirical R/
Narrow Spectrum
De-escalation? -no uniform definition
-no reduction of AB duration, costs or length of stay
-no effects on AMR -protective of mortality? bias!
large cluster-RCT required
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Increase MDR
Severely ill patient in ICU
Cost reduction
Link antibiotic use and development
of resistance
De-escalation: future
Rapid, adequate therapy
Narrow spectrum, reduced AB
Broad Spectrum empirical R/
Narrow Spectrum
De-escalation?
rather focus on early stop!
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•we need to move to more rapid culture-independent micro identification methods
•we need swift communication between micro lab and ICU: -leading to faster achievement of appropriate therapy -duration of empirical therapy may be limited
Even short courses of antibiotics cause selection of resistant bacteria
Harbarth Circulation 2000 Taconelli AAC 2010 Lefevre AAC 2013
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Rates of intestinal colonization by imipenem-resistant gram-negative bacilli in intensive care patients.
Laurence Armand-Lefèvre et al. Antimicrob. Agents Chemother. 2013;57:1488-1495
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E de Jong, Lancet Infect Dis March 2016
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E de Jong, Lancet Infect Dis march 2016
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• How quickly is the damage to the microbiota done and
how long does it last?
• Does sequential therapy with two different
antimicrobials increase damage or is it beneficial?
What about combination therapy?
• What is the impact of dosing and duration of therapy
on AMR selection?
De-escalation needs a more solid evidence base
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De-escalation: a revised view
Reevaluation d 2-3
Broad Spectrum empirical R/
Microbiology Clinical course
Discontinue unnecessary and companion AB
continue initial therapy
narrow spectrum monitor (PCT)
short course (<5d)
long course (7-10d)
figure adapted with permission
Jan Dewaele