antibiotics: the many vs. the few - critical care canada
TRANSCRIPT
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Antibiotics: The many vs. the few
Brian H Cuthbertson Chief of Critical Care Medicine
Sunnybrook Health Sciences Centre Professor, Critical Care Medicine
University of Toronto Toronto Canada
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There are only three responses to a new paper!
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• “This work agrees with my bias” • “I am smart enough to know that without
the need for a trial”
I already knew that!
• This disagrees with my personnel bias • No trial is going to convince me on this one
regardless of the size
I don’t believe it!
• I don’t believe it (but clever people are in the room!)
I have concerns with the generalisibility of the result!
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Antibiotics: The many vs. the few
The example – SDD!
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SDD- The background
• Hospital acquired infections significant problem in all hospital
• 20-50% critically ill suffer from HAIs
• Traditionally, HAI in critical illness were from Gram negative enteric bacteria
• This has changed with the rise of MRSA
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SDD- History
• First description in intensive care in 1983
• Flurry of publications from late 80s and 90s
• Large RCTs published in last 10 years
• Used in some areas of NW Europe (Holland)
• Not widely adopted elsewhere in the world
• Not used in ICU practice in North America
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What actually is SDD?
• ‘Selective decontamination’ NOT ‘sterilisation’
• Target enteric aerobic Gram negatives
• Gastric overgrowth and subsequent VAP
• Bacterial translocation and metastatic sepsis
• Attempts to not target anaerobes and Gram positives
• Beneficial bowel flora “Good bacteria”
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Which antibiotics, where?
• Topical oral/enteral, non-absorbable antibiotics for duration of ICU admission
– Polymyxin B
– Tobramycin
– Amphotericin B
• IV cefotaxime (or ciprofloxacin) for 4 days or until surveillance cultures demonstrate GIT decontamination
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It’s not new
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Extensively Studied
• At least 60 clinical trials identified on Medline
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So….
What is the problem with SDD?
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Why don’t we use it…
“There is no evidence”
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Why don’t we use it…
Does SDD benefit the individual to who it is delivered (the few)?
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36 RCT and 11 meta-analyses
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Effects of SDD on Survival
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De Smet, Bonten et al, NEJM, 2009
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• 36 trials, 6914 patients [17 more excluded]
• Topical plus systemic 17 trials, 4295 patients
• Omitted the De Smet study
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OR 0.75, 95% CI 0.65 to 0.87
SDD and mortality
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SDD and Resp. tract infection
0.28, 95% CI 0.20 to 0.38
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Our meta-analysis
0.73, 95% CI 0.65 to 0.81
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Does SDD benefit the individual to who it is delivered (the few)?
Yes!
Question…
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Question…
What further evidence do we need?
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Do we actually believe it benefits
the few?
Question…
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Do we believe it benefits the few?
“Overall, SDD benefits the patients to whom
it is delivered”
Median= 6, IQR=5-7, Importance= 6
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Do we believe it benefits the few?
“SDD reduces VAP”
Median=7, IQR= 5-8, Importance= 7
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Do we believe it benefits the few?
Median= 4, IQR= 3-5, Importance= 7
“There is no mortality benefit associated
with SDD”
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Do we believe it benefits the few?
“SDD is not on my unit’s list of clinical priorities”
Median= 8, IQR= 7-9, Importance= 6
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Do we believe it benefits the few? “The SDD evidence base is not generalizable
to my country ”
Mean= 5, IQR= 5-7, Importance= 6
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• “This work agrees with my bias” • “I am smart enough to know that without
the need for a trial”
I already knew that!
• This disagrees with my personnel bias • No trial is going to convince me on this one
regardless of the size
I don’t believe it!
• I don’t believe it (but clever people are in the room!)
I have concerns with the generalisibility of the result!
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Do we believe it benefits the few?
“It is ethically acceptable to conduct further RCTs
evaluating the effectiveness of SDD”
Median=6 , IQR=5-7
01
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1 2 3 4 5 6 7
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So do we believe it benefits the few?
No!
Question…
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“There's only two things I hate in this world. People who are intolerant of
other people's cultures and the Dutch”
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Question
Does SDD benefit the the ecology of the unit /
hospital (the many)?
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Why don’t we use it…
We’re worried about anti-microbial resistance
(the many)
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• Colonisation with resistant gram negatives in 16% of SDD pts vs 26% of controls (p = 0.001)
• Colonisation with VRE in 1% of each • No MRSA
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Cluster RCT of SDD in NEJM
• Background: SDD and SOD infection prevention measures in ICU but reported effects on patient outcome conflicting.
• Design: non-blinded RCT cross over design in 13 ICUs Netherlands
• Patients: 5939 ICU patients expected ventilation ≥ 48 hours and LOS ≥ 72 hours
• Interventions: Each ICU randomized to SDD, SOD, and standard care over 6 month period.
• Outcomes: 28 day mortality primary endpoint
De Smet, Bonten et al, NEJM, 2009
• Low rates of multi-resistant infections (5%) • No MRSA • Lower antibiotic use in SDD units
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10% 6% 12%
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“Widespread use of SDD and SOD
is justified”
“Widespread use of SDD and SOD
in intensive care units
with low levels of antibiotic resistance
is justified”
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Meta-analysis of SDD and antibiotic resistance- VRE
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Meta-analysis of SDD and antibiotic resistance- MRSA
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Meta-analysis of SDD and antibiotic resistance
Aminoglycosides Polymixins
Fluoroquinolones Cephalosporins
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Does SDD increase or reduce antibiotic use?
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So do we believe it harms the many?
Question…
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Do we believe it harms the many?
“SDD increases antibiotic resistance”
Median= 6 , IQR= 5-7, Importance= 9
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Do we believe it harms the many?
“SDD would increase C. Difficile infections”
Median= 5 , IQR= 5-5, Importance= 8
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Do we believe it harms the many?
“My concerns about antibiotic resistance limit my
willingness to participate in future RCT’s of SDD”
Mean= 4, IQR= 3-6
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Do we believe it harms the many? “I would be more likely to participate in an RCT if it included
pre, during and post-trial monitoring
of antibiotic resistance in all patients in the RCT ”
Mean= 9, IQR= 9-9
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“I am opposed to SDD”
ICU physicians
Micro / ID physicians
ICU pharmacists
ICU clinical leads
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“Overall the risks outweigh the benefits”
ICU physicians
Micro / ID physicians
ICU pharmacists
ICU clinical leads
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Do we believe it harms the many?
“There are conflicting opinions between
microbiologists and Intensive care clinicians”
Mean= 7, IQR= 6-9, Importance= 7
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Do we believe it harms the many?
• We interviewed world leading trialists
• They generally believed SDD was beneficial
• But still wanted further trials!!
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Conclusions
It’s a mess!
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Conclusions
We have equipoise but maybe shouldn’t!
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Programme of research
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• A multi-centre, cluster RCT (SuDDICU-RCT)
• An contemporaneous ecological study (e-SuDDICU)
• A concurrent prospective economic evaluation of SDD (SuDDICU-CEA)
Phase 3 research design
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SuDDICU design
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We hypothesise that-
• SDD will reduce hospital mortality
• SDD will be cost-effective
• SDD will not harm the ecology of the ICU
• SDD will not increase important antibiotic resistance patterns
Hypotheses
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Primary Outcomes
• The primary effectiveness outcome:- Hospital mortality
• The primary ecology outcome:- The difference in the incidence of antibiotic resistant organisms per 1000 patient admissions
• Primary CEA outcome- Cost-effectiveness over lifetime horizon