antibiotics: the many vs. the few - critical care canada
TRANSCRIPT
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
There are only three responses to a new paper!
• “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!
Antibiotics: The many vs. the few
The example – SDD!
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
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
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”
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
It’s not new
Extensively Studied
• At least 60 clinical trials identified on Medline
So….
What is the problem with SDD?
Why don’t we use it…
“There is no evidence”
Why don’t we use it…
Does SDD benefit the individual to who it is delivered (the few)?
36 RCT and 11 meta-analyses
Effects of SDD on Survival
De Smet, Bonten et al, NEJM, 2009
• 36 trials, 6914 patients [17 more excluded]
• Topical plus systemic 17 trials, 4295 patients
• Omitted the De Smet study
OR 0.75, 95% CI 0.65 to 0.87
SDD and mortality
SDD and Resp. tract infection
0.28, 95% CI 0.20 to 0.38
Our meta-analysis
0.73, 95% CI 0.65 to 0.81
Does SDD benefit the individual to who it is delivered (the few)?
Yes!
Question…
Question…
What further evidence do we need?
Do we actually believe it benefits
the few?
Question…
Do we believe it benefits the few?
“Overall, SDD benefits the patients to whom
it is delivered”
Median= 6, IQR=5-7, Importance= 6
Do we believe it benefits the few?
“SDD reduces VAP”
Median=7, IQR= 5-8, Importance= 7
Do we believe it benefits the few?
Median= 4, IQR= 3-5, Importance= 7
“There is no mortality benefit associated
with SDD”
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
Do we believe it benefits the few? “The SDD evidence base is not generalizable
to my country ”
Mean= 5, IQR= 5-7, Importance= 6
• “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!
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
02
03
0
Pe
rce
nt
1 2 3 4 5 6 7
So do we believe it benefits the few?
No!
Question…
“There's only two things I hate in this world. People who are intolerant of
other people's cultures and the Dutch”
Question
Does SDD benefit the the ecology of the unit /
hospital (the many)?
Why don’t we use it…
We’re worried about anti-microbial resistance
(the many)
• 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
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
10% 6% 12%
“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”
Meta-analysis of SDD and antibiotic resistance- VRE
Meta-analysis of SDD and antibiotic resistance- MRSA
Meta-analysis of SDD and antibiotic resistance
Aminoglycosides Polymixins
Fluoroquinolones Cephalosporins
Does SDD increase or reduce antibiotic use?
So do we believe it harms the many?
Question…
Do we believe it harms the many?
“SDD increases antibiotic resistance”
Median= 6 , IQR= 5-7, Importance= 9
Do we believe it harms the many?
“SDD would increase C. Difficile infections”
Median= 5 , IQR= 5-5, Importance= 8
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
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
“I am opposed to SDD”
ICU physicians
Micro / ID physicians
ICU pharmacists
ICU clinical leads
“Overall the risks outweigh the benefits”
ICU physicians
Micro / ID physicians
ICU pharmacists
ICU clinical leads
Do we believe it harms the many?
“There are conflicting opinions between
microbiologists and Intensive care clinicians”
Mean= 7, IQR= 6-9, Importance= 7
Do we believe it harms the many?
• We interviewed world leading trialists
• They generally believed SDD was beneficial
• But still wanted further trials!!
Conclusions
It’s a mess!
Conclusions
We have equipoise but maybe shouldn’t!
Programme of research
• 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
SuDDICU design
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
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