Antibiotic – Associated Diarrhea (AAD) and Clostridium Difficile Infection (CDI) Dario Conte, M.D. Gastroenterology and Endoscopy Unit Postgraduate School of Gastroenterology Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico – Milano Università degli Studi – Milano Gargnano - October 08 - 11, 2014
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Clostridium Difficile Infection (CDI) and Antibiotic ......PB – Meta-analysis of data up to 2013 Allen S.J. et al Lancet 2013 ; 382 : 1249 Study or Subgroup Beniwal 2003 Beausoleil
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Antibiotic – Associated Diarrhea (AAD) and Clostridium Difficile
Infection (CDI)
Dario Conte, M.D. Gastroenterology and Endoscopy Unit
Postgraduate School of Gastroenterology
Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico – Milano
Università degli Studi – Milano
Gargnano - October 08 - 11, 2014
There is no potential conflict of interest relevant to this lecture
Clinical scenario A.C. 86 year old man Chronic ischemic cardiomyopathy Type 2 DM Chronic renal insufficiency Past ischemic stroke Ongoing enteral nutrition via n-g tube
PNEUMONIA (PMN)
Hospital admission
Empirical AB regimen for PMN High frequency of CDI
• Supporting therapy alone obtains spontaneous resolution in 25 %
• In moderate to severe forms :
– metronidazole 500 mg t.i.d. orally or
– vancomycin 500 mg f.i.d. orally
– fidaxomycin : AB promisingly more selective
(ongoing RCT)
Duration of treatment : 10 – 14 days
CDI – Treatment (II)
Metronidazole and Vancomycine :
same effectiveness
Vancomycine should be preferred in :
- pregnant women
- intolerants to metronidazole
- compromised patients
In case of impossibility of oral route :
- metronidazole 500 mg / t.i.d.
CDI – Treatment (III)
Healing rate: 95 %
Alternative regimens:
- bacitracin 25.000 U f.i.d. / 7 – 14 days
- rifampicin 600 mg b.i.d. / 14 days
- cholestyramine
- toxin adsorbent polymers ( synsorb, tolevamar )
CDI - Relapse (I)
• 10 – 20 % relapse within two weeks (clinical relapse), due to:
– persistence of spores
– reinfection (50 %)
– resistance to therapy.
• Further period of treatment with metro for
10 – 14 days.
CDI – Relapse (II)
Alternatives for multiple relapses (no RCT ! )
• Metro/vanco for 4 – 6 weeks with progressively decreasing doses.
• Vanco plus cholestyramine
• Vanco + Rifampicin
• Probiotics (PB)
• Fecal microbiota transplantation (FMT)
C.Difficile Asymptomatic carrier
• Infants and children 80%
• Adults 0-3%
• Hospitalized population 20%
• Minor risk of developing CDI
• Reservoir
• Treatment not indicated • Failure in eradicating CDI infection
• Possible prolongation of carrier state
C. Difficile – Infection control Guidelines
• Drastic AB reduction
• Hands washing
• Fecal “isolation”
• Mandatory use of disposable gloves
• Environmental disinfection with sodium hypochloride
• Specific educational training of nursing and medical staff
CDI – Incidence reduction Milestones
2007 : the peak incidence of CDI in the UK
• Hand wash policy • “Bare below the elbow” • Isolation of infected patients • Reduction of the use of high–risk AB Year CDI /100,000 bed / day 2007 136.7 2010 20.5 Society for Healthcare Epidemiology of America (SHEA) Infectious Disease Society of America (IDSA)
Infect Control Hosp Epidemiol 2010; 31 : 431
Two further topics to be
elucidated
• PB in AAD and CDI prevention
• FMT (Fecal Microbiota Transplantion) for CDI
Effectiveness of PB in preventing AAD Systematic review (up to 2005)
Active PB : S. boulardii , L rhamnosus , Different mix
Flaws : same Author of the largest study , low quality of the studies included ( adequate sample size < 10% ), significant heterogeneity
Mc Farland L.V. et al Amer J Gastroenterol 2006; 101 : 812
PB for prevention
and treatment of AAD:
a systematic review and
meta-analysis Hampel S et al JAMA 2012; 507: 1959
PB for prevention and treatment of AAD A
systematic review and meta-analysis
• 63 RCT (11, 811 participants)
• No evidence of publication bias
• Overall random effect model (I² i.e. heterogeneity inconsistent with chance: 54%)
• RR 0.58 (95% CI 0.50 – 0.68)
• Risk difference – 0.07 (95% CI – 0.10 – 0.05)
• NNT 13 (95% CI – 10 – 19)
• I² 54%
• Results were relatively insensitive to subgroup analyses for PB types, participants, setting, AB types
Overall : “More research is needed to determine which PB are associated with the greatest efficacy and for which patients receiving which specific AB”
Hampel S. et al JAMA 2012; 507 : 1959
PB for prevention and treatment of CDI A systematic review and meta-analysis (I)
• 20 RCT (3818 participants) • No evidence of publication bias • RR 0.34 (95% CI 0.24 – 0.49) • I² 0% (the heterogeneity is completely consistent with chance) • Optimal information size 5676 ↓evidence for imprecision→quality moderate (GRADE)
Johnston B.C. et al Ann Intern Med 2012 ; 157 : 878
PB for prevention and treatment of CDI A systematic review and meta-analysis (II)
Control risk : 0 – 40 % . Two studies possibly done during CD outbreaks
Johnston B.C. et al Ann Intern Med 2012 ; 157 : 878
AAD and CDI in patients randomized to Placebo or S. boulardii
Placebo (# 98)
S. Boulardii (# 106)
OR (95% CI)
P
# % # %
AAD 13 (13.3) 16 (15.1) 1.16 (0.53 – 2.56) NS
CDI 2 (2.0) 3 (2.8) 1.40 (0.23 – 8.55) NS
Control risk of CDI
Colli A. et al Amer J Gastroenterol 2012; 107: 922
AAD AND CDI IN PATIENTS RANDOMIZED TO PLACEBO OR ACTIVE REGIMEN (VSL3)
Microbial preparation Placebo Risk Ratio Risk Ratio
M-H, Random, 95% CI
0.1 0.2 0.5 1 2 5 10
Favours Microbial preparation Favours Placebo
Funding may influence
trial results
Funding influence on trial results
Kolber MR et al Am J Gastroentrol 2014
PB - Overall considerations
ARE PB EFFICACIOUS IN PREVENTING
AAD and CDI ?
PB SHOULD NOT BE RECOMMENDED
If it is possible, implementing simple hygienic rules,
to obtain a CDI incidence lower than 2%,
even a magic “very effective” probiotic,
able to reduce the basal risk of 50% ,
would be not so useful:
to avoid one case of CDI the number of patients needed to treat
NNT would be > 100
Colli A et al Am J Gastroenterol 2014
«THE MAGIC BULLET»
FMT (Fecal Microbiota Transplantation) for CDI
Fecal bacteriotherapy, also called FMT, may be a useful treatment for CDI
through restoration of the intestinal microbiota
Eiseman B. et al Surgery 1958; 44 : 854
Systematic review of FMT for recurrent CDI
347 pts 92 % disease resolution
(only case series and reports are included )
Sough E. et al Can Infect Dis 2011; 53 : 994
Duodenal infusion of donor feces for recurrent CDI ( I )
42 patients randomly assigned to FMT, Vancomycin or Vancomycin plus bowel lavage
Planned number of patients per group : 40
Interim efficacy analysis (at predefined time ?)
Termination of the trial
Due to early termination, rate ratios for the primary end point (overall cure) were calculated with the exact 99.9 % CI (Haybitte – Peto rule, i.e. p < 0.001 for the primary end point)
Van Nood E. et al NEJM 2013 ; 360
Duodenal infusion of donor feces for recurrent CDI (II)
Cure (%) without relapse
Overall cure rate ratio of donor-feces infusion: 3.05 (99.9 % CI 1.08 – 290.05). QUITE AN IMPRECISE RESULT
van Nood E. et al NEJM 2013 ; 360
22 case series, 15 case reports and one RCT: 536 patients
467 cases (87%) experienced resolution of diarrhea
“NO severe adverse events were reported with FMT”
BUT
to detect a rare adverse event, i.e. < 1 : 1000 at least 3000 participants
should have been enrolled
FMT to treat CDI. A systematic review
Cammarota G et al. J Clin Gastroenterol 2014
Efficacy of combined jejunal and colonic FMT for recurrent CDI
• Very hot topic: be careful in drawing conclusions
Joannidis J.P. Why most published research findings are false?
PLoS Med 2005 ; 2 : 124
• > 30 studies registered and active on clin. Gov • e.g., Dutta S.K. : efficacy = 27/27 (!)
Dutta S. K. et al Clin Gastroenterol Hepatol 2014
Final considerations
A tendency in human thinking is to believe rather than disbelieve
Type 1 processing occurs by viewing something as more predictable and coherent than is really the case
Be skeptical
Kahneman D. Thinking, fast and slow. New York: Doubleday Canada, 2011 Schermer M. The believing brain. New York: Times Books, Henry Holt and Company, 2011
Acknowledgements
• To Christian Gluud, Dimitrinka Nikolova, Agostino Colli and Mirelli Fraquelli for their invaluable help
• To Sara Comparetti for her terrific work
• To all my Colleagues for continuos cooperation
• To all of you for patience in attending this lecture