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
Antibiotic – Associated Diarrhea (AAD)
High incidence during or after AB regimen (5-40%)
Mechanisms %
__________________________________________________
Aspecific 70 – 80
CD-related (CDI) 20
Other pathogens 2 – 3
Specific mechanism(s) molecule related 3 – 5
CDI - Pathogenesis
AB regimen
Abnormalities in intestinal microflora
Exposition to environmental
CD spores
CD colonization Symptomless A and B toxins CDI
CDI – Key points
• Iatrogenic infection, whose incidence is increasing due to the widespread use of large spectrum AB
• Any type of AB can be responsible
• Symptoms can arise during, soon after or within 4 - 8 weeks after AB withdrawal (max after 4 – 10 days of therapy)
• Antifungal and antiviral products too can be involved
CDI – Risk factors
• Age
• Severity of underlying disease
• Comorbidities
• Enteral nutrition
• Concomitant use of PPI
• Concomitant use of H2 blockers
• PGFE type 1 (NAP 1) strain
CDI – clinical spectrum
Ileal / hypoalbuminemia / ascites
Pseudomembranes
Fever
Leucocytosis
Diarrhea
CD
3%
Fulminant colitis
Pseudo- membranous
colitis
Moderate to severe
colitis
Mild to moderate diarrhea
Healthy carrier
50- 60%
3-20%
C. Difficile
• G+ bacillus
• Sporigenic
• Toxigenic Tox A Tox B
CDI – Diagnostic test
• Reference standard : cytotoxic assay
• Second generation ELISA – Simpler and faster
– Sensitivity 90 % ( three samples)
– Specificity 100 % : this performance refers to the analytic one (i.e. concerns the presence of the toxin, not of the disease)
CDI – Treatment (I) • Stop responsible AB ! (whenever possible)
• 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)
Control risk of CDI < 2%
Selinger C.P. et al J Hosp Infect 2013; 84 :159
PLACEBO ( # 112 ) ACTIVE ( # 117 ) P
# ( % ) # ( % )
AAD 10 (8.9 ) 5 (4.3) 0.19
CDI 0 (-) 0 ( - ) 1.0
30 D -
MORTALITY
4 (3.6) 2 (1.7) 0.44
..now, let us focus on the “most active” pb
i.e., lactobacilli and bifidobacteria
PB – Meta-analysis of data up to 2013
Allen S.J. et al Lancet 2013 ; 382 : 1249
Study or Subgroup
Beniwal 2003
Beausoleil 2007
Hickson 2007
Stockenhuber 2008
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 2.95, df = 3 (P = 0.40); I² = 0%
Test for overall effect: Z = 6.08 (P < 0.00001)
Events
13
7
7
17
44
Total
105
44
57
340
546
Events
23
16
19
63
121
Total
97
45
56
338
536
Weight
26.9%
16.9%
16.9%
39.3%
100.0%
M-H, Random, 95% CI
0.52 [0.28, 0.97]
0.45 [0.20, 0.98]
0.36 [0.17, 0.79]
0.27 [0.16, 0.45]
0.37 [0.27, 0.51]
Year
2003
2007
2007
2008
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
Lactobacilli and bifidobacteria to prevent AAD and CDI in older patients (PLACIDE) A randomized, double-blind, placebo - controlled, multicenter trial
Allen SJ et al Lancet 2013; 382 : 1249 - 57
Microbial preparation
Placebo OR (95% CI) P
# % # %
AAD 159/1470 (10.8) 153/1471 (10.4) 1.04 (0.83 - 1.32) NS
CDI 12/1470 (0.8) 17/1471 (1.2) 0.70(0.34 – 1.48) NS
Meta-analysis of studies, including Allen 2013
Lancet 2013; 382 : 1249
Study or Subgroup
Beniwal 2003
Beausoleil 2007
Hickson 2007
Stockenhuber 2008
Allen 2013
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.45; Chi² = 31.09, df = 4 (P < 0.00001); I² = 87%
Test for overall effect: Z = 2.18 (P = 0.03)
Events
13
7
7
17
159
203
Total
105
44
57
340
1470
2016
Events
23
16
19
63
153
274
Total
97
45
56
338
1471
2007
Weight
19.8%
17.8%
17.9%
21.0%
23.6%
100.0%
M-H, Random, 95% CI
0.52 [0.28, 0.97]
0.45 [0.20, 0.98]
0.36 [0.17, 0.79]
0.27 [0.16, 0.45]
1.04 [0.84, 1.28]
0.49 [0.25, 0.93]
Year
2003
2007
2007
2008
2013
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