Antibiotic Associated Diarrhea (AAD) and Clostridium Difficile Infection (CDI)

Transcription

1 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

2 There is no potential conflict of interest relevant to this lecture

3 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

4 Antibiotic Associated Diarrhea (AAD) High incidence during or after AB regimen (5-40%) Mechanisms % Aspecific CD-related (CDI) 20 Other pathogens 2 3 Specific mechanism(s) molecule related 3 5

5 CDI - Pathogenesis AB regimen Abnormalities in intestinal microflora CD colonization Exposition to environmental CD spores Symptomless A and B toxins CDI

6 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

7 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

8 CDI clinical spectrum Ileal / hypoalbuminemia / ascites Pseudomembranes Fever Leucocytosis Diarrhea CD 3-20% 50-60% 3% Healthy carrier Mild to moderate diarrhea Moderate to severe colitis Pseudomembranous colitis Fulminant colitis

9 C. Difficile G+ bacillus Sporigenic Toxigenic Tox A Tox B

10 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)

11 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 : days

12 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.

13 CDI Treatment (III) Healing rate: 95 % Alternative regimens: - bacitracin U f.i.d. / 7 14 days - rifampicin 600 mg b.i.d. / 14 days - cholestyramine - toxin adsorbent polymers ( synsorb, tolevamar )

14 CDI - Relapse (I) % relapse within two weeks (clinical relapse), due to: persistence of spores reinfection (50 %) resistance to therapy. Further period of treatment with metro for days.

15 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)

16 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

17 C. Difficile Infection control Drastic AB reduction Hands washing Fecal isolation Guidelines Mandatory use of disposable gloves Environmental disinfection with sodium hypochloride Specific educational training of nursing and medical staff

18 Society for Healthcare Epidemiology of America (SHEA) Infectious Disease Society of America (IDSA) Infect Control Hosp Epidemiol 2010; 31 : 431 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

19 Two further topics to be elucidated PB in AAD and CDI prevention FMT (Fecal Microbiota Transplantion) for CDI

20 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

21 PB for prevention and treatment of AAD: a systematic review and meta-analysis Hampel S et al JAMA 2012; 507: 1959

22 PB for prevention and treatment of AAD systematic review and meta-analysis A 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 ) Risk difference 0.07 (95% CI ) 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

23 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 ) 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

24 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

25 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 ( ) NS CDI 2 (2.0) 3 (2.8) 1.40 ( ) NS Control risk of CDI Colli A. et al Amer J Gastroenterol 2012; 107: 922

26 AAD AND CDI IN PATIENTS RANDOMIZED TO PLACEBO OR ACTIVE REGIMEN (VSL3) PLACEBO ( # 112 ) ACTIVE ( # 117 ) P # ( % ) # ( % ) AAD 10 (8.9 ) 5 (4.3) 0.19 CDI 0 (-) 0 ( - ) D - MORTALITY Control risk of CDI < 2% 4 (3.6) 2 (1.7) 0.44 Selinger C.P. et al J Hosp Infect 2013; 84 :159

27 ..now, let us focus on the most active pb i.e., lactobacilli and bifidobacteria

28 PB Meta-analysis of data up to 2013 Microbial preparation Placebo Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI Beniwal % 0.52 [0.28, 0.97] 2003 Beausoleil % 0.45 [0.20, 0.98] 2007 Hickson % 0.36 [0.17, 0.79] 2007 Stockenhuber % 0.27 [0.16, 0.45] 2008 Total (95% CI) % 0.37 [0.27, 0.51] Total events Heterogeneity: Tau² = 0.00; Chi² = 2.95, df = 3 (P = 0.40); I² = 0% Test for overall effect: Z = 6.08 (P < ) Favours Microbial preparation Favours Placebo Allen S.J. et al Lancet 2013 ; 382 : 1249

29 Lactobacilli and bifidobacteria to prevent AAD and CDI in older patients (PLACIDE) A randomized, double-blind, placebo - controlled, multicenter trial Microbial preparation Placebo OR (95% CI) P # % # % AAD 159/1470 (10.8) 153/1471 (10.4) 1.04 ( ) NS CDI 12/1470 (0.8) 17/1471 (1.2) 0.70( ) NS Allen SJ et al Lancet 2013; 382 :

30 Meta-analysis of studies, including Allen 2013 Microbial preparation Placebo Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI Beniwal % 0.52 [0.28, 0.97] 2003 Beausoleil % 0.45 [0.20, 0.98] 2007 Hickson % 0.36 [0.17, 0.79] 2007 Stockenhuber % 0.27 [0.16, 0.45] 2008 Allen % 1.04 [0.84, 1.28] 2013 Total (95% CI) % 0.49 [0.25, 0.93] Total events Heterogeneity: Tau² = 0.45; Chi² = 31.09, df = 4 (P < ); I² = 87% Test for overall effect: Z = 2.18 (P = 0.03) Favours Microbial preparation Favours Placebo Lancet 2013; 382 : 1249

31 Funding influence on trial results Funding may influence trial results Kolber MR et al Am J Gastroentrol 2014

32 PB - Overall considerations ARE PB EFFICACIOUS IN PREVENTING AAD and CDI? PB SHOULD NOT BE RECOMMENDED

33 «THE MAGIC BULLET» 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

34 FMT (Fecal Microbiota Transplantation) for CDI

35 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

36 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 < for the primary end point) Van Nood E. et al NEJM 2013 ; 360

37 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 ). QUITE AN IMPRECISE RESULT van Nood E. et al NEJM 2013 ; 360

38 FMT to treat CDI. A systematic review 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 Cammarota G et al. J Clin Gastroenterol 2014

39 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

40 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

41 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