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From Monoclonal Antibodies to Fecal Transplants: Current Concepts in the Management of Clostridium difficile George Risi, MD, Msc Infectious Disease Specialists,

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Presentation on theme: "From Monoclonal Antibodies to Fecal Transplants: Current Concepts in the Management of Clostridium difficile George Risi, MD, Msc Infectious Disease Specialists,"— Presentation transcript:

1 From Monoclonal Antibodies to Fecal Transplants: Current Concepts in the Management of Clostridium difficile George Risi, MD, Msc Infectious Disease Specialists, PC Missoula, MT

2 Issues to Discuss The complexity of the human gut microbiome when examined with 16sRNA The effects on the microbiome when antimicrobials are administered Clostridium difficile Diagnosis and treatment Recurrent disease Fecal transplant Monoclonal antibodies Probiotics

3 What Constitutes the Flora of a Complex Microbiome? Traditional efforts relied on culture of organisms in a variety of in-vitro systems The environment of several ecosytems (oceans, soil, the mouth, the colon, etc) cannot be duplicated Non-culture methods developed to further elucidate the organisms 16s RNA gene amplification by PCR has become the standard and most commonly used tool –For identifying organisms –For determining their relatedness

4 16s RNA Analysis DNA is transcribed into protein by the ribosome Composed of large and small segments The gene that codes for the small segment is the 16s DNA gene, aka 16s RNA This segment of DNA is crucial so has been evolutionarily conserved Slow evolution over time allows relatedness of organisms to be determined (molecular chronometer)

5 Woese CR et al, Proc Nat Acad Science 1990;87:4576 To date, 55 deep evolutionary divisions of Bacteria and 13 divisions of Archaea have been described (Ley, Cell 2006;124:837)

6 Application of 16s RNA PCR to the Human GI Tract 3 healthy individuals undergoing routine colonoscopy –Sampling of stool and biopsies from different segments of bowel wall 13,355 rRNA sequences examined 11,831 bacterial and 1,524 archaeal sequences, from which 395 bacterial phylotypes and one archaeal phylotype identified Of the 395 bacteria, 244 (62%) were novel, and 80% represented sequences from bacteria that had never been cultivated Eckburg et al, Science 2005;308:1635

7 WE WIN! The human intestinal tract contains approximately 10 14 (100 trillion) microbes The density in the colon is the highest recorded for any microbial habitat on earth The size of this population is 10 X greater than the total number of our own somatic cells There are > 100 X the number of genes in our own genome Backhed et al, Science 2005;307:1915

8 Backhed F et. al. Science 2005;307:1915 Diversity of Bacteria in the Human Intestine Firmicutes: Clostridium Eubacterium CFB: Cytophaga Flavobacterium Bacteroides Proteobacteria

9 The Gut Microbiota A “microbial organ” placed within a host organ –Composed of different cell lineages with a capacity to communicate with each other –Consumes, stores and redistributes energy –Mediates physiologically important chemical transformations –Can maintain and repair itself through self replication

10 Working Together There is a dynamic interplay between the microbiota of the GI tract, the intestinal epithelium, and the immune cells of the gut All 3 play a defensive role in protecting the host from any invading microbe Increasing appreciation of the role of gut microbes in the pathogenesis of –Obesity –Type 1 diabetes –Inflammatory bowel disease –Metabolic syndrome Wardwell, Curr Inf Dis Rep 2011;13:23

11 The Miracle of Antibiotics


13 What Happens to the Gastrointestinal Microbiome When an Individual is Prescribed Antibiotics?


15 Clostridium difficile

16 First Case 22 year old female, patient of Dr. William Osler “A miserable, emaciated creature in a wretched physical condition.” Underwent surgical resection of a gastric tumor on August 26, 1892 Postoperatively developed diarrhea that became progressively more severe Died on post op day 15 Postmortem report describes “diphtheritic colitis” Finney, Johns Hopkins Hosp Bull1893;4:53

17 Microbiology and Ecology An anaerobic, spore forming gram positive rod first described by Hall and O’Toole as a member of the normal flora of healthy infants in 1935 Due to the difficulty in cultivating the organism it was originally called Bacillus difficilis. Its current name was given 3 years later Closely related to C. sordellii but not to other toxigenic clostridia like C. perfringens, C. botulinum or C. tetani. Can be grown on selective media (CCFA)

18 Environmental Sources of C. difficile Soil Sand Mud Swimming pools Oceans and beaches Rivers Tap water

19 Are Animal Reservoirs Important in Human Disease?

20 Animals and Clostridium difficile Camels Elephants Horses and donkeys Carriage in household pets can range from 20-40% Strain typing indicates that humans share a wide variety of strains with other mammals C. difficile from food animals enters the human food chain Thielman and Wilson, Principles and Practice of Infectious Disease, 2010

21 Dual Modes of Existence Vegetative form –Found in the gut, survives in the environment for 4-6 hours –Susceptible to gastric acid, antibacterial soaps, alcohol based hand foams –Neutralization of stomach acid with pantoprazole may allow the vegetative form to become pathogenic Spore form –Found in the gut and in the environment –Spore formation induced by stressing the organism: exposure to the environment, exposure to antimicrobials, sub-lethal concentrations of microbicidal cleaning products –Resistant to stomach acid, antibacterial soaps and alcohol based hand foams –Can survive for years on surfaces

22 Toxin Production 5-25% of strains do not produce toxins and don’t cause disease Toxin A –308 kd enterotoxin and cytotoxin –Chemoattractant for neutrophils –Activator for macrophages and mast cells Toxin B –269 kd potent cytotoxin –Disrupts the actin cytoskeleton –Found to be a potent necrotizing enterotoxin –Probably acts synergistically with toxin A

23 Pathogenesis of Disease Three critical events necessary –Disruption of normal flora –Exposure to a toxigenic strain of organism and its ability to reach lower GI tract, establish colonization –One or more additional requirements, poorly characterized but include Advanced age Severe underlying disease Prolonged hospitalization Manipulation of the GI tract Acid neutralizing agents

24 Clinical Disease Spectrum Asymptomatic colonization most common, at least 50% of all persons infected Mild diarrhea with minimal discomfort, responds to withdrawal of the offending antimicrobial “Typical” CDAD with crampy abdominal pain, profuse diarrhea, low grade fever, leukocytosis Severe disease with fever > 40 0 and WBC > 50,000


26 Source: Up to Date 1 st case

27 Source: Up to Date


29 Hypervirulent Strains The most notorious was first identified in 1980’s –Restriction endonuclease analysis type BI, aka –North American pulsed field type 1 (NAP1), aka –Ribotype 027 Multiple outbreaks in US and Canada in early 2000’s –High level fluoroquinolone resistance –Hyperproduction of toxins A and B –Increased sporulation capacity –Enhanced adherence via a new binary toxin

30 Warny M et al. Lancet 2005;366:1079

31 The Pathogenicity Locus

32 Conflicting Results with EIA ParameterRange Sensitivity32-98.7% (Average 65%) Specificity92-100% Positive Predictive Value76.4-96% Negative Predictive Value88-100% 1.Stamper et al, J Clin Micro 2009;47:373-8 2.Musher DM et al, J Clin Micro 2007;45:2737-9 3.Sloan LM et al, J Clin Micro 2008;46:1996-2001 4.Gilligan PH et al, J Clin Micro 2008;46:1523-5 5.Ticehurst JR, J Clin Micro 2006;44:1145-9 6.Planche T et al Lancet Infect Dis 2008;8(12):777-84 Recently Published EIA Papers (1-6) It is time to abandon the EIA Carroll et. al. J Clin Micro 2011;49:S49


34 Treatment of CDAD Withdrawal of offending antibiotic when possible Avoid antiperistaltic agents Oral administration of rx optimal Metronidazole Vancomycin Fidaxomycin “Test of Cure” not appropriate due to prolonged carriage in cured individuals

35 Metronidazole Most isolates of C. difficile are highly susceptible Very well absorbed in the upper GI tract if no diarrhea With diarrhea fecal concentrations reach acceptable levels Recent data have shown it to be less effective than vancomycin overall Considered drug of choice for mild to moderately severe disease


37 Vancomycin No resistance documented to the levels reached in the colon Superior to metronidazole in severe disease Direct delivery to lower GI tract in the case of ileus IV much less effective

38 Fidaxomycin Good in-vitro activity vs C. diff May be less deleterious to the rest of the microbiome Equivalent to vancomycin in treatment Recurrent disease less (15% vs 25%) ONLY if NAP1 strain NOT involved Recently approved by FDA Fidaxomycin, a macrocyclic antibiotic

39 Recurrent Disease Chang J Y et al. J Infect Dis. 2008;197:435-438 Kyne, Lancet 2001;357:189

40 Recurrent Disease 15-30% of patients Lack of colonization resistance/restoration of gut microbiome Persistence of C. difficile spores in gut Failure to mount a significant antibody rise to toxins A and B 30-50% of cases of recurrent disease may not be due to relapse –Mean time to recurrence with same strain 14 days –Mean time to recurrence with new strain 42 days Once one relapse has happened chances of multiple recurrences go up –45% after 1 st recurrence –65% after two or more recurrences

41 Treatment Options for Recurrent Disease Retreat with same agent Switch to a different agent Treat followed by tapering dose of drug Fecal flora reconstitution Monoclonal antibody therapy

42 Fecal Flora Reconstitution Restoration of colonization resistance Extensive history of “biotherapy” in veterinary medicine –Cud transfers from normal cows –Transfaunation of young foals with diarrhea Small but impressive published experience in patients with refractory disease

43 Author Year Cases NG/NJ Enema orCured (%) colonoscope Eiseman 195841 3 4 (100) Bowden 1981161 1513 (81) Schwan 19841 1 1 (100) Tvede 19896 6 6 (100) Flotterod 19911 1 1 (100) Paterson 19947 7 7 (100) Lund 1998181 1715 (90) Gustaffson 1998 13 1313 (100) Persky 20001 1 1 (100) Faust 20026 6 6 (100) Aas 2003161615 (94) Jorup 20065 5 5 (100) Nieuwdorp 200874 3 7 (100) Rohlke 201019 1919 (100) TOTAL11923 96113 (94.9) Fecal Transplant Experience

44 Monoclonal Antibody Therapy Rationale: Inability to mount a protective response underlies susceptibility to recurrence The magnitude of the anti-toxin antibody response correlates with resistance to symptomatic infection Patients with highest titers of antibody titers were 44 X less likely to develop recurrence Kyne, Lancet 2001;357:189

45 Monoclonal Antibody Trial Randomized, double blind placebo controlled trial of MAB’s against toxins A/B in 200 patients Time to resolution of initial disease did not differ Rate of recurrence significantly lower in treatment group (7 vs 25%) also with NAP1 strain (8 vs 32%) Lowy et al NEJM 2010;362:197

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