1. The Changing Treatment of clostridium difficile infection (CDI)
Chris Longshaw, Ph.D
Assoc. Scientific Director, Anti-infectives (Astellas Medical Affairs Europe)
The views expressed in this presentation are my own and may not represent those of my employer

2. Gut microbiota & C. difficile spores are central to C
Gut microbiota & C. difficile spores are central to C.difficile pathogenesis
Britton RA, Young VB, Role of the Intestinal Microbiota in Resistance to
Colonization by Clostridium difficle, Gastroenterology (2014), doi: /j.gastro
Britton RA, Young VB, Role of the Intestinal Microbiota in Resistance to
Colonization by Clostridium difficle. Gastroenterology (2014), doi: /j.gastro
FDX/15/0026/EU, March 2015

3. Clostridium difficile
Management of CDI
Infection Control
Minimize spore contamination and horizontal transmission:
Surveillance/testing
Rapid isolation
Hand Hygiene/PPE
Cleaning/Disinfection
Antibiotic Stewardship
Minimize use of drugs known to predispose to CDI:
PPI’s
Clindamycin
Cephalosporins
Fluoroquinolones
Clostridium difficile
Infection
Infection Control
Antimicrobial Stewardship
Treatment
Treatment
Improvement of patients clinical condition

4. Treatment of CDI: 3 emerging strategies
Removal of high risk antibiotics (if possible)
Sequestration of toxin with resins
Antibiotic therapy
ABx with Broad spectrum activity against anaerobic microflora
Abx with Narrow spectrum activity against anaerobic microflora
Immunotherapy
Passive treatment
Active prophylaxis
Biotherapy
Probiotics
Prebiotics
Microflora replacement therapy

5. Broad spectrum antibiotics: Metronidazole is inferior to Vancomycin in the treatment of CDI
Data, recently published, from two Phase III studies of toxin-binding resin (RCT of Tolevamer vs MET vs VAN)
Vanomycin superior to Metronidazole for clinical cure in pooled analysis: V, 81.1% vs M, 72.7 (p=0.02)
Vancomycin also superior for severe CDI: V, 78.5% vs M, 66.3% (p=0.059)
Johnson S et al. Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From Two Multinational, Randomized, Controlled Trials
Clin Infect Dis. 2014;59:
Johnson S et al. Clin Infect Dis. 2014;59:

6. Risk of recurrence increases with prior history of CDI
The more times you have had CDI, the higher the risk you will get it again.
McFarland LV, et al. Am J Gastroenterol. 2002:97:
McFarland LV, et al. JAMA. 1994;271:
Recurrence not due to resistance, though broad spectrum antibiotics may slow recovery of protective microflora
Historically no reliable options for reducing risk of recurrence
McFarland LV, et al. Am J Gastroenterol. 2002:97:
McFarland LV, et al. JAMA. 1994;271:
FDX/15/0026/EU, March 2015

7. Improved sustained (symptomatic) cure with a narrow-spectrum antibiotic than with a broad-spectrum antibiotic
Primary and secondary endpoints in the pooled populations from Phase 3 studies
Fidaxomicin
Mullane KM & Gorbach S. Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti Infect Ther 2011; 9: 767–777.
Modified intention-to-treat (mITT) populations shown; similar results were observed in the per-protocol populations
Adapted from Mullane & Gorbach 2011; 9:

8. Impact of Broad- vs Narrow-spectrum antibiotics on major faecal microflora groups in 10 CDI patients during and after therapy
% Relative abundance of fecal microflora, qRT-PCR
Louie et al (2012). Fidaxomicin preserves the Intestinal Microbiome during and after Treatment of Clostridium difficile infection (CDI) and reduces both Toxin reexpression and Recurrene of CDI. Clinical Infect Dis, 55 (suppl 2): S132-S142 – generated from data in Table 3 (pS139)
Adapted from Louie et al (2012). Clinical Infect Dis, 55 (suppl 2): S132-S142
FDX/15/0026/EU, March 2015

9. Time to recovery of microflora and colonisation resistance (CR) is critical for preventing recurrence
76 CDI patients
42 vancomycin, 34 metronidazole
suspension
filtrate
+ C. difficile
Growth = no CR
Residual VAN CR
Abujamel T, Cadnum JL, Jury LA, Sunkesula VCK, Kundrapu S, et al. (2013) Defining the Vulnerable Period for Re-Establishment of Clostridium difficile Colonization after Treatment of C. difficile Infection with Oral Vancomycin or Metronidazole. PLoS ONE 8(10): e76269
Vancomycin: Colonisation resistance absent between 4-20 days after therapy
Metronidazole: CR not restored until 2 weeks after end of therapy
Abujamel, T. et al. (2013) PLoS ONE 8(10): e76269
FDX/15/0026/EU, March 2015

10. In clinical trials, most VAN relapses also occur between day 5-17 after end of therapy
FDX/15/0026/EU, March 2015

11. Profile of narrow-spectrum antibiotics
Fidaxomicin
(Astellas)
Surotamycin
(Cubist)
Cadezolid
(Actelion)
LFF571
(Novartis)
SMT19969 (Summit)
CRS3123 (Crestone)
NVB302 (Novacta)
Status
Marketed
Phase III (FT)
Phase II
Phase I
Bactericidal/
Bacteristatic
Cidal
Static/weakly cidal
Static
High levels in colon 
Low systemic absorption
Minimal disruption of gut microflora
Inhibit toxin production
Inhibit spore formation
Inhibit spore outgrowth
Fidaxomicin: Chaparro-Rojas & Mullane. Emerging Therapies for CDI: focus on fidaxomicin. Infection & Drug Resistance. 2013: 6; 41-53
All: Tsutsumi et al. Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review. Current Topics in Medicinal Chemistry. 2014: 14;
Chaparro-Rojas & Mullane. Infection and Drug Resistance. 2013:6;41-53
Tsutsumi et al. Current Topics in Med Chem. 2014: 14;

12. Reduction in environmental spore contamination by patients treated with a narrow spectrum antibiotic
Reduced shedding of spores was observed in patients treated with fidaxomicin compared with vancomycin in clinical studies1
Routine environmental screening at Guys & St Thomas hospital, London2
No additional IC interventions were implemented during study period
Treatment with fidaxomicin was associated with significantly decreased environmental contamination compared with treatment with metronidazole and/or vancomycin
p=0.02
p=0.02
Adapted from Biswas et al
38/66
Louie et al (2012). Fidaxomicin preserves the Intestinal Microbiome during and after Treatment of Clostridium difficile infection (CDI) and reduces both Toxin reexpression and Recurrene of CDI. Clinical Infect Dis, 55 (suppl 2): S132-S142
Biswas JS, Patel A, Otter JA, Wade P, Newsholme W, van Kleef E, Goldenberg SD, Reduction in Clostridium difficile environmental contamination by hospitalized patients treated with fidaxomicin, Journal of Hospital Infection (2015), doi: /j.jhin
25/68
68/264
47/272
Methods
Comparison of environmental contamination by C. difficile in the hospital rooms of CDI patients treated first-line with metronidazole and/or vancomycin (April-Sept 2012) or fidaxomicin (Oct 2012-June 2014)
Samples taken from four standardised areas in the rooms and cultured for C. difficile
Patients
66 patients received metronidazole and/or vancomycin and 68 received fidaxomicin
Ribotype of patient isolates matched environmental isolates in 75% (Met/Van) and 80% (FDX)
Louie et al., (2012) Clin Infect Dis; 55 (s2):S132-S142
Biswas et al., (2015) J Hosp Infect; doi: /j.jhin
FDX/15/0026/EU, March 2015

13. Immunotherapy: reduce effect of toxin
PASSIVE
IV Immunoglobulins (IVIG) or immune Whey
Anti-toxin Monoclonal Ab (Merck, UCB Pharma)
MK3415A in late Phase III
Adjunctive to antibiotic
ACTIVE
Toxoid vaccine (Sanofi)
ACAM-CDIFF in Phase III
Genetically inactivated bivalent toxoid vaccine (Pfizer)
- Phase II (granted FDA Fast track)
Recombinant toxin fusion vaccine (Valneva)
VLA84 in Phase II
FDX/15/0026/EU, March 2015

14. Biotherapy: bacteria to fight C. difficile
Direct Competition
Nontoxigenic C. difficile VP20621
Completed Phase 2
Recovery of protective gut microbiota
Probiotics
Saccharomyces boulardii; Lactobacillus spp. Bifidobacterium spp.
Single organism or mixtures
Prebiotics/Synbiotics
FOS, GOS
Faecal Microbiota Transplant
FOS - RCT (N=142) of CDI patients receiving FOS reported reduced relapse (8%) compared to placebo (34%) p<
FDX/15/0026/EU, March 2015

15. Biotherapy: Faecal Microbiota Transplant

16. van Nood E et al. N Engl J Med 2013;368:407-415

17. FMT rapidly evolving…

18. Risk Factors for CDI CDI Prior CDI Recent or prolonged hospitalisation
ICU stay
Exposure to C. difficile spores
Long Term Care Facility
Proton Pump Inhibitors
Enteral feeding tubes
Severe underlying illness
High Risk of CDI
Asymptomatic colonisation
Abdominal surgery
CDI
Ananthakrishnan, AN (2011). Nat. Rev. Gastroenterol. Hepatol. 8, 17–26
Cohen, et al., (2010) Infect Control Hosp Epidemiol 2010; 31(5):
Riddle & Dubberke (2014) Infect Dis Clin North Am September ; 23(3): 727–743.
Risk factors for CDI can be simplified into 3 main buckets: Exposure to C. difficile spores; Disturbed colonic microflora leading to impaired colonisation resistance; Insufficient humoral response leading to insufficient neutralisation of C. difficile toxin A/B.
- Patients with prior CDI are likely to have residual spores in their colon or be exposed to spores in their local environment
Patients on ICU are likely to have severe underlying illness which necessitates longer hospital stay. They are also more likely to have multiple medical interventions (antibiotics, surgery, ventilation, enteral feeding) that increase risk of CDI
Patients on gastric suppression therapy (PPI, H2 agonist, antacids) will have a higher gastric pH that may allow better survival of spores through stomach and have a disturbed microbiota
Patients on enteral feeding tubes may allow spores to bypass the stomach acid. They are also more likely to have a disturbed faecal microbiota
Patients undergoing abdominal surgery will have a distrurbed microbiota due to the surgey itself and also due to frequent broad sprectrum prophylaxis (cephalosporins/metronidazole)
Recent broad spectrum antibiotic or multiple antibiotics will have a direct effect on the faecal microbiota
Treatment with anti-neoplastic agents may disturb the faecal microbiotc directly (due to cytotoxic activity) but also may have effect on immune cells and intestinal MALT and intestinal barrier function
Old age leads to natural changes in the composition of the fecal microflora that may reduce colonisation resistance, also immunosenescence may reduce the ability of the humoral system to mount a sufficient response to toxin A/B
Patients with chronic renal disease may have increased levels of waste products in the blood eg uraemia which can reduce immune function and also cause intestinal dysbiosis and reduced intestinal barrier function which increases risk of infection. Renal patients are also more likely to spend time in hospital and receive antibiotics.
Patients with genetic IgG/IgA deficiency, with unmanaged HIV/AIDS or receiving immunosuppresive therapy, may have impaired ability to mount a humoral response to C. difficile toxin A/B
Although it is clear that C. difficile spores are ubiquitous in the environment and the healthcare setting is not the only reservoir for infection, the combination of environmental spore contamination with frequent use of broad spectrum antibiotics and an aged population with underlying co-morbidities means that hospitals and long term care facilities remain a risk factor for CDI
Patients with severe underlying illnesses are more likely to have frequent hospitilisation and to receive other interventions that are risk factors for CDI
All three risk buckets (spores, dysbiosis and insuffcient humoral response) are required for a patient to develop CDI. Patients exposed to spores and who have dysbiosis but high anti-toxin IgG titres may become colonised asymptomatically with C. difficile and may continue to shed spores in their stools. Patients with impaired immunity, and who have either a disturbed microflora or who are exposed to spores remain at high risk of developing CDI in the future.
IgG/IgA deficiency
Dysbiosis & reduced colonisation resistance
Insufficient antibody to toxin A/B
High Risk of CDI
Recent broad spectrum antibiotics
HIV/AIDS
Anti-neoplastic agents
Immunosuppressive therapy
Old Age (>65 yr)
Inflammatory Bowel Disease
Refs available on Request

19. Need to move from ‘Narrow thinking, treating Broad’ to ‘Thinking broad, Treating narrow’
Narrow spectrum antibiotics
Infection Control Interventions
Exposure to C. difficile spores
High Risk of CDI
Asymptomatic colonisation
CDI
Pooled IV Immunoglobulin
Risk factors for CDI can be simplified into 3 main buckets: Exposure to C. difficile spores; Disturbed colonic microflora leading to impaired colonisation resistance; Insufficient humoral response leading to insufficient neutralisation of C. difficile toxin A/B.
- Patients with prior CDI are likely to have residual spores in their colon or be exposed to spores in their local environment
Patients on ICU are likely to have severe underlying illness which necessitates longer hospital stay. They are also more likely to have multiple medical interventions (antibiotics, surgery, ventilation, enteral feeding) that increase risk of CDI
Patients on gastric suppression therapy (PPI, H2 agonist, antacids) will have a higher gastric pH that may allow better survival of spores through stomach and have a disturbed microbiota
Patients on enteral feeding tubes may allow spores to bypass the stomach acid. They are also more likely to have a disturbed faecal microbiota
Patients undergoing abdominal surgery will have a distrurbed microbiota due to the surgey itself and also due to frequent broad sprectrum prophylaxis (cephalosporins/metronidazole)
Recent broad spectrum antibiotic or multiple antibiotics will have a direct effect on the faecal microbiota
Treatment with anti-neoplastic agents may disturb the faecal microbiotc directly (due to cytotoxic activity) but also may have effect on immune cells and intestinal MALT and intestinal barrier function
Old age leads to natural changes in the composition of the fecal microflora that may reduce colonisation resistance, also immunosenescence may reduce the ability of the humoral system to mount a sufficient response to toxin A/B
Patients with chronic renal disease may have increased levels of waste products in the blood eg uraemia which can reduce immune function and also cause intestinal dysbiosis and reduced intestinal barrier function which increases risk of infection. Renal patients are also more likely to spend time in hospital and receive antibiotics.
Patients with genetic IgG/IgA deficiency, with unmanaged HIV/AIDS or receiving immunosuppresive therapy, may have impaired ability to mount a humoral response to C. difficile toxin A/B
Although it is clear that C. difficile spores are ubiquitous in the environment and the healthcare setting is not the only reservoir for infection, the combination of environmental spore contamination with frequent use of broad spectrum antibiotics and an aged population with underlying co-morbidities means that hospitals and long term care facilities remain a risk factor for CDI
Patients with severe underlying illnesses are more likely to have frequent hospitilisation and to receive other interventions that are risk factors for CDI
All three risk buckets (spores, dysbiosis and insuffcient humoral response) are required for a patient to develop CDI. Patients exposed to spores and who have dysbiosis but high anti-toxin IgG titres may become colonised asymptomatically with C. difficile and may continue to shed spores in their stools. Patients with impaired immunity, and who have either a disturbed microflora or who are exposed to spores remain at high risk of developing CDI in the future.
Dysbiosis & reduced colonisation resistance
Insufficient antibody to toxin A/B
High Risk of CDI
Whey-based protein therapy
Microbiome Replacement Therapy
Actoxumab
bezlotoxumab
(MK-3415A)

20. THANK YOU FOR YOUR ATTENTION
The views presented are those of the author and do not necessarily reflect the views of Astellas Pharma EMEA