CONVENTIONAL
TREATMENT OPTIONS
SLIDE RESOURCE SET
FDX/13/0068/EUb | August 2013
Snapshot of treatment for initial episodes
of Clostridium difficile infection (CDI)
Treatments used in an initial episode of CDI
in a 2008 European survey
0.2%
18%
Oral metronidazole
Intravenous metronidazole
11%
Oral vancomycin
Intracolonic vancomycin
71%
Bauer MP, et al. Lancet 2011;377:63–73.
FDX/12/0076/EUf | EK206
Rates of clinical cure for metronidazole
and vancomycin
p=0.36
Clinical cure (%)
100
p=0.02
98
p=0.006
97
97
90
Metronidazole
84
80
Vancomycin
74
60
40
20
0
37/
41
39/
40
Mild CDI
28/
38
30/
31
Severe CDI
66/
79
69/
71
All cases
Note: patients were stratified by mild or severe disease based on a severity assessment score developed
for this study. Patients received one point each for age >60 years, temperature >38.3°C, albumin level
<2.5 mg/dL, or peripheral white blood cell count >15,000 cells/mm 3 within 48 hours of enrolment. Two
points were given for endoscopic evidence of pseudomembranous colitis or treatment in an intensive care
unit. Patients with ≥2 points were considered to have severe CDI
Zar FA, et al. Clin Infect Dis 2007;45:302–7.
FDX/12/0076/EUf  EK205
Rates of clinical success for
metronidazole and vancomycin
Rates of clinical success in two identical, multicentre, randomised,
double-blind, parallel-group trials
p=NS
p=NS
p<0.05
Clinical success (%)
100
81.3
80
81.1
80.8
72.0
73.3
Study 301
(n=277)
Study 302
(n=260)
72.7
60
Metronidazole
(375 mg qid)
Vancomycin
(125 mg qid)
40
20
0
Pooled analysis
(n=537)
Clinical success was defined as diarrhoea resolution and
absence of severe abdominal discomfort due to CDI on Day 10;
NS, not significant; qid, four times daily
Johnson S, et al. Poster presented at IDWeek 2012; 818.
FDX/12/0076/Euj | OC104
Clinical limitations associated with
current treatments for CDI
• Although metronidazole and vancomycin are effective in a
first episode of CDI, therapy remains suboptimal
• Among the most significant drawbacks of current therapy
for CDI are:
– Rates of treatment failure with metronidazole of up to 18%1
– Rates of recurrent infection following treatment with
metronidazole and vancomycin of up to 25% within 30 days
following treatment2–4
– Risk of overgrowth of vancomycin-resistant enterococci (VRE) in
patients who are already colonised with VRE5
1.
2.
3.
4.
5.
Aslam S, et al. Lancet Infect Dis 2005;5:549–57;
Louie TL, et al. N Engl J Med 2011;364:422–31;
Lowy I, et al. N Engl J Med 2010;362:197–205;
Bouza E, et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4;
Al-Nassir WN, et al. Antimicrob Agents Chemother 2008;52:2403–6.
FDX/12/0087/EUu | slide 041
Is there an increasing treatment failure
rate with metronidazole?
Average rate of treatment failure in patients receiving metronidazole
Treatment failure (%)
25
20
18.3
15
10
5
3.6
2.4
0
1980s
1990s
Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57.
2000s
Note: the dates relate to the year of
publication not the year of the study
FDX/12/0076/EUf | EK213
The incidence of recurrent CDI
1st recurrence
of CDI
Initial episode of CDI
1.
2.
3.
4.
5.
Recurrence(s)
of CDI
Up to 25% of patients
have recurrent CDI1–3
Louie TJ, et al. N Engl J Med 2011;364:422–31;
Lowy I, et al. N Engl J Med 2010;362:197–205;
Bouza E, et al. Clin Microbiol Infect 2008;4(Suppl 7):S103–4;
McFarland LV, et al. Am J Gastroenterol 2002;97:1969–75;
McFarland LV, et al. JAMA 1994;271:1913–8.
~45–65% of patients have
further recurrences4,5
FDX/12/0076/EUb | SJ122
Rates of disease recurrence with
metronidazole and vancomycin (1)
29
Recurrence (%)
30
28
Metronidazole
21
20
10
21
Vancomycin
18
7
0
Pre-2000
Post-2000
Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57.
Combined
Note: the dates relate to the year of
publication not the year of the study
FDX/12/0076/EUa  MW303
Rates of disease recurrence with
metronidazole and vancomycin (2)
Rates of recurrence in two identical, multicentre, randomised,
double-blind, parallel-group trials
p=NS
p=NS
p=NS
50
Metronidazole
Vancomycin
Recurrence (%)
40
30
27.1
23.4
23.0
18.9 17.6
20
20.6
10
0
Study 301
(n=277)
Study 302
(n=260)
Johnson S, et al. Poster presented at IDWeek 2012; 818.
Pooled analysis
(n=537)
NS, not significant
FDX/12/0076/Euj | OC105
Rates of recurrence for metronidazole and
vancomycin grouped by age
CDI recurrence during 4-week follow-up in patients from
two pooled, randomised, double-blind, parallel-group trials
p=NS
p=NS
p=NS
Recurrence (%)
50
Metronidazole
40
30
20
Vancomycin
36.2
26.2
19.8 19.2
21.8
23.2
10
0
Age ≤65 years
•
Age >65 years
Age >75 years*
Recurrence increased with increasing age in metronidazole-treated subjects but
remained relatively stable in vancomycin-treated subjects
Johnson S, et al. Poster presented at IDWeek 2012; 818.
*Subset of subjects aged >65 years;
NS, not significant
FDX/12/0076/EUq | EB113
Rates of recurrence for metronidazole and
vancomycin grouped by sex
CDI recurrence during 4-week follow-up in patients from
two pooled, randomised, double-blind, parallel-group trials
p<0.05
p=NS
Recurrence (%)
50
Metronidazole
Vancomycin
40
30
20
23.7
22.5
24.0
17.4
10
0
Males
•
Females
Male subjects treated with vancomycin had significantly fewer (p<0.05) recurrences vs
males treated with metronidazole
Johnson S, et al. Poster presented at IDWeek 2012; 818.
NS, not significant
FDX/12/0076/EUq | EB112
Rates of recurrence for metronidazole and
vancomycin grouped by C. difficile strain
CDI recurrence during 4-week follow-up in patients from
two pooled, randomised, double-blind, parallel-group trials
p=NS
p=NS
Recurrence (%)
50
Metronidazole
40
Vancomycin
32.4
30
29.0
24.4
18.8
20
10
0
BI (027) strain
Non-BI (non-027) strain
Johnson S, et al. Poster presented at IDWeek 2012; 818.
BI, restriction-endonuclease analysis group BI strain of
C. difficile (also known as NAP1/027);
NS, not significant
FDX/12/0076/EUq | EB115
Differences in estimates of CDI recurrence
and its definition across Europe
Country
Estimate
Definition
Austria
16%
A second episode within 60 days of the first
Denmark
11%
Not reported
France
1%
Not reported
3%
>40 days after first episode
4%
Toxin-positive diarrhoea <30 days post treatment
14%
New CDI episode during the next chemotherapy course
18%
Within 8 weeks of the previous episode
36%
New CDI episode during 60-day follow-up, ≥48 hours after treatment
Germany
Ireland
3–4%,* 10%†
The
Netherlands
Relapse of CDI >8 weeks after first infection
16%
Episode occurring ≤8 weeks after onset of an earlier case
22%
Diarrhoea <30 days after initial clinical improvement
Poland
17%
Increased frequency of loose stools with new signs of severe colitis
Spain
6–18%
Switzerland
UK
4%
Not reported
Positive toxin or stool culture up to 3 months from first diagnosis
0–2%
30-day recurrence
8–11%
Toxin-positive diarrhoea up to 4 weeks following treatment
15%
Over 12 months
20%
Return of diarrhoea ≤30 days after completion of treatment
Wiegand PN, et al. J Hosp Infect 2012;81:1–14.
*Ribotypes 001, 014 and 078; †Ribotype 027
FDX/12/0076/EUq | EB107
Patients with CDI recurrence (%)
Vancomycin regimens for recurrent CDI
post hoc analysis from two trials (n=163)
80
*p<0.05 compared with vancomycin 1 g/day
70
60
50
40
*
30
20
*
10
0
Vancomycin
(1 g/day) ×
7–14 days
Vancomycin
(2 g/day) ×
7–14 days
McFarland LV, et al. Am J Gastroenterol 2002;97:1769–75.
Tapered
vancomycin
Pulsed
vancomycin
FDX/12/0076/EUr | SJ230
Rationale for a new treatment
• CDI remains a disease for which there are significant unmet
needs e.g.:
– Therapy to provide sustained clinical cure (defined as clinical cure
without recurrence)1
– Therapy to reduce recurrence (relapse and/or reinfection)1
– Better identification of patients at risk of recurrence or those for whom the
impact of recurrence would be most dramatic2
• New approaches under investigation but data from large-scale
randomised controlled trials are lacking3
• Management strategies to treat acute episodes of CDI effectively and
markedly reduce the risk of recurrence would represent a significant
therapeutic advance4
1.
2.
3.
4.
Cornely OA. Clin Microbiol Infect 2012;18(Suppl 6):28–35;
Kelly CP. Clin Microbiol Infect 2012;18(Suppl 6):21–7;
Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79;
Bouza E. Clin Microbiol Infect 2012;18(Suppl 6):5–12.
FDX/12/0076/EUk | MB145
Faecal microbiota therapy for CDI
Study
Indication
Eiseman et al. 1958.
Severe PMC
MacConnachie et al. 2009.
Patients
Administration
Outcome
4
Enema
Resolution in all patients
Recurrent CDI
15
NG tube
86.7% clinical response
Arkkila et al. 2010.
Recurrent CDI
37
Colonoscope
92% eradication
Khoruts et al. 2010.
Recurrent CDI
1
Colonoscope
Eradication
Yoon, Brandt. 2010.
Recurrent CDI/PMC
12
Colonoscope
100% clinical response
Rohike et al. 2010.
Recurrent CDI
19
Colonoscope
94.7% clinical response
Silverman et al. 2010.
Recurrent CDI
7
Enema
100% asymptomatic
Garborg et al. 2010.
Recurrent CDI
40
Endoscope
82.5% eradication
Russell et al. 2010.
Recurrent CDI
1
NG tube
Resolution of symptoms
Kelly et al. 2010.
Recurrent CDI
12
Colonoscope
100% clinical response
Mellow et al. 2010.
Recurrent CDI
13
Colonoscope
92.3% clinical response
Kassam et al. 2010.
CDI
14
Enema
100% clinical resolution
Kelly et al. 2011.
Recurrent CDI
26
Colonoscope
92% clinical resolution
Borody TJ, Khoruts A. Nat Rev Gastroenterol Hepatol 2012;9:88–96.
NG, nasogastric;
PMC, pseudomembranous colitis
FDX/12/0100/EUk | JC129
Faecal microbiota therapy for recurrent
CDI: study design
van Nood et al. trial
Oral vancomycin
500 mg qid, 14 days
Oral vancomycin
500 mg qid, 14 days
Bowel lavage 1×
Oral vancomycin
500 mg qid, 4 days
Bowel lavage 1×
Donor faeces 1×
Endpoints1,2
•
Diarrhoea (≥3×/day) and C. difficile toxin on Days 35 and 70
•
Quality of life, days spent in isolation, days admitted to the hospital, attributable costs
•
Psychological analysis of effect of faecal transplant
•
Follow-up 10 weeks, cross-over if failure in antibiotic group
1. van Nood E, et al. N Engl J Med 2013;368:407–15;
2. Protocol to: van Nood E, et al. N Engl J Med 2013;368:407–15.
qid, four-times daily
FDX/12/0100/EUk | JC132
Duodenal faecal microbiota
transplantation vs vancomycin plus lavage
p<0.001
p<0.001
p=0.008
Rates of cure
without relapse (%)
p=0.003
100
80
93.8
81.3
60
30.8
40
23.1
20
0
First infusion
of donor faeces
(n=16)
Infusion of donor
faeces overall
(n=16)
Vancomycin
(n=13)
Vancomycin with
bowel lavage
(n=13)
•
Study stopped after interim analysis
•
No significant differences in adverse events among study groups, except for mild
diarrhoea and abdominal cramping in the infusion group on the day of infusion
van Nood E, et al. N Engl J Med 2013;368:407–15.
FDX/12/0076/EUf | EK242
Microbiota diversity in patients before and
after faecal infusion versus healthy donors
Simpson’s
reciprocal index
250
200
150
100
50
0
Donors
van Nood E et al. N Engl J Med 2013;368:407-415
van Nood E, et al. N Engl J Med 2013;368:407–15.
Patients before
infusion
Patients after
infusion
FDX/12/0100/EUk | JC135
Faecal bacteriotherapy: limitations
• No supporting data from prospective, randomised controlled trials1–3
• Very limited data on long-term safety
– Administration via colonoscopy, nasogastric tube or retention enema
associated with some risk4
– Potential transmission of infectious agents contained in the donor stool
may also carry inherent risks4
• Acceptability of the procedure may be an issue5
– Patients and physicians reluctant to choose donor-faeces infusion at an
early stage6
1.
2.
3.
4.
5.
6.
Gough E, et al. Clin Infect Dis 2011;53:994–1002;
Anderson JL, et al. Aliment Pharmacol Ther 2012;36:503–16;
Guo B, et al. Aliment Pharmacol Ther 2012;35:865–75;
Aas J, et al. Clin Infect Dis 2003;36:580–5;
Hedge DD, et al. Ther Clin Risk Manag 2008;4:949–64;
van Nood E, et al. N Engl J Med 2013;368:407–15.
FDX/12/0076/EUk | MB137
Issues surrounding the clinical
application of faecal transplantation
•
Acceptability1–3
•
Patient selection
•
•
1.
2.
3.
4.
5.
6.
7.
–
Immunocompromised3,4
–
Concomitant antibiotic therapy5
–
Allergens (e.g. nuts)4
Donor screening
–
Epstein–Barr virus,5 cytomegalovirus,5 HIV,4–6 hepatitis A/B/C4–7
–
Syphilis,7 C. difficile5–7
–
Enteric pathogens including parasites5–7
–
No antibiotics in previous 3 months4
Cost
–
Screening6
–
Procedure-related6
Yoon SS, Brandt LJ. J Clin Gastroenterol 2010;44:562–6;
Hedge DD, et al. Ther Clin Risk Manag 2008;4:949–64;
Borody TJ, Khoruts A. Nat Rev Gastroenterol Hepatol 2012;9:88–96;
Bakken JS, et al. Clin Gastroenterol Hepatol 2011;9:1044–9;
van Nood E, et al. N Engl J Med 2013;368:407–15;
Rohlke F, Stollman N. Therap Adv Gastroenterol 2012;5:403–20;
Aas J, et al. Clin Infect Dis 2003;36:580–5.
FDX/12/0100/EUk | JC136