Conventional Treatment options

CONVENTIONAL TREATMENT OPTIONSSLIDE RESOURCE SET

FDX/13/0068/EUb | August 2013

Snapshot of treatment for initial episodes of Clostridium difficile infection (CDI)

Bauer MP, et al. Lancet 2011;377:63–73.

Treatments used in an initial episode of CDI in a 2008 European survey

71%

11%

18%

0.2%

Oral metronidazole

Intravenous metronidazole

Oral vancomycin

Intracolonic vancomycin

FDX/12/0076/EUf | EK206

Mild CDI Severe CDI All cases0

20

40

60

80

10090

7484

98 97 97Metronidazole

Vancomycin

Clin

ica

l cu

re (

%)

Rates of clinical cure for metronidazole and vancomycin

Zar FA, et al. Clin Infect Dis 2007;45:302–7.

p=0.006p=0.36 p=0.02

37/41

39/40

28/38

30/31

66/79

69/71

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/mm3 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 CDIFDX/12/0076/EUf EK205

Rates of clinical success for metronidazole and vancomycin

Johnson S, et al. Poster presented at IDWeek 2012; 818.

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

Study 301 (n=277)

Study 302(n=260)

Pooled analysis(n=537)

0

20

40

60

80

100

72 73.3 72.781.3 80.8 81.1

Metronidazole(375 mg qid)

Vancomycin(125 mg qid)

Clin

ica

l su

cce

ss (

%)

Rates of clinical success in two identical, multicentre, randomised, double-blind, parallel-group trials

p<0.05p=NSp=NS

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. Aslam S, et al. Lancet Infect Dis 2005;5:549–57;2. Louie TL, et al. N Engl J Med 2011;364:422–31;3. Lowy I, et al. N Engl J Med 2010;362:197–205;4. Bouza E, et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4;5. 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?

Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57.

Average rate of treatment failure in patients receiving metronidazole

1980s 1990s 2000s0

5

10

15

20

25

3.62.4

18.3

Tre

atm

en

t fa

ilure

(%

)

FDX/12/0076/EUf | EK213

Note: the dates relate to the year of publication not the year of the study

The incidence of recurrent CDI

1. Louie TJ, et al. N Engl J Med 2011;364:422–31;2. Lowy I, et al. N Engl J Med 2010;362:197–205;3. Bouza E, et al. Clin Microbiol Infect 2008;4(Suppl 7):S103–4;4. McFarland LV, et al. Am J Gastroenterol 2002;97:1969–75;5. McFarland LV, et al. JAMA 1994;271:1913–8.

1st recurrence of CDI

Recurrence(s) of CDI

~45–65% of patients have further

recurrences4,5

Up to 25% of patients have recurrent CDI1–3

Initial episode of CDI

FDX/12/0076/EUb | SJ122

Rates of disease recurrence with metronidazole and vancomycin (1)

Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57.

Pre-2000 Post-2000 Combined0

10

20

30

7

29

2118

28

21

Metronidazole

Vancomycin

Re

curr

en

ce (

%)

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)


Study 301 (n=277)

Study 302(n=260)

Pooled analysis(n=537)

0

10

20

30

40

50

27.1

18.923.023.4

17.620.6

Metronidazole

Vancomycin

Re

curr

en

ce (

%)

Rates of recurrence in two identical, multicentre, randomised, double-blind, parallel-group trials

p=NSp=NSp=NS

FDX/12/0076/Euj | OC105NS, not significant

Age ≤65 years Age >65 years Age >75 years*0

10

20

30

40

50

19.8

26.2

36.2

19.221.8 23.2

Metronidazole

Vancomycin

Re

curr

en

ce (

%)

Rates of recurrence for metronidazole and vancomycin grouped by age


Recurrence increased with increasing age in metronidazole-treated subjects but remained relatively stable in vancomycin-treated subjects

CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials

p=NSp=NSp=NS

*Subset of subjects aged >65 years;NS, not significant

FDX/12/0076/EUq | EB113

Males Females0

10

20

30

40

50

23.7 22.517.4

24.0

Metronidazole

Vancomycin

Re

curr

en

ce (

%)

Rates of recurrence for metronidazole and vancomycin grouped by sex


Male subjects treated with vancomycin had significantly fewer (p<0.05) recurrences vs males treated with metronidazole


p<0.05 p=NS

NS, not significantFDX/12/0076/EUq | EB112

Rates of recurrence for metronidazole and vancomycin grouped by C. difficile strain


BI (027) strain Non-BI (non-027) strain0

10

20

30

40

50

32.4

24.429.0

18.8

Metronidazole

Vancomycin

Re

curr

en

ce (

%)


p=NS p=NS

BI, restriction-endonuclease analysis group BI strain of C. difficile (also known as NAP1/027);

NS, not significantFDX/12/0076/EUq | EB115

Differences in estimates of CDI recurrence and its definition across Europe

Wiegand PN, et al. J Hosp Infect 2012;81:1–14.

Country Estimate Definition

Austria 16% A second episode within 60 days of the first

Denmark 11% Not reported

France 1% Not reported

Germany

3% >40 days after first episode

4% Toxin-positive diarrhoea <30 days post treatment

14% New CDI episode during the next chemotherapy course

Ireland18% Within 8 weeks of the previous episode

36% New CDI episode during 60-day follow-up, ≥48 hours after treatment

The Netherlands

3–4%,* 10%† 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% Not reported

Switzerland 4% Positive toxin or stool culture up to 3 months from first diagnosis

UK

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

*Ribotypes 001, 014 and 078; †Ribotype 027FDX/12/0076/EUq | EB107

Vancomycin regimens for recurrent CDIpost hoc analysis from two trials (n=163)

McFarland LV, et al. Am J Gastroenterol 2002;97:1769–75.

Vancomycin(1 g/day) ×7–14 days

Vancomycin(2 g/day) ×7–14 days

Tapered vancomycin

Pulsed vancomycin

0

10

20

30

40

50

60

70

80

Pa

tie

nts

wit

h C

DI

rec

urr

en

ce

(%

)

*

*

*p<0.05 compared with vancomycin 1 g/day

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. Cornely OA. Clin Microbiol Infect 2012;18(Suppl 6):28 –35;2. Kelly CP. Clin Microbiol Infect 2012;18(Suppl 6):21 –7;3. Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79; 4. Bouza E. Clin Microbiol Infect 2012;18(Suppl 6):5–12.

FDX/12/0076/EUk | MB145

Faecal microbiota therapy for CDI

Study Indication Patients Administration Outcome

Eiseman et al. 1958. Severe PMC 4 Enema Resolution in all patients

MacConnachie et al. 2009. 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

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.

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 daysBowel 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

qid, four-times dailyFDX/12/0100/EUk | JC132

Duodenal faecal microbiota transplantation vs vancomycin plus lavage

van Nood E, et al. N Engl J Med 2013;368:407–15.

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

First infusionof donor faeces

(n=16)

Infusion of donorfaeces overall

(n=16)

Vancomycin(n=13)

Vancomycin withbowel lavage

(n=13)

0

20

40

60

80

10081.3

93.8

30.823.1

p<0.001

p<0.001

p=0.008

p=0.003

Rat

es o

f cur

e w

ithou

t re

laps

e (%

)

FDX/12/0076/EUf | EK242

Microbiota diversity in patients before and after faecal infusion versus healthy donors

van Nood E, et al. N Engl J Med 2013;368:407–15.

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

50

0

100

150

200

250

Sim

pson

’s

reci

proc

al in

dex

Donors Patients beforeinfusion

Patients afterinfusion

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. Gough E, et al. Clin Infect Dis 2011;53:994–1002;2. Anderson JL, et al. Aliment Pharmacol Ther 2012;36:503–16;3. Guo B, et al. Aliment Pharmacol Ther 2012;35:865–75;4. Aas J, et al. Clin Infect Dis 2003;36:580–5;5. Hedge DD, et al. Ther Clin Risk Manag 2008;4:949–64;6. 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

– 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

1. Yoon SS, Brandt LJ. J Clin Gastroenterol 2010;44:562–6;2. Hedge DD, et al. Ther Clin Risk Manag 2008;4:949–64;3. Borody TJ, Khoruts A. Nat Rev Gastroenterol Hepatol 2012;9:88–96;4. Bakken JS, et al. Clin Gastroenterol Hepatol 2011;9:1044–9;5. van Nood E, et al. N Engl J Med 2013;368:407–15;6. Rohlke F, Stollman N. Therap Adv Gastroenterol 2012;5:403–20;7. Aas J, et al. Clin Infect Dis 2003;36:580–5.

FDX/12/0100/EUk | JC136

Documents

Conventional Treatment options