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INFECTION WITH CLOSTRIDIUM DIFFICILE

By Prof. Borody MD PhD FRACP FACG FACP

(with references/credits at the end of the article)updated 2/2/07

Human infection with Clostridium difficile (CD) can take many forms.

Those reading this section are probably interested in this topic

because they, or perhaps a friend, may be suffering with the more

severe effects of CD infection. However, there is a whole spectrum of

CD infections ranging from mild forms through to life threatening

clinical CD infections (1,14,25,31). These will now be described.

CD infection can exist in patients who can be clinically relatively

well – eg carriers of very mildly pathogenic bacteria. Some may have

recurrent mild to moderate diarrhea resembling Irritable Bowel

Syndrome (IBS) and may not be at all concerned with these symptoms. In

fact they may consider themselves to be perhaps part of the normal

spectrum of bowel behavior. Still others may have recurrent bouts of

severe cramps, diarrhea with or without `wind' and other symptoms.

Unless CD is diagnosed and causes these symptoms such patients could

well be labeled with a diagnosis of IBS.

Still other patients may have a condition indistinguishable from

colitis, with cramps, diarrhea, urgency, mucus and variable amounts of

blood (33). At sigmoidoscopy typical inflammation is seen and may

initially be diagnosed as `idiopathic' colitis (colitis of unknown

cause). This disorder can also be recurrent with red patches visible

on colonoscopy in some areas of the bowel or indeed throughout the

colon. This kind of colitis can respond to prednisone, Asacol (and

other forms of mesalazine) and other anti-colitis drugs because the

steroids and anti-inflammatory drugs non-specifically inhibit many

types of inflammation. Furthermore, drugs such as Asacol (5-ASA

compounds – see below) have their own anti-CD activity. They are

antibiotics which also possess anti-inflammatory action.

Lastly the most severe and often devastating CD infection can develop

into `pseudomembranous enterocolitis' with a specific type of

inflammation visible at colonoscopy. It may lead to fulminant colitis,

megacolon and even to death from colon perforation and peritonitis.

These latter conditions are generally uncommon (35). However, in

recent years we have seen the arrival in North America of a mutant CD

bacterium with markedly elevated levels of toxin production. This new

strain has a tendency to result in the more severe clinical conditions

described above and can more frequently cause pseudomembranous

enterocolitis, megacolon and perforation (36).

Chronic CD infection is estimated to occur in perhaps 15-30% of those

infected. In some, re-infection can occur with same or different

strain. Also, the small bowel may act as reservoir of spores, entering

the colon and there is recent evidence that the appendix may also act

as a reservoir of C. difficile. (37). Risk factors for relapse are

said to include :- the number of previous episodes, the need to use

antibiotics recurrently, female sex, use of stomach acid suppressants,

and older age groups. (3,34)

C difficile is acquired from contact with humans or objects harboring

these bacteria. It can be commonly acquired during hospitalization

with up to 30% of those who have spent a prolonged period in hospital

leaving the hospital carrying these bacteria in the bowel flora.

(12,13) This is particularly so if antibiotics had been administered

so disturbing the protection of the natural bowel flora. Non-hospital

acquisition of CD is occurring more frequently and again a course of

antibiotics may permit the growth of CD and `awake' a clinical condition.

Human infection occurs through ingestion (via the mouth) and if the

bacterium survives acid and bile on its passage into the bowel it may

be eradicated by the normal bowel flora. However, if the bowel flora

is suppressed because of concomitant use of antibiotics, CD can

colonize the flora and remain with the patient – generally for life.

In some individuals it seems that antibiotics are not required for

colonization to take place. This may be perhaps due to inadequate

defense of the naturally occurring flora within the bowel. CD is a

very hardy organism probably because it contains spores. Spores are

unable to be eradicated by any currently known antibiotic. One way of

eradicating spores is to autoclave the spore-containing specimen using

a sterilizer. Of course a patient cannot be placed in a sterilizer.

However some natural bacteria appear to be capable of inhibiting the

growth of CD and even eradicating the spores and this characteristic

has been used to develop `bacteriotherapy' which will be described below.

There are a number of therapies for C difficile-associated disorders:

a. Withdrawal of antibiotics

In many situations when antibiotics are stopped the normal flora

re-grows and the patient can actually lose the presence of the CD and

its toxins. In this situation the normal indigenous flora has not been

damaged enough by the antibiotics to lose its protective bacteria,

especially Bacteroides, the friendly Clostridia species and other

bacteria which are antagonistic to CD. This may be the mechanism by

which many recover spontaneously and indeed lose the CD. However, in

many situations even withdrawal of antibiotics does not lead to the

disappearance of CD which then may persist lifelong.

b. Metronidazole(Flagyl)

This is a first-line medication for treatment of CD infection but on

its own it is unlikely to eradicate CD and can cause nausea in higher

doses. From clinical experience it appears that if the bowel flora is

adequate then metronidazole together with the existing bowel flora may

at least terminate the clinical infection. (4,5,6)

c. Vancomycin

Equally powerful if not a better though more expensive anti-microbial

agent. Vancomycin's advantage is that it is not absorbed into the

blood stream and very rarely causes side effects. Some specialists

prefer a combination of metronidazole and vancomycin. Whereas

metronidazole has some theoretical problems such as peripheral nerve

damage with long term usage vancomycin does not have significant

complications when used orally long term. (4,5,7)

d. Rifampicin

Yet another anti-Clostridial antibiotic which has been found to be

useful in CD infection and can be used for longer periods but may have

side effects. We know it can be used for 1-2 years continuously since

rifampicin was part of the standard drug for treatment in tuberculosis

giving us safety experience with long-term usage.

e. Teichoplanin

This is a newer glycopeptide antibiotic related to vancomycin and is

not readily available. It has probably little advantage over

vancomycin unless resistance has developed and resistance is said to

be rare. (5,7)

f. Rifaxamin

Rifaximin is quickly becoming yet another useful medication in the

treatment of C difficile and like vancomycin is not absorbed from the

bowel. It is similar in its action to vancomycin, has high in-vitro

activity against C difficile and achieves high faecal concentrations

after oral administration. It can be also successful in those patients

who had failed metronidazole and vancomycin as well as combinations of

vancomycin and rifampicin. (38,39,40)

g. Nitazoxanide

Yet another antimicrobial agent added to our armory of fighting C.

difficile is Nitazoxanide. Also used in treatment of parasites,

nitazoxanide has in-vivo and in-vitro activity against C. difficile

and had recently been reported to be not only useful orally in

recurrent C. difficile but also in combination as an oral preparation

combined with vancomycin enemas. (42)

With antibiotics as a group various methods such as `pulsing',

combinations, tapering and combination with probiotics (beneficial

bacteria) – listed below – have been advocated by some – and indeed

useful in some individuals. Such combinations should not be discarded

as `anecdotal' and we should collect reports from individual successes

and cures, for in this way we may be able to design trials and test

better treatments. (9,10,25,26)

h. Cholestyramine(Questran) and Colestid granules

These are adsorbing agents to which CD toxins may attach so as not to

cause diarrhea and cramping. They do not eradicate CD but can reduce

the effects of the toxins. The powders can be difficult to mix with

fluids and may cause nausea. Helpful clinically to many, and also

lower cholesterol as a beneficial `side effect'. (8)

i. Antagonistic bacteria - Lactobacillus GG (Culturelle – in the US)

This lactobacillus is a probiotic which was isolated by Drs Sherwood

Gorbach and Barry Goldin (hence LGG) is available in many countries

for treatment of chronic CD infection symptoms. On its own LGG may

suppress CD. When combined with or preceded by vancomycin and

metronidazole it may be curative in some situations. In our experience

it is probably required in high doses and for longer periods of time.

The major advantage of LGG is its lack of side effects and potential

for cure in some patients. (11,15,27)

j. Steroids

Intravenous steroids have been used in refractory C. difficile colitis

in patients who are very ill and are not responding to metronidazole

and vancomycin.

k. Mesalazine

Mesalazine belongs to a group of medicines used in colitis called

5-Amino Salicylic Acid. This group includes azulfidine, mesalazine and

olsalazine. Mesalazine has anti-inflammatory actions in colitis, but

more importantly in CD it is an antibiotic (Lin and Pimentel, US

Patent 6,326,364-2001 ) which can retard the growth of CD and in

chronic CD infection can abolish the symptoms when taken continuously

at doses used in colitis. It is also much cheaper than is vancomycin

and has few side effects.

l. Saccharomyces boulardii

This is a friendly fungus which has activity against the C. difficile

toxins A and B. It colonizes the bowel transiently, has been proven to

give relief better than placebo but has never been able to eradicate

CD. It is useful especially in combinations to control symptoms

initially. (2,16,28)

m. Clostridium butyricum (Myiari 588 Strain)

This is a friendly Clostridium which can live normally in the human

flora, is quite safe and is available commercially in Japan, Korea and

China. It interferes with the growth of CD antagonizing its

multiplication. It is commonly used in Japanese hospitals to

successfully prevent CD being acquired and is given to patients on

admission to hospital. Little western literature is available on this

probiotic.

n. Immune Anti-C difficile Globulin

This is normal pooled human gammaglobulin which generally contains

antibodies to C difficile toxins and can be used in severe cases.

Generally not curative. (29,30,32)

o. Surgery

In severe cases of fulminant colitis or toxic megacolon removal of the

colon may be required, otherwise perforation, septic shock and death

may follow. Even surgery in these very severe cases may be too late to

save lives.

p. Restoration of Human Bowel Flora

Two methods have been used. Infusion into the bowel of freshly

cultured mix of bowel bacteria, or infusion of filtered, complete,

healthy human fecal bacteria. The first form has been reported by

Tvede et al in 1989 but is no longer available. A two-bacterial

per-enteroscope infusion has been available in Kansas City for years

and has been of considerable help to many patients. It uses

Bacteroides bacteria (the most common bacterium in the bowel) plus

healthy or beneficial E.coli as two antagonistic bacteria to CD. It

can rid the patient of CD and spores. Success rate is not known. (21)

The other method is the infusion of all the bacteria originating from

a healthy donor. This is now the recommended therapy for recurrent and

refractory C. difficile infection in North America. (42) It is the

therapy of last resort for severe C. difficile infection where other

therapies are failing and the patient continues to have marked

symptoms. Practicing physicians should be aware that patients now have

the option of total bowel flora infusion which may in some situations

be a life-saving procedure. This is the recommended therapy for

relapsing, severe CD infection where other therapies are failing and

the patient continues to have marked symptoms. The treatment uses

bowel flora (faeces) homogenized in sterile saline, often filtered,

and the slurry containing the total living protective bacteria is

infused into the bowel of the patient. This can be done through a

colonoscope under sedation, via enema, or through a naso-jejunal tube

to take care of the small bowel reservoir of CD.

Though perhaps aesthetically not very attractive this therapy is the

most reliable method available to kill the CD and its spores. Summing

up all published series and anecdotal reports the therapy has a

documented cure rate of well over 80%. (17,18,19,20,22,23,24) It is

carried out on a routine basis as a clinical service in Sydney,

Australia for patients with documented, chronic CD infection with a

success rate in CD eradication of > 90%.Sites in North America are now

becoming available.

REFERENCES:

1. Cleary RK. Clostridium difficile-associated diarrhoea and colitis:

Clinical manifestations, diagnosis and treatment. Dis Colon Rectum

1998;41:1435-1449.

2. Surawicz CM, McFarland LV, Elmer G. Chinn J. Treatment of recurrent

Clostridium difficile colitis with vancomycin and Saccharomyces

boulardii. Am J Gastroenterol. 1989;84:1285-1287.

3. Fekety R, McFarland LV, Elmer G, Chinn J. Recurrent Clostridium

difficile diarrhoea: characteristics of and risk factors for patients

enrolled in a prospective, randomised, double-blinded trial. Clin

Infect Dis. 1997:24:324-333.

4. Teasley DG, Gerding DN, Olson MM et al. Prospective randomised

trial of metronidazole versus vancomycin for Clostridium

difficile-associated diarrhoea and colitis. Lancet. 1983;2:1043-1046.

5. Wenisch C, Parschalk B, Hasenhundt M, Hirschl AM, Graninger W.

Comparison of vancomycin, teichoplanin, metronidazole, and fusidic

acid for the treatment of Clostridium difficile-associated diarrhoea.

Clin Infect Dis. 1996;22:813-818.

6. ASHP therapeutic position statement on the preferential use of

metronidazole for the treatment of Clostridium difficile-associated

disease. Am J Health Syst Pharm 1998;55:1407-1411.

7. De Lalla F, Nicolin R, Rinaldi E et al. Prospective study of oral

teichoplanin versus oral vancomycin for therapy of pseudomembranous

colitis and Clostridium difficile-associated diarrhoea. Antimicrob

Agents Chemother.1992;36:2192-2196.

8. Ariano RE, Zhanal GG, Harding GK. The role of anion-exchange resins

in the treatment of antibiotic-associated pseudomembranous colitis.

CMAJ. 1990;142:1049-1051.

9. Tedesco F. Treatment of recurrent antibiotic-associated

pseudomembranous colitis. Am. J Gastroenterol. 1982;77:220-221

10. Tedesco FJ, Gordon D, Fortson WC. Approach to patients with

multiple relapses of antibiotic-associated pseudomembranous colits. Am

J Gasteroenterol 1985;80:867-868

11. SJ, Freeman AR. Review article: the use of biotherapeutic

agents in the prevention and treatment of gastroenterological disease.

Aliment Pharmacol Ther.1998;12:807-822.

12. Fekety R, Kim KH, Brown D, Batts DH, Cudmore M, Silva J Jr.

Epidemiology of antibiotic-associated colitis: isolation of

Clostridium difficile from the hospital environment. Am J Med.

1981;70:906-908.

13. Kim KH, Fekety R, Batts DH et al. Isolation of Clostridium

difficile from the environment and contacts of patients with

antibiotic-associated colitis. J infect Dis. 1981;143:42-50.

14. CP, Pothoulakis C, LaMont J. Clostridium difficile colitis.

New Eng J. Med 1994;330:257-262.

15. Seal D, Borriello SP, Barclay, Welch A, Piper M, Bonnycastle M.

Treatment of relapsing Clostridium difficile diarrhoea by

administration of a non-toxigenic strain. Eur J Clin Microbiol

1987;6:51-53.

16. Surawicz CM, McFarland LV, Elmer G, Chinn J. Treatment of

recurrent Clostridium difficile colitis with vancomycin and

Saccharomyces boulardii. Am J Gastroenterol 1989;84:1285-1287

17. Persky SE, Brandt LJ. Treatment of recurrent Clostridium

difficile-associated diarrhoea by administration of donated stool

directly through a colonoscope. Am J Gastroenterol 2000;95:3283-5.

18. Eisman B, Silen W, Bascom GS, Kauver AJ. Fecal enema as an adjunct

in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854-9.

19. Bowden TA, Mansberger AR, Lykins LE. Pseudomembranous

enterocolitis: Mechanism of restoring flora homeostasis. Am Surg

1981:47:178-83.

20. Schwan A, Sjolin S, Trottestam U. Relapsing Clostridium difficile

enterocolitis cured by rectal infusion of homologous faeces. Lancet

1983;ii:845

21. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing

Clostridium difficile diarrhoea in six patients. Lancet 1989;i:1156-60.

22. Flotterod O, Hopen G. Refractory Clostridium difficile infection.

Untraditional treatment of antibiotic-induced colitis. Tidsskr Nor

Laegeforen 1991;111:1364-5.

23. Paterson DL, Irdell J, Whitby M. Putting back the bugs: Bacterial

treatment relieves chronic diarrhoea. Med J Aust 1994;160:232-3.

24. Lund-Tonnesen S, Berstad A, Schreiner A, et al. The effect of

faecal enema on five microflora-associated characteristics in patients

with antibiotic-associated diarrhoea. Scand J Gastroenterol 1999;34:580-6.

25. CP, Pothoulakis C, Lamont JT. Clostridium difficile colitis.

N Engl J M 330:257-262.

26. Tedesco FJ, Gordon D, Fortson WC. Approach to patients with

multiple relapses with antibiotic-associated pseudomembranous colitis.

Am J Gastroenterol 1985;80:867.

27. Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing

Clostridium difficile colitis with Lactobacillus GG. Lancet 1987;2:1519.

28. McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer

K. Randomized placebo-controlled trial of Saccharomyces boulardii in

combination with standard antibiotics for Clostridium difficile

disease. JAMA 1994;271: 1918.

29. Kyne L, Warndy M, Qamar A, CP. Asymptomatic carriage of

Clostridum difficile and serum levels of IgG antibody against toxin

A.N Engl J Med 20;342:390-397.

30. Leung DY, CP, Boguniewicz M, Pothoulakis C, Lamont JT,

A. T with intravenously administered gamma globulin of chronic

relapsing colitis induced by Clostridium difficile toxin. J. Paediatr

1991;118:633-637.

31. Kyne L, CP. Recurrent Clostridium difficile diarrhoea. Gut

2001;49:152-153.

32. Leung DY, CP, Boguniewicz M et al. Treatment with

intravenously administered gamma-globulin of chronic relapsing colitis

induced by Clostridium difficile toxin. J Pediatr 1991; 118:633-7.

33. Saad Fadi Yassan, Tonia M. Young-Fadok, Nizar N Zein, Darrell S

Pardi. Clostridium difficile-associated diarrhoea and colitis. Mayo

Clinic Proc.2001;76:725-730.

34. McFarland L. Surawicz CM, Stamm WE. Risk factors for Clostridium

difficile carriage and C difficile–associated diarrhoea in a cohort of

hospitalized patients. J Infectious Dis 1990;162:678-684.

35. Bartlett JG. Clostridium difficile: clinical considerations. Rev

Infec Dis.1990;12(suppl 2):S243-S251.

36. Riley TV. Epidemic Clostridium difficile. MJA 2006;185:133-134.

37. Mahajan LA, Hupertz V, Mahajan S, F, D. The Appendix: A

possible reservoir for Clostridium difficile. Am J. Gast. 2006:101:S392.

38. S, Galang M, Schriever C, C, Gerding D. Rifaximin

chaser following standard therapeutic cocktail for breaking the cycle

of multiple C. difficile diarrhea recurrences. Am J. Gast. 2006:101:S219.

39. Rubin DT, Sohi S, Gluthar M, T, Yadron N, Surma BL.

Rifaximin is effective and safe for the treatment of Clostridium

difficile-associated diarrhea. Am J. Gast. 2006:101:S208.

40. Berenbaum PL. Oral rifaximin in treatment of Clostridium

difficile-associated diarrhea. Am J. Gast. 2006:101:S199.

41. Korenfield S, Desai K, Gotian A, Brandt LJ. Vancomycin enemas and

nitazoxanide treatment of recurrent C. difficile colitis. Am J. Gast.

2006:101:S322.

42. Borody TJ, Leis S, Pang G, Wettstein AR. Fecal bacteriotherapy in

the treatment of recurrent C. difficile infection. (Up-To-Date)

(http://patients.uptodate.com/topic.asp?file=gi_dis/32751

Copyrighted 2002, Dr. Tom Borody & Clostridium Difficile Support

Group/Foundation. Certain information is copyrighted by the respective

individuals as noted with the references.