INFECTION WITH CLOSTRIDIUM DIFFICILE
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
diarrhoea 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 behaviour. Still others may have recurrent
bouts of severe cramps, diarrhoea with or without 'wind'
and other symptoms. Unless CD is diagnosed and causes these
symptoms such patients could well be labelled with a diagnosis
of IBS.
Still other patients may have a condition
indistinguishable from colitis, with cramps, diarrhoea,
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,
Salazopyrin, Mesasal, Salofalk, Asacol (all examples of
5-ASA-containing compounds) and other anti-colitis drugs
because the steroids and anti-inflammatory drugs non-specifically
inhibit many types of inflammation. Furthermore, drugs such
as 5-ASA compounds have their own anti-CD activity.
Lastly the most severe and even devastating
CD infection can develop into 'pseudomembranous enterocolitis'
(PMC) with specific type of inflammation visible at colonoscopy.
It may lead to fulminant colitis, megacolon and even to
death from colon perforation and peritonitis. However, these
latter conditions are generally uncommon (35).
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.
Risk factors for relapse are said to include the number
of previous episodes, the need to use antibiotics recurrently,
female sex, and older age groups. (3,34)
C difficile is acquired from contact with
humans or objects harbouring 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 also occurs 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, or if the bowel flora
has a deficiency of Bacteroides bacteria(21),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 defence 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 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 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 experience in long-term usage.
e. Teicoplanin
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)
With antibiotics as a group various methods such as 'pulsing',
combinations, tapering and combination with probiotics
- 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)
f. Cholestyramine (Questran) and Colestid
granules These are adsorbing agents to
which CD toxins attach so as not to cause diarrhoea 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)
g. Antagonistic bacteria - Lactobacillus
GG; Valia yoghurt in Australia (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 or preceded with 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)
h. 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) One possible concern remains the
risk of fungaemia and infection of human organs with the
Saccharomyces(36).
i. 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 commonly given to patients
on admission to hospital. Little western literature is
available on this probiotic.
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)
j. 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.
k. Restoration of Human Bowel Flora (Human Probiotics
Infusion)
Two methods have been used. Infusion into the bowel of
freshly cultured mix of bowel bacteria, or infusion of
filtered, complete, healthy human faecal 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 several
patients and has been of help. It uses Bacteroides bacteria
(the most common bacterium in the bowel) plus healthy
or beneficial E.coli as two antagonistic bugs 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 the standard
therapy of last resort 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 to kill the CD and
its spores and if we count up all published 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, at the
Centre for Digestive Diseases for patients with documented,
chronic CD infection. All methods described above can
be used and success rate in CD eradication is > 90%.
For further information on Human Probiotic Infusion see
www.probiotictherapy.com.au
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, tiecoplanin, 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 teicoplanin 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
colitis. Am J Gastroenterol 1985;80:867-868
11. Lewis 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. Kelly 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. Kelly 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 of antibiotic-associated pseudomembranous
colitis. Am J Gastroenterol 1985;80:867-868.
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, Kelly CP. Asymptomatic carriage
of Clostridium difficile and serum levels of IgG antibody
against toxin A.N Engl J Med 20;342:390-397.
30. Leung DY, Kelly CP, Boguniewicz M, Pothoulakis C, Lamont
JT, Flores 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, Kelly CP. Recurrent Clostridium difficile diarrhoea.
Gut 2001;49:152-153.
32. Leung DY, Kelly 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. Niault M, Thomas F, Prost J, et al. Fungaemia due to
Saccharomyces species in a patient treated with enteral
Saccharomyces boulardii. Clinical Infectious Diseases 1999;28:930
Back
Home
|
