INFECTION WITH CLOSTRIDIUM DIFFICILE

By Prof. Thomas Borody MD PhD FRACP FACG FACP

(with references/credits at the end of the article)

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:

  1. 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.

  1. 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)

  1. 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)

  1. 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.

  1. 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)

  1. 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)

  1. 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)

  1. 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)

  1. 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)

  1. 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.

  1. 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.                                    

  1. 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)

  1. 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.

i) 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)

  1. 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.

  1. 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.

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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.