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). Nonetheless, in recent years an epidemic form of CD has emerged with high mortality and morbidity and urgent treatment needs to be initiated especially in those of co-morbidity, the infirm and the elderly
Chronic CD infection is estimated to occur in perhaps 15-30% of those infected. In some, re-infection can occur with the 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. A stool test negative for CD does not necessarily mean the CD is gone. CD may be difficult to detect on a stool test and sometimes recurrent testing may be necessary. Better tests including PCR are under development currently.
- 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) Vancomycin can also be delivered via an enema.
- 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. Nitazoxanide
This is a novel anti-parasite agent which has also been found to have activity against C. difficile. It can work especially in combination with other drugs and can suppress in some patients and eradicate CD in others.
- f. 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)
- g. Rifaximin
Rifaximin is a non absorbable alternative to Vancomycin. It has cured resistant CD and can be used as enemas in the treatment of chronic relapsing infection.
- h. 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)
- i. 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)
- j. 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).
- k. 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.
- 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)
- l. 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. Being used more frequently as a life saving procedure colectomy is being used as if C. difficile Colitis behaves in a similar fashion to idiopathic colitis. Unfortunately, the major drawback is the patients do not lose their C. difficile which continues to be present in post colectomy patients. Furthermore, faecal implantation which is effective even in patients with severe C. difficile will no longer work after colectomy.
- m. 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
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