####The bacterium and the disease *Clostridium difficile* is a Gram-positive, strictly anaerobic, spore-forming bacterium that has been recognised since the 1930s, but was only recognised as a pathogen and the cause of antibiotic-associated diarrhoea and colitis about 30 years ago. The spectrum of *C. difficile* infection (CDI) ranges from mild, self-limiting diarrhoea, to serious diarrhoea, to pseudomembranous colitis (PMC) and life-threatening fulminant colitis. The bacterium can be detected in a small proportion of healthy individuals (about 4%), but in hospitalised populations can reach levels of 30% or more without causing symptoms. It is commonly found harmlessly in neonates. ####Pathogenesis and epidemiology The stages in the disease process are usually: * The normal protective properties of the gut – especially the colonisation resistance promoted by the normal resident bacteria (microflora) of the healthy of the gut – are compromised by antibiotics or less frequently by other therapeutic agents. * If *C. difficile* spores are in the local environment of the patient, the colon becomes colonised via the oral route. * The bacterium evades the immune response and multiplies, producing toxins A and B. If a patient is susceptible – that is, is unable to withstand the insult of the toxins, probably as a result of lowered or inadequate immunity – pathology results. The use of proton-pump inhibitors and H2 antagonists has been proposed as a cause of increased susceptibility to CDI, but the link is not yet proved. Symptoms ranging from diarrhoea of varying severity to fulminant colitis are caused by the destruction of enterocytes, a loss of absorptive capacity, leakage of electrolyte and an influx of inflammatory cells – predominantly neutrophils, which produce in the more severe cases the pseudomembrane typical of PMC (see Figure 1 and Figure 2). There are many different strains of *C. difficile* recognised worldwide, and typing is traditionally done by a PCR ribotyping method developed by the Anaerobe Reference Laboratory in Cardiff, Wales. Ribotypes are numbered sequentially from 001. This has become the standard typing method in Europe, but pulse-field gel electrophoresis (PFGE) and restriction endonuclease analysis (REA) are often used in North America. ####Current status *Clostridium difficile* infection was uncommon until the early 1990s, but the disease has certainly increased over the past decade or so – with a consequent increasing burden on health service providers. Evidence is accumulating to suggest that the disease may be increasing in severity, and much of this is due to the emergence of the hypervirulent, epidemic 027 strain (see below). The number of cases in many of our hospitals has now reached levels that are generally higher than those caused by the better-known methicillin-resistant *Staphylococcus aureus* (MRSA). Figures for Scotland up to 2005, the last year of voluntary reporting to Health Protection Scotland, are summarised in Figure 3. In 2006, Scotland, like some other countries in Europe, began mandatory reporting; figures for 2007 were 6,035 cases per year – a total based only on patients aged over 65 years. *Clostridium difficile* infection is the most common cause of healthcare-associated (nosocomial) diarrhoea and results in much morbidity in elderly hospital patients. Mortality has been associated with the disease, mainly as a contributory factor, but is being noted much more commonly on death certificates. In the recent outbreak at the Vale of Leven Hospital in Dunbartonshire (Dec 2007–June 2008), where 18 out of 55 infected patients died, *C. difficile* was either the direct or contributory cause noted on the death certificates. A high proportion of these patients appeared to be infected with the 027 strain (see below). Although not normally considered a problem in the community, CDI is certainly acquired there and it is not uncommon for patients to be carrying the bacterium on admission to hospital. It is possible that the bacterium has always been more common in the community than generally realised; our studies published in 1982 showed it to be as common as *Salmonella* spp and *Campylobacter jejuni* as causing diarrhoea in the community which requires hospital admission. [1] In the past few years there have been several notable outbreaks of CDI in the UK, all of which have been the subject of intense media coverage. The Healthcare Commission became involved in outbreaks at Stoke Mandeville in Buckinghamshire,[2] and Maidstone and Tunbridge Wells in Kent.[3] Most recently, an independent enquiry has reported on the outbreak at the Vale of Leven Hospital.[4] The reports all severely criticised the poor standards in hygiene and patient care. The latest data on CDI cases and mortality in all acute hospitals in Scotland from December 2007 to May 2008 has recently been published by Health Protection Scotland. This puts the situation at the Vale of Leven into perspective as it covers the same period and includes Vale of Leven data.[5] ####Transmission of *C. difficile* Our early understanding of the disease assumed that the bacterium was of endogenous origin: small numbers of *C. difficile* that were present in the colon were allowed to flourish after the normal microbiota was severely affected by antibiotic exposure. However, this does not explain the occurrence of outbreaks. When carefully looked for in the healthy adult population the organism is rarely encountered. It is now accepted that *C. difficile* is an infectious agent and is spread by faecal–oral transmission of spores from patient to patient, or from contaminated environment to patient. ####The hypervirulent strain The recognition of a hypervirulent strain firstly in Canada and the USA, and more recently in England, the Netherlands and Belgium, has brought the organism to the attention of the general public as the latest ‘superbug’. Clinicians familiar with the disease suggested early in the North American outbreaks that a strain of increased virulence was probably responsible for the problem.[6,7] This strain is now known in North America as REA type BI or PFGE type NAP1, and in Europe as PCR ribotype 027. In the UK ribotype 027 was first recognised as causing a problem at Stoke Mandeville Hospital in Buckinghamshire, where at least 12 deaths were reported from 150 cases in the period February–June 2004. It is now the most commonly isolated ribotype within England and Wales. The strain was first seen in Scotland in late 2006, but no other instances were recognised for a year. However, early in 2008 more cases of 027 infection appeared as exemplified by the recent outbreak at the Vale of Leven Hospital (see above). It appears that the new hypervirulent strain (BI/NAP1 or ribotype 027) has the following characteristics: * Compared to other commonly encountered strains it produces higher than normal levels of toxins A and B in vitro and this probably also occurs in vivo. * There is a deletion in the gene tcdC, which normally negatively regulates toxin production – resulting in a constant maximum level of transcription of toxin genes. The strain belongs to ribotype 027 and toxinotype III. * It is resistant to fluoroquinolone antibiotics such as ciprofloxacin and moxifloxacin. It produces an additional toxin – the binary toxin. This is not unique to this strain, and its importance in pathogenesis is unknown * The North American and European strains were likely to be from an identical parent clone, but molecular subtyping is demonstrating divergence of strains over time. * The disease that it causes is more severe than other strains of *C. difficile*, with more colectomies required and more deaths attributable to it. It is becoming apparent that the deletion in the toxin-regulating gene is not restricted to the 027 ribotype so a family of super strains may soon become apparent. Recent figures for Europe, published in July 2008,[8] indicate that 16 countries have now experienced disease due to ribotype 027, with outbreaks documented in nine of them and sporadic cases in the other seven. In the Netherlands, 50% of hospitals investigated for ribotype 027 have been shown to have patients infected with this strain, compared to 76% in England. To date in Scotland, few hospitals have been checked for 027 (n=18), but it has been found in 50% of those investigated. (For an update on the hypervirulent strain and other news on CDI in Europe see the [European Study Group for *Clostridium difficile* website.)](http://www.escmid.org/sites/index_f.aspx?par=2.5) ####Treatment options for C. difficile-associated disease Many patients, especially in wards for the elderly, carry *C. difficile* asymptomatically, and detection of the organism in the stool is not an indication to treat. If the disease is mild, no treatment may be necessary as the symptoms may resolve naturally. For more severe disease, stopping the administration of the precipitating antibiotic is the first option. If this is not possible or ineffective, administration of metronidazole or oral vancomycin is recommended. Although both work equally well in most patients, the former is usually used initially with the latter being reserved for more severe or unresponsive disease. Recent studies, however, have demonstrated that vancomycin is superior for cases of severe disease. As many as 30% of patients suffer a recurrence after initial resolution of symptoms, and of these a majority have multiple recurrences. These recurrences could be a real relapse or a re-infection with the same or a different strain of *C. difficile*. This common problem of recurrent CDI – together with the anathema of treating a disease caused by antibiotics with another antibiotic – has necessitated a thorough review of treatment schedules. However, a handful of new antibiotics are currently on trial, and OPT80 is showing much promise. OPT80 is a very narrow spectrum anti-clostridial drug, resistance to which does not seem to occur readily.[9] Alternative treatment options fall into four main areas: 1. Probiotics 2. ‘Faecal transplants/enemas’ – where stools donated from a healthy donor are placed in the bowel in an attempt to restore the normal microbiota 3. Absorbents for toxins – to eliminate them from the gut 4. Immunotherapy – either active or (probably more usefully) passive immunisation – usually targeted to neutralisation of toxins #####Probiotics and faecal transplants/enemas Currently, the probiotic approach has not produced any spectacular results and recently some rather poorly designed studies utilising proprietary yoghurt-like drinks have not been at all well received. However, probiotics have an inherent appeal as re-establishing the protective properties of a normal, healthy bowel flora is likely to be massively beneficial. This is highlighted by the apparent great success of instilling normal faeces into the gut. Although not a very ‘tasteful’ approach, several small studies have shown extremely good results. A properly controlled study is currently underway in the Netherlands. #####Eliminating toxins Removal of toxins from the gut lumen by means of binding agents has always been an attractive proposition. Phase two trials of tolevamer, an orally-administered binder of toxins A and B, showed great promise. However, recently-completed phase three trials in North America and Europe, where the toxin binder was compared to treatments with either vancomycin or metronidazole, demonstrated that it was inferior to vancomycin and metronidazole for treatment. That said, useful additional information came out of these extensive studies demonstrating that vancomycin was far superior to metronidazole for patients with severe disease. Patients treated with tolevamer did suffer fewer relapses than patients treated with antibiotics, but because of the differential efficacies as a result of disease severity it is still uncertain whether the binding agent will have any role in prevention of relapses, either alone or in combination with an antibiotic. #####Immunotherapy Immunological approaches also have much appeal, and both active and passive immunisation schemes are in development. As of August 2008, several companies, both large and small, are investigating immunotherapeutic approaches for CDI. Concerns have been expressed that active vaccination may not work because patients who are susceptible may be unable to respond to natural challenge, and may therefore be unable to respond to a vaccine. The use of monoclonal antibodies for passive therapy, although likely to work as demonstrated in animal models, may be prohibitively expensive. Cheaper alternatives for passive therapy have shown some promise, in particular the use of an antitoxin IgA-enriched fraction of milk from cows (‘mucomilk’), which has been vaccinated with toxoid. ####Infection control Many of our hospitals and institutions caring for the elderly are now highly contaminated with spores of *C. difficile*, and increasing numbers of susceptible, antibiotic-treated patients are propagating the organism. Infection control is difficult but its importance cannot be overestimated. Control measures include regular surveillance, isolation or barrier nursing, personal hygiene and intensive cleaning of affected wards to remove the bacterial spore load. Spores of *C. difficile* are resistant to alcohol-based antiseptics (alcohol hand-washing gels are ineffective), and chlorine-based disinfectants are only partially effective with the concentrations required not well tolerated by patients or cleaning staff. Hydrogen peroxide vapour is showing promise for room decontamination, but only when patients are not present. The need for isolating infected patients or barrier nursing them in outbreaks, together with their increased lengths of stay in hospital – especially for those who experience recurring disease – has resulted in considerable extra costs in the order of several thousand pounds per patient. Possibly the most useful method for reducing CDI is to ensure strict adherence to antibiotic prescribing policies. Restricting the use of those antibiotics such as third generation oral cephalosporins and clindamycin, which are known to precipitate the disease, is well recognised but crucially important. Fluoroquinolones – once not thought to precipitate the disease – now seem to select for the new fluoroquinolone-resistant 027 strains. Cautious use of these drugs is therefore also recommended. ####Further risks and research The association of *C. difficile* with animals has been long recognised. Disease symptoms similar to those of humans have been recognised in dogs and horses, and more recently C. difficile infections have been shown to cause much economic loss in piglets. Until very recently, the possibility that infected animals posed a zoonotic threat has not received much serious consideration; however, a ribotype previously seen mainly in pigs (ribotype 078, toxinotype V) is being observed more frequently in humans, and in the Netherlands it is now the third most common isolate in humans. [10] Other at-risk groups are being recognised or suspected, including paediatric patients and peripartum women. Over the next few years the significance of such groups should become clearer. Future research must concentrate on a) developing improved diagnostic methods; b) increasing our knowledge of what makes a strain virulent; c) increasing our knowledge of the mechanisms by which the host becomes resistant or susceptible to infection; d) developing new therapies; and e) perhaps most crucially, developing disinfecting/cleaning methods that remove the spores from the patient environment. Additionally, antibiotic prescribing policies should be tailored to decrease the precipitation of disease, and improved surveillance must be instituted with mandatory reporting and specialist laboratories. An editorial written by the author has recently been published in a *Clostridium difficile* special issue of the *Journal of Medical Microbiology*.[11] 2007-01-21T17:26:27Z None declared. 55 2006-05-16T00:00:00Z 2008-10-09T00:00:00Z clostridium-difficile-associated-disease-an-increasing-burden 2006-05-16T00:00:00Z

*Clostridium difficile* infection is primarily a healthcare-acquired problem which mainly affects the elderly and can be fatal. In many UK hospitals, levels of this infection have overtaken those of MRSA. The pattern of this disease appears to be changing, with more severe symptoms and a wider range of people at risk of infection. In an extensively revised version of this article, Professor Ian Poxton reviews the challenges involved in preventing and treating *Clostridium difficile* infections.

2009-03-25T09:21:07Z