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  3. Clostridium Difficile: an increasing problem for infection control and healthcare practitioners.A review of the international research evidence.

Clostridium Difficile: an increasing problem for infection control and healthcare practitioners.A review of the international research evidence.

In spite of heightened awareness of infection control issues and the introduction of continuously improving infection control policies and programmes, healthcare- associated infection continues to be a common occurrence. One nosocomial pathogen Clostridium difficile is one of the more common infective cause of diarrhoea in hospital patients; it is becoming an increasing problem in Japan and is also found in up to 30% of patients on antibiotics who remain asymptomatic (Modena et al, 2005). Worsley (1998) describes how Clostridium difficile can cause a range of distressing patient symptoms; varying from mild diarrhoea to sever explosive diarrhoea with life-threatening pseudo-membranous colitis; and is associated with antibiotic use. The increased incidence of cases can lead to prolonged in-patient hospital stays and incur increased financial costs and patients can suffer from recurrence of the infection even after treatment.

A voluntary surveillance scheme reported 43,672 case of Clostridium difficile throughout England, Wales, and Northern Ireland in 2004 (Health Protection Agency, 2005). This figure almost doubled the figures reported for the year 2001 which totalled 22,008 (Choudhari, 2005). Although it could be said that some of this increase could be due to improved laboratory testing and reporting practices, the marked increase in cases has led to voluntary surveillance being changed to a mandatory reporting scheme in many countries.

The serious implications of this infection, along with anecdotal evidence of its increase, have generated a need to discover what can be done, in the hospital setting, to decrease its incidence. Examination of the literature identified certain recurrent themes. These included: the link between antibiotics use and Clostridium difficile, the study of the efficacy of probiotic use in the prevention and treatment of Clostridium difficle and the examination of the effect of infection control measures on the incidence of the infection. Other studies not able to be classified under these themes included: one studying the recurrence of Clostridium difficile (McFarland et al, 1999); one examining the incidence of stool colonisation of health workers (Carmeli et al, 1998) and two studies examining predisposing risk factors of those patients getting C. difficile (Kyne et al, 2002) and those dying from the disease or undergoing colectomy surgery (Dallal et al, 2002).


Gould and Brooker (2000) describe Clostridium difficile as being a gram-

positive, anaerobic bacterium which forms spores under adverse conditions. These spores are resistant to desiccation and heat and are therefore able to survive in the environment for long periods; germinating when conditions return to those favourable for growth (Gould & Brooker, 2000). This makes effective management of the infection difficult as only certain cleaning products are efficient at destroying these spores (Wilcox et al, 2003). Clostridium difficile (found usually in the large intestine in low numbers only), are kept in check by 'good' bacteria which populate the intestine (DH, 2006). However, when commensal bacteria are destroyed or their numbers suppressed (as occurs in patients on antibiotic therapy) Clostridium difficile multiplies, releasing Toxins A and B which damage the cells of intestinal epithelium and result in the patient developing profuse watery diarrhoea (Gammon 1995). Maintaining effective control measures to prevent spread of the infection is made difficult because the organism is excreted in the faeces of affected patients and bacterial spores are found in large numbers in the surrounding environment (Worsley, 1998). Transmission occurs by ingestion (faecal-oral route) or through direct inoculation of the bowel through contaminated equipment (e.g. sigmoid scope) (Worsley, 1998) and generally, in hospitals, transmission occurs via the hands of care staff or by direct contact with affected patients or a contaminated hospital environment (Zafar et al, 1998). The infection is diagnosed by detecting specific Toxins A and B in faecal samples (Healthcare Commission, 2005).

Of the studies examined in the literature search, all those which identified risk factors of Clostridium difficile (17 out of 21 studies) agreed that prior antibiotic use was implicated in its incidence (e.gs. Ludlam et al, 1999, Worsley, 1998, Zafar et al, 1998). Some studies actually mentioned specific antibiotics causing increased risk; e.g. Aminopenicillins, cephalasporins and Clindamycin (D'Souza et al 2002, Barbut & Meynard 2002, Impallomeni et al, 1995). Agreement was also reached in all studies that the infection affected the elderly population most. Risk factors mentioned in some of the studies included severe underlying disease (Zafar et al 1998, Madeo et al 1999) and those undergoing surgery (HPA 2005) or staying in intensive care (D'Souza et a1 2000, Barbut & Meynard 2002). These findings were supported by the National Clostridium difficile Standards Group (DH, 2003a) who specified risk factors as being those of prior antibiotic exposure and certain 'host immunity' and who promoted surveillance by testing diarrhoeal samples in those patients over 65 years only.

The link between antibiotic use and Clostridium difficile

Having already established that prior antibiotic exposure is the main risk factor for developing C. difficile, it is important to scrutinise the studies which specifically examine this link in more detail. Five out of the total 24 studies were able to be categorised under this theme as they aimed in some way to prove the link between antibiotic use and C. difficile incidence. Three examined the link between this nosocomial infection and specific antibiotics e.g. Cephalosporins (Ludlam et al, 1999), Cefotaxime (Impallomeni et al, 1995) and Quinolone use (Yip et al, 2002). Harbarth, et al's study (2001) aimed to test the hypothesis that extended prophylaxis increased Clostridium difficile-associated diarrhoea (CDAD) and the remaining study compared the clinical characteristics of those patients on antibiotics who did not (Modena et al, 2005). The studies originated from varying locations; two were from the United Kingdom, two from the U.S.A. and one from Canada. Thus there may be regional differences in practice to consider when analysing results. The studies, however, were strengthened by the majority studying large groups (e.g. Impallomeni et al, 1995) examined 1037 patients, Harbarth et al, 2001: 2641 patients, Ludlam et al, 1999: 2157 case patients) and having studies performed over longer times varying from 11 months (Modena et al, 2005) to 4 years (Harbarth et al, 2001). Those studies including control groups (Yip et al, 2002) Ludlam et al, 19999 & Modena et al, 2005) were made more robust by ensuring that the control groups matched case patients in age, gender, and by same date of admission and duration of stay. The study by Impallomeni et al (1995), although comparing C. difficile incidence with antibiotic expenditure, was weakened by having no control patient group to compare results to: this created uncertainty a to whether cases were linked or whether the increased cases over the winter months were die to usual seasonal increase. Those examining variables [including Modena et al (2005], Yip et al (2002) and Harbarth et al (2001)] were strengthened by considering confounding of these and made conclusions only from those variables proved significant.

All the studies proved some link between C. difficile incidence and antibiotic use: Ludlam et al's (1999) study showed that cases fell from 98 to 45 when Cephalosporin use was restricted, in contrast to the control group where cases increased; Harbarth et al's study (2001) showed significant predictors of incidence to be Cephalosporin and Beta- lactamase antibiotic use; Yip et al (2002) identified significant variables of CDAD to be prior exposure to Ciprofloxacin and Cephalosporin, and Impallomeni et al {1995) found 1 in 5 patients on Cefotaxime developed C.difficile. An increased length of hospital stay was also indicated by four out of the five results as being either a risk factor or as a result of C. difficile. This could be because those patients staying longer have increased exposure to the infection or because those patients with C.difficile stay longer due to symptoms and necessary treatment. Extended length of stay was demonstrated to vary between 39.5 days (Ludlam et al, 1999) and 62 days (lmpallomeni et al, 1995) compared to 19 days and 21 days (respectively) with control cases. The results of Ludlam et al's interventional study (1999) could be related easily to practice in that increased costs of antibiotic use resulting from implementing antibiotic policy (?8062) were compared to those estimated savings generated by the release of wasted bed days by having 53 1ess cases of C.difficile (?212,000).

Conflicting results occurred in some studies: Modena et a1 (2005) did not prove narrow or broad spectrum beta-lactamase antibiotics to cause increased risk of C.difficile. This is in contrast to the results of Harbarth et al (2001) which showed exposure to the same antibiotics as significant predictors of CDAD. The results of the same study (Harbarth et al, 2001) proved contrary to what might have been expected. It would be natural to presume that if C.difficile incidence is linked to antibiotic use, then prolonged antibiotic prophylaxis might result in increased incidence. However, results demonstrated no increased risk; indicating that even very short doses of antibiotics may be sufficient to predispose patients to C.difficile (Harbarth et al, 2001). Having demonstrated the link exists between antibiotic use and C.difficile incidence and acknowledging that antibiotic use cannot be avoided altogether; although more prudent use is called for (Worsley, 1998); it is appropriate to discover what measures may be taken to prevent or manage the incidence of CDAD. One such measure evident in the literature review is that of Probiotic use.

Probiotic use in the prevention and treatment of Clostridium difficile

Six of the twenty-four studies selected, examined the use of probiotics. Three of these examined how effective probiotic use was in relation to prevention and treatment of C. difficile and included a literature review (McFarland, 2005), a critique of meta-analysis results (Bandolier, 2002) and a meta-analysis examining nine studies (D'Souza et al, 2002). One study compared the effects of probiotics (Lactobacillus and Bifidobacterium bifidum) against a pre-biotic (fructo-oligosaccharides-FOS) [Madeo et al 1999]. The remaining 2 studies; that of Barbut & Meynard, 2002 and Gagan, 2003; reviewed D'Souza et al's meta-analysis (2002), therefore failing to provide any additional research findings.

All research studies identified were of sound method consisting of randomised, double-blind control trials of probiotics given with antibiotics compared to a control group given placebo and antibiotics. Madeo et al's study (1999) also examined a third group given a probiotic and antibiotics, comparing the action of this against the other two groups. The actual probiotic substances studied varied between trials. The meta-analysis (which was of more benefit than a single study as it compared 9 trials in total) included four trials using a yeast- Saccharomyces boulardii, four using lactobacilli and one a strain of an enterococcus producing lactic acid (D'Souza et al, 2002). This variation, along with other differences in study characteristics [differing doses were administered over periods ranging from 5 days (Gotz et al, 1979) to 49 days (McFarland et al, 1995: both cited by D'Souza et al, 2002) and patients were treated with different antibiotics] made it difficult to compare study results (Gagan, 2003). The studies were also disadvantaged by small sample sizes ranging from 20 patients (Orrhage et al, cited by D'Souza, 2002) to 388 patients (Adam et al 1977, cited by D'Souza et al, 2002). Results of D'Souza et al's (2002) meta-analysis and Bandolier's review (2002) were made less applicable by their examination of a wide range of patient ages (only 3 studies out of 16 examined those over 65). Whereas Madeo et al's (1999) study gained strength by examining those patients considered to be in the most 'at risk' age range- 66-95 years. Results of each of D'Souza et al's (2002) studies were consistent in that they measured the same thing: the percentage of patients without diarrhoea comparing those of treatment groups to placebo groups. In contrast, the other studies measured results as a percentage to those who developed diarrhoea. All the meta-analysis trials except one demonstrated a higher percentage of patients without diarrhoea in the active group than the placebo group (D'Souza et al, 2002). However, it could be argued that different antibiotics were studied over the 9 trials which might alter the risk of patients getting diarrhoea and may have affected their response to probiotics. On average, results demonstrated 17% more patients with less diarrhoea were in the active group than the placebo group. The greatest range in results were those of Orrhage et al which showed 80% of patients without diarrhoea in the active group compared to 30% without diarrhoea in the control group. Interestingly, this study examined patients treated with the antibiotic Clindamycin - one of those antibiotics previously identified as causing increased risk of Clostridium difficile. Although failing to provide evidence that probiotics are beneficial in the treatment of C.difficile, the results led D'Souza et al (2002) to conclude that probiotics can be used to prevent antibiotic-associated diarrhoea and that both S. boulardii and lactobacilli have the potential for this. These results, however, conflict with those of Madeo et al (1999) who found no evidence to support the idea that Lactobacillus combined with B.bifidum decreases the incidence of antibiotic-associated diarrhoea (AAD). Their trial results showed none of the patients receiving FOS developed diarrhoea compared to 13% of those on probiotics and 11% of those receiving placebo. It could be argued that the failure of the probiotic group could be because inadequate doses were given, or that these probiotics may be ineffective in this particular combination and as patients from the three groups were receiving different antibiotic therapy this again leads to difficulty comparing results and may make conclusions misleading.

Overall, the findings from the studies on probiotics demonstrated some benefit in their use in decreasing the incidence of antibiotic-associated diarrhoea. However, results were conflicting and the author found difficulty relating results to practice as there was little or no consensus as to which probiotics should be given with which antibiotic and no clarity on the doses required to make probiotics effective (Gagan, 2003). Most of the studies acknowledge the advantages of probiotics as being: their natural form; their ease of administration; their cost-effectiveness compared to antibiotic treatment of Clostridium difficile and their relatively few side effects (Gagan, 2003, McFarland, 2005, D'Souza et al, 2002). As many probiotic products are available 'over the counter' in supermarkets (e.g. Yakullt, Actimel) at relatively low cost, patients could be advised to take one of these products daily when prescribed antibiotics and their effect observed locally to note for decrease in incidence of Clostridium difficile.

Having discovered that probiotic use is effective only for the prevention of Clostridium difficile, it is important to examine those factors evident in the literature review which highlight what infection control measures may assist in effective management of this nosocomial infection.

The effect of infection control measures on the incidence of Clostridium difficile.

Studies examining the effect of infection control measures on the incidence of C.difficile (9 in total), varied in method and included four descriptive articles written by those working within the field of Infection Control (Hateley, 1997; Gammon, 1995; Worsley, 1998; Miller et al, 1998), two 'in vivo' studies (Zafar et al, 1998, Lai et al, 1997) and three research studies examining the action of cleaning chemicals on Clostridium difjicile spores (Wilcox et al, 2002, Block 2004 & Wullt et al, 2003).

Analysis of the descriptive articles revealed repeated endorsement of certain infection control measures. These included those measures designed to prevent the spread of Clostridium difficile by direct and indirect contact. They included: early isolation of those patients suspected of having C.difficile and use of enteric precautions (Hateley, 1997, Zafar et al, 1998, Gammon, 1995, Worsley, 1998); stringent, frequent cleaning of the environment to reduce microbial load (Zafar et al, 1998, Worsley, 1998, Hateley, 1997, Wilcox et al, 2003) and effective hand hygiene. This was regarded as the "single most important method of preventing cross-infection" (Hateley 1997: 576) [Gammon, 1995, Zafar et al, 1998, Worsley, 1998]. Despite anecdotal evidence demonstrating a lack of compliance to hand washing as being a problem in infection control, this was acknowledged by only one study (Worsley, 1998).

When examining the prevention of Clostridium difficile, there was also consensus from the studies that restriction of antibiotic use was required (e.g. Hateley, 1997, Worsley, 1998). This view was supported by the findings from Lai et a1's study (1997) [which discovered that the introduction of a range of Infection Control measures; although reducing C.difficile incidence from 2.25% to 1.32%; failed to reduce figures to baseline level due to the affect of antibiotic use] and has also been previously illustrated by other studies of the literature review.

Agreement was reached within the two studies which discussed actual treatment of Clostridium difficile; both stating that it should initially include stopping antibiotic therapy and then, if necessary, be treated with oral Metronidazole or oral Vancomycin for more severe cases (Gammon, 1995 & Hateley, 1997). This was supported by review of local hospital policy, although this differed slightly in that Vancomycin use was to be introduced only for patients with recurrent C.difficile infections (Swansea NHS Trust, 2002).

There were very few research studies aiming to prove the positive effect of infection control measures on C.difficile incidence. However, one could argue that if certain measures have been demonstrated from expert consensus to be effective in reducing spread of C. difficile infection; then it would unethical to not carry out these precautions in order to perform clinical trials. Those research studies which did examine general IC measures were not of robust method but did examine incidence within the clinical area- one was an interventional study (Zafar et al, 1998) and one a case-control study (Lai et al, 1997). The interventional study did demonstrate that various infection control measures reduced incidence by 60% (Zafar et al, 1998) and was performed using a large study group over 6 years. However, several measures were introduced at once (including patient isolation/education programmes regarding hand washing/ triclosan soap use/ phenolic disinfection). Therefore, it was not possible to conclude which measures were effective. As no control group was used in the study to compare results to, a spontaneous decrease in incidence could not be excluded (Zafar et al, 1998). The study would also benefit from being revisited some time after its completion to evaluate if compliance with measures had continued and incidence figures continued at the reduced rate.

The results from the three robust, research studies examining the effects of specific different agents were used in each study. Thus making it impossible to conclude from consensus that one certain agent was suitable for clinical use. Wullt et al (2003) found acidified nitrate and peractyl ions effective and safe to use; Block (2004) found Perasafe more active than sodium dichloroisocyanurate and Wilcox et al (2003) examined hypochlorite use. Block's study (2004) was made more relevant for application to practice by testing the action of sporicidal agents on those surfaces found typically in clinical areas e.g. stainless steel and floor covering material. Results did demonstrate that certain agents were capable of sporicidal effectiveness against C.difficile spores. However, as these were in vitro studies, further research needs to be performed in order to evaluate the success of these products within the clinical environment.

Review of the available literature has demonstrated that much of the research found, even those studies of robust method, has been weakened in some way (e.g. by small sample groups, trials over short periods, having no control groups). The strongest group of research trials identified were those examining probiotics. Even though results demonstrated probiotics to be of benefit; the study authors themselves acknowledge the need for further large randomised trials to examine the efficacy of probiotics in preventing antibiotic-associated diarrhoea especially the identification of the optimal dose needed and cost benefits (D'Souza et al, 2002). This had led the author to conclude that, although probiotics may be useful, more research is needed to instruct clinical staff and further larger studies needed to establish their cost-effectiveness. In the future probiotic use could be targeted at those patients deemed 'high risk' of developing CDAD - e.g. the elderly, those on antibiotic therapy, and those with severe underlying illness.

All studies examined agreed on the link between antibiotic use and Clostridium difficile although some study results were conflicting. However, consensus throughout the literature review was that the incidence of nosocomial C.difficile could be decreased by more careful antibiotic prescribing and from avoidance of those antibiotics proved to be 'high risk' (e.g.s Yip et al, 2001; Worsley, 1998).

Surprisingly few research studies existed aiming to prove the effect of infection control measures. Evidence about this theme was, however, provided by experts in the field of Infection Control and given strength by repeated consensus throughout the studies. It could be argued that, in order for these measures to be implemented effectively, adequate funding needs to be made available to ensure that nurse staffing levels are adequate and appropriate cleaning contracts are procured which provide enough domestic staff to perform daily, stringent cleaning. Another problem that must be acknowledged when considering infection control measures is that of compliance. Although evidence is presented repeatedly in the literature review regarding the importance of early isolation of patients (Zafar et al, 1998; Hateley, 1997; Worsley, 1998; Gammon, 1995); interim findings from a national survey of healthcare Trusts in England have demonstrated that, whilst staff acknowledged the importance of this infection control measure, 40% of trusts were not routinely isolating patients (Healthcare Commission, 2005). This fact underlines the importance of continued education of patients and staff in order to emphasise the serious implications of Clostridium difficile and to improve compliance with infection control practices, as was outlined in the literature (Zafar et al, 1998; Hateley, 1997; Worsley, 1998). The literature review results could be used in clinical practice to educate staff and to ensure that local infection control precautions are evidence-based and are performed at the optimum level to prevent further increased incidence of Clostridium difficile.

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University of Wales
Dr. John Gammon

Dr Gammon is recognised as an international authority on infection prevention and control. Currently, he is a Non -Executive Director of Carmarthenshire NHS Hospital Trust and Deputy Head of the School of Health Science, at Swansea University, Wales, UK. He has practiced as an infection control practitioner for many years and been instrumental in Wales in establishing infection control services. Furthermore he has lead on the establishment infection control courses, and national guidance on hospital and community infection prevention strategies. He has been central to the development of, evidence based, international guidance on patient isolation. His research interests include patient isolation, standard precautions and hand decontamination. He has published a number of research papers and continues to advise the Welsh Government on infection control practice and strategy. He acts as key advisor to a number of commercial companies involved in infection control. His focus of academic interest for the last few years has been the education and professional development of practitioners and specifically infection control practitioners. This has included e-learning course as well as Masters programmes in infection control.