Control of Clostridium difficile infection in the hospital setting.

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Control of Clostridium difficile infection in the hospital setting Expert Rev. Anti infect. Ther. 12(4), 457–469 (2014)

Camilla Wiuff1, Heather Murdoch1 and John E Coia*2 1 Health Protection Scotland, 5 Cadogan Street, Glasgow, G2 6QE, UK 2 Department of Clinical Microbiology, Scottish Microbiology Reference Laboratories, New Lister Building, Glasgow Royal Infirmary, 10–16 Alexandra Parade, Glasgow, G31 2ER, UK *Author for correspondence: Tel.: +44 141 201 8663 [email protected]

Clostridium difficile infection (CDI) has emerged as a leading challenge in the control of healthcare-associated infection (HCAI). The epidemiology of CDI has changed dramatically, this is associated with emergence of ‘hypervirulent’ strains, particularly PCR ribotype 027. Despite the epidemic spread of these strains, there are recent reports of decreasing incidence from healthcare facilities where multi-facetted targeted control programs have been implemented. We consider these changes in epidemiology and reflect on the tools available to control CDI in the hospital setting. The precise repertoire of measures adopted and emphasis on different interventions will vary, not only between healthcare systems, but also within different institutions within the same healthcare system. Finally, we consider both the sustainability of reductions already achieved, and the potential to reduce CDI further. This takes account of newly emerging data on more recent changes in the epidemiology of CDI, and the potential of novel interventions to decrease the burden of disease. KEYWORDS: antimicrobial stewardship • Clostridium difficile infection • hospital epidemiology • infection prevention and control measures • nosocomial infection

Clostridium difficile infection (CDI) has been recognized for over 30 years as a leading infectious cause of antibiotic-associated diarrhea, with symptoms ranging from mild or moderate diarrhea to pseudomembranous colitis, which can lead to toxic megacolon, sepsis and death. In recent years, CDI has emerged as one of the leading challenges in the control of healthcare-associated infection (HCAI). In a meta-analysis of 26 studies published between 1998 and April 2013, Zimlichman and colleagues found that CDI was the fourth commonest HCAI and accounted for over 15% of the estimated US$10 billion annual financial burden of HCAI in the US, with an average additional cost of US$11,285 per case [1]. In the Southeastern US, C. difficile has replaced methicillin-resistant Staphylococcus aureus as the most common etiology of HCAI in community hospitals [2]. The epidemiology of CDI has changed dramatically since 2004, and its presence in healthcare settings and the community has resulted in comprehensive multidisciplinary initiatives in healthcare facilities, and national strategies and action plans in the affected countries, to prevent and control the further informahealthcare.com

10.1586/14787210.2014.894459

spread, which is considered as a severe threat to patient safety and public health [3–5]. The main focus has been to improve diagnostic methods, awareness and education, infection prevention and control procedures, environmental cleaning and antimicrobial stewardship in hospital settings. Such changes in practice introduced to prevent CDI have prompted personnel across the entire healthcare continuum to re-evaluate wider approaches and perspectives within healthcare facilities, thus reaching far beyond procedures that only affect CDI patients [6]. Pathogenesis

In most patients, CDI develops as a result of antibiotic treatment and acquisition of C. difficile spores, via the fecal–oral route, which germinate into viable bacteria in the small intestine (FIGURE 1). Previous exposure to antibiotics remains the main risk factor for development of CDI. Treatment with antibiotics disturbs the normal gut flora and thereby favors proliferation of C. difficile and colonization of the large intestine, particularly with those strains that are resistant to the administered antibiotics [7]. However, the patient

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Wiuff, Murdoch & Coia

Clostridium difficile is spread via the fecal-oral route. The organism is ingested either as the vegetative form or as hardy spores, which can survive for long periods in the environment and can traverse the acidic stomach

In the large intestine, C. difficile-associated disease can arise if the normal flora has been disrupted by antibiotic therapy

In the small intestine, spores germinate into the vegetative form

Pseudomembrane

C. difficile

Toxins

Monocyte C. difficile reproduces in the intestinal crypts, releasing toxins A and B, causing severe inflammation. Mucous and cellular debris are expelled, leading to the formation of pseudomembranes

Neutrophil

Toxin A attracts neutrophils and monocytes, and toxin B degrades the colonic epithelial cells, both leading to colitis, pseudomembrane formation, and watery diarrhea

Figure 1. Pathogenesis of Clostridium difficile infection. Reprinted with permission from [123] Ó Cleveland Clinic Foundation. All rights reserved (2006).

remains at risk of CDI after the antibiotic treatment has been stopped due to the disrupted gut flora, regardless of antibiotic resistance. All types of antibiotics have been implicated in the development of CDI, but some are associated with a higher risk of CDI than others including clindamycin, cephalosporins and fluoroquinolones. Development of disease is a consequence of C. difficile producing toxins A and B that cause severe inflammation and damage the colonic epithelium, and attract neutrophils and monocytes, which in turn leads to further destruction of the colonic epithelium and fluid accumulation. Cellular debris and 458

mucous accumulation can lead to the formation of pseudomembranes usually associated with a severe form of CDI. Virulence of the invading strains of C. difficile is linked to the production of enterotoxins (toxins A and B). Conflicting evidence exists as to whether certain PCR ribotypes (genotypes) cause more severe disease and higher mortality than others [8–12]. Acquisition of the hardy spores usually occurs in hospitals as a result of environmental contamination, suboptimal hand hygiene in healthcare workers, shared toilet facilities and medical equipment. It is estimated that the incubation period is

Expert Rev. Anti infect. Ther. 12(4), (2014)


Control of CDI in the hospital setting

rather short with CDI developing 2–3 days after acquisition [6]. However, exposure to antibiotics has a much longer lasting effect on the gut flora and colonized patients remain at risk for CDI for 3 months or longer after they have stopped antibiotic treatment [13]. Susceptibility of the host also plays a major role in the pathogenesis of CDI. In particular, elderly over 65 years of age and patients with comorbidities are at elevated risk of developing CDI, due to the inability to mount a specific IgG response to toxins A and B [14,15], which has also been associated with a higher risk of developing recurrent disease [16]. Changing epidemiology of CDI

The re-emergence of CDI as a major cause of hospital infection, morbidity and mortality was completely unanticipated at the start of this millennium [17]. Since the beginning of the 2000, the epidemiology of CDI has changed dramatically with both increases in incidence rates and increasing rates of complications and mortality, with multiple outbreaks reported in the US, Canada and Europe [18–21]. A changing pattern in the epidemiology of CDI was reported as early as 2001 in Pennsylvania and Quebec [18,22,23]. Outbreaks caused by a new emerging variant of C. difficile designated with BI/NAP1/027 were reported in Canada (Quebec), followed by reports from the US and Europe [19,21,24]. The change in the epidemiology of C. difficile has been associated with the emergence of the hypervirulent 027 variant, due to its increased ability to produce the two toxins A and B, as a result of a change in the production of the negative regulator protein (tcdC) (due to mutation or deletion) and the production of an additional toxin (the binary toxin) [12,19]. The development of resistance to fluoroquinolones in PCR ribotype 027 is assumed to have contributed to its spread [8,19,21,25]. Until recently, the evolution and global spread of C. difficile were poorly understood, but with the use of whole-genome sequencing and phylogenetic analysis, new insights have developed. By sequencing a global collection of 027 strains, it was demonstrated that the two separate lineages of 027 originating in the North Eastern US independently acquired a mutation conferring resistance to fluoroquinolones, of which one spread throughout the US and the other spread throughout Europe [26]. These findings support the hypothesis that the immense selective pressure from fluoroquinolone use in the US and other countries has played a significant role in the acquisition and maintenance of these two lineages within healthcare settings and has highlighted interconnectedness of global healthcare systems due to human travel. In the US, the rate of CDI increased from 3.82/1000 discharges in 2000 to 8.75/1000 discharges in 2008, with a disproportionate increase among patients above 65 years of age [6]. Recently, incidence rates have started to plateau in the US with 8.2 cases/1000 hospitalizations reported in 2010 [27]. In England, a voluntary laboratory-based surveillance scheme reported an increase in reports from 20,000 in 2001 to 46,000 in 2005; a trend that continued further while being monitored under a informahealthcare.com

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new national mandatory surveillance program reaching 55,499 cases in 2007/2008 in patients aged 65 years and over [28]. The mortality among patients involved in the Quebec outbreak, with an epicenter in Montreal hospitals, was 6.9% [21], and 11 and 12% among patients involved in two major outbreaks in the UK at the Stoke-Mandeville hospital in 2003 and 2004, respectively (which was not documented at the time, but retrospectively reported by the Department of Health, Healthcare Commission, 2006). In the Quebec outbreak, this corresponded to a fourfold increase compared with the national average mortality in 1997 of 1.5% [29]. In a recent panEuropean survey, 2% of patients with CDI died as a result of the infection [30]. However, other variants of C. difficile have also caused outbreaks and contributed to the worldwide spread of this infection. A European hospital-based survey showed that although 65 different variants (identified as PCR ribotypes) were reported, most countries had a local distribution with only three or four common types accounting for the majority of all infections with PCR ribotype 014/020 (16%), 001 (9%) and 078 (8%) being the most common types, while 027 accounted for 5% of cases investigated [30]. Ribotype 078, which is also considered hypervirulent due to elevated toxin production, has recently spread in Europe [31]. The relative pathogenicity of the toxigenic strain types is still unclear but may be influenced by the PaLoc locus (which includes loci encoding toxins A and B), which has been found to diverge in successful epidemic types of C. difficile relative to nonepidemic strains [11,12,32]. Despite the emergence and spread of hypervirulent strains of C. difficile, there have recently been reports of decreasing incidence from hospital settings where multifaceted targeted control programs have been implemented as a matter of urgency. In the 4-year period from 2007 to 2010, significant reductions in the incidence of CDI have been observed in England (54%) and Scotland (72%), following implementation of infection control and practice guidelines and nationwide programs to control and reduce CDI [28,33]. Moreover, mandatory surveillance of CDI combined with government targets for reductions in CDI incidence were implemented across the UK to ensure that CDI was a top priority and that the outcome was monitored [34,35]. Controlling CDI in hospital settings

In order to assess the control of CDI within hospital settings, it is essential to have good surveillance systems to detect clusters and outbreaks and to assess the impact of interventions. The spread of C. difficile in hospital settings is inherently related to the ability of this microorganism to form spores and survive in the hospital environment on hard surfaces, equipment and patient items [36]. Patients and healthcare workers can transmit (or acquire) C. difficile from contact with contaminated surfaces [37], which eventually can lead to transmission via the fecal–oral route. As a result, approaches to control CDI are focused on precautions aimed at preventing transmission in 459

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hospital settings combined with prudent usage of antibiotics in order to reduce the individual risk to patients. Precise diagnosis is an important prerequisite for improving infection control practice and treatment of patients.


Diagnostic issues

Diagnosis of CDI remains a challenge and relies on both assessment of symptoms and laboratory testing. Imprecise diagnosis has implications for infection control practice and patient management. Due to low sensitivity and specificity of stand-alone toxin enzyme immunoassay tests, a two-step laboratory testing algorithm is the preferred approach. The issue of low positive predictive value (i.e., risk of false-positive results) of stand-alone tests is a particular challenge in low prevalence settings. If the number of cases is decreasing due to effective interventions, then it is important to continuously evaluate the diagnostic laboratory testing methods and algorithms. The two-step algorithm used widely in the UK includes an initial screening step using either Glutamate Dehydrogenase (GDH) test or PCR, followed by a confirmatory step using either toxin enzyme immunoassay or cytotoxicity assay [38]. Although the cell culture cytotoxicity test has greater sensitivity than the toxin enzyme immunoassay, a recent study of more than 10,000 patients demonstrated that the algorithm combination of a very sensitive first step test (GDH or nucleic acid amplification) followed by a toxin enzyme immunoassay test yielded very good overall performance characteristics [39]. Many laboratories favor the use of toxin enzyme immunoassay as the confirmatory test, as opposed to cell culture cytotoxicity, as this can be performed on automated platforms, is less technically demanding and potentially allows results to be issued on the day of sample receipt. Clearly, this is desirable to optimize both the clinical and infection control management of the patient. Both the cell cytotoxicity assay (a cell culture toxin inactivation test) and cytotoxigenic culture are considered reference methods for the laboratory diagnosis of CDI [40], but the patient outcome associated with these reference tests and the two-step algorithm (approach) has never been thoroughly evaluated in a multicenter study. A recent study by Planche and colleagues including more than 10,000 patients validated all laboratory test results (obtained on diarrheal stool samples) against clinical outcome in a multicenter setting, which minimized the risk of confounding by other ‘random’ factors affecting the outcome (without being directly associated with the test result) [39]. The study showed that only a positive cell cytotoxicity assay result was associated with clinical outcome, including a higher 30-day all-cause mortality and an 8% excess all-cause mortality (16.6 vs 8.9%) and both mortality (9.03 vs 6.05/ 1000 inpatient days), and other clinical indicators were worse than in the negative control group. In contrast, a positive cytotoxigenic culture result, when the cell cytotoxicity assay was negative, was not associated with a worse outcome than the negative control group (with both reference tests being 460

negative). The latter group of ‘positive cytotoxigenic culture + negative cytoxicity assay’ was described as a new diagnostic category of ‘potential C. difficile excretors’, which are patients with diarrhea that is unlikely to be due to C. difficile but who possibly can cause cross-transmission. As expected, no stand-alone test adequately reproduced the results of either of the two reference methods. Diagnosis based on PCR as a stand-alone test resulted in 81% more positive results than the superior reference method (the cell cytotoxicity assay). The use of stand-alone PCR testing may have led to overdiagnosis of CDI in some settings in the US and elsewhere as this approach was recommended in the recent American Gastroenterological Society guidance [41]. A Canadian review of PCR testing showed 10-times less complications in patients diagnosed only by being PCR positive in contrast to toxinbased testing [42]. A report of increasing prevalence of CDI combined with decreasing severity (and mortality) of cases may support this hypothesis [27]. The above-mentioned multicenter study also compared the two-step algorithms with the reference methods and confirmed that the two-step algorithms improved the accuracy of diagnosis of CDI and recommended the use of either GDH assay or PCR as the initial screening test followed by a toxin immunoassay [39]. The performance of these two combinations against the preferred reference method was nearly identical. Surveillance: local & global

Surveillance has been identified as one of the key measures in preventing and controlling CDI [43]. Surveillance of CDI should be used to continuously monitor and identify increases in CDI incidence and severity in specific areas at an early stage in order to implement changes in practice and evaluate the impact and effectiveness of infection prevention efforts. Feedback of surveillance data and its interpretations to senior management, including directors, governing boards and administrators, via the established communication system is considered essential to preventing and controlling CDI in hospital settings [20,44,45]. Standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates to compare units, hospitals and wider healthcare systems with one another and to evaluate the effectiveness of interventions to control CDI. When surveying the CDI incidence in countries across Europe, there was significant variation in testing frequency from 3 to 141 CDI tests conducted per 10,000 patient days; and countries with high clinical suspicion and frequent testing also reported the highest CDI rates [30]. Moreover, a point prevalence study in a multicenter setting in Spain evaluated 988 unformed stools (from 897 patients) and found that two out of three CDI episodes were either undiagnosed or misdiagnosed due to lack of clinical suspicion (48% of episodes) or due to using an nonsensitive test (19% of episodes) [46]. In a recent European point prevalence study, when 3800 unformed stools (from >450 hospitals in 20 countries) were tested using a validated two-step testing algorithm, it was observed that one in four samples had been missed due to lack of Expert Rev. Anti infect. Ther. 12(4), (2014)



clinical suspicion and 23% of patients had been misdiagnosed due to inadequate laboratory diagnostic test [47]. Those findings suggest that under-ascertainment could be an issue, particularly in countries with very low CDI incidence rates. Attempts have been made in both the US and Europe to harmonize case definitions in order to allow national comparisons and benchmarking. In the US, federal agencies focus mainly on the National Health Safety Network definition, which uses a positive laboratory test result (‘LabID Event’), including toxins A and/or B positive or a toxin-producing C. difficile organism detected by culture or other laboratory means performed on a stool sample. The results are further classified by the time and location based on the timing of admission to a facility and previous discharge, and whether the episode is recurrent disease [48]. In Europe, where about half of the countries perform CDI surveillance, the case definition recommended by ESCMID (which also includes a positive laboratory result) [20] is widely accepted, and nationwide rates are standardized by patient days, but testing and reporting frequencies and classification of CDI (into community and healthcare-associated disease) vary greatly due to varying national surveillance requirements ranging from voluntary to fully mandatory schemes with financial penalties for increasing incidence (ECDIS-net survey/personal communication Axel Kola). Surveillance should be facility (or service) wide and include a rate per reporting period per patient days (or similar hospital activity data) in order to express the per-day patient risk for CDI and enables comparison within the setting [6]. Moreover, ‘local surveillance’ systems that complement the wider surveillance system for the facility/service should be available to identify local increases in incidence and severity in real time to inform targeted interventions in local areas as early as possible. Statistical process control charts are a useful tool in monitoring rates and providing a visual representation of when CDI (rates) are out of control. Typically, baseline data on infection rates should be collected for 25 measuring points (e.g., months or quarters) after which outliers are identified as infection rates above 2–3 standard deviations from the mean of the previous data points [49,50]. The lack of adequate surveillance requirements, both facility/ service wide and locally, and standardization and implementation of case definitions can have consequences clinically and impair the ability to monitor changes in the epidemiology of CDI. A recent pan-European point prevalence study of hospital patients with diarrhea, involving 482 hospitals, highlighted that on a single day, 82 patients with diarrhea due to C. difficile toxin in hospitals across Europe were not diagnosed due to lack of clinical suspicion [47]. Although CDI is primarily considered a HCAI, this perception is now being challenged as CDI developing in persons outside hospitals are increasingly being reported [51–55]. The European CDC and CDC recommend using a definition of community CDI that require that patients should have onset of symptoms in the community or within 48 h of admission to a informahealthcare.com

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healthcare facility, provided that the onset was more than 12 weeks after the last discharge from a healthcare facility [20,56]; however, modifications of this definition occurred widely among published surveillance data [57]. A clear and consistent definition of CDI is necessary to distinguish between healthcare-acquired and community-acquired CDI and to understand the relationship between the epidemiology of CDI in the community and hospitals. With the introduction of sequence-based subtyping techniques, it has become apparent that more hospital CDI patients than expected lack epidemiological links to previous symptomatic CDI patients and that conventional typing techniques in some instances have linked unrelated cases wrongly due to lack of discriminatory power of the nonsequence-based techniques [58]. When investigating all CDI cases over a 3-year period in the region of Oxfordshire (England), using whole-genome sequencing, only 35% of patients had a genotype related to that of a previous patient, while 45% of cases were infected with types genetically distinct from all previous cases, suggesting a considerable reservoir of C. difficile outside of the healthcare setting where CDI was acquired [59]. Hand hygiene

Numerous investigations conducted over the past 40 years have confirmed the important role that contaminated HCWs’ hands play in the transmission of a range of healthcare-associated infections including CDI. All aspects of this key intervention have been reviewed comprehensively elsewhere including the underpinning evidence [60]. As part of the multimodal hand hygiene improvement strategy set out within those guidelines, WHO has identified ‘5 moments’ for hand hygiene: before touching a patient, before a clean/aseptic procedure, after body fluid exposure risk, after touching a patient and after touching patient surroundings. Although the use of alcohol-based hand rubs (AHBRs) has become popular in recent years to facilitate hand hygiene compliance, studies have demonstrated that washing with soap and water are significantly more effective than using AHBR at removing C. difficile spores from the hands of HCWs [61,62]. This probably reflects a dilutional effect, as neither AHBR nor soap and water is sporicidal. Nonetheless, we are unaware of any studies in acute care settings that demonstrate either an increase in CDI with ABHR use or a decrease in CDI with traditional hand washing with soap and water. Meticulous hand washing using liquid soap and running water and paper towels is recommended for all staffs after contact with body substances or body fluids (including feces) or after contact with the environment of a patient with an enteric illness, that is, diarrhea (and/or vomiting) including CDI. As has been outlined above, AHBR are not as effective in removing C. difficile spores from hands and should therefore not be the only hand-hygiene measure when caring for suspected or confirmed CDI patients. Washing of hands using liquid soap, running water and paper towels are also recommended after removal of gloves and aprons. Patients and visitors should be 461

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strongly encouraged to wash their hands with liquid soap and running water, especially before eating, after using the toilet and when entering and leaving the care setting to minimize the risk of spore ingestion.


Contact precautions

As C. difficile is an anaerobic bacterium, the organism itself will not remain viable in the environment; however, its spores are known to survive for extended periods of time (months or years) and are resistant to many detergents and disinfectants [36,63,64]. C. difficile is transmitted via spores that are picked up either by direct contact with an infected (or colonized) person or by indirect contact with a contaminated surface and then swallowed. Carriage rates in hospital patients have been reported to vary from 6–11% at admission to 4–21% following admission [65] and from 4.4% at admission with a further 3% becoming colonized following admission [66]. Once patients are symptomatic, that is, have diarrhea, then spores can be disseminated in large numbers and result in high levels of contamination. Symptomatic CDI patients are considered the main source of contamination of the environment of care facilities. Studies have shown significant environmental contamination with C. difficile spores, particularly of frequently touched surfaces, such as toilet handles, commodes and bedrails [67–70]. Aerosol generation of spores during toilet flushing has also been demonstrated [71,72]. Patient care equipments and in particular rectal thermometers, blood pressure cuffs, commodes and stethoscopes have been implicated in cross-transmission of CDI [68,69]. Therefore, single use or patient-dedicated care equipment for each CDI patient is recommended if possible [43,44,56]. The key infection control interventions, therefore, focus on isolation of the symptomatic patient, effective hand washing, use of personal protective equipment (disposable gloves and aprons), environmental cleaning and decontamination and the use of dedicated communal care equipment where possible. Contact precautions are used in addition to standard infection control precautions to prevent and control infections spread by direct contact with the patient or indirectly from the immediate care environment and including care equipment [44]. Patients known or suspected to have CDI should be isolated in a single room with en-suite facilities or with an allocated commode [3,43,56,73,74]. The duration of the contact precautions including isolation of the patients for specific organisms is crucial; however, there is not always specific evidence to quantify this. There is currently broad consensus of expert opinion within the main sources of evidence-based guidance that patients should remain in isolation until they are at least 48-h symptom free [43,56]. In a long-term care facility, during an outbreak, where 51% of patients were asymptomatic carriers of toxigenic C. difficile, environmental culture demonstrated shedding of spores from both symptomatic CDI patients and asymptomatic carriers [75]. Another recent study showed that shedding commonly continued for periods up to 1 month following resolution of symptoms [76]. The authors recommended continuation of contact 462

precautions for up to 1 month after completion of treatment on this basis. Interestingly, their findings showed that after 5 weeks the spore shedding was almost negligible, and the authors have suggested that this could be used to put a time frame around any extension of precautions required. These findings were similar to that of a prospective observational study, which showed that shedding of C. difficile spores decreased 5–6 weeks after treatment [77]. It can be concluded that some colonization may persist for a period of around 1 month after cessation of treatment, and it is thought that this is due to the length of time required for the normal gut flora to re-establish. Although there is currently insufficient evidence for a widespread change in practice, extending contact precautions for colonized patients to duration of hospital stay may be worth consideration in an outbreak situation when there are difficulties in establishing control [78]. Cleaning & disinfection

Cleaning and disinfection have to focus on frequently touched surfaces (e.g., bedrails, over bed table, bedside commode, lavatory surfaces in patient bathrooms, doorknobs) and equipment in the immediate vicinity of the patient. There is a consensus of evidence that the use of chlorine-containing agents at a concentration of at least 1000 p.p.m. available chlorine is effective in decontamination of environments contaminated with C. difficile spores [3,43,73,74]. There has been a focus on the development of novel technologies to decontaminate the hospital environment targeted at C. difficile. These include hydrogen peroxide vapor (HPV) [79–85], UV disinfection [86–88], steam cleaning [89] and novel disinfectants [90,91]. However, a recent study comparing eight different methods of terminal disinfection including microfiber cloths, steam, HPV and chlorine-releasing agents concluded that the use of chlorine-releasing agents was as effective and more expensive methods as HPV [92]. There are also several practical and health and safety issues associated with the use of novel disinfection methods such as time required, requirement for rooms to be cleaned with detergent prior to the use of the novel methods; and in the case of hazardous cleaning methods, the requirement for rooms to be vacant during the decontamination process. While some novel technologies are currently being used within the National Health Service (e.g., microfiber cloths and steam cleaning) [93], further research is required to adequately assess these in terms of efficacy, cost, potential hazards and user safety. The potential benefit of extended disinfection of the environment for patients recovering from CDI would depend on the evidence for asymptomatic carriage and shedding of C. difficile spores following successful treatment for CDI. Is there a role for screening of asymptomatic patients?

There is emerging evidence that asymptomatic carriers may be playing a more important role in transmission of CDI than previously assumed. Using the highly discriminatory molecular subtyping method, multilocus variable number tandem repeats Expert Rev. Anti infect. Ther. 12(4), (2014)



analysis, it was shown that 29% of hospital-associated CDI cases were infected by strains highly associated with those of previous asymptomatic carriers, while 30% were infected with strains associated with those of previous (symptomatic) cases of CDI [94]. Direct transmission events from prior room occupants with asymptomatic carriers were also identified; and room surfaces were contaminated with strains closely matching those of previous asymptomatic carriers. In a prospective study using whole-genome sequencing, which has the ultimate discriminatory power, C. difficile strains of asymptomatic carriers were examined and compared with strains of cases from the same geographical region in the past 12 months and following 3 months. Although 72% of asymptomatic colonized patients carried toxigenic strains from common disease-causing lineages, direct transmission events could not be identified, possibly due to the study being too small [95] The authors concluded that even if transmission from any one carrier is relatively rare, asymptomatic carriage may still play a major role in the spread of C. difficile as carriage is common. Both these findings are in line with the findings of previous studies (using less discriminatory typing methods) [75,96] and support the hypothesis that a considerable proportion of transmissions arises from asymptomatic carriers. However, a controlled trial is required to evaluate the utility of screening for C. difficile carriers and the impact of extending isolation precautions to include asymptomatic carriers until the time of discharge (or for a fixed period of time). The potential benefit of universal screening of all asymptomatic patients was examined in a mathematical model [97]. It was concluded that a hospital cost saving of US$16,071/ 1000 admissions could be obtained when assuming a colonization rate of 10% and a compliance rate of 75%. This was based on the costs and quality-adjusted life-years resulting from colonization pressures, secondary cases, duration of isolation and contact precautions required. Although interesting, this study is based on a number of assumptions and does not include the cost of start up and maintenance of testing. Evidence-based guidance published in 2008 [98] recommends that patients who are without signs or symptoms of CDI should not be tested routinely. A number of evidence-based reasons have been given for this recommendation: • A positive result in an asymptomatic patient is often a false positive; • Obtaining samples is costly in terms of staff and laboratory time; • A positive result may result in a decision that treatment for CDI should be initiated, which could have the unintended consequence that it could increase the risk of the patient developing CDI in the future. Antimicrobial stewardship

Exposure to antimicrobials is the single most important risk factor for developing CDI. Use of antimicrobials for treatment for infection and prophylaxis is the key to the management of a plethora of medical conditions, but leads to disturbance of informahealthcare.com

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the normal gut flora, allowing C. difficile to proliferate in the colon, attach to the gastrointestinal epithelial cells and produce toxins that may lead to CDI. In principle, any antimicrobial agent can predispose for CDI, but some agents have been more frequently implicated in CDI than others [99]. Implementation of a facility wide antimicrobial stewardship program is therefore essential to controlling and preventing CDI [41,43,56,100]. Antimicrobial stewardship programs aimed at reducing the risk of HCAI (and in particular CDI) minimizes the antimicrobial exposure of patients in hospital settings and includes restriction of antimicrobials associated with a high risk of CDI (e.g., cephalosporins, aminopenicillins, fluoroquinolones and clindamycin) in order to reduce the number of patients predisposed to CDI. However, changes in antimicrobial prescribing practices do not prevent transmission of infection, and antimicrobial stewardship should therefore always be implemented in combination with infection prevention and control measures. Detailed guidelines for the development of institutional antimicrobial stewardship programs have been published by the Infectious Diseases Society of America and the Society of Healthcare Epidemiology of America in 2007 [101]. A recent Cochrane review examined the effectiveness of interventions to improve antimicrobial prescribing practices and to reduce ‘collateral damage’ (including development of CDI and infection/colonization with antimicrobial-resistant pathogens) in 89 published studies (reporting on 95 interventions) in hospital settings [102]. Overall, the studies showed that the interventions improved prescribing practices, and interventions intended to decrease excessive prescribing were associated with reduction in occurrence of CDI. Five studies reported on change in antimicrobial prescribing practices and outcome data on occurrence of CDI [103–107]. All reported change in the intended direction with regards to prescribing practices, targeting broad-spectrum antimicrobials (including clindamycin, cephalosporins and fluoroquinolones) and three of the studies found significant reductions in CDI incidence [103,104,107]. However, most studies are associated with considerable bias and/or confounding as they are often conducted in specific healthcare settings, and due to the fact that most interventions to improve prescribing practices are implemented in combination with infection control measures. As antimicrobial use is unnecessary or inappropriate in as many as 50% of the cases and interventions to improve antibiotic prescribing can reduce occurrence of CDI, restriction of antimicrobial use and avoiding unnecessary prescribing are the key to controlling CDI [102]. Practice guidelines typically recommend stopping all antimicrobials that are not clearly required, to minimize the frequency and duration of antimicrobial therapy and the number of agents prescribed [41,43,56] and to limit prophylaxis to a single dose [108]. Moreover, in order to identify excessive or inappropriate use, frequent reviews (preferably daily) of all patients treated with antimicrobials are considered as a good clinical practice. A reduction in overall antimicrobial use has played a role in controlling at least two large institutional outbreaks [109,110], while other outbreaks have 463

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and some other settings, is that it is possible to control epidemic C. difficile within the healthcare setting. This is Recommendation Ref. despite the facts that we are treating older Stop any antimicrobial that is not clearly required [43] and sicker patients in our hospitals, that there are increasing pressures on healthProspective audit of antimicrobial use with direct interaction and [99] care resources and that the practice of feedback to the prescriber, performed by either an infectious diseases physician or a clinical pharmacist with infectious diseases training, can modern medicine is crucially dependent result in reduced inappropriate use of antimicrobials on the use of antibiotics, all of which factors are known to increase the risk of Documentation of indication for prescribing and compliance with policy [113] CDI. These reductions in healthcareReview frequency, type of agent, duration, route of administration [43] associated CDI have been achieved by results and de-escalate if required the implementation of a range of surveilRestrict high-risk agents in treatment and prophylaxis [100] lance and control measures that have been reviewed here. However, the packUse of surveillance data to inform policy and prescribing practice [109,110] age of measures employed in different Limit surgical prophylaxis to a single dose [106] settings and the emphasis on, or even inclusion of, particular components has been controlled successfully by the implementation of infection varied in different settings. On the one hand, this reassures us control measures alone [21] or via a ‘bundle’ approach compris- that one size need not necessarily fit all. On the other hand, ing education, early case finding, expanded infection control there is a lack of clarity over the relative effectiveness of the measures, development of a CDI infection management team individual control measures. This hampers our ability to preand antimicrobial stewardship [78]. The principle features of dict the incremental benefit that might accrue from augmentasuch an antimicrobial stewardship program are outlined tion of existing measures by the implementation of further in TABLE 1. controls. Equally, in a climate of increasing fiscal constraints, it The sustainability and effectiveness of interventions to will be important to determine measures that might be safely improve prescribing practices in hospitals and other healthcare discontinued without adversely impacting outcomes. settings are dependent on multiple factors and require a sysThere are also outstanding questions regarding the sustaintematic approach to development of a culture that embeds a ability of some of these interventions in the longer term. For cautious behavior toward antimicrobial use. In Scotland, a example, in Scotland, the implementation of an antimicrobial national coordinated antimicrobial stewardship program includ- stewardship program, introduced in tandem with other infecing a national leadership structure, a network of local tion prevention and control measures, has led to significant ‘antimicrobial management teams’ to support implementation, reductions in the use of third-generation cephalosporins, clindacombined with national and local systems to collect and com- mycin, co-amoxyclav and fluoroquinolones. This has been temmunicate data on antimicrobial prescribing, antimicrobial resis- porally associated with reductions in healthcare-associated CDI. tance and CDI incidence [111,112] and an educational framework However, this has been paralleled by concomitant increases in and training materials has resulted in significant changes in the use of other agents, particularly gentamicin [117]. Major antimicrobial prescribing practices with a temporal association changes in trends in orthopedic antimicrobial prophylaxis have with decreasing CDI incidence [113]. The use of systematic also been observed in England, including increases in the use measures (‘prescribing indicators’) of the quality and quantity of flucloxacillin and gentamicin and co-amoxiclav, due to conof antimicrobial use, and monthly measurements and feedback cerns about CDI [118]. To date, there is no evidence that this to hospital and primary care prescribers, has improved compli- has been associated either with adverse treatment outcomes or ance with prescribing (and prophylaxis) policy and improved toxicity issues. However, concerns around the potential risk of documentation of prescribing, both leading to sustained such ‘collateral damage’ emerging remain. In an analogous improvements in the wider health service [114,115]. A similar manner to the implementation of immunization programs, as national program on improvement of antimicrobial prescribing the number of CDI cases falls, the perceived risk of CDI practice is now being implemented across the National Health recedes in the minds of prescribers with an understandable Service in England [116]. increased reluctance to continue to comply with the stewardship policy. In addition, the longer term impact on the patterns Expert commentary & five-year view of circulating pathogens and their associated antimicrobial susThe control of C. difficile in the healthcare environment con- ceptibility resulting from this profound alteration in selective tinues to present a major challenge for infection prevention pressure remain largely unknown. and control. However, there are some positive developments The other key questions confronting those healthcare systems that provide some grounds for a degree of optimism for the that have demonstrated success in control of the spread of C. future. The good news, as has been demonstrated in the UK difficile are whether or not there is an ‘irreducible minimum’


Table 1. Principle features of an antimicrobial stewardship programme.

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level of CDI, and if so, has this been achieved? It would certainly appear from UK data that the rate of reduction has plateaued [33]. This may be accounted for by changes in the underlying epidemiology of CDI. First, as has been discussed, community-associated CDI is an increasing problem, particularly in association with long-term care facilities. However, this increased community burden may also impact upon the healthcare setting in various ways. Some patients with communityassociated CDI will require hospital admission to manage their disease, thus contributing to the institutional CDI burden. However, these patients may then be the source of further healthcare-associated cases, either by direct transmission or by means of environmental contamination. Clearly, there is a need for a better understanding of the epidemiology community-associated CDI and the development of targeted interventions to reduce the burden of disease. As has also been highlighted, it is increasingly apparent from recent molecular studies of transmission that in areas where the spread of epidemic C. difficile has been controlled, symptomatic patients may no longer be the main source of further infections [59]. This has led to renewed interest in the potential role of carriers of toxigenic C. difficile who do not themselves have CDI, although they may have diarrhea due to another cause, but may be a potential source of environmental contamination or infection for other patients in the healthcare environment. A recent prospective cohort study of asymptomatic carriage has used whole-genome sequencing to detect potential onward transmission from asymptomatic cases. Although several plausible transmission events to asymptomatic carriers were identified, in this relatively small study, no clear evidence of onward transmission from an asymptomatic case was seen. However, as the authors note, transmission events from any one asymptomatic carrier are likely to be relatively rare, but as asymptomatic carriage is common, it may still be an important source of CDI [95]. It may even be possible that other factors such as antibiotic therapy may increase shedding of C. difficile from such colonizd patients, as has been previously demonstrated in a mouse model [119]. Once again, there is a need to clarify the potential role of carriage in the epidemiology of healthcareassociated CDI, and in particular to establish whether or not there are any infection control measures that will be justified

Review

or effective in managing this potential source of infection. Further evolution of existing control strategies, and the deployment of new methods and approaches, will continue. Despite efforts to optimize diagnostic strategies based around currently available tests (either alone or in combination), and attempts to better define the correlation between results of those tests and clinical outcomes, it is apparent that there is still considerable room for improvement in laboratory testing methods for CDI. Novel antibiotics with activity against C. difficile, particularly where these shorten the duration of symptoms or reduce the rate of recurrent infection, will play a role in reducing the pool of infected patients and the extent of environmental contamination. Environmental decontamination technologies that are less disruptive to routine care, and the availability of sporicidal disinfectants that are less damaging to other materials within the healthcare environment, will help to reduce the burden of organisms and spores that are a reservoir for further infections. Within the next few years, the precise role of immunization [120], either in primary prevention or in the prevention of recurrence and reinfection, will emerge in tandem with strategies to target those groups of patients most likely to benefit from their application. Finally, our knowledge of the pathogenesis of CDI, and in particular the underlying dysbiosis of the intestinal microbiota, is expanding exponentially [121]. Building on the success of fecal microbiota transplantation in treatment of CDI [122], we will likely see an accompanying development of therapeutic approaches to protect or augment the composition of the gut microbiome to reduce the likelihood of developing CDI, and more sophisticated approaches to reconstitute the bowel flora in those who do develop infection. Financial & competing interests disclosure

JE Coia has received honoraria for preparation and presentation of educational material, advisory board membership and travel from Pfizer and Astellas, and has received grants for clinical research from Pfizer and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Clostridium difficile infection (CDI) remains a leading healthcare-associated infection challenge. • Multifacetted intervention strategies have demonstrated success in controlling CDI in different healthcare systems, but the precise contribution of individual strategy components remains uncertain. • The epidemiology of CDI continues to evolve, and the contribution of community-associated disease and the potential role of asymptomatic carriage need to be better defined. • There is still significant room for improvement in CDI diagnostic strategies. • Recurrent CDI remains an important challenge. • The availability of sporicidal disinfectants that are less damaging to other materials within the healthcare environment would be helpful. • Immunization and measures to address the underlying dysbiosis of the intestinal microbiota in CDI are likely to be important in the future.

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the BI/NAP1/027 strain. Antimicrob Agents Chemother 2008;52(9):3180-7

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