Changes in the Prevalence of Clostridium Difficile Infection in the United Kingdom - Essay Example

? Changes in the Prevalence of Clostridium difficile infection in United Kingdom Table of Contents Characteristics of Bacteria Pathophysiology of Infection 1 Presentation of the Disease 3 Risk Factors 4 Importance in Public Health 5 Recent Clinical Guidelines for Diagnosis and Treatment Background 7 Basic Principles 7 Patient Approach 8 Laboratory Diagnosis 8 Classification of CDI 9 Rational Antibiotic Use 10 Other Treatment Options 11 Improvement of CDI Surveillance 11 Current Statistics on CDI Occurrence Prevalence 12 Total Bed Days due to CDI 13 Temporal Pattern of CDI Prevalence 13 Prevalence Among the Elderly 15 Points of Improvement Better diagnosis 16 Improving treatment of infectious diseases 16 Conclusion 17 References 18 Characteristics of the Bacteria Clostridium difficile is a resilient Gram-positive, anaerobic, toxin-producing bacillus that normally inhabits the gut of infants, and it is not as common in adults. In fact, it was first isolated by Hall and O’Toole in 1935 from a healthy neonate. It was named ‘difficile’ because of the difficulty in culturing the bacterium on conventional media. The life cycle of the bacilli begins in the spore form. In unfavorable circumstances, they produce spores to allow them to live survive the poor living conditions outside the human body, such as bedding, furniture, medical equipment, as well as skin and jewelry of caregivers, so they can thrive once inside a new host. Upon ingestion, it germinates and colonizes the colon. At this point in their lives they also produce exotoxins A and B. The genes that encode these toxins, tcdA and tcdB, are regulated by tcdR and tcdC. All of these are found at the pathogenicity locus (Martinez, Leffler and Kelly, 2012). Pathophysiology of Infection Since the bacterium’s population is regulated by other microorganisms in the gut, oral intake of antibiotics that disturb these protective microorganisms can facilitate the pathological reproduction and toxin production of C. difficile, causing antimicrobial-associated, self-infection (Department of Health and Health Protection Agency, 2008). It was in the late 1970s when C. difficile toxins were recognized as the main cause of antibiotic-associated pseudomembranous colitis (Martinez, Leffler and Kelly, 2012). Because of this pathophysiology, C. difficile infection (CDI) is likely among those with a recent history of broad spectrum antibiotic treatment (Department of Health and Health Protection Agency, 2008). For most of the population who do not have the bacterium in their normal gut flora, they can be infected by coming in contact with infected patients, asymptomatic carriers or inoculated surfaces. Although many cases were hospital-acquired, 9.3% of CDI incidence in Germany (n = 703) and 20-30 cases per 100, 000 of British population did not have recent history of hospital visit or antibiotic use (Department of Health and Hospital Protection Agency, 2008). The community-acquired CDI takes the fecal-oral route. The spores of C. difficile are the transmissible form of the bacterium, and when ingested, germinate and produce toxins A and B, causing diarrhea and colitis (Department of Health and Health Protection Agency, 2008). Presentation of the Disease The disease can be asymptomatic, or it can cause mild to severe diarrhea, with or without pseudomembranous colitis or bowel inflammation. According to Martinez, Leffler and Kelly (2012), abdominal discomfort and nausea may be seen, especially in mild to moderate infection. Technically, CDI in patients aged 2 years and above is defined as 1) positive C. difficile-toxin assay, loose stools that take the shape of the container (Bristol type 5-7), toxic megacolon or ileostomy, with or without the benefit of bacterial culture, 2) pseudomembranous colitis, as determined through lower gastrointestinal endoscopy or Computed Tomography (CT Scan), or 3) histopathologic post-mortem evaluation of bowel inflammation and C. difficile infection (Department of Health and Health Protection Agency, 2008). Unfortunately, for CDI initially presenting with Ileus, there is minimal or absence of diarrhea, causing delays in the diagnosis and treatment. In this case, CDI can only be diagnosed in the presentation of fever, leukocytosis, abdominal pain and diffuse tenderness, as well as abdominal distention. Because of diarrhea and inflammation, common complications include dehydration and perforation, respectively. Both of these may present with bloody stool or vomit, although these are unusual. If not managed early, it can lead to vomiting, sepsis, hemodynamic instability, organ failure, such as peritonitis, renal failure, and respiratory distress, and even death (Martinez, Leffler and Kelly, 2012). A particular strain of this species, pulse field type (NAP1) ribotype 027 or BI/NAPI/027, has been found to be more virulent. Studies on this strain confirmed its association with more severe presentation, increased therapeutic failure, higher colectomy rates, greater relapse, and higher mortality rates. This increased virulence is partly due to deletions in the inhibitory tcdC gene, resulting to increased toxin production (Department of Health and Health Protection Agency, 2008). The newer isolates also exhibited higher level of resistance to fluoroquinolones (Martinez, Leffler and Kelly, 2012). Risk factors Other risk factors include co-morbidities, resulting to frequent hospitalizations, and old age. More than 80% of C. difficile infections affected people aged 65 years and over (Health Protection Agency, n. d.). Since age is uncontrollable, the most significant controllable risk factor that is gaining much attention is recent history of antibiotic use, which is within two weeks before the symptoms first presented. In fact, a study revealed that one out of five hospitalized patients under antibiotics was infected by C. difficile. Resistance to fluoroquinolone or extended-spectrum cephalosporins has also been implicated in causing CDI outbreaks (Department of Health and Health Protection Agency, 2008). Aside from this class of drugs, antacids, such as COX-1 inhibitory NSAID and proton pump inhibitors, also increases the risk of CDI. Health status is also an important factor in CDI, since low or absent concentrations of serum IgG antibody had been found to cause greater risk of CDI among hospitalized patients colonized by C. difficile. The presence of co-morbidities and subsequent immunodeficiency may thus increase the risk of acquiring CDI. Another way of looking at it is that the presence of co-morbidities necessitates a patient to take drugs such as antibiotics and antacids. Taking everything together, it is likely that co-morbidities and relative immunodeficiency of the elderly population make them more susceptible to CDI (Martinez, Leffler and Kelly, 2012). Moreover, because of its infective nature, CDI’s prevalence can also be influenced by environmental factors, such as the number of patients in the healthcare facility and the availability of healthcare staff (Polgreen, et al., 2010). The World Health Organization considers poverty as a significant risk factor in acquiring an infection (Brundtland, 1999). This comes as no surprise, since the lack of financial resources disables a household from having a spacious and clean environment, nutritious food, as well as easy access to medications. Importance in Public Health For those acquiring CDI from the hospital, the infection is associated with excess lengths of hospital stays and subsequent increase in healthcare costs (Polgreen, et al., 2010). Since a significant risk factor of CDI is old age, this disease should concern the health sector now more than ever, because of the aging hospital population. C. difficile currently causes a higher incidence of hospitalizations compared to the more infamous methicillin-resistant Staphylococcus aureus. Between the years 1999 and 2004, there was about 35% increase in mortality rates per year. The rate of CDI being reported as the cause of death was seven times the rate of all other intestinal infections combined. At present, overall case fatality rate of CDI is estimated to be more than 2% (Martinez, Leffler and Kelly, 2012). Because it can cause significant morbidity and mortality to a great number of people at any given time, it can result to substantial increase in healthcare costs. In the US alone, CDI management costs $3.2 billion a year (Polgreen, et al., 2010). Recurrent CDI infection, or presence of diarrhea within three months after completion of metronidazole or vancomycin, also poses a significant challenge to health officials, since it has been reported in 15% to 30% of patients successfully treated with standard therapy. Although mild or moderate symptoms can be managed by close monitoring, severe ones need a repeat cycle of antibiotic therapy. Multiple recurrences usually demand a prolonged tapering course of oral vancomycin, which lasts for more than 50 days (Martinez, Leffler and Kelly, 2012). These effects on health have far-reaching social implications. CDI, especially if with recurrence, keeps children from going to school and prevents adults from being productive members of the community. Since health is a right of everyone, a high prevalence of CDI costs a country substantial amounts of money for its prevention and management. This money could have been allotted to other programs, such as education, infrastructure, and technology (Brundtland, 1999). Recent Clinical Guidelines for Diagnosis and Treatment Background In the decade of 1990s and the early half of 2000s, particularly in periods 1996 to 1997 and 2001 to 2002, CDI in increased across all age groups, most significantly in the elderly age group. A similar pattern was observed in Canada and the USA, although these countries suffered more morbidity and mortality, as well as increased risk of relapse (Department of Health and Health Protection Agency, 2008). From 1999 to 2004, CDI in United States accounted for approximately seven times the rate of all other intestinal infections combined. Within this span of time, the case fatality rate of CDI jumped from 1.5% in 1997 to 6.9% in 2004 (Martinez, Leffler and Kelly, 2012). Outbreaks have also been noted in England, Netherlands, Belgium, and France. All of these have been caused by the emergence of the new NAPI strain. Because of this, increased testing and patient risk profiling, as well as environmental hygiene, have been enforced to curtail CDI (Department of Health and Health Protection Agency, 2008; Martinez, Leffler and Kelly, 2008). Basic Principles The revision of clinical guidelines is based on three basic tenets: 1) CDI is a diagnosis in its own right, 2) the safety of patients is the primary objective, and 3) infection control should involve everyone. These make all healthcare providers responsible for initiating efficient diagnosis, improving patient compliance to hygiene and medications, and maintaining sterility. Facilities, on the other hand, are looked upon to provide resources for diagnosis, management, surveillance, audit, environmental cleaning, and education. In addition, they provide the links among healthcare providers and information to the public (Department of Health and Health Protection Agency, 2008). Patient Approach A multidisciplinary team composed of microbiologist, infectious disease specialist, gastroenterologist or surgeon, dietician, nurse, and antimicrobial pharmacist should be available to respond to CDI. In dealing with patients presenting with diarrhea, it is thus important for clinicians should highly consider an infectious etiology at the onset. Because of this, proper measures should be taken in order to prevent the spread of the agent. The patient must be isolated to prevent healthy ones from contracting the disease. Gloves and aprons must be worn for all contacts with the patient and their environment. Hand washing with soap and water should be done before and after patient contact. However, before medications can be given, bacterial culture or isolation should be done (Department of Health and Health Protection Agency, 2008). Laboratory Diagnosis In providing a definitive diagnosis, laboratory examination of stool specimen should be available seven days a week. However, this should be requested judiciously. Only types 5 – 7 stools should undergo further C. difficile toxin assay (Department of Health and Health Protection Agency, 2008). The most widely used diagnostic test is the rapid enzyme immunoassay (EIAs), which detects the presence of C. difficile exotoxins A and B in the specimen. Aside from obtaining results within two to four hours, the technique is relatively inexpensive and convenient (Martinez, Leffler and Kelly, 2012). For patients who only presents with Ileus, toxic megacolon or pseudomembranous colitis, colonoscopy is the ancillary diagnostic of choice. Results of laboratory examination should be delivered as soon as possible. Treatment is initiated and retest is deferred for patients who have been symptomatic for 28 days, unless there is resolution or recurrence of symptoms. If negative results are obtained, a retest after 24 hours is recommended for those highly suspected of CDI. Other laboratory tests such as complete blood count (CBC) and measurement of blood lactate levels are important in the classification of CDI (Department of Health and Health Protection Agency, 2008). Classification of CDI Before initiating treatment, each CDI should be classified according to severity before initiating treatment. Asymptomatic carriers without clinical presentation are given no treatment. Mild CDI is characterized by less than three loose stools per day. It is not associated with increased white blood cell (WBC) count. On the other hand, moderate CDI is characterized by 3 – 5 stools per day, with WBC increase not more than 15 x 109 cells/L. This is a stricter classification compared to that developed by Leffler and Lamont in 2009, which classified CDI to mild to moderate if the patient had less than 12 stools per day. Severe infection, aside from causing WBC count of more than 15 x 109 cells/L, results to acute serum creatinine elevation (more than 50% increase above baseline), temperature of 38.5°C, or abdominal or radiologic signs of severe colitis. A life-threatening CDI involves hypotension, as well as partial or complete Ileus or toxic megacolon. Blood lactate levels of more than 5 mmol/L indicate poor survival (Department of Health and Health Protection Agency, 2008). Rational Antibiotic Use Because overuse of antibiotics had been implicated in the rise of CDI, rational antibiotic use had been advocated. Prescribing narrow-spectrum antibiotics alone or in combination both for empirical and definitive treatment has been recommended. In contrast, broad-spectrum clindamycin, second- and third-generation cephalosporins, fluoroquinolones, carbapenems and long-course aminopenicillins should be avoided to prevent bacterial resistance against these antibiotics (Department of Health and Health Protection Agency, 2008). For treatment of CDI, patients with mild and moderate CDI are prescribed with oral metronidazole, 400 – 500 mg every eight hours (TID) for 10 – 14 days. On the other hand, severe CDIs are treated with oral vancomycin 125 mg every six hours (QID) for the same duration. If there is no resolution of symptoms, dose of vancomycin can be increased to 500 mg. Intravenous (IV) metronidazole 500 mg TID, oral rifampicin 300 mg twice a day (BID) or IV immunoglobin (400 mg/kg) may be added to the treatment of severe CDI. If the case is life-threatening, oral vancomycin is increased to 500 mg QID for 10 – 14 days via nasogastric tube or rectal installation with IV metronidazole 500 mg TID (Department of Health and Health Protection Agency, 2008). This is in line with the worldwide accepted treatment of initial CDI (Martinez, Leffler and Kelly, 2012). In a 2007 randomized controlled trial comparing the two antibiotics, metronidazole resulted to an overall treatment response rate of 84%, significantly lower than that posted by vancomycin (97%). Stratifying the data based on disease severity, the difference between the antibiotics was most pronounced in the more severe states. This is the reason why metronidazole is recommended for mild to moderate CDI, but vancomycin is the first line for severe ones. However, despite being the first line of CDI treatment, the published treatment failure rates for metronidazole increased from 2.5% to 18.2% in 2000, at a time when worldwide prevalence of the disease was increasing. It is possible that the resistance of currently circulating strains of C. difficile against metronidazole is still increasing. As such, there is still discussion as to whether the more expensive vancomycin should replace metronidazole as the first-line for CDI. Deterrent to this move is the possibility of increasing the prevalence of vancomycin-resistant enterococcus infection (Martinez, Leffler and Kelly, 2012). Other treatment options Aside from treating dehydration by providing oral rehydration salts or IV fluids, colectomy should be considered, especially for those with cecal dilatation greater than 10 cm (Department of Health and Health Protection Agency, 2008). Improvement of CDI Surveillance Aside from changes in clinical approach to CDI, observation of CDI epidemiology had been revised as well. For one, the definition of increased incidence has become strict. It is declared whenever there are multiple new cases, occurring more than two days post-admission of a CDI patient, in a 28-day period on a ward. On the other hand, an outbreak is declared when two or more cases caused by the same strain related in time and place over a defined period relative to the date of onset of the first case (Department of Health and Health Protection Agency, 2008). Current Statistics on CDI Occurrence To determine whether the imposed measures are effective, statistics were looked into. Their interpretation is as important as the data itself, and should be the basis of future decisions regarding healthcare policies influencing CDI. Prevalence One of the more common measures of frequency is prevalence. In this case, annual prevalence of CDI is the proportion of the population in United Kingdom who had CDI within the year. This statistic is based on both the incidence and duration of disease. Because CDI is a relatively acute illness, the prevalence of this infectious disease implies the risk of its spread (Dicker, 1992). Decreasing the prevalence of the disease is important to make it easy for health systems to manage CDI (Brundtland, 1999). A steady decrease in the prevalence of CDI has been noted since 2008. From as high as 55, 498 cases reported between 2007 and 2008, it was decreased to 36, 095 the following year. Rate per 100, 000 population subsequently decreased from 111.3 to 72.0. From April 2009 to March 2010, the prevalence was noted to be 25, 604, or 50.7 per 100, 000 population, and from April 2010 to March 2011, it was 21, 707 (42.7 per 100, 000). Recently, the total number of reported CDI cases between April 2011 and March 2012 was 18, 005 (35. 4 per 100, 000), representing a 17% reduction in CDI prevalence (Hospital Protection Agency, 2012a). Evidently, employed changes in care for CDI patients led to this decrease in the risk of acquiring the infection. Total bed days due to CDI To prove that the decrease of incidence was the primary reason why prevalence of CDI decreased from 2007 to present, rate per 100, 000 bed days was computed. This measure is currently the standard of reporting incidence rates (McClurg, 2012). Looking at the data, similar to prevalence rates, CDI rate per 100, 000 bed days continuously decreased between 2007 to 2012, with the greatest reduction noted between 2007 to 2008 and 2008 to 2009 (Hospital Protection Agency, 2012b). The latter of which correspond to the year when maximal decrease in prevalence of CDI was noted. However, the goal of 39 per 100, 000 bed days was only achieved in 2011. According to McClurg (2012), this is a result of a comprehensive effort in reducing CDI cases, which includes promotion of good hand hygiene and chlorine-based disinfectant cleaning regime for environmental cleanliness to healthcare staff and the general public. The judicious prescription and use of medications, particularly of antibiotics and proton pump inhibitors, also has a significant contribution. It is also important that the implementation of plans is ensured. Temporal pattern of CDI prevalence Looking at the seasonal pattern of CDI between 2007 and 2012, number of CDI cases generally improves within April to December, particularly April to September. On the other hand, the first trimester was marked with an increase in CDI prevalence (Hospital Protection Agency, 2012c). Such seasonal pattern of CDI has also been reported in other countries. This has been attributed to the increase in the incidence of Influenza during the relatively more humid winter season, thereby heightening antimicrobial use. As discussed above, this results to a greater risk for future CDI infection. In a retrospective study conducted using the 1998 – 2005 data from four US census regions, monthly peaks for CDI also occurred in the first trimester, particularly in March. Using a time-series analysis, it is highly correlated with the increase in rates of Influenza recorded in January and February (Polgreen, et al., 2010). This relation is unexpected, since Influenza is a viral illness. As such, antibiotic treatment is unnecessary. It is also suggested that the prescription of antimicrobial agents to patients with Influenza is based on the observation that Influenza increases the likelihood of contracting secondary bacterial illness. However, prevention of secondary bacterial infection through antimicrobial prophylaxis has yet to be proven. Some have admitted that clinicians use antibiotics for patients presenting with flu-like symptoms, since many respiratory bacterial infection comes with the same presentation. Glaringly, the current use of antibiotics for antibiotics is irrational. Moreover, Influenza accounts for 10% to 30% of excess antimicrobial use among children (Polgreen, et al., 2010). Despite these findings providing answers regarding the seasonality of CDI, it poses further questions to the nature of this temporal pattern. First, since it is highly possible that winter-prevalent viral infections other than Influenza also contribute to the seasonality of CDI, determining the amount of their contribution should help policy makers decide which viruses they should focus prevention to. The contribution of other factors, such as the temporal pattern of hospital admission or staff shortages, in increasing the incidence of CDI should also be investigated. Moreover, it is also important to find out whether the seasonality of CDI is due to surveillance bias. Since the incidence of other gastrointestinal infection peaks during the winter months, healthcare workers at this time may order for CDI in all their diarrhea cases, much more frequent than they did during the other seasons. Because more people are subjected to testing during the winter, more CDI cases may be reported at this time compared to other months of the year, even if CDI infection actually does not follow a seasonal pattern (Polgreen, et al., 2010). Prevalence among the elderly The proportion of CDI patients belonging to the elderly population, for the year 2007 to 2012, ranged between 83% and 76%. This proportion was decreased significantly in the first trimester (January to March) of 2008 (-2.02) and 2010 (-2.72), as well as the second trimester (April to June) of 2009 (-3.3) and 2011 (-1.93). In contrast, it increased significantly in the last trimester (October to December) of 2008 (+2.0), July to December 2009 (+1.68), and third trimester (July to August) of 2010 (+1.6) and 2011 (+1.6) (Hospital Protection Agency, 2012c). This can be explained with temporal pattern of CDI, and its relation with the prevalence of other infectious diseases. During winter, people across all ages are more susceptible to certain infection, such as Influenza. At this time, the increase in antimicrobial intake is seen regardless of age. This is in contrast with other seasons, in which infectious diseases and subsequent antibiotic use became less, especially among children and working adults. As a result, the increase in the antibiotic use of the general population during the winter months makes all age strata more susceptible to CDI, thereby offsetting the disadvantage of the elderly, which are perennially at high risk of CDI because of their relative immunodeficiency and presence of co-morbidities. Points of Improvement Better diagnosis Despite the availability of commercial C. difficile toxin assay kits, their sensitivity, specificity, and predictive values were not yet independently evaluated (Department of Health and Health Protection Agency, 2008). In fact, the commonly-used EIA had shown limited sensitivity with frequent false negative outcomes. Although more sensitive tests such as clostridial glutamate dehydrogenase, tissue culture cytotoxicity and polymerase chain reaction (PCR) are available, its wide-scale use is still under study (Martinez, Leffler and Kelly, 2012). Identification of the gold standard for laboratory diagnosis may improve the epidemiologic values of CDI. Improving treatment of infectious diseases Since there is evidence that the temporal pattern of CDI prevalence is associated with the prevalence of other infectious diseases, such as Influenza, preventing these diseases by improving health and hygiene, together with enhancing their diagnosis, should limit the use of antimicrobial treatment. This can be done by developing new drugs and vaccines through intensified research. This is an important strategy in dealing with infectious diseases in general, because, currently, the gamut of effective, commercially-available antimicrobial drugs is gradually decreasing with the increasing resistance of microbes against these agents (Brundtland, 1999). Department of Health and National Health Service Guidelines should also consider putting a premium on non-pharmacologic interventions for CDI. It should be reiterated that discontinuation of predisposing antibiotics is vital in preventing the progression of CDI. In fact, the standard initial therapy for mild CDI is the discontinuation of all antibiotic therapy and monitoring of the patient’s progress, while moderate infection only necessitates symptomatic treatment. Probiotics, like Lactobacillus spp. or Saccharomyces boulardii, can also be used as adjunctive therapy. The option of fecal transplantation or surgery should also be given, especially in cases of Ileus. Once developed, human monoclonal antibodies against C. difficile endotoxins A and B, in conjunction with pharmacotherapy, may also be an effective CDI treatment, especially for prevention of recurrence (Martinez, Leffler and Kelly, 2012). Conclusion CDI is a gastrointestinal infection that causes diarrhea, which, if not managed, can lead to serious health problems, or even death. Since many countries have been affected by this disease, especially between 1997 and 2001, prevention of its fecal-oral route of transmission and its efficient management have been the aim of many health policy bodies. In UK, results showed that efforts of the Department of Health and National Health Services have been effective. However, there is still room for improvement, and better diagnosis and antibiotic use may be the best targets to prevent widespread infection C. difficile. References Brundtland, G. H., 1999. Removing Obstacles to Healthy Development. Geneva, Switzerland: World Health Organization Department of Health and Health Protection Agency, 2008. Clostridium difficile infection: How to deal with the problem. London: Department of Health. Dicker, R. C., 1992. Principles of Epidemiology. Second Edition. Atlanta: US Department of Health and Human Services. Health Protection Agency, n. d. Clostridium difficile. [online] Available at: [Accessed 2 February 2013] Health Protection Agency, n. d. Inclusion criteria for reporting C. difficile infection to the surveillance system. [online] Available at: [Accessed 2 February 2013] Health Protection Agency, 2012a. Table 1: Total counts and rates of CDI by financial year (April 2007 to March 2012). London: Health Protection Agency Health Protection Agency, 2012b. Table 2: Trust apportioned counts and rates of CDI by financial year (April 2007 to March 2012). London: Health Protection Agency Health Protection Agency, 2012c. Table 3: Counts of CDI by quarter (April 2007 to Match 2011). London: Health Protection Agency Martinez, F. J., Leffler, D. A., and Kelly, C. P., 2012. Clostridium difficile outbreaks: prevention and treatment strategies. Risk Management and Healthcare Policy, 5, pp. 55-64. McClurg, L., 2012. Infection Prevention and Control Report. London: National Health Services. Polgreen, P. M., Yang, M., Bohnett, L. C., and Cavanaugh, J. E., 2010. A Time-Series Analysis of Clostridium difficile and Its Seasonal Association with Influenza. Infect Control Hosp Epidemiol, 31(4), pp. 382-387. Read More