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C. difficileInfection: Changing Epidemiology and Management Paradigms

C. difficileInfection: Changing Epidemiology and Management Paradigms Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/02/2020 Citation: Clinical and Translational Gastroenterology (2015) 6, e99; doi:10.1038/ctg.2015.24 & 2015 the American College of Gastroenterology All rights reserved 2155-384X/15 www.nature.com/ctg CLINICAL/NARRATIVE REVIEW C. difficile Infection: Changing Epidemiology and Management Paradigms 1 1 Stephen M. Vindigni, MD, MPH and Christina M. Surawicz, MD The incidence of Clostridium difficile infection (CDI) has been rising in hospitals, long-term care facilities, and within the community. Cases have been more severe with more complications, deaths, and higher healthcare-associated costs. With the emergence of a hypervirulent strain of C. difficile and the increasing prevalence of community-acquired CDI among healthy patients without traditional risk factors, the epidemiology of C. difficile has been evolving. This changing epidemiology requires a change in management. Taking into account new risk factors for CDI and growing subpopulations of affected individuals, diagnostic, treatment, and prevention approaches need to be adjusted. Clinical and Translational Gastroenterology (2015) 6, e99; doi:10.1038/ctg.2015.24; published online 9 July 2015 Subject Category: Clinical Review INTRODUCTION CDI has shown a steady rise. This has continued to the current time. The incidence of Clostridium difficile has been rising steadily The greatest increase in cases has been seen in hospital over the past two decades with subsequent increases in settings. From the 1990s to 2000, CDI rates remained relatively mortality, prolonged hospital stays with higher level care, and stable across all age groups as shown in Figure 1. Since then, 1,2 a substantial rise in healthcare costs. In fact, not only is the incidence of CDI has increased from approximately 30–40 C. difficile infection (CDI) the most common cause of hospital- cases per 100,000 population in the mid 1990s to 84 cases per acquired diarrhea, it has replaced methicillin-resistant 100,000 population in 2005. McDonald et al. describe an Staphylococcus aureus as the most common hospital- increase in CDI from 264,000 cases in 1996 to 978,000 cases in 2–4 acquired infection overall. 2003. Similarly, the US Agency for Healthcare Research and C. difficile is a gram-positive, rod-shaped, spore-forming Quality’s Healthcare Cost and Utilization Project identifies 24,200 anaerobe with the ability to produce enterotoxin A and hospital stays for patients with a principal CDI diagnosis (85,700 cytotoxin B (linked to the tcdA and tcdB genes, respectively), for CDI among all-listed diagnoses) in 1993 compared with which are responsible for its virulence. Toxin B activates 110,600 hospital stays in 2009 for a primary CDI diagnosis monocyte cytotoxin release and is significantly more potent 11 (336,600 for CDI among all-listed diagnoses). Although this than enterotoxin A, which causes local tissue injury. C. difficile database is a limited, nationwide sample of inpatient hospital is known to cause disease through release of these two toxins. stays, it illustrates a four-fold increase in the number of Clinically, there is a wide spectrum of C. difficile presentations hospitalizations over a 16-year time period. CDI was associated ranging from asymptomatic carriage to severe, life threaten- 11 with at least 1% of all hospital stays in 2009. 6–8 ing, fulminant colitis, and toxic megacolon. Using patient discharge data, similar trends are seen. Traditionally, C. difficile strains unable to produce one or both Nationally, among adult, non-maternal hospital discharges, of these toxins were considered as non-pathogenic; however, there were 7.4 per 1,000 hospitalizations for CDI in 2003 there is now evidence that some strains may also produce a compared with 13.5 per 1,000 in 2012. Surveillance efforts binary toxin transcribed from the ctdA and ctdB genes. The have also demonstrated increased morbidity and mortality significance of this binary toxin on the pathogenicity of C. difficile among CDI patients. Death certificates with enterocolitis due is unknown. The BI/NAP1/027 strain produces this toxin as well to C. difficile as the primary cause of death increased from 793 as markedly increased levels of Toxin A and Toxin B, which may in 1999 to 7,483 in 2008; the age-adjusted death rate rose contribute to its hypervirulence. This new development may 15%. Similar trends in CDI incidence have been seen in 14–16 explain the rising incidence and severity of CDI. Canada and throughout Europe. CHANGING EPIDEMIOLOGY CHANGING POPULATIONS AT RISK While C. difficile has been linked to disease since at least the Several subpopulations are disproportionately affected by 1970s, it was not until 2000 that the incidence and severity of C. difficile and have higher associated morbidity and mortality. Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA Correspondence: Stephen M. Vindigni, MD, Division of Gastroenterology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356424, Seattle, Washington 98195-6424, USA. E-mail: [email protected] Received 2 March 2015; accepted 4 May 2015 Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/02/2020 Changing Epidemiology and Management of CDI Vindigni and Surawicz Figure 1 Rates of Clostridium difficile infection among hospitalized patients aged ≥ 65 years, by age group—National Hospital Discharge Survey, United States, 1996–2009 (from Centers for Disease Control and Prevention. Morb Mortal Wkly Rep (MMWR) 2011;60(34):1171. 4,17 Table 1 Risk factors for Clostridium difficile infection persons ≥ 65 years old will continue to rise. Moreover, comparing 2000 with 2003, a greater number of hospitalized Antibiotic exposure patients with a CDI discharge diagnosis were transferred to a Older age (65 or older) long-term care facility. Various potential explanations for this rise among the elderly have been proposed, including Prior, lengthy hospitalization or long-term care facility exposure residence at long-term care facilities, increased use of Comorbidities: malignancy, cystic fibrosis, inflammatory bowel antibiotics and proton pump inhibitors, and decreased host disease, diabetes mellitus, cirrhosis, chronic kidney disease, 4,18 defenses. immunodeficiency, solid organ or hematopoietic stem cell transplantation Patients with IBD are also at increased risk of developing CDI. In this population, CDI prevalence was 1.7% compared Other medication exposure: chemotherapy, immunosuppressants, proton pump inhibitors with 0.4% of the general population. Among IBD patients, those with ulcerative colitis had a higher CDI incidence (2.8%) Prior gastrointestinal surgery compared with Crohn’s disease patients (1.0%). Therefore, Consumption of processed meats any IBD patient presenting with flare symptoms should Presence of gastrostomy or jejunostomy tube be tested for C. difficile toxin to rule out disease. It remains unclear whether this higher CDI prevalence is related to Adapted from refs. 1, 17, and 34. increased antibiotic exposure, more frequent contact with healthcare settings, or an immunocompromised state. Multiple theories have been proposed to explain the overall These include the elderly, immunocompromised individuals rise in CDI—hospitalized patients are often older and sicker, (including patients receiving chemotherapy or following solid there is increased use of broader spectrum antibiotics (e.g., organ transplantation), patients with inflammatory bowel fluoroquinolones resulting in resistance patterns), and inade- 2,4,17,18 disease (IBD), and patients with significant co-morbidities quate prevention measures in healthcare settings. It is beyond CDI. Table 1 lists the various risk factors for CDI. not known if the widespread use of waterless, alcohol-based While the elderly have always been at increased risk of hand gels contributes to the nosocomial spread of C. difficile, developing CDI, much of the rise in hospital-acquired cases although several studies have shown no increase in CDI with 20,21 has been seen in patients over the age of 65. In fact, the rate of increased use of these hand gels in lieu of handwashing. CDI discharge diagnoses was seven-fold higher in patients There is also increased testing among patients who present ≥ 65 years compared with patients aged 45–64 years with diarrhea. (Po0.001). Patients with CDI were nearly 20 years older (67.9 years vs. 48.1 years) and patients ≥ 85 years had the EMERGENCE OF COMMUNITY STRAINS highest rate (1,089 per 100,000 population), compared with only 11 per 100,000 for patients under 18 years old. In 2008, Despite the rise in CDI-related hospitalizations worldwide, the C. difficile ranked as the 18th leading cause of death among population affected appears to have evolved since 2000. persons aged ≥ 65; 93% of C. difficile-associated deaths Historically, CDI has been associated with antibiotic use, occurred in persons aged ≥ 65. As the US population although there is a growing number of patients who present continues to age, it is not unexpected that CDI rates among with diarrheal symptoms and are diagnosed with CDI without Clinical and Translational Gastroenterology Changing Epidemiology and Management of CDI Vindigni and Surawicz Table 2 CDI classification and symptom onset Disease classification Symptom onset HCF onset, HCF-associated CDI 448 h after admission but before discharge from an HCF Community-associated CDI Community onset or within 48 h of HCF admission, if symptom onset was 412 weeks after last HCF discharge Community onset, HCF-associated CDI Community onset or within 48 h of HCF admission, if symptom onset was ≤ 4 weeks after last HCF discharge Indeterminate CDI Does not meet criteria for above disease classifications Unknown CDI Lack of available data; unable to classify CDI, Clostridium difficile infection; HCF, healthcare facility. Adapted from refs. 5 and 24. 22,23 any prior antimicrobial exposure. These are frequently hand hygiene at the hospital and community level; the impact healthy adults without significant medical comorbidity. There- on food safety practices and animal exposure is less defined. fore, it has become reality that prior antibiotic exposure can no A major factor in the development of community-acquired CDI was the identification of the hypervirulent, toxigenic strain, longer be assumed. Furthermore, it is hypothesized that there BI/NAP1/O27. Spiking between 2002 and 2006 as an is an emergence of community strains of C. difficile. To better international epidemic, this new strain has resulted in more characterize CDI by exposure setting and timing, disease severe clinical presentations requiring longer hospitalizations classifications have been established as described in 5,24 and resultant rises in healthcare costs. In particular, this strain Table 2. has been linked to severe cases of CDI, especially among the Although CDI-related discharges started to stabilize in elderly. This is likely related to 16 times greater toxin A 2009, overall CDI rates have continued to rise. This finding production and 23 times greater toxin B production with high is mostly attributable to community acquisition diagnosed in rates of fluoroquinolone resistance. The strain was initially outpatient care settings. It is estimated that community- identified following outbreaks in Canada, the United States, acquired CDI may now account for up to 40% of CDI cases. 32,33 and Europe. Since then, there have been other strains, These patients tend to be younger and healthier without recent 3,25 such as PCR ribotypes 001, 018, 078, and 106 which have hospitalization, antibiotic exposure or co-morbidities. had associated outbreaks. The mode of transmission within the community remains There has also been a rise of proton pump inhibitors therapy unclear. Exposure to C. difficile is through the fecal–oral route among outpatients. There is increasing epidemiologic evidence followed by an incubation period that may lead to infection, that the long-term use of proton pump inhibitors may increase the colonization, or complete clearance. Otten et al. suggest that 35,36 risk of CDI, but perhaps not recurrent CDI (RCDI). The exposure does not necessarily dictate disease—some per- mechanisms for this are not known, but may be related to a higher sons become colonized, others develop clinical disease, some gastric pH decreasing colonization resistance. may develop disease with clearance, and some persons may have relapse. The determinants of which category a person falls into are unclear. For those persons who develop disease, CHANGING MANAGEMENT infection may be cleared as vegetative cells and spores are While the C. difficile organism and the populations it targets eradicated, but infection may recur. have both been evolving over the past 20 years, science has There are four proposed sources of C. difficile exposure within not stalled. There has been the development of new diagnostic the community—person–person contact, animal–person con- testing strategies for C. difficile. In the 1990s, immunoassays tact, food contamination, and environment–person contact. were the primary diagnostic modality; however, current testing Since infected persons shed C. difficile, person–person transmis- approaches have been modified to include more sensitive and sion is the most reasonable hypothesis for community-level specific molecular tests, such as polymerase chain reaction acquisition; this mode of transmission has been clearly demon- (PCR) that allows for earlier detection and more rapid strated in hospital settings. Situations have also been identified treatment. This nucleic acid amplification test is more sensitive by which employees carry spores home exposing family than toxin enzyme immunoassay tests and C. difficile culture members to C. difficile (e.g., healthcare workers, daycare and more specific than glutamate dehydrogenase testing; it is centers, and veterinary clinics). Animals also shed C. difficile, also widely available and has become the test of choice for including dogs, cats, horses, and calves, which should be rapid diagnosis of CDI. Despite the increased cost of PCR considered as a potential mode of transmission in agricultural compared with immunoassays, it is a more cost-effective testing settings. Various studies have identified C. difficile in food choice as it offers earlier detection, increased accuracy, and products, including ground meat and water, although there is no allows for more rapid treatment; it also allows for isolation of 28–30 clear evidence of disease transmission. Finally, environ- CDI patients and prevents further spread of infection. Despite mental surfaces may become contaminated which is a common this, one challenge with PCR is the risk of overdiagnosis, 26,27 concern in healthcare settings, but extends to the community. particularly in asymptomatic carriers who may be less likely to 37–40 This lack of a clear understanding of how community-acquired spread spores and contribute to the infection burden. CDI is transmitted illustrates the need for a multidisciplinary Additionally, this improved, highly sensitive, and specific test approach including improved home cleaning practices and may explain some of the increased identification of cases and Clinical and Translational Gastroenterology Changing Epidemiology and Management of CDI Vindigni and Surawicz Table 3 Treatment for C. difficile infection CDI Clinical presentation Regimen Considerations Mild–moderate Diarrhea Metronidazole 500 mg p.o. t.i.d. Avoid in pregnancy or with No signs of severe or complicated disease ×10 days breast-feeding. Alternative: Fidaxomicin 200 mg p.o. Change to vancomycin if no b.i.d. × 10 days response within 72 h Severe Albumin o3 g/dl Vancomycin 125 mg p.o. q.i.d. Increase to 250–500 mg p.o. Abdominal distention ×10 days q.i.d. if poor response WBC 415,000 Complicated Fever Metronidazole 500 mg IV t.i.d. and Includes patients with ileus, Significant leukocytosis (435,000) or leukopenia vancomycin 500 mg p.o. q.i.d. recent abdominal surgery, or o2,000) +/− vancomycin enemas 500 mg inability to take p.o. Hypoalbuminemia p.r. q.i.d. These patients should be Abdominal distention +/ − ileus +/− shock with admitted to the intensive care hypotension or evidence of end-organ failure unit. +/− elevation in serum lactate (42.2 mmol/l) or Consider surgery consult to C-reactive protein consider surgical approaches to treatment Recurrent CDI episode within 8 weeks of previous episode 1st recurrence: repeat metronidazole, Consider FMT after vancomycin, or fidaxomicin 3 recurrences 2nd recurrence: pulsed vancomycin regimen: 125 mg q.i.d. × 10 days, then 125 mg daily every 3 days × 10 doses CDI, Clostridium difficile infection; FMT, fecal microbiota transplantation; IV, intravenous; RCT, randomized control trial; WBC, white blood cell. Adapted from refs. 1 and 6. a 1 Recent guidelines recommend a 10-day course of therapy for treatment of mild-to-moderate CDI; this is also the length of therapy in the RCT of these drugs. If the patient is not clinically improved, then therapy can be extended or changed. explain the rise in CDI prevalence. Since widespread use of immune system activation, and protection from invasive bacteria, C. difficile PCR may also pick up asymptomatic carriers, also known as colonization resistance. Research on the testing is only indicated in symptomatic patients. microbiome continues to grow, particularly over the past several As CDI has emerged as a common hospital-acquired years. C. difficile is a prime example where altered microbiota infection and has become increasingly more prevalent in the contribute to disease; therefore, strategies to restore the community, the approach to reduction of risk factors and intestinal microbiome may be effective as a treatment modality. management has become more challenging requiring more Given the high rates of CDI recurrence and lack of uniformly creative solutions. successful therapy, there has been growing interest in fecal Traditionally, metronidazole and vancomycin have been the microbiota transplantation (FMT). FMT is a treatment that directly mainstays of CDI treatment with the newer antibiotic, alters—and restores—the gut microbiome. FMT is the delivery of fidaxomicin, as an alternative. Patients treated with fidaxomi- stool from a healthy donor into the colon of a patient with RCDI, cin had lower recurrence rates of CDI compared with either by the upper gastrointestinal route, such as nasoduodenal vancomycin in clinical trials; however, its use has been limited infusion or into the colon by enema or colonoscopy. Meta- somewhat by its high cost. Treatment regimens are often analyses of the hundreds of published cases and series show an dictated by disease severity as detailed in Table 3. efficacy of 90% and a landmark randomized control trial showed Despite effective treatment options for primary CDI, efficacy in RCDI patients given stool by the nasoduodenal route recurrence rates are 10–20%, with rates up to 40–65% after compared with vancomycin therapy; a more recent randomized a first recurrence. With recurrence, treatment is often more control trial also shows colonoscopic infusion to be more effective 48–51 challenging and clinical presentations may be more severe. A than vancomycin. FMTwith colonoscopic delivery has been first recurrence can be treated with the same initial antibiotic demonstrated to be a cost-effective intervention for RCDI (i.e., vancomycin, metronidazole, or fidaxomicin), unless the compared with oral vancomycin. recurrence is severe in which case vancomycin is indicated. While treatment of CDI is an important area for ongoing There is interest in fidaxomicin as a treatment for RCDI since research, prevention efforts also need to be enhanced to recurrence rates for primary CDI were lower than for counteract the growing epidemic, both for the individual vancomycin, but the drug has not been studied for RCDI patient and in interrupting transmission. specifically. Other regimens include the use of the adjunct There is interest in the role of probiotics for prevention. probiotic, Saccharomyces boulardii and intravenous immune While there is good evidence for two probiotics that prevent 42,43 globulin. There is ongoing research into a monoclonal antibiotic-associated diarrhea (Lactobacillus rhamnosus GG antibody to toxins A and B to treat recurrences and several and S. boulardii), there is less evidence that they prevent 44–46 53 vaccines are in development as well. CDI. A meta-analysis concluded that there was moderate Furthermore, as research into the intestinal microbiome efficacy for probiotics in prevention of CDI, but this combined continues to progress, we are learning more about the complex, studies of many different probiotics or mixtures of probiotics in interdependent ecosystem responsible for food digestion, varied clinical settings. 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Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med 2012; 172: if the material is not included under the Creative Commons license, 191–193. users will need to obtain permission from the license holder to 51. Cammarota G, Masucci L, Ianiro G et al. Randomised clinical trial: faecal microbiota reproduce the material. To view a copy of this license, visit http:// transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015; 41: 835–843. creativecommons.org/licenses/by-nc-sa/4.0/ Clinical and Translational Gastroenterology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Translational Gastroenterology Wolters Kluwer Health

C. difficileInfection: Changing Epidemiology and Management Paradigms

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Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/02/2020 Citation: Clinical and Translational Gastroenterology (2015) 6, e99; doi:10.1038/ctg.2015.24 & 2015 the American College of Gastroenterology All rights reserved 2155-384X/15 www.nature.com/ctg CLINICAL/NARRATIVE REVIEW C. difficile Infection: Changing Epidemiology and Management Paradigms 1 1 Stephen M. Vindigni, MD, MPH and Christina M. Surawicz, MD The incidence of Clostridium difficile infection (CDI) has been rising in hospitals, long-term care facilities, and within the community. Cases have been more severe with more complications, deaths, and higher healthcare-associated costs. With the emergence of a hypervirulent strain of C. difficile and the increasing prevalence of community-acquired CDI among healthy patients without traditional risk factors, the epidemiology of C. difficile has been evolving. This changing epidemiology requires a change in management. Taking into account new risk factors for CDI and growing subpopulations of affected individuals, diagnostic, treatment, and prevention approaches need to be adjusted. Clinical and Translational Gastroenterology (2015) 6, e99; doi:10.1038/ctg.2015.24; published online 9 July 2015 Subject Category: Clinical Review INTRODUCTION CDI has shown a steady rise. This has continued to the current time. The incidence of Clostridium difficile has been rising steadily The greatest increase in cases has been seen in hospital over the past two decades with subsequent increases in settings. From the 1990s to 2000, CDI rates remained relatively mortality, prolonged hospital stays with higher level care, and stable across all age groups as shown in Figure 1. Since then, 1,2 a substantial rise in healthcare costs. In fact, not only is the incidence of CDI has increased from approximately 30–40 C. difficile infection (CDI) the most common cause of hospital- cases per 100,000 population in the mid 1990s to 84 cases per acquired diarrhea, it has replaced methicillin-resistant 100,000 population in 2005. McDonald et al. describe an Staphylococcus aureus as the most common hospital- increase in CDI from 264,000 cases in 1996 to 978,000 cases in 2–4 acquired infection overall. 2003. Similarly, the US Agency for Healthcare Research and C. difficile is a gram-positive, rod-shaped, spore-forming Quality’s Healthcare Cost and Utilization Project identifies 24,200 anaerobe with the ability to produce enterotoxin A and hospital stays for patients with a principal CDI diagnosis (85,700 cytotoxin B (linked to the tcdA and tcdB genes, respectively), for CDI among all-listed diagnoses) in 1993 compared with which are responsible for its virulence. Toxin B activates 110,600 hospital stays in 2009 for a primary CDI diagnosis monocyte cytotoxin release and is significantly more potent 11 (336,600 for CDI among all-listed diagnoses). Although this than enterotoxin A, which causes local tissue injury. C. difficile database is a limited, nationwide sample of inpatient hospital is known to cause disease through release of these two toxins. stays, it illustrates a four-fold increase in the number of Clinically, there is a wide spectrum of C. difficile presentations hospitalizations over a 16-year time period. CDI was associated ranging from asymptomatic carriage to severe, life threaten- 11 with at least 1% of all hospital stays in 2009. 6–8 ing, fulminant colitis, and toxic megacolon. Using patient discharge data, similar trends are seen. Traditionally, C. difficile strains unable to produce one or both Nationally, among adult, non-maternal hospital discharges, of these toxins were considered as non-pathogenic; however, there were 7.4 per 1,000 hospitalizations for CDI in 2003 there is now evidence that some strains may also produce a compared with 13.5 per 1,000 in 2012. Surveillance efforts binary toxin transcribed from the ctdA and ctdB genes. The have also demonstrated increased morbidity and mortality significance of this binary toxin on the pathogenicity of C. difficile among CDI patients. Death certificates with enterocolitis due is unknown. The BI/NAP1/027 strain produces this toxin as well to C. difficile as the primary cause of death increased from 793 as markedly increased levels of Toxin A and Toxin B, which may in 1999 to 7,483 in 2008; the age-adjusted death rate rose contribute to its hypervirulence. This new development may 15%. Similar trends in CDI incidence have been seen in 14–16 explain the rising incidence and severity of CDI. Canada and throughout Europe. CHANGING EPIDEMIOLOGY CHANGING POPULATIONS AT RISK While C. difficile has been linked to disease since at least the Several subpopulations are disproportionately affected by 1970s, it was not until 2000 that the incidence and severity of C. difficile and have higher associated morbidity and mortality. Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA Correspondence: Stephen M. Vindigni, MD, Division of Gastroenterology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356424, Seattle, Washington 98195-6424, USA. E-mail: [email protected] Received 2 March 2015; accepted 4 May 2015 Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/02/2020 Changing Epidemiology and Management of CDI Vindigni and Surawicz Figure 1 Rates of Clostridium difficile infection among hospitalized patients aged ≥ 65 years, by age group—National Hospital Discharge Survey, United States, 1996–2009 (from Centers for Disease Control and Prevention. Morb Mortal Wkly Rep (MMWR) 2011;60(34):1171. 4,17 Table 1 Risk factors for Clostridium difficile infection persons ≥ 65 years old will continue to rise. Moreover, comparing 2000 with 2003, a greater number of hospitalized Antibiotic exposure patients with a CDI discharge diagnosis were transferred to a Older age (65 or older) long-term care facility. Various potential explanations for this rise among the elderly have been proposed, including Prior, lengthy hospitalization or long-term care facility exposure residence at long-term care facilities, increased use of Comorbidities: malignancy, cystic fibrosis, inflammatory bowel antibiotics and proton pump inhibitors, and decreased host disease, diabetes mellitus, cirrhosis, chronic kidney disease, 4,18 defenses. immunodeficiency, solid organ or hematopoietic stem cell transplantation Patients with IBD are also at increased risk of developing CDI. In this population, CDI prevalence was 1.7% compared Other medication exposure: chemotherapy, immunosuppressants, proton pump inhibitors with 0.4% of the general population. Among IBD patients, those with ulcerative colitis had a higher CDI incidence (2.8%) Prior gastrointestinal surgery compared with Crohn’s disease patients (1.0%). Therefore, Consumption of processed meats any IBD patient presenting with flare symptoms should Presence of gastrostomy or jejunostomy tube be tested for C. difficile toxin to rule out disease. It remains unclear whether this higher CDI prevalence is related to Adapted from refs. 1, 17, and 34. increased antibiotic exposure, more frequent contact with healthcare settings, or an immunocompromised state. Multiple theories have been proposed to explain the overall These include the elderly, immunocompromised individuals rise in CDI—hospitalized patients are often older and sicker, (including patients receiving chemotherapy or following solid there is increased use of broader spectrum antibiotics (e.g., organ transplantation), patients with inflammatory bowel fluoroquinolones resulting in resistance patterns), and inade- 2,4,17,18 disease (IBD), and patients with significant co-morbidities quate prevention measures in healthcare settings. It is beyond CDI. Table 1 lists the various risk factors for CDI. not known if the widespread use of waterless, alcohol-based While the elderly have always been at increased risk of hand gels contributes to the nosocomial spread of C. difficile, developing CDI, much of the rise in hospital-acquired cases although several studies have shown no increase in CDI with 20,21 has been seen in patients over the age of 65. In fact, the rate of increased use of these hand gels in lieu of handwashing. CDI discharge diagnoses was seven-fold higher in patients There is also increased testing among patients who present ≥ 65 years compared with patients aged 45–64 years with diarrhea. (Po0.001). Patients with CDI were nearly 20 years older (67.9 years vs. 48.1 years) and patients ≥ 85 years had the EMERGENCE OF COMMUNITY STRAINS highest rate (1,089 per 100,000 population), compared with only 11 per 100,000 for patients under 18 years old. In 2008, Despite the rise in CDI-related hospitalizations worldwide, the C. difficile ranked as the 18th leading cause of death among population affected appears to have evolved since 2000. persons aged ≥ 65; 93% of C. difficile-associated deaths Historically, CDI has been associated with antibiotic use, occurred in persons aged ≥ 65. As the US population although there is a growing number of patients who present continues to age, it is not unexpected that CDI rates among with diarrheal symptoms and are diagnosed with CDI without Clinical and Translational Gastroenterology Changing Epidemiology and Management of CDI Vindigni and Surawicz Table 2 CDI classification and symptom onset Disease classification Symptom onset HCF onset, HCF-associated CDI 448 h after admission but before discharge from an HCF Community-associated CDI Community onset or within 48 h of HCF admission, if symptom onset was 412 weeks after last HCF discharge Community onset, HCF-associated CDI Community onset or within 48 h of HCF admission, if symptom onset was ≤ 4 weeks after last HCF discharge Indeterminate CDI Does not meet criteria for above disease classifications Unknown CDI Lack of available data; unable to classify CDI, Clostridium difficile infection; HCF, healthcare facility. Adapted from refs. 5 and 24. 22,23 any prior antimicrobial exposure. These are frequently hand hygiene at the hospital and community level; the impact healthy adults without significant medical comorbidity. There- on food safety practices and animal exposure is less defined. fore, it has become reality that prior antibiotic exposure can no A major factor in the development of community-acquired CDI was the identification of the hypervirulent, toxigenic strain, longer be assumed. Furthermore, it is hypothesized that there BI/NAP1/O27. Spiking between 2002 and 2006 as an is an emergence of community strains of C. difficile. To better international epidemic, this new strain has resulted in more characterize CDI by exposure setting and timing, disease severe clinical presentations requiring longer hospitalizations classifications have been established as described in 5,24 and resultant rises in healthcare costs. In particular, this strain Table 2. has been linked to severe cases of CDI, especially among the Although CDI-related discharges started to stabilize in elderly. This is likely related to 16 times greater toxin A 2009, overall CDI rates have continued to rise. This finding production and 23 times greater toxin B production with high is mostly attributable to community acquisition diagnosed in rates of fluoroquinolone resistance. The strain was initially outpatient care settings. It is estimated that community- identified following outbreaks in Canada, the United States, acquired CDI may now account for up to 40% of CDI cases. 32,33 and Europe. Since then, there have been other strains, These patients tend to be younger and healthier without recent 3,25 such as PCR ribotypes 001, 018, 078, and 106 which have hospitalization, antibiotic exposure or co-morbidities. had associated outbreaks. The mode of transmission within the community remains There has also been a rise of proton pump inhibitors therapy unclear. Exposure to C. difficile is through the fecal–oral route among outpatients. There is increasing epidemiologic evidence followed by an incubation period that may lead to infection, that the long-term use of proton pump inhibitors may increase the colonization, or complete clearance. Otten et al. suggest that 35,36 risk of CDI, but perhaps not recurrent CDI (RCDI). The exposure does not necessarily dictate disease—some per- mechanisms for this are not known, but may be related to a higher sons become colonized, others develop clinical disease, some gastric pH decreasing colonization resistance. may develop disease with clearance, and some persons may have relapse. The determinants of which category a person falls into are unclear. For those persons who develop disease, CHANGING MANAGEMENT infection may be cleared as vegetative cells and spores are While the C. difficile organism and the populations it targets eradicated, but infection may recur. have both been evolving over the past 20 years, science has There are four proposed sources of C. difficile exposure within not stalled. There has been the development of new diagnostic the community—person–person contact, animal–person con- testing strategies for C. difficile. In the 1990s, immunoassays tact, food contamination, and environment–person contact. were the primary diagnostic modality; however, current testing Since infected persons shed C. difficile, person–person transmis- approaches have been modified to include more sensitive and sion is the most reasonable hypothesis for community-level specific molecular tests, such as polymerase chain reaction acquisition; this mode of transmission has been clearly demon- (PCR) that allows for earlier detection and more rapid strated in hospital settings. Situations have also been identified treatment. This nucleic acid amplification test is more sensitive by which employees carry spores home exposing family than toxin enzyme immunoassay tests and C. difficile culture members to C. difficile (e.g., healthcare workers, daycare and more specific than glutamate dehydrogenase testing; it is centers, and veterinary clinics). Animals also shed C. difficile, also widely available and has become the test of choice for including dogs, cats, horses, and calves, which should be rapid diagnosis of CDI. Despite the increased cost of PCR considered as a potential mode of transmission in agricultural compared with immunoassays, it is a more cost-effective testing settings. Various studies have identified C. difficile in food choice as it offers earlier detection, increased accuracy, and products, including ground meat and water, although there is no allows for more rapid treatment; it also allows for isolation of 28–30 clear evidence of disease transmission. Finally, environ- CDI patients and prevents further spread of infection. Despite mental surfaces may become contaminated which is a common this, one challenge with PCR is the risk of overdiagnosis, 26,27 concern in healthcare settings, but extends to the community. particularly in asymptomatic carriers who may be less likely to 37–40 This lack of a clear understanding of how community-acquired spread spores and contribute to the infection burden. CDI is transmitted illustrates the need for a multidisciplinary Additionally, this improved, highly sensitive, and specific test approach including improved home cleaning practices and may explain some of the increased identification of cases and Clinical and Translational Gastroenterology Changing Epidemiology and Management of CDI Vindigni and Surawicz Table 3 Treatment for C. difficile infection CDI Clinical presentation Regimen Considerations Mild–moderate Diarrhea Metronidazole 500 mg p.o. t.i.d. Avoid in pregnancy or with No signs of severe or complicated disease ×10 days breast-feeding. Alternative: Fidaxomicin 200 mg p.o. Change to vancomycin if no b.i.d. × 10 days response within 72 h Severe Albumin o3 g/dl Vancomycin 125 mg p.o. q.i.d. Increase to 250–500 mg p.o. Abdominal distention ×10 days q.i.d. if poor response WBC 415,000 Complicated Fever Metronidazole 500 mg IV t.i.d. and Includes patients with ileus, Significant leukocytosis (435,000) or leukopenia vancomycin 500 mg p.o. q.i.d. recent abdominal surgery, or o2,000) +/− vancomycin enemas 500 mg inability to take p.o. Hypoalbuminemia p.r. q.i.d. These patients should be Abdominal distention +/ − ileus +/− shock with admitted to the intensive care hypotension or evidence of end-organ failure unit. +/− elevation in serum lactate (42.2 mmol/l) or Consider surgery consult to C-reactive protein consider surgical approaches to treatment Recurrent CDI episode within 8 weeks of previous episode 1st recurrence: repeat metronidazole, Consider FMT after vancomycin, or fidaxomicin 3 recurrences 2nd recurrence: pulsed vancomycin regimen: 125 mg q.i.d. × 10 days, then 125 mg daily every 3 days × 10 doses CDI, Clostridium difficile infection; FMT, fecal microbiota transplantation; IV, intravenous; RCT, randomized control trial; WBC, white blood cell. Adapted from refs. 1 and 6. a 1 Recent guidelines recommend a 10-day course of therapy for treatment of mild-to-moderate CDI; this is also the length of therapy in the RCT of these drugs. If the patient is not clinically improved, then therapy can be extended or changed. explain the rise in CDI prevalence. Since widespread use of immune system activation, and protection from invasive bacteria, C. difficile PCR may also pick up asymptomatic carriers, also known as colonization resistance. Research on the testing is only indicated in symptomatic patients. microbiome continues to grow, particularly over the past several As CDI has emerged as a common hospital-acquired years. C. difficile is a prime example where altered microbiota infection and has become increasingly more prevalent in the contribute to disease; therefore, strategies to restore the community, the approach to reduction of risk factors and intestinal microbiome may be effective as a treatment modality. management has become more challenging requiring more Given the high rates of CDI recurrence and lack of uniformly creative solutions. successful therapy, there has been growing interest in fecal Traditionally, metronidazole and vancomycin have been the microbiota transplantation (FMT). FMT is a treatment that directly mainstays of CDI treatment with the newer antibiotic, alters—and restores—the gut microbiome. FMT is the delivery of fidaxomicin, as an alternative. Patients treated with fidaxomi- stool from a healthy donor into the colon of a patient with RCDI, cin had lower recurrence rates of CDI compared with either by the upper gastrointestinal route, such as nasoduodenal vancomycin in clinical trials; however, its use has been limited infusion or into the colon by enema or colonoscopy. Meta- somewhat by its high cost. Treatment regimens are often analyses of the hundreds of published cases and series show an dictated by disease severity as detailed in Table 3. efficacy of 90% and a landmark randomized control trial showed Despite effective treatment options for primary CDI, efficacy in RCDI patients given stool by the nasoduodenal route recurrence rates are 10–20%, with rates up to 40–65% after compared with vancomycin therapy; a more recent randomized a first recurrence. With recurrence, treatment is often more control trial also shows colonoscopic infusion to be more effective 48–51 challenging and clinical presentations may be more severe. A than vancomycin. FMTwith colonoscopic delivery has been first recurrence can be treated with the same initial antibiotic demonstrated to be a cost-effective intervention for RCDI (i.e., vancomycin, metronidazole, or fidaxomicin), unless the compared with oral vancomycin. recurrence is severe in which case vancomycin is indicated. While treatment of CDI is an important area for ongoing There is interest in fidaxomicin as a treatment for RCDI since research, prevention efforts also need to be enhanced to recurrence rates for primary CDI were lower than for counteract the growing epidemic, both for the individual vancomycin, but the drug has not been studied for RCDI patient and in interrupting transmission. specifically. Other regimens include the use of the adjunct There is interest in the role of probiotics for prevention. probiotic, Saccharomyces boulardii and intravenous immune While there is good evidence for two probiotics that prevent 42,43 globulin. There is ongoing research into a monoclonal antibiotic-associated diarrhea (Lactobacillus rhamnosus GG antibody to toxins A and B to treat recurrences and several and S. boulardii), there is less evidence that they prevent 44–46 53 vaccines are in development as well. CDI. A meta-analysis concluded that there was moderate Furthermore, as research into the intestinal microbiome efficacy for probiotics in prevention of CDI, but this combined continues to progress, we are learning more about the complex, studies of many different probiotics or mixtures of probiotics in interdependent ecosystem responsible for food digestion, varied clinical settings. 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Clinical and Translational Gastroenterology – Wolters Kluwer Health

Published: Jul 1, 2015

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