REVIEW URRENT C OPINION
The changing epidemiology of Clostridium difficile infection Hitoshi Honda a and Erik R. Dubberke b
Purpose of review Clostridium difficile infection (CDI) is a growing concern and has a substantial impact on morbidity and mortality. Epidemiology of CDI has dramatically changed over the last decade. Diagnostic and treatment strategies are even more complicated given the wide variety of available diagnostic methods and the emergence of refractory or recurrent CDI. This review is intended to provide information on current CDI epidemiology and guidance for evidence-based diagnosis and management strategies. Recent findings Various studies from the United States, Europe, and Canada revealed increased incidence of CDI since 2000. Although CDI has long been associated with healthcare settings, recent studies indicate it is more common in the community than previously recognized. For diagnostic strategies, newer testing methods, including nucleic acid amplification tests, have enhanced sensitivity compared with toxin testing, but at the expense of decreased specificity. New agents for treating CDI are being developed and higher quality data to support fecal microbiota transplantation for treating recurrent CDI are emerging. Summary CDI epidemiology continues to evolve. Prompt recognition and an evidence-based treatment approach is the key to successfully manage CDI. Further, studies on diagnostic and therapeutic strategies are needed to further improve patient outcomes. Keywords Clostridium difficile, diagnosis, epidemiology, treatment
INTRODUCTION Clostridium difficile infection (CDI) is one of the leading causes of healthcare-associated infections [1]. CDI has contributed to substantial morbidity and mortality in the United States, Canada, and Europe [2 ,3 ,4]. First recognized as the cause of antibiotic-associated colitis in 1978 [5], the incidence of CDI has dramatically increased since the year 2000. In addition to increases in CDI noted in hospitals, there have been other changes in the epidemiology of CDI identified over the last decade. There has been increased recognition of CDI with onset in long-term care facilities and in the community, and the severity and attributable mortality due to CDI have increased [6,7]. Fluoroquinolones, previously associated with a low risk of CDI, and proton pump inhibitors have been associated with an increased risk for CDI [8,9 ]. There have also been reports of increases in metronidazole treatment failures. New diagnostics have been developed, but how to best implement them is not yet clear. &&
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Fortunately, not all recent changes in CDI have been bad. Fidaxomicin became only the second antimicrobial approved for the treatment of CDI [10 ]. There are many other agents being studied for the treatment of CDI and prevention of CDI recurrence, including antimicrobials, nontoxigenic C. difficile, and monoclonal antibodies. In addition, several companies are developing vaccines for primary prophylaxis to prevent CDI. This review &&
a
Division of Infection Prevention, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan and bDivision of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Correspondence to Hitoshi Honda, MD, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8524, Japan. Tel: +1 81 42 323 5111; fax: +1 81 42 323 9205; e-mail: hondah@ hotmail.com Curr Opin Gastroenterol 2014, 30:54–62 DOI:10.1097/MOG.0000000000000018 Volume 30 Number 1 January 2014
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The changing epidemiology of CDI Honda and Dubberke
KEY POINTS
CDI is 5–10%, resulting in over 14 000 deaths per year in the United States, and costs the US healthcare system over $2.1 billion per year [12,13,14 ]. A potential explanation for part of the increasing CDI burden and severity is the emergence of the current epidemic strain. This strain has several names based on the method used to characterize the organism: restriction enzyme analysis BI, North American Pulsed Field Gel Electrophoresis type1 (NAP1) and PCR ribotype 027 (i.e., BI/NAP1/027) [2 ]. The strain was first identified as the cause of severe outbreaks of CDI in the United States and Canada, and subsequently in the United Kingdom and Europe [2 ,3 ]. It is not entirely clear why the BI/NAP1/027 strain is able to cause severe outbreaks, but some in-vitro studies indicate this strain may produce more toxin than other C. difficile strains, and it may be more efficient at producing spores [15]. Some recent studies indicate the incidence of CDI in long-term care facilities (LTCFs) and community settings is higher than previously recognized. In 2006, the state of Ohio mandated CDI reporting from hospitals and LTCFs. When including recurrent CDI, there were more total cases of CDI with onset in LTCFs than in acute care hospitals (7953 cases versus 6376) [16]. The Centers for Disease Control and Prevention (CDC) Emerging Infections Program found that almost 50% of all initial CDI cases had onset in the community [6]. Among cases with onset in a healthcare facility, approximately half had onset in a LTCF and the other half had onset in an acute care hospital. In the same report, it was noted that in the CDC National Healthcare Safety Network data approximately half of CDI cases treated in acute care facilities were present on admission. &
CDI incidence and severity are at historic highs. Fluoroquinolones and proton pump inhibitors are often over prescribed and have been associated with the increased risk for CDI. Only patients with clinically significant diarrhea should be tested for C. difficile, specially, if highly sensitive NAAT testing is used.
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Current published guidelines recommend to treat an initial episode of CDI based on disease severity. Fidaxomicin was approved after the publication of current guidelines.
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FMT was demonstrated to be effective for preventing recurrent CDI in a randomized controlled trial. Optimal methods for donor screening, stool preparation, and FMT administration are unclear.
will cover these aspects of the changing epidemiology of CDI.
CLOSTRIDIUM DIFFICILE INFECTION BURDEN OF DISEASE CDI incidence has substantially increased in healthcare settings over the past decade (Fig. 1). Based on discharge diagnosis code data from the Healthcare Utilization Project (HCUP) in the United States, the incidence of CDI listed as any diagnosis increased from 3.82 per 1000 discharges in 2000 to 8.75 per 1000 discharges in 2008 (Fig. 2) [11]. Increased severity of CDI has been observed as well, with increases in patient transfer to the ICU, colectomy, and deaths due to CDI. The attributable mortality of
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Number of 400 000 CDI cases
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FIGURE 1. Number of discharges from US nonfederal, acute care hospitals assigned the International Classification of Disease – 9 – Clinical Modification (ICD-9-CM) code for CDI (008.45). Data to create figure downloaded from http:// hcupnet.ahrq.gov/HCUPnet.jsp on August 20, 2012. 0267-1379 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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CDI cases/ 10.00 1000 discharges 9.00 8.00 7.00 6.00 5.00 4.00 3.00 2.00 1.00
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FIGURE 2. Rate of discharges from US nonfederal, acute care hospitals assigned the International Classification of Disease – 9 – Clinical Modification (ICD-9-CM) code for CDI (008.45) per 1000 discharges. Data to create figure downloaded from http://hcupnet.ahrq.gov/HCUPnet.jsp on August 20, 2012.
RISK FACTORS FOR CLOSTRIDIUM DIFFICILE INFECTION Risk factors associated with CDI have been investigated in numerous studies. Prior antimicrobial use is a well known risk factor for developing CDI. Antimicrobials alter the healthy fecal microbiome, allowing C. difficile to colonize, overgrow, and produce toxins if a C. difficile exposure occurs before the fecal microbiome is able to return to a healthy state. Traditionally, clindamycin has been associated with CDI, and it remains an important predisposing risk factor today [17]. Numerous studies have also found cephalosporins to be associated with a high risk of developing CDI as well [5]. More recently, fluoroquinolone exposure has been strongly correlated with CDI. This coincided with the emergence of the BI/NAP1/027 strain, which in general is highly resistant to fluoroquinolones [8]. Exposure to gastric acid suppressive agents has also been identified as a risk factor associated with developing CDI [18,19]. The mechanism of action for gastric acid suppression in the causal pathway of CDI is not known. As an obligate anaerobe, the vegetative cells of C. difficile die within minutes after exposure to air. Therefore, C. difficile acquisition involves the ingestion of C. difficile spores, which are resistant to gastric acid. Rather than being in the causal pathway of CDI, gastric acid suppression may be a surrogate marker for patients at increased risk of CDI [9 ,20]. Another important risk factor predisposing to CDI is C. difficile exposure. Within a healthcare setting the population is enriched with patients at risk for CDI. As a result, relative to other settings, the &&
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concentration of patients with CDI is high. Thus, risk of exposure to C. difficile in a healthcare facility is high as well. Studies have demonstrated that length of stay in the hospital is a risk factor for CDI. It has also been demonstrated that CDI pressure, or the number of patients with CDI on the same hospital ward as patients without CDI, is also an important risk factor for CDI [21]. More recently, underlying gastrointestinal illness, specially inflammatory bowel diseases (IBD), has been recognized as an emerging risk factor for CDI. Patients with IBD frequently develop CDI, and this is likely multifactorial. As an autoimmune disease, IBD is associated with an altered immune response and is frequently managed with immunosuppressive agents. In addition, these patients are frequently hospitalized and exposed to antimicrobials [22]. It is also possible that dysbiosis might be associated with developing CDI in patients with IBD, as these patients are at risk for community-onset CDI even without antimicrobial exposure.
DIAGNOSIS The first step to consider before testing a patient for C. difficile is whether or not the patient has a clinical syndrome compatible with the diagnosis of CDI, and whether there may be other explanations for the presence of diarrhea (e.g., laxative exposures). This is because asymptomatic colonization with C. difficile is more common than CDI. Current diagnostic tests detect the presence of C. difficile, or its toxins, in stool, and by themselves are not diagnostic for CDI. Therefore, it is possible to have false Volume 30 Number 1 January 2014
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The changing epidemiology of CDI Honda and Dubberke
positive tests for CDI; that is, asymptomatic C. difficile carriers can test positive, specially with highly sensitive tests [23]. A recent, multicenter study from England demonstrated that C. difficile carriers might be overdiagnosed by highly sensitive tests (e.g., culture, nucleic acid amplification test) [24]. In this study, clinical data were available from 6524 inpatient episodes of diarrhea. The crude mortality of patients whose stool was positive by cytotoxicity cell assay was 17%. This was significantly higher than the crude mortality of patients negative by cytotoxicity cell assay and positive by toxigenic culture (10%, P ¼ 0.04) and higher than patients negative by cytotoxicity cell assay and toxigenic culture (9%, P < 0.001). This indicates that the lower specificity of more sensitive tests may be problematic when diagnosing CDI. The impact of false positive test results has not been adequately studied, but theoretically can lead to adverse events. Patients with false positive tests will end up in contact precautions, and contact precautions have been associated with adverse events [25]. These patients will also be started on CDI therapy, which once stopped, paradoxically, may increase the patient’s risk for CDI [26]. Also, hospital-onset CDI incidence is now reported to the Centers for Medicare and Medicaid Services (CMS), and hospital-onset CDI incidence may be used to determine value-based CMS reimbursement. Excessive false positive tests may result in a decrease in reimbursement to the hospital. To minimize false positive test results, C. difficile testing should be restricted only to those patients with clinically significant diarrhea, ideally without other explanations for the diarrhea, and automatic repeat testing after a negative test should be avoided. The ‘best’ method to diagnose CDI has not been established. Assays that detect C. difficile in stool can be split into two general categories – assays that detect toxin (cytotoxicity cell assay and toxin enzyme immunoassays) and assays that detect the organism (culture for C. difficile, glutamate dehydrogenase assays, and nucleic acid amplification tests). The cytotoxicity cell assay is the most sensitive method to detect C. difficile toxins in stool and it has good specificity for CDI. However, it is relatively labor intensive and can take up to 48 h to have results. C. difficile toxin enzyme immunoassays (EIA) are widely used because of low cost, ease of use, and rapid turn-around time. The greatest concern with these assays is that they are the least sensitive of commercially available C. difficile diagnostics. However, these assays have good specificity for CDI [23]. The most sensitive method for detecting C. difficile in stool, when performed properly, is
culture. However, this method is mainly used for epidemiological investigation and can be impractical because of a slow turn-around time [27]. Of note, the most sensitive method for detecting C. difficile may not be the best method when attempting to diagnose CDI, as discussed above. In addition, C. difficile isolates recovered also need to be tested for toxin production or toxin genes (toxigenic culture). Not all C. difficile strains are able to produce toxin, and toxin production is necessary for C. difficile to cause disease. Another method to detect C. difficile in stool is with glutamate dehydrogenase (GDH) assays. GDH is an enzyme constitutively produced by C. difficile. However, as all C. difficile strains produce GDH irrespective of the ability to produce toxin, a positive GDH assay should always be followed with an assay that detects toxin or toxin genes. Nucleic acid amplification tests (NAAT) have been commercially available in the United States since 2009. These assays detect toxin genes. These are the most sensitive assays to detect C. difficile after culture, and in general are rapid. The high sensitivity of NAATs to detect the organism is offset by a concomitant decrease in the specificity for CDI [23]. Several investigators have studied diagnostic algorithms for CDI [27–29]. With this approach, all stools are tested with one type of assay. Most commonly, a highly sensitive assay is used to screen stools (e.g., GDH), and positive tests are confirmed with a toxin EIA or NAAT. An algorithm approach to the diagnosis of CDI is currently recommended in the United Kingdom (https://www.gov.uk/govern ment/publications/updated-guidance-on-the-diag nosis-and-reporting-of-clostridium-difficile) [30 ]. This guidance recommends a two-step strategy using either GDH or NAAT followed by C. difficile toxin EIA. Again, whether this strategy results in improved patient outcomes compared with careful patient selection and a well validated toxin EIA alone is not known. According to these guidelines, patients positive by GDH or NAAT but negative by toxin EIA are not considered to have CDI, and treatment is not recommended in this scenario. &
TREATMENT Supportive care should be provided as indicated, and precipitating antimicrobials should be discontinued whenever possible. Historically, metronidazole was widely used for treating CDI, although it has never received an indication for treating CDI by the Food and Drug Administration (FDA). Metronidazole was already available in generic form when several trials indicated it was noninferior to oral vancomycin [31]. Because it was significantly less
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expensive than oral vancomycin, oral metronidazole became the mainstay of CDI therapy. More recently, there were several studies that found an increase in metronidazole treatment failures. The historical response rates to metronidazole were over 85%; however, the more recent studies identified response rates of only 62–78% [32–35]. In 2007, a randomized control trial comparing vancomycin to metronidazole in which patients were stratified based on CDI severity was published [36 ]. Patients with severe CDI were more likely to have responded to therapy in 6 days if they received vancomycin compared with metronidazole (response rate 97 versus 76%, P ¼ 0.02). Currently published guidelines recommend CDI treatment based on severity of CDI and whether the patient has had past episodes of CDI (Table 1) [27,28]. A caveat to the treatment recommendations is that there are no validated criteria for CDI severity, and not all guidelines use the same CDI severity grading scheme. In general, patients with severe CDI tend to have leukocytosis, acute kidney injury, more severe diarrhea, and tend to be older and sicker compared to patients with mild to moderate diarrhea. Severe, complicated CDI are those patients who are sick enough to require the management of their CDI in an ICU. It is recommended to treat a first or second episode of mild to moderate CDI with metronidazole 500 mg orally three times a day for 10–14 days, and patients with severe CDI should be treated with oral vancomycin 125 mg orally four times a day for 10–14 days. Patients with severe, complicated CDI should receive both intravenous metronidazole 500 mg three times a day and oral vancomycin 500 mg four times a day. There are no data to indicate that there is a synergy between metronidazole and vancomycin. Rather, the goal of the combination is to get active drug to the site of infection as quickly as possible. Intravenous metronidazole is not used alone because of concerns it is inferior to oral vancomycin for severe CDI. Oral vancomycin is given at a higher dose because of concerns that these patients often had a partial or complete ileus. Vancomycin enemas are often given for severe, complicated CDI, specially, if a complete ileus is present. These are also the patients who need a surgical consult, because colectomy or diverting loop ileostomy with vancomycin infusions may be lifesaving [37 ,38 ]. It is recommended to treat patients with two prior episodes of CDI with an oral vancomycin taper or pulsed vancomycin, regardless of disease severity. At first, the patient should receive 10–14 days of oral vancomycin 125 mg four times a day. A taper then involves reducing the number of doses per day over time, such as decrease to three times a day for a &&
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week, twice a day for a week, once a day for a week, then once every other day for two weeks. A pulse involves going from four times a day for 10–14 days immediately to once every other day. The theory behind this approach is to allow healthy flora to return with decreasing the dose of vancomycin, but to continue to suppress any residual C. difficile prior to return of protective flora. Fidaxomicin became the second drug to receive the FDA indication for treatment of CDI in 2011. As approval came after publication of the major CDI clinical guidelines, there are currently no published recommendations on when fidaxomicin is appropriate. Fidaxomicin is a novel antimicrobial that is more specific for C. difficile, with relative sparing of residual fecal flora compared with oral vancomycin [39]. In its phase 3 trials, patients with a first or second episode of CDI were eligible to participate. Fidaxomicin was noninferior to oral vancomycin for initial response to therapy. However, patients who received fidaxomicin were significantly less likely to develop recurrent CDI compared to patients who received oral vancomycin (relative risk 0.53; 95% confidence interval 0.39–0.72) [40]. Overall, fidaxomicin reduced persistent diarrhea, recurrence or death by 40% (P < 0.0001) [40]. Of note, the fidaxomicin trials excluded patients with multiply recurrent CDI, so it is unclear if a single 10-day course of fidaxomicin is sufficient to significantly reduce the risk of recurrent CDI among these patients. There are numerous adjunctive treatments for CDI described in the literature. Probiotics are commonly recommended as an adjunct to prevent CDI. No probiotic has been demonstrated to be efficacious in the prevention of recurrent CDI when studied rigorously. Several recent meta-analyses indicate probiotics may be effective as primary prophylaxis [41,42]. However, the incidences of CDI in the placebo arms of the studies that demonstrate the greatest benefit are several folds higher than one would expect in that population, suggesting there may be bias favoring the probiotics in those studies. Cholesterol binders are no better than placebo, and can bind oral vancomycin [43]. Rifaximin may be helpful to prevent recurrent CDI. However, resistance can develop very rapidly [44]. A small case series has found fidaxomicin given after pulsed oral vancomycin may be beneficial [45]. Fecal microbiota transplantation (FMT) has proven to be highly efficacious in a recent randomized controlled trial [46 ]. Patients with recurrent CDI were randomized to one of three arms: 4–5 days of oral vancomycin followed by bowel prep and FMT administered by nasogastric tube, 14 days of oral &&
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The changing epidemiology of CDI Honda and Dubberke Table 1. Treatment option for Clostridium difficile infection CDI classification Mild to moderate disease
Severe disease
Treatment recommendations from published guidelines Metronidazole 500 mg orally three times daily for 10–14 days
Vancomycin 125 mg orally four times daily for 10–14 days
Alternate treatments
Comments
Vancomycin 125 mg orally four times daily for 10–14 days
Vancomycin doses higher than 125 mg are not recommended, have not been associated with better outcomes, and increase costs
Fidaxomicin 200 mg orally twice a day for 10 days
Fidaxomicin associated with improved sustained clinical response compared to oral vancomycin
Fidaxomicin 200 mg orally twice a day for 10 days
Vancomycin associated with quicker response to therapy compared to metronidazole for severe CDI No sufficiently validated methods to recommend to identify patients with severe CDI Vancomycin doses higher than 125 mg are not recommended, have not been associated with better outcomes, and increase costs Fidaxomicin associated with improved sustained clinical response compared to oral vancomycin
Severe, complicated disease
Vancomycin 500 mg orally four times daily
Other adjunctive treatments that have been given for severe, complicated CDI with variable efficacy include tigecycline and intravenous immunoglobulin
The goal is to get active drug to the colon as soon as possible. No data to support synergistic effect or increased efficacy with higher doses of oral vancomycin
PLUS Metronidazole 500 mg intravenously every 8 h Consider also Vancomycin retention enema 125 mg to 500 mg in 100 to 500 ml normal saline four times a day
Vancomycin enema is indicated if concern for ileus. Optimal dosing, volume, and frequency remain unclear
Surgery consult for colectomy or diverting loop ileostomy with vancomycin colonic lavage
Ideal timing to pursue surgical therapy remains unclear
Recurrent disease, first recurrence (second episode of CDI)
Manage as first episode of CDI
Recurrent disease, second or later recurrence (at least third episode)
Vancomycin 125 orally four times daily for 10–14 days followed by vancomycin taper or pulse:
Rifaximin ‘chaser:’ Vancomycin 125 orally four times daily for 10–14 days followed by rifaximin 200–550 mg orally twice daily for 14–28 days
Observational data indicate risk of recurrence cut in half with tapered or pulsed dose vancomycin
Example of taper:
Fidaxomicin 200 mg orally twice a day for 10 days
C. difficile can develop resistance to rifaximin quickly
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Treatment recommendations from published guidelines
Alternate treatments
Comments
125 mg three times daily for 7 days
Fidaxomicin ‘chaser:’ Vancomycin 125 orally four times daily for 10–14 days followed by fidaxomicin 200 mg orally twice a day for 10 days
Patients with multiply recurrent CDI excluded from fidaxomicin trials
125 mg twice daily for 7 days
FMT
Ideal method for donor screening, stool preparation, and FMT administration unresolved issues
125 mg once daily for 7 days 125 mg every other day for 14 days Example of pulse: 125 mg every other day for 14 days FMT; fecal microbiota transplantation.
vancomycin, or 14 days of oral vancomycin with a bowel prep at day 4 or 5. The success of a single FMT at preventing recurrent CDI was 81%, compared with 31 and 23% for the oral vancomycin arms, respectively. However, there remain several unknowns related to FMT. Unresolved issues include what is necessary for optimal donor screening, best method for stool preparation, and whether more invasive methods for administering FMT (e.g., colonoscopy or nasoduodenal tube) are any better than a simple enema.
FUTURE OF CLOSTRIDIUM DIFFICILE INFECTION The future of CDI appears promising. The incidence of CDI in the HCUP data appears to be leveling off since 2006 (Figs. 1 and 2). This may be due to the enhanced efforts of hospitals to prevent CDI. Emerging data on CDI epidemiology are becoming more robust. Advances in studying the interplay between C. difficile, the fecal microbiome, and host immunity are improving our understanding of CDI pathogenesis and leading to new therapeutic and prevention strategies. Several new antimicrobial treatments for CDI are being studied, such as the Cubist drug CB-183315 and the Novartis drug LFF571. Like fidaxomicin, they appear to reduce the risk of recurrent CDI compared with oral vancomycin. A patented strain of nontoxigenic C. difficile given for 7–14 days after the completion of CDI treatment was associated with a 60% reduction in recurrent CDI compared with placebo in a phase 2 trial [47]. Merck is currently conducting phase 3 studies of monoclonal antibodies against 60
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C. difficile toxins. There was a 75% reduction in recurrent CDI among the patients who received study drug compared to placebo in the phase 2 study [48]. There are also several companies developing vaccines. A toxoid vaccine being developed by Sanofi-Pasteur has entered phase 3 study (clinicaltrials.gov identifier NCT01887912).
CONCLUSION CDI incidence remains at historically high levels, and in the United States results in over 14 000 deaths and costs over $2.1 billion per year. These increases have been associated with the emergence of the BI/NAP1/027 strain of C. difficile. New diagnostics have been developed, but the optimal method to diagnose CDI remains unclear. Testing only patients with a clinical picture compatible with CDI will improve the performance of the diagnostics. Current published guidelines recommend to stratify treatment based on CDI severity. However, existing guidelines do not provide direction on which patients would best benefit from fidaxomicin. Several novel therapeutic and prevention strategies are being studied, with the promise to significantly reduce the morbidity and mortality because of CDI in the future. Acknowledgements H.H. has no disclosures. Conflicts of interest E.R.D. has received research funding from Optimer, Viropharma, Sanofi-Pasteur, and Merck, and has Volume 30 Number 1 January 2014
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functioned as a consultant for Sanofi-Pasteur, Merck, Rebiotix, and Pfizer. H.H. reports no conflicts of interest relevant to this article.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 2011; 32:387–390. 2. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene&& variant strain of Clostridium difficile. N Engl J Med 2005; 353:2433– 2441. This is the first article to describe epidemic strain (BI/NAP1/027 strain) in the United States. This study also describes potential association between the emergence of the epidemic strain and fluoroquinolone resistance. 3. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional & outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442–2449. This study describes the deletion of repressor gene (tcdC gene) was associated with the disease severity. 4. Kuijper EJ, Coignard B, Tu¨ll P. Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol and Infect 2006; 12 (Suppl 6):2–18. 5. Bartlett JG. Detection of Clostridium difficile infection. Infect Control and Hosp Epidemiol 2010; 31 (Suppl 1):S35–S37. 6. Centers for Disease Control and Prevention (CDC). Vital signs: preventing Clostridium difficile infections. MMWR Morb Mortal Wkly Rep 2012; 61: 157–162. 7. Kelly CP, LaMont JT. Clostridium difficile – more difficult than ever. N Engl J Med 2008; 359:1932–1940. 8. Pe´pin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 41:1254– 1260. 9. Lowe DO, Mamdani MM, Kopp A, et al. Proton pump inhibitors and hospi&& talization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis 2006; 43:1272–1276. This study highlights that the use of proton pump inhibitor likely contributed to developing CDI. 10. Louie T, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for && Clostridium difficile Infection. N Engl J Med 2011; 364:422–431. This is the first randomized clinical trial to show that fidaxomicin was noninferior to vancomycin to treat CDI. 11. Association for Professional in Infection Control and Epidemiology. APIC implementation guide. Guide to preventing Clostridium difficile infection. Available at http://apic.org/Resource_/EliminationGuideForm/59397fc63f9043d1-9325-e8be75d86888/File/2013CDiffFinal.pdf [Accessed 2 June 2013] 12. Hall AJ, Curns AT, McDonald LC, et al. The roles of Clostridium difficile and norovirus among gastroenteritis-associated deaths in the United States, 1999–2007. Clin Infect Dis 2012; 55:216–223. 13. Dubberke ER, Butler AM, Reske KA, et al. Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients. Emerg Infect Dis 2008; 14:1031. 14. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the Healthcare & System. Clin Infect Dis 2012; 55 (Suppl 2):S88–S92. This review article nicely describes both clinical and economic burden of CDI in the United States. 15. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366:1079–1084. 16. Campbell RJ, Giljahn L, Machesky K, et al. Clostridium difficile infection in Ohio hospitals and nursing homes during 2006. Infection Control Hosp Epidemiol 2009; 30:526–533. 17. Bartlett JG. Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis 1994; 18 (Suppl 4):S265–S272. 18. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005; 294:2989–2995.
19. Dubberke ER, Reske KA, Yan Y, et al. Clostridium difficile-associated disease in a setting of endemicity: identification of novel risk factors. Clin Infect Dis 2007; 45:1543–1549. 20. Dial S, Delaney JA, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ 2006; 175:745–748. 21. Huang SS, Datta R, Platt R. Risk of acquiring antibiotic-resistant bacteria from prior room occupants. Arch Intern Med 2006; 166:1945–1951. 22. Ben-Horin S, Margalit M, Bossuyt P, et al. Combination immunomodulator and antibiotic treatment in patients with infl ammatory bowel disease and Clostridium difficile infection. Clin Gastroenterol Hepatol 2009; 7:981– 987. 23. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin microbiol 2011; 49:2887–2893. 24. Planche TD, Davies KA, Coen PG, et al. Differences in outcome according to C. difficile testing method: a prospective multicenter diagnostic validation study of C. difficile infection. Lancet Infect Dis 2013. (in press). 25. Stelfox HT, Bates DW, Redelmeier DA. Safety of patients isolated for infection control. JAMA 2003; 290:1899–1905. 26. Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole A randomized, placebo-controlled trial. Ann Intern Med 1992; 117:297– 302. 27. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431– 455. 28. Bauer MP, Kuijper EJ, Van Dissel JT, et al. European Society of Clinical Microbiology and Infectious Diseases: treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2009; 15:1067– 1079. 29. Gerding DN, Muto CA, Owens RC. Treatment of Clostridium difficile infection. Clin Infect Dis 2008; 46 (Suppl 1):S32–S42. 30. United Kingdom, department of health. Updated guidance on the & diagnosis and reporting of Clostiridium difficile. https://www.gov.uk/govern ment/uploads/system/uploads/attachment_data/file/146808/dh_133016.pdf [Accessed 13 July 2013] This is the UK guideline for diagnosing CDI. This article provides algorithm-based CDI diagnosis. 31. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomized trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983; 2:1043–1046. 32. Belmares J, Gerding DN, Parada JP, et al. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect 2007; 55:495–501. 33. Fernandez A, Anand G, Friedenberg F. Factors associated with failure of metronidazole in Clostridium difficile-associated disease. J Clin Gastroenterol 2004; 38:414–418. 34. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005; 40:1586–1590. 35. Pe´pin J, Alary M-E, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005; 40:1591–1597. 36. Zar FA, Bakkanagari SR, Moorthi K, Davis MB. A comparison of vancomycin && and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302–307. This study highlights the better clinical efficacy of vancomycin treatment than metronidazole therapy in patients with severe CDI. 37. Stewart DB, Hollenbeak CS, Wilson MZ. Is colectomy for fulminant C. difficile & colitis life saving? A systematic review. Colorectal Dis 2013; 15:798– 804. This study is a comprehensive review of surgical management for CDI. 38. Neal MD, Alverdy JC, Hall DE, et al. Diverting loop ileostomy and colonic && lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg 2011; 254:423–429. This study demonstrates the alternative surgical approach to total colectomy for surgically indicated CDI. Diverting loop ileostomy may reduce the postoperative mortality because of the nature of less invasive surgical procedure compared with total colectomy. 39. Louie TJ, Emery J, Krulicki W, et al. OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile infection. Antimicrob Agents Chemother 2009; 53:261–263. 40. Crook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis 2012; 55 (Suppl 2):S93–S103. 41. Johnston BC, Ma SS, Goldenburg JZ, et al. Probiotics for the prevention of clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Int Med 2012; 157:878–888.
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Large intestine 42. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2013; 5:CD006095. 43. Mogg GA, George RH, Youngs D, et al. Randomized controlled trial of colestipol in antibiotic-associated colitis. Br J Surg 1982; 69:137–139. 44. Johnson S, Schriever C, Patel U, et al. Rifaximin Redux: treatment of recurrent Clostridium difficile infections with rifaximin immediately postvancomycin treatment. Anaerobe 2009; 15:290–291. 45. Johnson S, Gerding DN. Fidaxomicin ‘Chaser’ regimen following vancomycin for patients with multiple Clostridium difficile recurrences. Clin Infect Dis 2013; 56:309–310.
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46. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. New Engl J Med 2013; 368:407– 415. Randomized controlled trial demonstrating FMT is highly effective at preventing recurrent CDI. 47. Treatment With VP20621 (Non-Toxigenic Clostridium difficile; NTCD) http://ir.viropharma.com/releasedetail.cfm?ReleaseID=758059 [Accessed 6 August 2013]. 48. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010; 362:197– 205.
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The changing epidemiology of Clostridium difficile infection Hitoshi Honda a and Erik R. Dubberke b
Purpose of review Clostridium difficile infection (CDI) is a growing concern and has a substantial impact on morbidity and mortality. Epidemiology of CDI has dramatically changed over the last decade. Diagnostic and treatment strategies are even more complicated given the wide variety of available diagnostic methods and the emergence of refractory or recurrent CDI. This review is intended to provide information on current CDI epidemiology and guidance for evidence-based diagnosis and management strategies. Recent findings Various studies from the United States, Europe, and Canada revealed increased incidence of CDI since 2000. Although CDI has long been associated with healthcare settings, recent studies indicate it is more common in the community than previously recognized. For diagnostic strategies, newer testing methods, including nucleic acid amplification tests, have enhanced sensitivity compared with toxin testing, but at the expense of decreased specificity. New agents for treating CDI are being developed and higher quality data to support fecal microbiota transplantation for treating recurrent CDI are emerging. Summary CDI epidemiology continues to evolve. Prompt recognition and an evidence-based treatment approach is the key to successfully manage CDI. Further, studies on diagnostic and therapeutic strategies are needed to further improve patient outcomes. Keywords Clostridium difficile, diagnosis, epidemiology, treatment
INTRODUCTION Clostridium difficile infection (CDI) is one of the leading causes of healthcare-associated infections [1]. CDI has contributed to substantial morbidity and mortality in the United States, Canada, and Europe [2 ,3 ,4]. First recognized as the cause of antibiotic-associated colitis in 1978 [5], the incidence of CDI has dramatically increased since the year 2000. In addition to increases in CDI noted in hospitals, there have been other changes in the epidemiology of CDI identified over the last decade. There has been increased recognition of CDI with onset in long-term care facilities and in the community, and the severity and attributable mortality due to CDI have increased [6,7]. Fluoroquinolones, previously associated with a low risk of CDI, and proton pump inhibitors have been associated with an increased risk for CDI [8,9 ]. There have also been reports of increases in metronidazole treatment failures. New diagnostics have been developed, but how to best implement them is not yet clear. &&
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Fortunately, not all recent changes in CDI have been bad. Fidaxomicin became only the second antimicrobial approved for the treatment of CDI [10 ]. There are many other agents being studied for the treatment of CDI and prevention of CDI recurrence, including antimicrobials, nontoxigenic C. difficile, and monoclonal antibodies. In addition, several companies are developing vaccines for primary prophylaxis to prevent CDI. This review &&
a
Division of Infection Prevention, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan and bDivision of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Correspondence to Hitoshi Honda, MD, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8524, Japan. Tel: +1 81 42 323 5111; fax: +1 81 42 323 9205; e-mail: hondah@ hotmail.com Curr Opin Gastroenterol 2014, 30:54–62 DOI:10.1097/MOG.0000000000000018 Volume 30 Number 1 January 2014
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The changing epidemiology of CDI Honda and Dubberke
KEY POINTS
CDI is 5–10%, resulting in over 14 000 deaths per year in the United States, and costs the US healthcare system over $2.1 billion per year [12,13,14 ]. A potential explanation for part of the increasing CDI burden and severity is the emergence of the current epidemic strain. This strain has several names based on the method used to characterize the organism: restriction enzyme analysis BI, North American Pulsed Field Gel Electrophoresis type1 (NAP1) and PCR ribotype 027 (i.e., BI/NAP1/027) [2 ]. The strain was first identified as the cause of severe outbreaks of CDI in the United States and Canada, and subsequently in the United Kingdom and Europe [2 ,3 ]. It is not entirely clear why the BI/NAP1/027 strain is able to cause severe outbreaks, but some in-vitro studies indicate this strain may produce more toxin than other C. difficile strains, and it may be more efficient at producing spores [15]. Some recent studies indicate the incidence of CDI in long-term care facilities (LTCFs) and community settings is higher than previously recognized. In 2006, the state of Ohio mandated CDI reporting from hospitals and LTCFs. When including recurrent CDI, there were more total cases of CDI with onset in LTCFs than in acute care hospitals (7953 cases versus 6376) [16]. The Centers for Disease Control and Prevention (CDC) Emerging Infections Program found that almost 50% of all initial CDI cases had onset in the community [6]. Among cases with onset in a healthcare facility, approximately half had onset in a LTCF and the other half had onset in an acute care hospital. In the same report, it was noted that in the CDC National Healthcare Safety Network data approximately half of CDI cases treated in acute care facilities were present on admission. &
CDI incidence and severity are at historic highs. Fluoroquinolones and proton pump inhibitors are often over prescribed and have been associated with the increased risk for CDI. Only patients with clinically significant diarrhea should be tested for C. difficile, specially, if highly sensitive NAAT testing is used.
&&
Current published guidelines recommend to treat an initial episode of CDI based on disease severity. Fidaxomicin was approved after the publication of current guidelines.
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FMT was demonstrated to be effective for preventing recurrent CDI in a randomized controlled trial. Optimal methods for donor screening, stool preparation, and FMT administration are unclear.
will cover these aspects of the changing epidemiology of CDI.
CLOSTRIDIUM DIFFICILE INFECTION BURDEN OF DISEASE CDI incidence has substantially increased in healthcare settings over the past decade (Fig. 1). Based on discharge diagnosis code data from the Healthcare Utilization Project (HCUP) in the United States, the incidence of CDI listed as any diagnosis increased from 3.82 per 1000 discharges in 2000 to 8.75 per 1000 discharges in 2008 (Fig. 2) [11]. Increased severity of CDI has been observed as well, with increases in patient transfer to the ICU, colectomy, and deaths due to CDI. The attributable mortality of
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Number of 400 000 CDI cases
346 805
350 000 300 000 250 000 200 000 150 000 100 000
138 954
50 000
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09
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06 20
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FIGURE 1. Number of discharges from US nonfederal, acute care hospitals assigned the International Classification of Disease – 9 – Clinical Modification (ICD-9-CM) code for CDI (008.45). Data to create figure downloaded from http:// hcupnet.ahrq.gov/HCUPnet.jsp on August 20, 2012. 0267-1379 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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CDI cases/ 10.00 1000 discharges 9.00 8.00 7.00 6.00 5.00 4.00 3.00 2.00 1.00
10 20
09 20
08 20
07 20
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FIGURE 2. Rate of discharges from US nonfederal, acute care hospitals assigned the International Classification of Disease – 9 – Clinical Modification (ICD-9-CM) code for CDI (008.45) per 1000 discharges. Data to create figure downloaded from http://hcupnet.ahrq.gov/HCUPnet.jsp on August 20, 2012.
RISK FACTORS FOR CLOSTRIDIUM DIFFICILE INFECTION Risk factors associated with CDI have been investigated in numerous studies. Prior antimicrobial use is a well known risk factor for developing CDI. Antimicrobials alter the healthy fecal microbiome, allowing C. difficile to colonize, overgrow, and produce toxins if a C. difficile exposure occurs before the fecal microbiome is able to return to a healthy state. Traditionally, clindamycin has been associated with CDI, and it remains an important predisposing risk factor today [17]. Numerous studies have also found cephalosporins to be associated with a high risk of developing CDI as well [5]. More recently, fluoroquinolone exposure has been strongly correlated with CDI. This coincided with the emergence of the BI/NAP1/027 strain, which in general is highly resistant to fluoroquinolones [8]. Exposure to gastric acid suppressive agents has also been identified as a risk factor associated with developing CDI [18,19]. The mechanism of action for gastric acid suppression in the causal pathway of CDI is not known. As an obligate anaerobe, the vegetative cells of C. difficile die within minutes after exposure to air. Therefore, C. difficile acquisition involves the ingestion of C. difficile spores, which are resistant to gastric acid. Rather than being in the causal pathway of CDI, gastric acid suppression may be a surrogate marker for patients at increased risk of CDI [9 ,20]. Another important risk factor predisposing to CDI is C. difficile exposure. Within a healthcare setting the population is enriched with patients at risk for CDI. As a result, relative to other settings, the &&
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concentration of patients with CDI is high. Thus, risk of exposure to C. difficile in a healthcare facility is high as well. Studies have demonstrated that length of stay in the hospital is a risk factor for CDI. It has also been demonstrated that CDI pressure, or the number of patients with CDI on the same hospital ward as patients without CDI, is also an important risk factor for CDI [21]. More recently, underlying gastrointestinal illness, specially inflammatory bowel diseases (IBD), has been recognized as an emerging risk factor for CDI. Patients with IBD frequently develop CDI, and this is likely multifactorial. As an autoimmune disease, IBD is associated with an altered immune response and is frequently managed with immunosuppressive agents. In addition, these patients are frequently hospitalized and exposed to antimicrobials [22]. It is also possible that dysbiosis might be associated with developing CDI in patients with IBD, as these patients are at risk for community-onset CDI even without antimicrobial exposure.
DIAGNOSIS The first step to consider before testing a patient for C. difficile is whether or not the patient has a clinical syndrome compatible with the diagnosis of CDI, and whether there may be other explanations for the presence of diarrhea (e.g., laxative exposures). This is because asymptomatic colonization with C. difficile is more common than CDI. Current diagnostic tests detect the presence of C. difficile, or its toxins, in stool, and by themselves are not diagnostic for CDI. Therefore, it is possible to have false Volume 30 Number 1 January 2014
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The changing epidemiology of CDI Honda and Dubberke
positive tests for CDI; that is, asymptomatic C. difficile carriers can test positive, specially with highly sensitive tests [23]. A recent, multicenter study from England demonstrated that C. difficile carriers might be overdiagnosed by highly sensitive tests (e.g., culture, nucleic acid amplification test) [24]. In this study, clinical data were available from 6524 inpatient episodes of diarrhea. The crude mortality of patients whose stool was positive by cytotoxicity cell assay was 17%. This was significantly higher than the crude mortality of patients negative by cytotoxicity cell assay and positive by toxigenic culture (10%, P ¼ 0.04) and higher than patients negative by cytotoxicity cell assay and toxigenic culture (9%, P < 0.001). This indicates that the lower specificity of more sensitive tests may be problematic when diagnosing CDI. The impact of false positive test results has not been adequately studied, but theoretically can lead to adverse events. Patients with false positive tests will end up in contact precautions, and contact precautions have been associated with adverse events [25]. These patients will also be started on CDI therapy, which once stopped, paradoxically, may increase the patient’s risk for CDI [26]. Also, hospital-onset CDI incidence is now reported to the Centers for Medicare and Medicaid Services (CMS), and hospital-onset CDI incidence may be used to determine value-based CMS reimbursement. Excessive false positive tests may result in a decrease in reimbursement to the hospital. To minimize false positive test results, C. difficile testing should be restricted only to those patients with clinically significant diarrhea, ideally without other explanations for the diarrhea, and automatic repeat testing after a negative test should be avoided. The ‘best’ method to diagnose CDI has not been established. Assays that detect C. difficile in stool can be split into two general categories – assays that detect toxin (cytotoxicity cell assay and toxin enzyme immunoassays) and assays that detect the organism (culture for C. difficile, glutamate dehydrogenase assays, and nucleic acid amplification tests). The cytotoxicity cell assay is the most sensitive method to detect C. difficile toxins in stool and it has good specificity for CDI. However, it is relatively labor intensive and can take up to 48 h to have results. C. difficile toxin enzyme immunoassays (EIA) are widely used because of low cost, ease of use, and rapid turn-around time. The greatest concern with these assays is that they are the least sensitive of commercially available C. difficile diagnostics. However, these assays have good specificity for CDI [23]. The most sensitive method for detecting C. difficile in stool, when performed properly, is
culture. However, this method is mainly used for epidemiological investigation and can be impractical because of a slow turn-around time [27]. Of note, the most sensitive method for detecting C. difficile may not be the best method when attempting to diagnose CDI, as discussed above. In addition, C. difficile isolates recovered also need to be tested for toxin production or toxin genes (toxigenic culture). Not all C. difficile strains are able to produce toxin, and toxin production is necessary for C. difficile to cause disease. Another method to detect C. difficile in stool is with glutamate dehydrogenase (GDH) assays. GDH is an enzyme constitutively produced by C. difficile. However, as all C. difficile strains produce GDH irrespective of the ability to produce toxin, a positive GDH assay should always be followed with an assay that detects toxin or toxin genes. Nucleic acid amplification tests (NAAT) have been commercially available in the United States since 2009. These assays detect toxin genes. These are the most sensitive assays to detect C. difficile after culture, and in general are rapid. The high sensitivity of NAATs to detect the organism is offset by a concomitant decrease in the specificity for CDI [23]. Several investigators have studied diagnostic algorithms for CDI [27–29]. With this approach, all stools are tested with one type of assay. Most commonly, a highly sensitive assay is used to screen stools (e.g., GDH), and positive tests are confirmed with a toxin EIA or NAAT. An algorithm approach to the diagnosis of CDI is currently recommended in the United Kingdom (https://www.gov.uk/govern ment/publications/updated-guidance-on-the-diag nosis-and-reporting-of-clostridium-difficile) [30 ]. This guidance recommends a two-step strategy using either GDH or NAAT followed by C. difficile toxin EIA. Again, whether this strategy results in improved patient outcomes compared with careful patient selection and a well validated toxin EIA alone is not known. According to these guidelines, patients positive by GDH or NAAT but negative by toxin EIA are not considered to have CDI, and treatment is not recommended in this scenario. &
TREATMENT Supportive care should be provided as indicated, and precipitating antimicrobials should be discontinued whenever possible. Historically, metronidazole was widely used for treating CDI, although it has never received an indication for treating CDI by the Food and Drug Administration (FDA). Metronidazole was already available in generic form when several trials indicated it was noninferior to oral vancomycin [31]. Because it was significantly less
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expensive than oral vancomycin, oral metronidazole became the mainstay of CDI therapy. More recently, there were several studies that found an increase in metronidazole treatment failures. The historical response rates to metronidazole were over 85%; however, the more recent studies identified response rates of only 62–78% [32–35]. In 2007, a randomized control trial comparing vancomycin to metronidazole in which patients were stratified based on CDI severity was published [36 ]. Patients with severe CDI were more likely to have responded to therapy in 6 days if they received vancomycin compared with metronidazole (response rate 97 versus 76%, P ¼ 0.02). Currently published guidelines recommend CDI treatment based on severity of CDI and whether the patient has had past episodes of CDI (Table 1) [27,28]. A caveat to the treatment recommendations is that there are no validated criteria for CDI severity, and not all guidelines use the same CDI severity grading scheme. In general, patients with severe CDI tend to have leukocytosis, acute kidney injury, more severe diarrhea, and tend to be older and sicker compared to patients with mild to moderate diarrhea. Severe, complicated CDI are those patients who are sick enough to require the management of their CDI in an ICU. It is recommended to treat a first or second episode of mild to moderate CDI with metronidazole 500 mg orally three times a day for 10–14 days, and patients with severe CDI should be treated with oral vancomycin 125 mg orally four times a day for 10–14 days. Patients with severe, complicated CDI should receive both intravenous metronidazole 500 mg three times a day and oral vancomycin 500 mg four times a day. There are no data to indicate that there is a synergy between metronidazole and vancomycin. Rather, the goal of the combination is to get active drug to the site of infection as quickly as possible. Intravenous metronidazole is not used alone because of concerns it is inferior to oral vancomycin for severe CDI. Oral vancomycin is given at a higher dose because of concerns that these patients often had a partial or complete ileus. Vancomycin enemas are often given for severe, complicated CDI, specially, if a complete ileus is present. These are also the patients who need a surgical consult, because colectomy or diverting loop ileostomy with vancomycin infusions may be lifesaving [37 ,38 ]. It is recommended to treat patients with two prior episodes of CDI with an oral vancomycin taper or pulsed vancomycin, regardless of disease severity. At first, the patient should receive 10–14 days of oral vancomycin 125 mg four times a day. A taper then involves reducing the number of doses per day over time, such as decrease to three times a day for a &&
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week, twice a day for a week, once a day for a week, then once every other day for two weeks. A pulse involves going from four times a day for 10–14 days immediately to once every other day. The theory behind this approach is to allow healthy flora to return with decreasing the dose of vancomycin, but to continue to suppress any residual C. difficile prior to return of protective flora. Fidaxomicin became the second drug to receive the FDA indication for treatment of CDI in 2011. As approval came after publication of the major CDI clinical guidelines, there are currently no published recommendations on when fidaxomicin is appropriate. Fidaxomicin is a novel antimicrobial that is more specific for C. difficile, with relative sparing of residual fecal flora compared with oral vancomycin [39]. In its phase 3 trials, patients with a first or second episode of CDI were eligible to participate. Fidaxomicin was noninferior to oral vancomycin for initial response to therapy. However, patients who received fidaxomicin were significantly less likely to develop recurrent CDI compared to patients who received oral vancomycin (relative risk 0.53; 95% confidence interval 0.39–0.72) [40]. Overall, fidaxomicin reduced persistent diarrhea, recurrence or death by 40% (P < 0.0001) [40]. Of note, the fidaxomicin trials excluded patients with multiply recurrent CDI, so it is unclear if a single 10-day course of fidaxomicin is sufficient to significantly reduce the risk of recurrent CDI among these patients. There are numerous adjunctive treatments for CDI described in the literature. Probiotics are commonly recommended as an adjunct to prevent CDI. No probiotic has been demonstrated to be efficacious in the prevention of recurrent CDI when studied rigorously. Several recent meta-analyses indicate probiotics may be effective as primary prophylaxis [41,42]. However, the incidences of CDI in the placebo arms of the studies that demonstrate the greatest benefit are several folds higher than one would expect in that population, suggesting there may be bias favoring the probiotics in those studies. Cholesterol binders are no better than placebo, and can bind oral vancomycin [43]. Rifaximin may be helpful to prevent recurrent CDI. However, resistance can develop very rapidly [44]. A small case series has found fidaxomicin given after pulsed oral vancomycin may be beneficial [45]. Fecal microbiota transplantation (FMT) has proven to be highly efficacious in a recent randomized controlled trial [46 ]. Patients with recurrent CDI were randomized to one of three arms: 4–5 days of oral vancomycin followed by bowel prep and FMT administered by nasogastric tube, 14 days of oral &&
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The changing epidemiology of CDI Honda and Dubberke Table 1. Treatment option for Clostridium difficile infection CDI classification Mild to moderate disease
Severe disease
Treatment recommendations from published guidelines Metronidazole 500 mg orally three times daily for 10–14 days
Vancomycin 125 mg orally four times daily for 10–14 days
Alternate treatments
Comments
Vancomycin 125 mg orally four times daily for 10–14 days
Vancomycin doses higher than 125 mg are not recommended, have not been associated with better outcomes, and increase costs
Fidaxomicin 200 mg orally twice a day for 10 days
Fidaxomicin associated with improved sustained clinical response compared to oral vancomycin
Fidaxomicin 200 mg orally twice a day for 10 days
Vancomycin associated with quicker response to therapy compared to metronidazole for severe CDI No sufficiently validated methods to recommend to identify patients with severe CDI Vancomycin doses higher than 125 mg are not recommended, have not been associated with better outcomes, and increase costs Fidaxomicin associated with improved sustained clinical response compared to oral vancomycin
Severe, complicated disease
Vancomycin 500 mg orally four times daily
Other adjunctive treatments that have been given for severe, complicated CDI with variable efficacy include tigecycline and intravenous immunoglobulin
The goal is to get active drug to the colon as soon as possible. No data to support synergistic effect or increased efficacy with higher doses of oral vancomycin
PLUS Metronidazole 500 mg intravenously every 8 h Consider also Vancomycin retention enema 125 mg to 500 mg in 100 to 500 ml normal saline four times a day
Vancomycin enema is indicated if concern for ileus. Optimal dosing, volume, and frequency remain unclear
Surgery consult for colectomy or diverting loop ileostomy with vancomycin colonic lavage
Ideal timing to pursue surgical therapy remains unclear
Recurrent disease, first recurrence (second episode of CDI)
Manage as first episode of CDI
Recurrent disease, second or later recurrence (at least third episode)
Vancomycin 125 orally four times daily for 10–14 days followed by vancomycin taper or pulse:
Rifaximin ‘chaser:’ Vancomycin 125 orally four times daily for 10–14 days followed by rifaximin 200–550 mg orally twice daily for 14–28 days
Observational data indicate risk of recurrence cut in half with tapered or pulsed dose vancomycin
Example of taper:
Fidaxomicin 200 mg orally twice a day for 10 days
C. difficile can develop resistance to rifaximin quickly
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Large intestine Table 1 (Continued) CDI classification
Treatment recommendations from published guidelines
Alternate treatments
Comments
125 mg three times daily for 7 days
Fidaxomicin ‘chaser:’ Vancomycin 125 orally four times daily for 10–14 days followed by fidaxomicin 200 mg orally twice a day for 10 days
Patients with multiply recurrent CDI excluded from fidaxomicin trials
125 mg twice daily for 7 days
FMT
Ideal method for donor screening, stool preparation, and FMT administration unresolved issues
125 mg once daily for 7 days 125 mg every other day for 14 days Example of pulse: 125 mg every other day for 14 days FMT; fecal microbiota transplantation.
vancomycin, or 14 days of oral vancomycin with a bowel prep at day 4 or 5. The success of a single FMT at preventing recurrent CDI was 81%, compared with 31 and 23% for the oral vancomycin arms, respectively. However, there remain several unknowns related to FMT. Unresolved issues include what is necessary for optimal donor screening, best method for stool preparation, and whether more invasive methods for administering FMT (e.g., colonoscopy or nasoduodenal tube) are any better than a simple enema.
FUTURE OF CLOSTRIDIUM DIFFICILE INFECTION The future of CDI appears promising. The incidence of CDI in the HCUP data appears to be leveling off since 2006 (Figs. 1 and 2). This may be due to the enhanced efforts of hospitals to prevent CDI. Emerging data on CDI epidemiology are becoming more robust. Advances in studying the interplay between C. difficile, the fecal microbiome, and host immunity are improving our understanding of CDI pathogenesis and leading to new therapeutic and prevention strategies. Several new antimicrobial treatments for CDI are being studied, such as the Cubist drug CB-183315 and the Novartis drug LFF571. Like fidaxomicin, they appear to reduce the risk of recurrent CDI compared with oral vancomycin. A patented strain of nontoxigenic C. difficile given for 7–14 days after the completion of CDI treatment was associated with a 60% reduction in recurrent CDI compared with placebo in a phase 2 trial [47]. Merck is currently conducting phase 3 studies of monoclonal antibodies against 60
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C. difficile toxins. There was a 75% reduction in recurrent CDI among the patients who received study drug compared to placebo in the phase 2 study [48]. There are also several companies developing vaccines. A toxoid vaccine being developed by Sanofi-Pasteur has entered phase 3 study (clinicaltrials.gov identifier NCT01887912).
CONCLUSION CDI incidence remains at historically high levels, and in the United States results in over 14 000 deaths and costs over $2.1 billion per year. These increases have been associated with the emergence of the BI/NAP1/027 strain of C. difficile. New diagnostics have been developed, but the optimal method to diagnose CDI remains unclear. Testing only patients with a clinical picture compatible with CDI will improve the performance of the diagnostics. Current published guidelines recommend to stratify treatment based on CDI severity. However, existing guidelines do not provide direction on which patients would best benefit from fidaxomicin. Several novel therapeutic and prevention strategies are being studied, with the promise to significantly reduce the morbidity and mortality because of CDI in the future. Acknowledgements H.H. has no disclosures. Conflicts of interest E.R.D. has received research funding from Optimer, Viropharma, Sanofi-Pasteur, and Merck, and has Volume 30 Number 1 January 2014
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The changing epidemiology of CDI Honda and Dubberke
functioned as a consultant for Sanofi-Pasteur, Merck, Rebiotix, and Pfizer. H.H. reports no conflicts of interest relevant to this article.
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46. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. New Engl J Med 2013; 368:407– 415. Randomized controlled trial demonstrating FMT is highly effective at preventing recurrent CDI. 47. Treatment With VP20621 (Non-Toxigenic Clostridium difficile; NTCD) http://ir.viropharma.com/releasedetail.cfm?ReleaseID=758059 [Accessed 6 August 2013]. 48. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010; 362:197– 205.
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