<i>Clostridioides difficile </i>infection in adults: Epidemiology, microbiology, and pathophysiology

Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology

Authors:: J Thomas Lamont, MD; Johan S Bakken, MD, PhD; Ciarán P Kelly, MD
Section Editor:: Stephen B Calderwood, MD
Deputy Editor:: Milana Bogorodskaya, MD

Literature review current through: Jan 2024.

This topic last updated: Jan 17, 2023.

INTRODUCTION — Clostridioides difficile is the causative organism of antibiotic-associated colitis [1]. Colonization of the intestinal tract occurs via the fecal-oral route and is facilitated by disruption of normal intestinal flora (often due to antimicrobial therapy). (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)

Issues related to epidemiology and microbiology of C. difficile infection (CDI) will be reviewed here. Clinical manifestations, diagnosis, prevention, and treatment of CDI are discussed separately. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridioides difficile infection: Prevention and control" and "Clostridioides difficile infection in adults: Treatment and prevention".) (Related Pathway(s): Clostridioides difficile infection: Treatment of adults with an initial or recurrent infection.)

EPIDEMIOLOGY

Overview — Antibiotic-associated diarrhea and colitis were well established soon after widespread use of antibiotics [2]. In 1978, C. difficile was identified as the causative pathogen in the majority of cases of antibiotic-associated colitis; many early cases were attributed to clindamycin [2,3]. Increasing use of penicillins and cephalosporins led to the implication of these antibiotic classes as precipitants as well.

From 2003 to 2006, CDI was observed to be more frequent, severe, refractory to standard therapy, and more likely to relapse than previously described [2]. These observations have been reported throughout North America and Europe and have been attributed to the emergence of a new strain designated BI, NAP1, or ribotype 027 (these designations are based on different methods for strain typing and all refer to the same strain, previously known as strain NAP1/BI/027 and now simply as 027). This strain appears to be more virulent than other strains [4], which may be attributable to increased toxin production compared with previous strains. Fluoroquinolone use has strongly correlated with the emergence of this strain [5], and development of fluoroquinolone resistance by outbreak strains appears to have been associated with the increasing frequency of CDI outbreaks [6]. (See 'PCR ribotype 027 strain' below.)

Since 2005, CDI due to ribotype 078 has emerged in the Netherlands; the severity is similar to CDI caused by ribotype 027. Ribotype 078 appears to affect a younger patient population, is more frequently community associated, and is genetically similar to porcine isolates [7]. Among 1366 Dutch patients hospitalized between 2006 and 2009, CDI was associated with a 2.5-fold increase in 30-day mortality (95% CI 1.4-4.3) [8].

A cross-sectional study demonstrated that ribotype may not be a significant predictor of severe CDI. Among 310 CDI cases, including 34 severe cases, the association between ribotypes 027 and 078 and severity was not statistically significant after adjustment for other covariables [9].

In 2011, an estimated 453,000 initial cases of CDI occurred in the United States; there were also an estimated 83,000 first CDI recurrences and 29,300 patients died [10]. Between 2011 and 2017, there was a decline in the incidence of CDI (154.9 to 143.6 per 100,000 persons), primarily driven by a decrease in health care associated infections [11].

Nosocomial infection — Dramatic increases in the incidence and severity of health care-associated CDI occurred after 2000, particularly in patients over age 65. However, between 2011 and 2017 the incidence of health care-associated CDI decreased from 99.6 to 73.3 per 100,000 population [11].

C. difficile carriage occurs in 8 to 10 percent of adults residing in hospitals or long-term care facilities (the carrier rate among healthy adults is about 3 percent) [12-15]. Asymptomatic C. difficile carriers are capable of shedding C. difficile spores and serve as a reservoir for environmental contamination to other hospitalized patients [16,17]. In one study including more than 250 patients without diarrhea admitted to the hospital, 79 percent were not colonized with C. difficile at the time of admission, 15 percent were colonized with a toxinogenic strain of C. difficile, and 6 percent were colonized with a nontoxinogenic strain [18]. Surprisingly, there were no differences between patients colonized with a toxinogenic strain of C. difficile and uncolonized patients with regards to recent health care contact or antimicrobial exposures. Furthermore, stool toxin concentrations in asymptomatic carriers are similar to those in patients with diarrhea and colitis [15].

New exposure and colonization by C. difficile are more likely to lead to CDI, while patients previously colonized with C. difficile are more likely to remain asymptomatic during their hospitalization [19,20]. The magnitude of this difference was illustrated in a prospective review of 810 hospitalizations, including 618 patients with new C. difficile exposure and 192 patients with previously known C. difficile colonization [20]. Newly exposed patients developed CDI much more frequently than colonized patients (4.5 versus 1.1 percent).

These observations have been noted even when carriers and symptomatic patients are colonized with identical strains. In addition, outbreaks are frequently caused by a single strain of C. difficile even though many bacterial strains may exist in the given hospital environment [21]. As an example, two outbreaks in the same hospital were attributed to a single strain, although 31 distinct strains were isolated from 98 patients in the institution [22].

Some potential explanations for these epidemiologic observations are discussed below. Careful adherence to infection control policies is critical to successful control of C. difficile. (See 'Pathophysiology' below and "Infection prevention: Precautions for preventing transmission of infection".)

Community-associated infection — The incidence of community-associated CDI (defined as disease in patients not hospitalized during the 12 weeks prior to diagnosis) has remained unchanged between 2011 and 2017 [11].

Unusually severe CDI has been reported in populations previously thought to be at low risk, including peripartum women and healthy individuals living in the community without a history of antibiotic use, recent hospitalization, or other risk factors for C. difficile-associated disease [23-25]. As a result, consideration of C. difficile-associated infection is warranted even in the absence of a history of antibiotic exposure or recent hospitalization. Exposure to retail food products and domestic animals has been postulated as potential sources of CDI [26,27].

Recurrent infection — Recurrent CDI is defined by resolution of CDI symptoms while on appropriate therapy, followed by reappearance of symptoms within two to eight weeks after treatment has been stopped [1]. Up to 25 percent of patients experience recurrent CDI within 30 days of treatment [28]. Less commonly, recurrent CDI can occur as late as two months after discontinuation of treatment. In the United States in 2011, approximately 83,000 patients had at least one recurrence [10].

Once patients have experienced one recurrence, they are at significantly increased risk for further recurrences (multiply recurrent CDI [mrCDI]). In one retrospective cohort study including more than 45,000 patients with CDI in the United States between 2001 and 2012, the annual incidence of mrCDI increased by 189 percent (from 0.0107 to 0.0309 cases per 1000 person-years) [29]. Those who developed mrCDI were older (median age 56 versus 49 years), more likely to be female, and more likely to have used antibiotics, proton-pump inhibitors, or corticosteroids within 90 days of CDI diagnosis. Other factors associated with increased risk for mrCDI included chronic kidney disease and residence in a nursing home. The observed increase in incidence of mrCDI was independent of known risk factors for CDI, raising the possibility that the biology is different from that of CDI in general.

TRANSMISSION — Patients with C. difficile carriage are a reservoir for environmental contamination in the presence or absence of clinical infection. C difficile is highly transmissible via the fecal-oral route by ingestion of spores. The organism can be cultured readily from the hospital environment, including items and inert surfaces in patient rooms as well as the hands, clothing, and stethoscopes of health care workers [30,31].

The organism is also transmitted readily between hospital roommates [12,22]. One retrospective study noted that receipt of antibiotics by prior bed occupants was associated with increased risk for CDI in subsequent patients [32]. Measures for prevention of C. difficile transmission in hospital settings are discussed separately. (See "Clostridioides difficile infection: Prevention and control".)

Patients harboring toxinogenic C. difficile (detected via nucleic acid amplification) in their stool are capable of serving as a source for transmission of infection to others, regardless of whether toxin is detected (via enzyme immunoassay) [33].

Study of C. difficile transmission using whole genome sequencing has suggested that transmission is more likely to occur from patients with diarrhea related to active CDI than from patients with asymptomatic colonization [34].

RISK FACTORS — Antibiotic use is the most widely recognized and modifiable risk factor for CDI [35-38]. Other established risk factors include advanced age, hospitalization, and severe comorbid illness [37]. Additional risk factors include enteral feeding, gastrointestinal surgery, obesity, cancer chemotherapy, hematopoietic stem cell transplantation, inflammatory bowel disease, cirrhosis, and possibly gastric acid suppression [2,37,39-46]. The association between cancer chemotherapy and CDI may be related to the antimicrobial effect of chemotherapeutic agents and/or their immunosuppressive effects [47].

Risk factors for recurrent CDI include age >65 years, severe underlying medical disorders, need for ongoing therapy with concomitant antibiotics during treatment for CDI, serum creatinine ≥1.2 mg/dL, and lack of an antibody-mediated immune response to C. difficile toxins especially toxin B [48-54].

Risk factors for complications associated with CDI (perforation, toxic megacolon, colectomy, admission to intensive care unit, death) include older age, abnormal blood tests (white blood cell count <4000 cells/microL or ≥20,000 cells/microL, albumin <25 g/L, blood urea nitrogen >7 mmol/L, and C-reactive protein ≥150 mg/L), and abnormal vital signs (heart rate >90/minute, respiratory rate >20/minute) [55].

CDI can also occur in the absence of any risk factors [56,57].

Antibiotic use — Two major roles for antibiotics in the pathogenesis of C. difficile have been described. First, antibiotics disrupt the barrier function of the normal colonic microbiota, providing a niche for C. difficile to multiply and elaborate toxins [58]. In a small series of patients with CDI, for example, absence of Bacteroides species (a predominant species in normal colonic microbiota) was noted during CDI but returned following resolution of symptoms [59]. Second, development of C. difficile resistance to clindamycin or fluoroquinolones appears to play an important role in disease due to strains with increased virulence [5,60].

Antibiotic stewardship plays an important role in controlling CDI rates [1,61]. (See "Antimicrobial stewardship in hospital settings" and "Antimicrobial stewardship in outpatient settings".)

The antibiotics most frequently implicated in predisposition to CDI include fluoroquinolones, clindamycin, and broad-spectrum penicillins and cephalosporins (table 1) [5,60,62-65]. However, any antibiotic can predispose to colonization by C. difficile, including metronidazole and vancomycin, which are the major antibiotics used to treat CDI [66]. The use of broad-spectrum antimicrobials, use of multiple antibiotic agents, and increased duration of antibiotic therapy all contribute to the incidence of CDI [67-69].

The earliest cases of C. difficile were attributed to clindamycin, and it remains an important culprit [2,70]. A strain of C. difficile highly resistant to clindamycin was implicated in large outbreaks in the early 1990s [60]. The use of clindamycin is a specific risk factor for this strain, and colonization with the clindamycin-resistant strain increases risk for developing CDI.

Increasingly widespread use of fluoroquinolones has been correlated with C. difficile–associated diarrhea. In addition, fluoroquinolone resistance of the hypervirulent strain ribotype 027 (previously known as NAP1/BI/027) may be an important factor in nosocomial outbreaks caused by these virulent strains [5,71]. (See 'PCR ribotype 027 strain' below.)

The degree and duration of CDI risk after cessation of antibiotic treatment are not well understood. One case-control study including 337 patients with C. difficile suggested that risk was increased during antibiotic therapy and in the period of three months after cessation of therapy; the risk was highest during the first month after antibiotic use [72].

Perioperative antibiotic prophylaxis also confers risk for CDI, especially if a hospital is experiencing an outbreak of CDI.

A "herd effect" of antibiotic use has been postulated (ie, that patients not on antibiotics in regions where antibiotic use is high are at greater risk for CDI than patients not on antibiotics in regions where antibiotic use is low) [73].

Advanced age — Age seems to promote the frequency and severity of CDI. In a 2002 Quebec outbreak, the frequency of CDI among persons ≥65 years was 10-fold higher than that observed in younger adults [74]. This age-related association was also noted as early as the 1980s, prior to the epidemic emergence of hypervirulent C. difficile strains [75,76].

The reasons for this association are uncertain and may be multifactorial. Host factors, such as diminished immune response to CDI, may play a role. Alternatively, older individuals may have other comorbidities that place them at a cumulative increased risk for CDI, such as greater likelihood to require hospitalization, antibiotic use, or inherent dysbiosis.

Gastric acid suppression — Gastric acid suppression (with proton pump inhibitors [PPIs] or histamine 2 receptor antagonists) has been associated with an increased risk of CDI [23,77-88].

The risk of CDI ranges from 1.4 to 2.75 times higher among patients with PPI exposure compared with those without PPI exposure [89]. However, a causal association has not been established and the relationship between the risk of CDI and PPI dose and duration of use is uncertain [90,91].

Discontinuation of unnecessary PPIs is reasonable although there is insufficient evidence for routine discontinuation of PPIs as a measure for preventing CDI [92].

MICROBIOLOGY — C. difficile is an anaerobic gram-positive, spore-forming, toxin-producing bacillus first described in 1935 (picture 1 and picture 2) [93]. It was named "difficult clostridium" because of difficulty related to its isolation and growth on conventional media. C. difficile can exist in spore and vegetative forms. Outside the colon, it survives in spore form; spores are resistant to heat, acid, and antibiotics. Once spores are in the intestine, they convert to their fully functional vegetative, toxin-producing forms and become susceptible to killing by antimicrobial agents.

C. difficile was initially observed as a component of the intestinal microbiota in healthy newborns [93]. The pathogenic role of C. difficile was first appreciated in the 1970s when C. difficile toxin was observed in the stools of patients with antibiotic-associated pseudomembranous colitis [3,94]. This organism is now recognized as the cause of pseudomembranous colitis and other variant forms of diarrhea and colitis usually in patients exposed to antibiotics. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)

Toxins — C. difficile releases two potent exotoxins that mediate colitis and diarrhea: toxin A and toxin B. The organism is rarely invasive, and nontoxinogenic strains do not cause CDI. C. difficile toxins contain a series of contiguous repeated units at the carboxyl terminus. For toxin A, this region is important for toxin A carbohydrate receptor binding to facilitate intracellular transport as well as for antibody binding in enzyme-linked immunosorbent assays [95].

Once intracellular, toxins A and B inactivate regulatory pathways mediated by Rho family proteins that are involved in cytoskeleton structure and signal transduction via guanosine triphosphate. This disruption leads to cell retraction and rounding in tissue culture assays and as shallow ulcerations on the intestinal mucosal surface [96,97]. Both toxins also disrupt intercellular tight junctions [98,99].

In vivo, stool toxin levels correlate with disease severity [100]. Toxin A causes inflammation leading to intestinal fluid secretion and mucosal injury [101,102]. Mediators in these pathways include arachidonic acid metabolites, substance P, tumor necrosis factor, and interleukin (IL)-8, IL-6, and IL-1 [103-106]. Toxin A directly activates neutrophils, and both toxin A and B can promote neutrophil chemotaxis to localize in pseudomembranes and the underlying intestinal mucosal layer [107,108].

Toxin B is a major factor for the virulence of C. difficile and is more than 10 times more potent than toxin A on a molar basis for mediating colonic mucosal damage [97,109,110]. Thus, strains lacking toxin A can be as virulent as strains with both toxins [108,109,111-113]. Conversely, CDI-associated clinical isolates that produce toxin A but minimal or no toxin B have been identified; hence, toxin A appears to also contribute to CDI pathogenesis [114].

A minority of C. difficile clinical isolates (10 to 30 percent) are nontoxinogenic [70,115] and do not produce toxins in vivo or in vitro; these strains can colonize the gastrointestinal tract and grow normally in culture media but are not pathogenic [116].

PCR ribotype 027 strain — A "hypervirulent" strain, PCR ribotype 027 (previously known as NAP1/BI/027) has been implicated as the responsible pathogen in selected C. difficile outbreaks since the early 2000s. The previous name of this strain reflected its characteristics demonstrated by different methods for strain typing: pulsed-field gel electrophoresis (NAP1), restriction endonuclease analysis (BI), and polymerase chain reaction (027). This strain is now referred to solely as ribotype 027. Interestingly, this strain may not be hypervirulent in a nonepidemic setting [117].

Characteristics of this strain that contribute to the clinical and epidemiologic observations include (see 'Epidemiology' above):

●Ribotype 027 produces binary toxin, an additional toxin that is always absent in other C. difficile strains [70,118,119]. Binary toxin is related to the iota-toxin found in Clostridium perfringens; its role in C. difficile pathogenesis is not fully understood [120,121].

●Some studies suggest ribotype 027 produces substantially larger quantities of toxins A and B than other C. difficile strains both in vitro and in vivo [122,123].

●Ribotype 027 is toxinotype III; most other C. difficile strains are toxinotype 0 [122,124]. Toxinotyping is based on analysis of the pathogenicity locus (PaLoc) of the C. difficile genome; this is the region that includes the genes for toxin A (tcdA), toxin B (tcdB), and neighboring regulatory genes.

●Ribotype 027 has a partial deletion of tcdC, a gene in the pathogenicity locus that is responsible for downregulation of toxin production [124,125]. This may contribute to the enhanced capability for production of toxins A and B.

●Ribotype 027 is resistant to fluoroquinolones in vitro; this was an infrequent observation in C. difficile strains prior to 2001 [5,71,74,124].

Lower clinical cure rates and increased recurrence rates have been observed among patients infected with the epidemic 027 strain compared with patients infected with nonepidemic strains [126-128]. This strain has also been associated with severe disease, severe outcome (intensive care unit admission, colectomy, or death within 30 days), and death within 14 days [129,130]. However, the hypervirulent strain's genomic makeup and altered toxin-producing capabilities do not fully explain the increasing frequency and severity of disease, since historic isolates of ribotype 027 possessing binary toxin genes and tcdC deletions have also been described [124]. However, a new observation is the increased resistance to fluoroquinolones; historic isolates of ribotype 027 were not as resistant to fluoroquinolones as the contemporary ones. A selective advantage afforded by increased resistance to a particular antimicrobial has also been observed previously; the highly clindamycin-resistant strain was associated with epidemics in the late 1980s and early 1990s [60].

PATHOPHYSIOLOGY

Overview — C. difficile is capable of elaborating exotoxins that act upon intestinal epithelial cells and inflammatory cells, leading to tissue injury and diarrhea (figure 1).

Pathogen and host factors probably play important roles in the evolving epidemiology of CDI. C. difficile diarrhea is mediated by genes for toxin A (tcdA) and toxin B (tcdB), which inactivate members of the Rho family of guanosine triphosphatases (Rho GTPases), leading to colonocyte death, loss of intestinal barrier function, and neutrophilic colitis [131]. Toxin production and other microbiologic factors are outlined in detail above (see 'Microbiology' above). Host factor responses include toxin A and B antibody production, interleukin (IL)-8 levels, and intestinal toxin receptors [51,132-135].

Serum antitoxin antibodies are the best described host factor protecting against C. difficile pathogenesis. Asymptomatic carriers demonstrate higher serum levels of immunoglobulin (Ig)G antibodies against toxin A than patients who develop clinical CDI [51,132-134]. In a prospective study of 271 hospitalized patients, those with low or undetectable levels of antitoxin A antibodies were significantly more likely to develop diarrhea than those with detectable antibodies against toxin A (odds ratio 48, 95% CI 3.4-678) [31,132]. Mounting a serum antibody response to toxin A during an initial episode of CDI was associated with relative protection against recurrent CDI [51,136].

Colonization with nontoxinogenic strains also affords protection. This observation suggests that the initial colonizing strain may occupy a microbial niche in the large intestine that is protective against superinfection with a new toxin-producing C. difficile strain [19,137,138].

A common polymorphism in the IL-8 gene promoter is associated with increased risk for CDI and recurrence [135,139,140]. This was suggested in a report of 125 hospitalized patients (42 with C. difficile disease, 42 with C. difficile–negative diarrhea, and 41 without diarrhea) [135]. The frequency of an IL-8 allele with a single nucleotide polymorphism (genotype AA, responsible for increased IL-8 production) was significantly associated with development of C. difficile diarrhea in comparison with the two control groups (39 versus 16 and 17 percent, respectively). CDI patients also had higher median fecal IL-8 levels compared with control patients.

Recurrent disease — The mechanism of CDI recurrence following initial infection is not fully understood. It may be due to the presence of persistent spores from the initial infection (relapse) or reinfection by exogenous C. difficile.

Impairment of the host immune response to C. difficile toxins may also be an important mechanism for recurrence. Asymptomatic carriers of C. difficile tend to have high serum antibody levels against C. difficile toxins [132], while patients with recurrent CDI tend to have lower antitoxin antibody levels than patients with a single brief episode of diarrhea [51,133,136,141].

Antibiotic resistance does not appear to be a factor in recurrence. However, treatment with metronidazole or vancomycin for an initial episode of CDI may alter the colonic microenvironment (with regard to microbiota or other factors), potentially increasing susceptibility to reinfection and recurrence. (See "Clostridioides difficile infection in adults: Treatment and prevention".)

C. difficile in neonates — The absence of intestinal receptors for C. difficile toxins may be protective against CDI. Although this observation has been made in an animal neonate model, it is speculated that it may also play a role in protection against C. difficile in human newborns [142]. These individuals have a relatively high asymptomatic C. difficile carriage rate (up to 100 percent) in the setting of elevated C. difficile toxin stool titers [142-144]. Serum and stool Ig levels subsequently develop by two years of age in about 60 percent of healthy children and are detectable through adulthood [145,146].

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●Beyond the Basics topic (see "Patient education: Antibiotic-associated diarrhea caused by Clostridioides difficile (Beyond the Basics)")

SUMMARY

●Epidemiology – Clostridioides difficile is a significant nosocomial pathogen and can cause both health-care associated and community-associated infection. Dramatic increases in the severity and refractoriness of C. difficile infection (CDI) in multiple outbreaks around the world have been attributed, in part, to the 027 strain. (See 'Epidemiology' above and 'PCR ribotype 027 strain' above.)

●Transmission – C difficile is highly transmissible via the fecal-oral route by ingestion of spores. Transmission is more likely to occur from patients with diarrhea than from patients with asymptomatic colonization. (See 'Transmission' above.)

●Risk factors – Although CDI can occur in the absence of any risk factors, the most common risk factors for CDI include antibiotic use, advanced age, hospitalization, and severe comorbid illness.

•Antibiotics associated with CDI – The antibiotics most frequently implicated in predisposition to CDI include fluoroquinolones, clindamycin, penicillins, and cephalosporins. (See 'Antibiotic use' above.)

•Recurrent CDI – Risk factors for recurrent CDI include age >65 years, severe underlying medical disorders, need for ongoing therapy with concomitant antibiotics during treatment for CDI, serum creatinine ≥1.2 mg/dL, and lack of an antibody-mediated immune response to C. difficile toxins, especially toxin B. (See 'Risk factors' above.)

•Complications – Risk factors for complications associated with CDI (perforation, toxic megacolon, colectomy, admission to intensive care unit, death) include older age, abnormal blood tests (eg, leukopenia or leukocytosis, hypoalbuminemia, acute kidney injury), and abnormal vital signs. (See 'Risk factors' above.)

●Pathophysiology

•Colonization of C. difficile occurs via the fecal-oral route usually in the context of disrupted intestinal microbiota due to antimicrobial therapy. (See 'Pathophysiology' above.)

•C. difficile produces two toxins that bind to receptors on intestinal epithelial cells, leading to inflammation and diarrhea. Individuals with low or undetectable levels of antibody against C. difficile toxins are more likely to develop diarrhea than those with detectable anti-toxin antibody levels. (See 'Toxins' above and 'Pathophysiology' above.)

McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66:987.
Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 2006; 145:758.
Bartlett JG, Moon N, Chang TW, et al. Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 1978; 75:778.
Miller M, Gravel D, Mulvey M, et al. Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality. Clin Infect Dis 2010; 50:194.
Pépin 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.
He M, Miyajima F, Roberts P, et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat Genet 2013; 45:109.
Goorhuis A, Bakker D, Corver J, et al. Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin Infect Dis 2008; 47:1162.
Hensgens MP, Goorhuis A, Dekkers OM, et al. All-cause and disease-specific mortality in hospitalized patients with Clostridium difficile infection: a multicenter cohort study. Clin Infect Dis 2013; 56:1108.
Walk ST, Micic D, Jain R, et al. Clostridium difficile ribotype does not predict severe infection. Clin Infect Dis 2012; 55:1661.
Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015; 372:825.
Guh AY, Mu Y, Winston LG, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes. N Engl J Med 2020; 382:1320.
McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989; 320:204.
Zacharioudakis IM, Zervou FN, Pliakos EE, et al. Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis. Am J Gastroenterol 2015; 110:381.
Riggs MM, Sethi AK, Zabarsky TF, et al. Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007; 45:992.
Pollock NR, Banz A, Chen X, et al. Comparison of Clostridioides difficile Stool Toxin Concentrations in Adults With Symptomatic Infection and Asymptomatic Carriage Using an Ultrasensitive Quantitative Immunoassay. Clin Infect Dis 2019; 68:78.
Curry SR, Muto CA, Schlackman JL, et al. Use of multilocus variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission. Clin Infect Dis 2013; 57:1094.
Blixt T, Gradel KO, Homann C, et al. Asymptomatic Carriers Contribute to Nosocomial Clostridium difficile Infection: A Cohort Study of 4508 Patients. Gastroenterology 2017; 152:1031.
Alasmari F, Seiler SM, Hink T, et al. Prevalence and risk factors for asymptomatic Clostridium difficile carriage. Clin Infect Dis 2014; 59:216.
Blossom DB, McDonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis 2007; 45:222.
Shim JK, Johnson S, Samore MH, et al. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 1998; 351:633.
Hirschhorn LR, Trnka Y, Onderdonk A, et al. Epidemiology of community-acquired Clostridium difficile-associated diarrhea. J Infect Dis 1994; 169:127.
Samore MH, Venkataraman L, DeGirolami PC, et al. Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996; 100:32.
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.
Centers for Disease Control and Prevention (CDC). Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb Mortal Wkly Rep 2005; 54:1201.
Hecker MT, Riggs MM, Hoyen CK, et al. Recurrent infection with epidemic Clostridium difficile in a peripartum woman whose infant was asymptomatically colonized with the same strain. Clin Infect Dis 2008; 46:956.
Gould LH, Limbago B. Clostridium difficile in food and domestic animals: a new foodborne pathogen? Clin Infect Dis 2010; 51:577.
Loo VG, Brassard P, Miller MA. Household Transmission of Clostridium difficile to Family Members and Domestic Pets. Infect Control Hosp Epidemiol 2016; 37:1342.
Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect 2012; 18 Suppl 6:21.
Ma GK, Brensinger CM, Wu Q, Lewis JD. Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: A Cohort Study. Ann Intern Med 2017; 167:152.
Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol 1995; 16:459.
Kim KH, Fekety R, Batts DH, et al. Isolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis. J Infect Dis 1981; 143:42.
Freedberg DE, Salmasian H, Cohen B, et al. Receipt of Antibiotics in Hospitalized Patients and Risk for Clostridium difficile Infection in Subsequent Patients Who Occupy the Same Bed. JAMA Intern Med 2016; 176:1801.
Mawer DPC, Eyre DW, Griffiths D, et al. Contribution to Clostridium Difficile Transmission of Symptomatic Patients With Toxigenic Strains Who Are Fecal Toxin Negative. Clin Infect Dis 2017; 64:1163.
Kong LY, Eyre DW, Corbeil J, et al. Clostridium difficile: Investigating Transmission Patterns Between Infected and Colonized Patients Using Whole Genome Sequencing. Clin Infect Dis 2019; 68:204.
Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003; 51:1339.
Wiström J, Norrby SR, Myhre EB, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001; 47:43.
Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011; 365:1693.
Guh AY, Adkins SH, Li Q, et al. Risk Factors for Community-Associated Clostridium difficile Infection in Adults: A Case-Control Study. Open Forum Infect Dis 2017; 4:ofx171.
Kyne L, Sougioultzis S, McFarland LV, Kelly CP. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol 2002; 23:653.
Bliss DZ, Johnson S, Savik K, et al. Acquisition of Clostridium difficile and Clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding. Ann Intern Med 1998; 129:1012.
Kamthan AG, Bruckner HW, Hirschman SZ, Agus SG. Clostridium difficile diarrhea induced by cancer chemotherapy. Arch Intern Med 1992; 152:1715.
Bishara J, Farah R, Mograbi J, et al. Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis 2013; 57:489.
Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007; 5:339.
Singh H, Nugent Z, Yu BN, et al. Higher Incidence of Clostridium difficile Infection Among Individuals With Inflammatory Bowel Disease. Gastroenterology 2017; 153:430.
Yan D, Chen Y, Lv T, et al. Clostridium difficile colonization and infection in patients with hepatic cirrhosis. J Med Microbiol 2017; 66:1483.
Reigadas E, Alcalá L, Gómez J, et al. Breakthrough Clostridium difficile Infection in Cirrhotic Patients Receiving Rifaximin. Clin Infect Dis 2018; 66:1086.
Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993; 17:109.
D'Agostino RB Sr, Collins SH, Pencina KM, et al. Risk estimation for recurrent Clostridium difficile infection based on clinical factors. Clin Infect Dis 2014; 58:1386.
Hu MY, Katchar K, Kyne L, et al. Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology 2009; 136:1206.
Tedesco FJ, Gordon D, Fortson WC. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis. Am J Gastroenterol 1985; 80:867.
Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001; 357:189.
Pépin J, Routhier S, Gagnon S, Brazeau I. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006; 42:758.
Gupta SB, Mehta V, Dubberke ER, et al. Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence. Clin Infect Dis 2016; 63:730.
Kelly CP, Poxton IR, Shen J, et al. Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. Clin Infect Dis 2020; 71:81.
Abou Chakra CN, McGeer A, Labbé AC, et al. Factors Associated With Complications of Clostridium difficile Infection in a Multicenter Prospective Cohort. Clin Infect Dis 2015; 61:1781.
Centers for Disease Control and Prevention (CDC). Surveillance for community-associated Clostridium difficile--Connecticut, 2006. MMWR Morb Mortal Wkly Rep 2008; 57:340.
Abrahamian FM, Talan DA, Krishnadasan A, et al. Clostridium difficile Infection Among US Emergency Department Patients With Diarrhea and No Vomiting. Ann Emerg Med 2017.
Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 2014; 146:1547.
Johnson S, Clabots CR, Linn FV, et al. Nosocomial Clostridium difficile colonisation and disease. Lancet 1990; 336:97.
Johnson S, Samore MH, Farrow KA, et al. Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med 1999; 341:1645.
Kazakova SV, Baggs J, McDonald LC, et al. Association Between Antibiotic Use and Hospital-onset Clostridioides difficile Infection in US Acute Care Hospitals, 2006-2012: An Ecologic Analysis. Clin Infect Dis 2020; 70:11.
Gurwith MJ, Rabin HR, Love K. Diarrhea associated with clindamycin and ampicillin therapy: preliminary results of a cooperative study. J Infect Dis 1977; 135 Suppl:S104.
Tedesco FJ, Barton RW, Alpers DH. Clindamycin-associated colitis. A prospective study. Ann Intern Med 1974; 81:429.
Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 2013; 68:1951.
Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother 2013; 57:2326.
Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994; 330:257.
Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998; 40:1.
Stevens V, Dumyati G, Fine LS, et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011; 53:42.
Tabak YP, Srinivasan A, Yu KC, et al. Hospital-level high-risk antibiotic use in relation to hospital-associated Clostridioides difficile infections: Retrospective analysis of 2016-2017 data from US hospitals. Infect Control Hosp Epidemiol 2019; 40:1229.
Geric B, Rupnik M, Gerding DN, et al. Distribution of Clostridium difficile variant toxinotypes and strains with binary toxin genes among clinical isolates in an American hospital. J Med Microbiol 2004; 53:887.
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.
Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother 2012; 67:742.
Brown KA, Jones M, Daneman N, et al. Importation, Antibiotics, and Clostridium difficile Infection in Veteran Long-Term Care: A Multilevel Case-Control Study. Ann Intern Med 2016; 164:787.
Pépin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005; 173:1037.
Falsen E, Kaijser B, Nehls L, et al. Clostridium difficile in relation to enteric bacterial pathogens. J Clin Microbiol 1980; 12:297.
Campbell RR, Beere D, Wilcock GK, Brown EM. Clostridium difficile in acute and long-stay elderly patients. Age Ageing 1988; 17:333.
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.
Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010; 170:772.
Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010; 170:784.
Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis 2011; 53:1173.
Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107:1011.
Tleyjeh IM, Abdulhak AB, Riaz M, et al. The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis. PLoS One 2013; 8:e56498.
Tariq R, Singh S, Gupta A, et al. Association of Gastric Acid Suppression With Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis. JAMA Intern Med 2017.
Wombwell E, Chittum ME, Leeser KR. Inpatient Proton Pump Inhibitor Administration and Hospital-Acquired Clostridium difficile Infection: Evidence and Possible Mechanism. Am J Med 2018; 131:244.
Watson T, Hickok J, Fraker S, et al. Evaluating the Risk Factors for Hospital-Onset Clostridium difficile Infections in a Large Healthcare System. Clin Infect Dis 2018; 66:1957.
D'Silva KM, Mehta R, Mitchell M, et al. Proton pump inhibitor use and risk for recurrent Clostridioides difficile infection: a systematic review and meta-analysis. Clin Microbiol Infect 2021.
Inghammar M, Svanström H, Voldstedlund M, et al. Proton-Pump Inhibitor Use and the Risk of Community-Associated Clostridium difficile Infection. Clin Infect Dis 2021; 72:e1084.
Mehta P, Nahass RG, Brunetti L. Acid Suppression Medications During Hospitalization as a Risk Factor for Recurrence of Clostridioides difficile Infection: Systematic Review and Meta-analysis. Clin Infect Dis 2021; 73:e62.
US Food and Drug Administration. FDA Drug Safety Communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm (Accessed on February 14, 2012).
Barletta JF, El-Ibiary SY, Davis LE, et al. Proton Pump Inhibitors and the Risk for Hospital-Acquired Clostridium difficile Infection. Mayo Clin Proc 2013; 88:1085.
Freedberg DE, Salmasian H, Friedman C, Abrams JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol 2013; 108:1794.
McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66:e1.
Hall IC, O'Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe Bacillus difficilis. Am J Dis Child 1935; 49:390.
George RH, Symonds JM, Dimock F, et al. Identification of Clostridium difficile as a cause of pseudomembranous colitis. Br Med J 1978; 1:695.
Price SB, Phelps CJ, Wilkins TD, Johnson JL. Cloning of the carbohydrate-binding portion of the toxin a gene of Clostridium difficile. Curr Microbiol 1987; 16:55.
Just I, Selzer J, Wilm M, et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995; 375:500.
Riegler M, Sedivy R, Pothoulakis C, et al. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995; 95:2004.
Brito GA, Sullivan GW, Ciesla WP Jr, et al. Clostridium difficile toxin A alters in vitro-adherent neutrophil morphology and function. J Infect Dis 2002; 185:1297.
Hecht G, Koutsouris A, Pothoulakis C, et al. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 1992; 102:416.
Akerlund T, Svenungsson B, Lagergren A, Burman LG. Correlation of disease severity with fecal toxin levels in patients with Clostridium difficile-associated diarrhea and distribution of PCR ribotypes and toxin yields in vitro of corresponding isolates. J Clin Microbiol 2006; 44:353.
Lima AA, Innes DJ Jr, Chadee K, et al. Clostridium difficile toxin A. Interactions with mucus and early sequential histopathologic effects in rabbit small intestine. Lab Invest 1989; 61:419.
Sears CL, Kaper JB. Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion. Microbiol Rev 1996; 60:167.
Castagliuolo I, Riegler M, Pasha A, et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis. J Clin Invest 1998; 101:1547.
Mahida YR, Makh S, Hyde S, et al. Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. Gut 1996; 38:337.
Melo Filho AA, Souza MH, Lyerly DM, et al. Role of tumor necrosis factor and nitric oxide in the cytotoxic effects of Clostridium difficile toxin A and toxin B on macrophages. Toxicon 1997; 35:743.
Warny M, Keates AC, Keates S, et al. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest 2000; 105:1147.
Pothoulakis C, Sullivan R, Melnick DA, et al. Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes. J Clin Invest 1988; 81:1741.
Souza MH, Melo-Filho AA, Rocha MF, et al. The involvement of macrophage-derived tumour necrosis factor and lipoxygenase products on the neutrophil recruitment induced by Clostridium difficile toxin B. Immunology 1997; 91:281.
Lyras D, O'Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009; 458:1176.
Alfa MJ, Kabani A, Lyerly D, et al. Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile responsible for a nosocomial outbreak of Clostridium difficile-associated diarrhea. J Clin Microbiol 2000; 38:2706.
Moncrief JS, Zheng L, Neville LM, Lyerly DM. Genetic characterization of toxin A-negative, toxin B-positive Clostridium difficile isolates by PCR. J Clin Microbiol 2000; 38:3072.
Limaye AP, Turgeon DK, Cookson BT, Fritsche TR. Pseudomembranous colitis caused by a toxin A(-) B(+) strain of Clostridium difficile. J Clin Microbiol 2000; 38:1696.
Kuehne SA, Cartman ST, Heap JT, et al. The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010; 467:711.
Lin Q, Pollock NR, Banz A, et al. Toxin A-Predominant Pathogenic Clostridioides difficile: A Novel Clinical Phenotype. Clin Infect Dis 2020; 70:2628.
Hung YP, Lin HJ, Wu TC, et al. Risk factors of fecal toxigenic or non-toxigenic Clostridium difficile colonization: impact of Toll-like receptor polymorphisms and prior antibiotic exposure. PLoS One 2013; 8:e69577.
McFarland LV, Elmer GW, Stamm WE, Mulligan ME. Correlation of immunoblot type, enterotoxin production, and cytotoxin production with clinical manifestations of Clostridium difficile infection in a cohort of hospitalized patients. Infect Immun 1991; 59:2456.
Cloud J, Noddin L, Pressman A, et al. Clostridium difficile strain NAP-1 is not associated with severe disease in a nonepidemic setting. Clin Gastroenterol Hepatol 2009; 7:868.
Spigaglia P, Mastrantonio P. Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol 2002; 40:3470.
Popoff MR, Rubin EJ, Gill DM, Boquet P. Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain. Infect Immun 1988; 56:2299.
McEllistrem MC, Carman RJ, Gerding DN, et al. A hospital outbreak of Clostridium difficile disease associated with isolates carrying binary toxin genes. Clin Infect Dis 2005; 40:265.
Barbut F, Decré D, Lalande V, et al. Clinical features of Clostridium difficile-associated diarrhoea due to binary toxin (actin-specific ADP-ribosyltransferase)-producing strains. J Med Microbiol 2005; 54:181.
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.
Alonso CD, Pollock NR, Garey KW, et al. Higher In Vivo Fecal Concentrations of Clostridioides difficile Toxins A and B in Patients With North American Pulsed-Field Gel Electrophoresis Type 1/Ribotype 027 Strain Infection. Clin Infect Dis 2022; 75:2019.
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005; 353:2433.
Rupnik M, Avesani V, Janc M, et al. A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium difficile isolates. J Clin Microbiol 1998; 36:2240.
Petrella LA, Sambol SP, Cheknis A, et al. Decreased cure and increased recurrence rates for Clostridium difficile infection caused by the epidemic C. difficile BI strain. Clin Infect Dis 2012; 55:351.
Marsh JW, Arora R, Schlackman JL, et al. Association of relapse of Clostridium difficile disease with BI/NAP1/027. J Clin Microbiol 2012; 50:4078.
Walker AS, Eyre DW, Wyllie DH, et al. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin Infect Dis 2013; 56:1589.
See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis 2014; 58:1394.
Rao K, Micic D, Natarajan M, et al. Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality. Clin Infect Dis 2015; 61:233.
Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372:1539.
Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000; 342:390.
Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991; 118:633.
Warny M, Vaerman JP, Avesani V, Delmée M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun 1994; 62:384.
Jiang ZD, Garey KW, Price M, et al. Association of interleukin-8 polymorphism and immunoglobulin G anti-toxin A in patients with Clostridium difficile-associated diarrhea. Clin Gastroenterol Hepatol 2007; 5:964.
Kelly CP. Immune response to Clostridium difficile infection. Eur J Gastroenterol Hepatol 1996; 8:1048.
Sambol SP, Merrigan MM, Tang JK, et al. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002; 186:1781.
Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA 2015; 313:1719.
Jiang ZD, DuPont HL, Garey K, et al. A common polymorphism in the interleukin 8 gene promoter is associated with Clostridium difficile diarrhea. Am J Gastroenterol 2006; 101:1112.
El Feghaly RE, Stauber JL, Deych E, et al. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis 2013; 56:1713.
Aboudola S, Kotloff KL, Kyne L, et al. Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A. Infect Immun 2003; 71:1608.
Eglow R, Pothoulakis C, Itzkowitz S, et al. Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor. J Clin Invest 1992; 90:822.
Jangi S, Lamont JT. Asymptomatic colonization by Clostridium difficile in infants: implications for disease in later life. J Pediatr Gastroenterol Nutr 2010; 51:2.
Mårdh PA, Helin I, Colleen I, et al. Clostridium difficile toxin in faecal specimens of healthy children and children with diarrhoea. Acta Paediatr Scand 1982; 71:275.
Viscidi R, Laughon BE, Yolken R, et al. Serum antibody response to toxins A and B of Clostridium difficile. J Infect Dis 1983; 148:93.
Kelly CP, Pothoulakis C, Orellana J, LaMont JT. Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding. Gastroenterology 1992; 102:35.

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Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology

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