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In this randomized trial of fidaxomicin as compared with vancomycin in 629 patients, oral fidaxomicin was shown to be noninferior to oral vancomycin in the treatment of C. difficile infection and was associated with lower rates of recurrence. Clostridium difficile infection generally occurs after exposure to broad-spectrum antibiotics. The incidence and severity of C. difficile infection are increasing. The increases have been ascribed to the emergence of a hypervirulent C. difficile strain, known variously as North American Pulsed Field type 1 (NAP1), restriction-endonuclease analysis (REA) type BI, or polymerase-chain-reaction ribotype 027 (referred to collectively as the NAP1/BI/027 strain). 1 – 4 Furthermore, the rates of death associated with C. difficile infection are rising, 5 – 7 and the infection is occurring in populations that were previously considered to be at low risk, such as young, healthy persons living in the community and . . .

Background. An epidemic strain of Clostridium difficile designated by restriction endonuclease analysis (REA) as group BI has caused multiple outbreaks of severe C. difficile infection (CDI). The treatment response of patients infected with this strain is uncertain. Methods. Clostridium difficile isolates were collected from 2 phase 3 clinical trials comparing fidaxomicin to vancomycin and typed using REA. Clinical cure and recurrence outcomes were analyzed by strain type of the infecting organism, BI and non-BI, using both univariate and multivariate analyses. Results. From 999 patients, 719 isolates were available for typing (356 fidaxomicin treated and 363 vancomycin treated). BI was the most common REA group (34% of isolates). Patients infected with BI had lower cure rates (86.6%; 214 of 247) than those infected with non-BI strains (94.3%; 445 of 472) (P < .001). The cure rate difference between the BI and non-BI patients was significant for both vancomycin (P = .02) and fidaxomicin (P = .007). BI patients had a recurrence rate of 27.4% (51 of 186), compared with a recurrence rate of 16.6% (66 of 397) in non-BI patients (P = .002). By multivariate analysis, BI infection was statistically significant as a risk factor for reduced cure (odds ratio [OR], 0.48; 95% confidence interval [CI], .27—.85; P = .030) and for increased recurrence (OR, 1.57; 95% CI, 1.01—2.45; P = .046). Conclusions. The clinical cure rate of patients infected with the epidemic BI C. difficile strain is lower than the cure rate of those infected with non-BI strains whether treated with fidaxomicin or vancomycin. Similarly, the CDI recurrence rate is increased in patients with the BI strain compared with patients with other C. difficile strains.

Trevor Lawley and colleagues report whole-genome sequencing of a large global collection of Clostridium difficile , the most common cause of healthcare-associated infection in the developed world. Their phylogenetic analysis traces the spread of this pathogen through healthcare-associated epidemics worldwide. Epidemic C. difficile (027/BI/NAP1) has rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key events in evolutionary history leading to its emergence and the subsequent patterns of global spread remain unknown. Here, we define the global population structure of C. difficile 027/BI/NAP1 using whole-genome sequencing and phylogenetic analysis. We show that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance–conferring mutation and a highly related conjugative transposon. The two epidemic lineages showed distinct patterns of global spread, and the FQR2 lineage spread more widely, leading to healthcare-associated outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid transcontinental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.

Clostridium difficile toxins revisited Clostridium difficile , the most common cause of infectious diarrhoea in hospitals in Europe and North America, produces two toxins. Their relative importance has been widely debated, and although animal studies had indicated that purified toxin A alone can induce most of the pathology observed in C. difficile infections, a recent Nature paper ( http://go.nature.com/oh6un5 ) suggested that the other toxin, toxin B, was the main cause of disease symptoms. Now a new study, involving C. difficile strains producing either toxin A or toxin B alone and — for the first time — a double-mutant strain producing neither, demonstrates that both toxins are important for disease, and need to be considered for diagnosis and treatment. Clostridium difficile , an important nosocomial pathogen, produces two toxins. Studies with purified toxins have indicated that only toxin A is important for pathogenesis, but recently it has been suggested that toxin B causes the majority of the disease symptoms in the context of a bacterial infection. These authors demonstrate that both toxins are important for disease and will need to be considered for diagnosis and treatment. Clostridium difficile infection is the leading cause of healthcare-associated diarrhoea in Europe and North America 1 , 2 . During infection, C. difficile produces two key virulence determinants, toxin A and toxin B. Experiments with purified toxins have indicated that toxin A alone is able to evoke the symptoms of C. difficile infection, but toxin B is unable to do so unless it is mixed with toxin A or there is prior damage to the gut mucosa 3 . However, a recent study indicated that toxin B is essential for C. difficile virulence and that a strain producing toxin A alone was avirulent 4 . This creates a paradox over the individual importance of toxin A and toxin B. Here we show that isogenic mutants of C. difficile producing either toxin A or toxin B alone can cause fulminant disease in the hamster model of infection. By using a gene knockout system 5 , 6 to inactivate the toxin genes permanently, we found that C. difficile producing either one or both toxins showed cytotoxic activity in vitro that translated directly into virulence in vivo . Furthermore, by constructing the first ever double-mutant strain of C. difficile, in which both toxin genes were inactivated, we were able to completely attenuate virulence. Our findings re-establish the importance of both toxin A and toxin B and highlight the need to continue to consider both toxins in the development of diagnostic tests and effective countermeasures against C. difficile .

Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (±2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0—14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15—31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (±6.4) days for relapses and 14.7 (±6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates. Clinical Trials Registration. NCT00314951 and NCT00468728.

In this prospective cohort study of patients admitted to hospitals in Quebec and Ontario, 2.8% of patients had Clostridium difficile infection and 3.0% had asymptomatic C. difficile colonization during hospitalization. Most patients with C. difficile infection had the NAP1 strain. Clostridium difficile is the leading cause of health care–associated infectious diarrhea. 1 After exposure to C. difficile, some patients remain asymptomatic, whereas others have illness ranging from mild diarrhea to fulminant colitis. 2 Outbreaks of C. difficile infection in North America and Europe have been attributed to the emergence of an epidemic strain (North American pulsed-field gel electrophoresis [PFGE] type 1 [NAP1]). 3 , 4 Risk factors for C. difficile infection include antibiotic use, advanced age, increased severity of underlying illness, prior hospitalization, use of feeding tubes, gastrointestinal surgery, and use of proton-pump inhibitors. 5 , 6 Variability in host factors may explain the wide spectrum . . .

Key Points Clostridium difficile infection (CDI) is a continually evolving global health-care problem Community-onset CDI is increasing and multiple potential reservoirs of infection exist including environmental sources, animals, asymptomatic patients and symptomatic patients Highly discriminatory typing techniques such as whole-genome sequencing and multi-locus variable-number tandem-repeat analysis offer the potential for illuminating previously under-recognized routes of C. difficile transmission The optimal approach to sampling and testing for CDI remains a contentious issue Multi-step algorithms are recommended to improve diagnostic sensitivity and specificity Clostridium difficile infection (CDI) is a global health-care problem and represents an important infection in both health-care facilities and the wider community. Here, the authors describe advances in understanding of CDI epidemiology, transmission and diagnosis, which are all key factors in the management of CDI. Clostridium difficile infection (CDI) continues to affect patients in hospitals and communities worldwide. The spectrum of clinical disease ranges from mild diarrhoea to toxic megacolon, colonic perforation and death. However, this bacterium might also be carried asymptomatically in the gut, potentially leading to 'silent' onward transmission. Modern technologies, such as whole-genome sequencing and multi-locus variable-number tandem-repeat analysis, are helping to track C. difficile transmission across health-care facilities, countries and continents, offering the potential to illuminate previously under-recognized sources of infection. These typing strategies have also demonstrated heterogeneity in terms of CDI incidence and strain types reflecting different stages of epidemic spread. However, comparison of CDI epidemiology, particularly between countries, is challenging due to wide-ranging approaches to sampling and testing. Diagnostic strategies for C. difficile are complicated both by the wide range of bacterial targets and tests available and the need to differentiate between toxin-producing and non-toxigenic strains. Multistep diagnostic algorithms have been recommended to improve sensitivity and specificity. In this Review, we describe the latest advances in the understanding of C. difficile epidemiology, transmission and diagnosis, and discuss the effect of these developments on the clinical management of CDI.

There have been increases in both the rate and the severity of C. difficile –associated disease. This report details the emergence of an epidemic strain, BI/NAP1, in eight health care facilities over the past five years. This strain is associated with increased resistance to fluoroquinolone as well as the presence of a novel toxin known as binary toxin CDT. This report details the emergence of an epidemic strain, BI/NAP1, in eight health care facilities over the past five years. This strain is associated with increased resistance to fluoroquinolone as well as the presence of a novel toxin known as binary toxin CDT. Clostridium difficile is a gram-positive, anaerobic, spore-forming bacillus that can cause pseudomembranous colitis and other C. difficile –associated diseases. Studies during the 1970s showed that two toxins, A and B, were involved in the pathogenesis of C. difficile –associated disease. 1 – 5 Transmission occurs primarily in health care facilities, where exposure to antimicrobial drugs (the major risk factor for C. difficile –associated disease) and environmental contamination by C. difficile spores are more common. 6 Certain strains of C. difficile have a propensity to cause outbreaks, including multistate outbreaks in health care facilities. 7 Because these outbreak-associated strains are resistant to certain antimicrobial agents, . . .

Background. Marked increases in Clostridium difficile infection (CDI) incidence, driven by epidemic strain spread, is a global phenomenon. Methods. The Clostridium difficile Ribotyping Network (CDRN) was established in 2007 as part of enhanced CDI surveillance in England, to facilitate the recognition and control of epidemic strains. We report on changes in CDI epidemiology in England in the first 3 years of CDRN. Results. CDRN received 12 603 fecal specimens, comprising significantly (P < .05) increasing numbers and proportions of national CDI cases in 2007–2008 (n = 2109, 3.8%), 2008–2009 (n = 4774, 13.2%), and 2009–2010 (n = 5720, 22.3%). The C. difficile recovery rate was 90%, yielding 11 294 isolates for ribotyping. Rates of 9 of the 10 most common ribotypes changed significantly (P < .05) during 2007–2010. Clostridium difficile ribotype 027 predominated, but decreased markedly from 55% to 36% and 21% in 2007–2008, 2008–2009, and 2009–2010, respectively. The largest regional variations in prevalence occurred for ribotypes 027, 002, 015, and 078. Cephalosporin and fluoroquinolone use in CDI cases was reported significantly (P < .05) less frequently during 2007–2010. Mortality data were subject to potential reporting bias, but there was a significant decrease in CDI-associated deaths during 2007–2010, which may have been due to multiple factors, including reduced prevalence of ribotype 027. Conclusions. Access to C. difficile ribotyping was associated with significant changes in the prevalence of epidemic strains, especially ribotype 027. These changes coincided with markedly reduced CDI incidence and related mortality in England. CDI control programs should include prospective access to C. difficile typing and analysis of risk factors for CDI and outcomes.

In the first half of 2003, the number of C. difficile infections (22.5 per 1000 admissions) increased in Quebec, Canada. This outbreak was associated with fluoroquinolone and cephalosporin use as well as an increase in C. difficile –associated mortality (to 6.9 percent) and colectomy (to 1.9 percent). The outbreak strain was found to have enhanced virulence, as suggested by the presence of binary toxin genes and the partial deletion of a toxin-repressor gene. In the first half of 2003, the number of C. difficile infections (22.5 per 1000 admissions) increased in Quebec, Canada. This outbreak was associated with fluoroquinolone and cephalosporin use as well as an increase in C. difficile –associated mortality and colectomy. Clostridium difficile is the leading cause of nosocomial infectious diarrhea. 1 The most important risk factor for C. difficile –associated diarrhea is prior antibiotic use. 2 Some patients remain asymptomatic after exposure to C. difficile, whereas illness ranging from mild diarrhea to fulminant colitis develops in others. 2 Only 1 to 5 percent of affected patients have severe disease, leading to colectomy, intensive care, or death. 3 , 4 The best-described C. difficile virulence factors are toxins A and B, encoded by the genes tcdA and tcdB, respectively. 5 Together with two regulatory genes ( tcdC and tcdD ) and a porin gene ( tcdE ), . . .