Emergence of a Ribotype 244 Strain of Clostridium difficile Associated With Severe Disease and Related to the Epidemic Ribotype 027 Strain

Lim, Sze K; Stuart, Rhonda L.; Mackin, Kate E.; Carter, Glen P.; Kotsanas, Despina; Francis, Michelle J; Easton, Marion; Dimovski, Karolina; Elliott, Briony; Riley, Thomas V.; Hogg, Geoffrey G; Paul, Eldho; Korman, Tony M.; Seemann, Torsten; Stinear, Timothy P.; Lyras, Dena; Jenkin, Grant A.

doi:10.1093/cid/ciu203

Cited by 115 publications

(101 citation statements)

References 38 publications

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“…Initial clinical cure (defined as no diarrhea for 2 consecutive days after completion of standard-of-care antibiotic therapy administered for ≤16 days) was an exploratory end point. Secondary analyses included the rate of recurrent C. difficile infection in the subgroup of participants in the modified intention-to-treat population who had an initial clinical cure, as well as in prespecified subgroups of participants with risk factors for recurrent C. difficile infection or for adverse outcomes related to C. difficile infection: an age of 65 years or older, 20,21 a history of C. difficile infection, 3,4 compromised immunity, 22,23 clinically severe C. difficile infection (defined as a Zar score ≥2; scores range from 1 to 8, with higher scores indicating more severe infection), 24 and infection with a strain associated with poor outcomes (strain 027, 20,25-27 078, 28 or 244 29,30 ). A secondary end point was the rate of sustained cure (i.e., initial clinical cure of the baseline episode of C. difficile infection and no recurrent infection through 12 weeks), also known as global cure or sustained clinical response.…”

Section: Prespecified End Pointsmentioning

confidence: 99%

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

et al. 2017

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BACKGROUNDClostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODSWe conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTSIn both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.: CONCLUSIONSAmong participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. 306T h e ne w e ngl a nd jou r na l o f m e dicine I n high-income countries, Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. 1,2 After completing initial antibiotic therapy, up to 35% of patients have recurrent C. difficile infection, 3,4 which is more difficult to treat and is associated with more hospitalizations, more severe outcomes, and higher costs than the first infection and a 50 to 60% chance of repeat recurrent infections. 5,6 Currently, no therapy has been approved to prevent recurrent C. difficile infection.Passive or active immunization against C. difficile toxins A and B is protective in animals that are challenged with toxigenic C. difficile, 7-9 which underscores the key importance of the toxins in causing the symptoms of C. difficile infection. The relative biologic importance of toxins A and B in C. difficile infection is controversial, but it may be host species-dependent. 10-12 Neutralization of both toxins appears to be necessary for maximal protection in rodents, but neutralization of toxin...

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Section: Prespecified End Pointsmentioning

confidence: 99%

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

et al. 2017

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“…Zealand (De Almeida et al, 2013;Eyre et al, 2015;Lim et al, 2014), RT 176 in parts of Europe (Polivkova et al, 2016), and RT 251 in Australia (unpublished data). What is driving the emergence of these strains is unclear, however, their increased virulence may also be due to polymorphisms in the tcdB RBD, in which clade 2 has the highest diversity of all the clades .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

Elliott

Androga

Knight

et al. 2017

Infection, Genetics and Evolution

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Over the recent decades, Clostridium difficile infection (CDI) has emerged as a global public health threat. Despite growing attention, C. difficile remains a poorly understood pathogen, however, the exquisite sensitivity offered by next generation sequencing (NGS) technology has enabled analysis of the genome of C. difficile, giving us access to massive genomic data on factors such as virulence, evolution, and genetic relatedness within C. difficile groups. NGS has also demonstrated excellence in investigations of outbreaks and disease transmission, in both small and large-scale applications. This review summarizes the molecular epidemiology, evolution, and phylogeny of C. difficile, one of the most important pathogens worldwide in the current antibiotic resistance era.

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“…These strain types have been identified locally 33 , highlighting the need for epidemiological vigilance when it comes to C. difficile. New variants will also continue to emerge, as recently seen in Australia with ribotype 244 strains 34 . The development of fluoroquinolone resistance has been linked to the global spread of ribotype 027 strains 35 , but why other strain types become more or less prevalent is not always clear 34 .…”

mentioning

confidence: 97%

“…New variants will also continue to emerge, as recently seen in Australia with ribotype 244 strains 34 . The development of fluoroquinolone resistance has been linked to the global spread of ribotype 027 strains 35 , but why other strain types become more or less prevalent is not always clear 34 . Without ongoing monitoring, it will be difficult to ascertain changes in strain type within the local population.…”

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confidence: 97%

The complex factors that contribute to Clostridium difficile infection

Mackin

Lyras

2015

Microbiol. Aust.

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Over the past decade Clostridium difficile has emerged as a serious public health issue, causing both hospital-based epidemics and community-associated disease. The most commonly recognised cause of antibiotic-associated diarrhoea in the human population, C. difficile was initially seen as a nuisance pathogen causing limited disease in the hospital setting. However, the emergence of ‘hypervirulent' strain types, associated with an increase in both morbidity and mortality, has made it a pathogen of great concern worldwide. Infection with C. difficile is also being increasingly documented in animals, with suggestions that animals destined for human consumption may provide a reservoir for disease. The use of antibiotics is considered the main risk factor for the development of human infection; however, many other factors such as strain type, patient age, and host immune response all contribute to disease caused by C. difficile.

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Emergence of a Ribotype 244 Strain of Clostridium difficile Associated With Severe Disease and Related to the Epidemic Ribotype 027 Strain

Abstract: Our findings demonstrate the pathogenic potential of this RT244 C. difficile strain and emphasize the importance of ongoing surveillance for emergent strains.

Cited by 115 publications

References 38 publications

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

The complex factors that contribute to Clostridium difficile infection

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