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      Time-kill kinetics of cadazolid and comparator antibacterial agents against different ribotypes of Clostridium difficile

      1 , 1 , 1 , 1 , 2 , 3

      Journal of Medical Microbiology

      Microbiology Society

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          Most cited references 16

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          Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial.

          Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA. In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728. Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI -4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI -4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin. Optimer Pharmaceuticals. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Production of actin-specific ADP-ribosyltransferase (binary toxin) by strains of Clostridium difficile.

            In addition to the two large clostridial cytotoxins (TcdA and TcdB) certain strains of Clostridium difficile produce an actin-specific ADP-ribosyltransferase, or binary toxin. PCR reactions were developed to detect genes encoding the enzymatic (cdtA) and binding (cdtB) components of the binary toxin and 170 representative strains were tested to assess the prevalence of the toxin. Positive PCR results (n=59) were confirmed by immunoblotting and ADP-ribosyltransferase assay. PCR ribotype and toxinotype (restriction fragment length polymorphism analysis of genes for TcdA and TcdB) correlated with possession of binary toxin genes. All strains with cdtA and cdtB belonged to toxin-variable toxinotypes and five toxin-producing groups of strains have been described according to the presence or absence of TcdA, TcdB and binary toxin. Result indicate that ca. 6.4% of toxigenic isolates of C. difficile referred to the Anaerobe Reference Unit from UK hospitals have cdtA and cdtB genes.
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              Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain.

              Rates and severity of Clostridium difficile infection (CDI) in hospitals in North America and Europe have increased since 2000 and correlate with dissemination of an epidemic strain characterized by higher than usual toxin A and B production, the presence of a third toxin, binary toxin, and high-level resistance to fluoroquinolone antibiotics. The strain, which is restriction endonuclease analysis group BI, pulse-field gel electrophoresis type NAP1, and polymerase chain reaction ribotype 027, is designated BI/NAP1/027. How this strain has become so widely distributed geographically and produces such severe CDI is the subject of active investigation. The deletion at position 117 of the tcdC gene, a repressor of toxin A and B production, is one possible contributor to increased levels of the toxins. The role of binary toxin is unknown. Recent isolates of BI/NAP1/027 were found to be resistant to fluoroquinolones, which is likely to contribute to the dissemination of this strain. Other virulence factors such as increased sporulation and surface layer protein adherence are also under investigation. Infections caused by this organism are particularly frequent among elderly hospitalized patients, in whom the attributable 30-day mortality is greater than 5%. Major risk factors for BI/NAP1/027 infection include advanced age, hospitalization, and exposure to specific antimicrobials, especially fluoroquinolones and cephalosporins. When CDI is severe, vancomycin treatment is more effective than metronidazole; for mild disease either agent can be used. Control of hospital outbreaks caused by BI/NAP1/027 is difficult but possible through a combination of barrier precautions, environmental cleaning, and antimicrobial stewardship.
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                Author and article information

                Journal
                Journal of Medical Microbiology
                Microbiology Society
                0022-2615
                1473-5644
                September 01 2018
                September 01 2018
                : 67
                : 9
                : 1402-1409
                Affiliations
                [1 ] 1​Evotec (UK), Alderley Park, Cheshire, SK10 4TG, UK
                [2 ] 2​Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
                [3 ] †​Present address: Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
                Article
                10.1099/jmm.0.000808
                © 2018

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