Extended-pulsed #fidaxomicin versus #vancomycin for #Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial

Prof Benoit Guery, MD, Prof Francesco Menichetti, MD, Veli-Jukka Anttila, MD, Nicholas Adomakoh, MBBS, ProfJose Maria Aguado, MD, Karen Bisnauthsing, BSc, Areti Georgopali, MD, Simon D Goldenberg, MD, Andreas Karas, MD, Gbenga Kazeem, PhD, Chris Longshaw, PhD, Jose Alejandro Palacios-Fabrega, PhD, Prof Oliver A Cornely, MD, Maria J G T Vehreschild, MD for the EXTEND Clinical Study Group††Members listed in the appendix

Published: 19 December 2017 / DOI: http://dx.doi.org/10.1016/S1473-3099(17)30751-X

© 2017 Elsevier Ltd. All rights reserved.

 

Summary

Background

Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin.

Methods

In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7–25) or vancomycin (125 mg oral capsules, four times daily on days 1–10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967.

Findings

Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0–20·7], p=0·030; odds ratio 1·62 [95% CI 1·04–2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug.

Interpretation

Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection.

Funding

Astellas Pharma, Inc.

Keywords: Antibiotics; Drugs Resistance; Clostridium difficile; Fidaxomicin; Vancomycin.

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#Surveillance of #antibiotic #resistance among common #Clostridium difficile ribotypes in #HK (Sci Rep., abstract)

[Source: Scientific Reports, full page: (LINK). Abstract, edited.]

Surveillance of antibiotic resistance among common Clostridium difficile ribotypes in Hong Kong

Viola C. Y. Chow, Thomas N. Y. Kwong, Erica W. M. So, Yolanda I. I. Ho, Sunny H. Wong,
Raymond W. M. Lai & Raphael C. Y. Chan

Scientific Reports 7, Article number: 17218 (2017) / doi:10.1038/s41598-017-17523-7

Received: 14 August 2017 – Accepted: 27 November 2017 – Published online: 08 December 2017

 

Abstract

Incidence of Clostridium difficile infection (CDI) is rapidly increasing and it poses a major health burden globally. However, data regarding the epidemiology of CDI in Asia are limited. We aimed to characterize the antimicrobial susceptibility patterns of common ribotypes of toxigenic C. difficile in Hong Kong. Fifty-three PCR ribotypes were identified among 284 toxigenic C. difficile clinical isolates. The five most prevalent ribotypes were 002 (13%), 017 (12%), 014 (10%), 012 (9.2%), and 020 (9.5%). All tested C. difficile strains remained susceptible to metronidazole, vancomycin, meropenem and piperacillin/tazobactam, but highly resistant to cephalosporins. Of the fluoroquinolones, highest resistance to ciprofloxacin was observed (99%), followed by levofloxacin (43%) and moxifloxacin (23%). The two newly emerged PCR ribotypes, 017 and 002, demonstrated high levels of co-resistance towards clindamycin, tetracycline, erythromycin and moxifloxacin. PCR ribotypes 017 and 002 with multi-drug resistance are rapidly emerging and continuous surveillance is important to monitor the epidemiology of C. difficile to prevent outbreaks of CDI.

Keywords: Antibiotics; Drugs Resistance; Clostridium difficile; HK.

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Effect of #antibiotic #stewardship on the #incidence of #infection and #colonisation with antibiotic-resistant #bacteria and #Clostridium difficile infection… (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis

David Baur, MD†, Beryl Primrose Gladstone, PhD†, Francesco Burkert, MD, Elena Carrara, MD, Federico Foschi, MD, Stefanie Döbele, MD, Prof Evelina Tacconelli, PhD

†Contributed equally

Published: 16 June 2017 / Article has an altmetric score of 1 / DOI: http://dx.doi.org/10.1016/S1473-3099(17)30325-0

© 2017 Elsevier Ltd. All rights reserved.

 

Summary

Background

Antibiotic stewardship programmes have been shown to reduce antibiotic use and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on the incidence of infections and colonisation with antibiotic-resistant bacteria.

Methods

For this systematic review and meta-analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Studies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infections and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I2 method.

Findings

We included 32 studies in the meta-analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35–0·68; p<0·0001), extended-spectrum β-lactamase-producing Gram-negative bacteria (48%; 0·52, 0·27–0·98; p=0·0428), and meticillin-resistant Staphylococcus aureus (37%; 0·63, 0·45–0·88; p=0·0065), as well as the incidence of C difficile infections (32%; 0·68, 0·53–0·88; p=0·0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0·69, 0·54–0·88; p=0·0030), especially hand-hygiene interventions (0·34, 0·21–0·54; p<0·0001), than when implemented alone. Antibiotic stewardship did not affect the IRs of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria. Significant heterogeneity between studies was detected, which was partly explained by the type of interventions and co-resistance patterns of the target bacteria.

Interpretation

Antibiotic stewardship programmes significantly reduce the incidence of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic stewardship interventions to reduce the burden of infections from antibiotic-resistant bacteria.

Funding

German Center for Infection Research.

Keywords: Antibiotics; Drugs Resistance; Clostridium Difficile.

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#Transmissibility of #Clostridium difficile without contact #isolation: results from a prospective observational study with 451 patients (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

Transmissibility of Clostridium difficile without contact isolation: results from a prospective observational study with 451 patients

Andreas F. Widmer, MD1, Reno Frei, MD2, Stefan Erb, MD1, Anne Stranden, PhD1, Ed J. Kuijper, PhD3, Cornelis W. Knetsch, PhD3, and Sarah Tschudin-Sutter, MD1

Author Affiliations: 1  Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; 2  Division of Clinical Microbiology, University Hospital Basel, Basel, Switzerland; 3 Section Experimental Microbiology, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

Corresponding Author: Dr. Sarah Tschudin-Sutter, MD MSc Division of Infectious Diseases and Hospital Epidemiology University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland Tel.: +41 61 328 68 10, Fax: +41 61 265 38 54 E-Mail: Sarah.Tschudin@usb.ch

 

Abstract

Background

Contact precautions are recommended by health authorities in Europe and the US for patients with Clostridium difficile infection (CDI). Recently, the significance of nosocomial transmission has been challenged by screening on admission studies and whole-genome sequencing, providing evidence for an endogenous source of C. difficile. We discontinued contact precautions for CDI patients, except for patients infected with hypervirulent ribotypes or with stool incontinence, to determine the rate of transmission.

Methods

From 01/2004 to 12/2013, contacts of each index case with CDI were screened for toxigenic C. difficile by culturing rectal swabs. Transmission was defined as possible if toxigenic C. difficile was detected in contacts, as probable if the identical PCR-ribotype was identified in index-contact pairs, and as confirmed if next-generation sequencing (NGS) revealed clonality of strains.

Results

451 contacts were exposed to 279 index patients nursed in two-to-four-bed-rooms. Toxigenic C. difficile was detected in 6.0% (27/451) after a median contact time of five days. Identical ribotypes were identified in six index-contact pairs, accounting for probable transmission in 1.3% (6/451). NGS was performed for 4/6 pairs with identical strains, and confirmed transmission in two contact patients.

Conclusions

The rate of transmission of toxigenic, predominantly non-hypervirulent C. difficile was low and no outbreaks were recorded over a 10-year period after discontinuing contact precautions for patients with CDI who were not severely incontinent and who used dedicated toilets.

As contact precautions may lead to lower levels of care, their implementation needs to balanced against the risk of nosocomial transmission.

Key words: C. difficile – transmission – contact precautions – screening acute-care hospital

Received July 22, 2016.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Keywords: Clostridium Difficile; Nosocomial Outbreaks.

—–

Lack of #adherence to #SHEA-IDSA #treatment #guidelines for #Clostridium difficile #infection is associated with increased #mortality (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Lack of adherence to SHEA-IDSA treatment guidelines for Clostridium difficile infection is associated with increased mortality

I. Patel†, M. Wungjiranirun*,†, T. Theethira, J. Villafuerte-Galvez, N. Castillo, M. Akbari, C. D. Alonso, D. A. Leffler and C. P. Kelly

Author Affiliations: Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA

*Corresponding author. E-mail: manida9@gmail.com

† These authors contributed equally to this research work and manuscript.

Received May 13, 2016. Revision requested June 8, 2016. Revision received September 1, 2016. Accepted September 8, 2016.

 

Abstract

Objectives

The objective of this study was to determine our institution’s compliance with 2010 Society for Healthcare Epidemiology of America and IDSA Clostridium difficile infection (CDI) treatment guidelines and their respective outcomes.

Methods

We collected clinical parameters, laboratory values, antibiotic therapy and clinical outcomes from the electronic medical records for all patients hospitalized at our institution with a diagnosis of CDI from December 2012 to November 2013. We specifically evaluated whether SHEA-IDSA treatment guidelines were followed and evaluated the associations between guideline adherence and severe outcomes including mortality.

Results

We identified 230 patients with CDI meeting inclusion criteria during the study period. Of these, 124 (54%) were appropriately treated, 46 (20%) were under-treated and 60 (26%) were over-treated. All-cause 90 day mortality was 17.4% overall; 43.5% in the under-treated group versus 12.9% in those appropriately treated (P < 0.0001) and 10.9% in those appropriately treated plus over-treated (P < 0.0001). Similarly, 90 day mortality attributed to CDI was 21.7% in those under-treated versus 8.9% in those appropriately treated (P = 0.03) and 8.2% in those either appropriately treated or over-treated (P = 0.015). Severe-complicated CDI occurred in 46 patients. In this subgroup, there was a non-significant trend towards increased mortality in under-treated patients (56.7%) compared with appropriately treated patients (37.5%, P = 0.35). Under-treatment was also associated with a higher rate of CDI-related ICU transfer (17.4% versus 4.8% in those appropriately treated, P = 0.023).

Conclusions

Adherence to CDI treatment guidelines is associated with improved outcomes especially in those with severe disease. Increased emphasis on provision of appropriate, guideline-based CDI treatment appears warranted.

© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Keywords: Clostridium Difficile.

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Effect of a #national 4C #antibiotic #stewardship #intervention on the clinical and molecular #epidemiology of #Clostridium difficile infections in a region of #Scotland: a non-linear time-series analysis (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Articles

Effect of a national 4C antibiotic stewardship intervention on the clinical and molecular epidemiology of Clostridium difficile infections in a region of Scotland: a non-linear time-series analysis

Dr Timothy Lawes, MSc, José-María Lopez-Lozano, PhD, Cesar A Nebot, MSc, Gillian Macartney, MSc, Rashmi Subbarao-Sharma, MSc, Karen D Wares, MSc, Carolyn Sinclair, MSc, Ian M Gould, MBChB

Published: 04 November 2016 / DOI: http://dx.doi.org/10.1016/S1473-3099(16)30397-8

© 2016 Elsevier Ltd. All rights reserved.

 

Summary

Background

Whereas many antibiotics increase risk of Clostridium difficile infection through dysbiosis, epidemic C difficile ribotypes characterised by multidrug resistance might depend on antibiotic selection pressures arising from population use of specific drugs. We examined the effect of a national antibiotic stewardship intervention limiting the use of 4C antibiotics (fluoroquinolones, clindamycin, co-amoxiclav, and cephalosporins) and other infection prevention and control strategies on the clinical and molecular epidemiology of C difficile infections in northeast Scotland.

Methods

We did a non-linear time-series analysis and quasi-experimental study to explore ecological determinants of clinical burdens from C difficile infections and ribotype distributions in a health board serving 11% of the Scottish population. Study populations were adults (aged ≥16 years) registered with primary carer providers in the community (mean 455 508 inhabitants) or admitted to tertiary level, district general, or geriatric hospitals (mean 33 049 total admissions per month). A mixed persuasive-restrictive 4C antibiotic stewardship intervention was initiated in all populations on May 1, 2009. Other population-specific interventions considered included limiting indications for macrolide prescriptions, introduction of alcohol-based hand sanitiser, a national hand-hygiene campaign, national auditing and inspections of hospital environment cleanliness, and reminders to reduce inappropriate use of proton-pump inhibitors. The total effect of interventions was defined as the difference between observations and projected scenarios without intervention. Primary outcomes were prevalence density of C difficile infection per 1000 occupied bed-days in hospitals or per 100 000 inhabitant-days in the community.

Findings

Between Jan 1, 1997, and Dec 31, 2012, we identified 4885 cases of hospital-onset C difficile infection among 1 289 929 admissions to study hospitals, and a further 1625 cases of community-onset C difficile infection among 455 508 adults registered in primary care. Use of 4C antibiotics was reduced by 50% in both hospitals (mean reduction 193 defined daily doses per 1000 occupied bed-days, 95% CI 45–328, p=0·008) and the community (1·85 defined daily doses per 1000 inhabitant-days, 95% CI 0·23–3·48, p=0·025) during antibiotic stewardship. Falling 4C use predicted rapid declines in multidrug-resistant ribotypes R001 and R027. Hospital-onset C difficile infection prevalence densities were associated with fluoroquinolone, third-generation cephalosporin, macrolides, and carbapenem use, exceeding hospital population specific total use thresholds. Community-onset C difficile infection prevalence density was predicted by recent hospital C difficile infection rates, introduction of mandatory surveillance in individuals older than 65 years, and primary-case use of fluoroquinolones and clindamycin exceeding total use thresholds. Compared with predictions without intervention, C difficile infection prevalence density fell by 68% (mean reduction 1·01 per 1000 occupied bed-days, 0·27–1·76, p=0·008) in hospitals and 45% (0·083, 0·045–0·121 cases per 100 000 inhabitant-days, p<0·0001) in the community, during antibiotic stewardship. We identified no significant effects from other interventions.

Interpretation

Limiting population use of 4C antibiotics reduced selective pressures favouring multidrug-resistant epidemic ribotypes and was associated with substantial declines in total C difficile infections in northeast Scotland. Efforts to control C difficile through antibiotic stewardship should account for ribotype distributions and non-linear effects.

Funding

NHS Grampian Microbiology Endowment Fund.

Keywords: UK; Scotland; Antibiotics; Drugs Resistance; Clostridium difficile.

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More than 50% of #Clostridium difficile Isolates from #Pet #Dogs in #Flagstaff, #USA, Carry #Toxigenic Genotypes (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE

More than 50% of Clostridium difficile Isolates from Pet Dogs in Flagstaff, USA, Carry Toxigenic Genotypes

Nathan E. Stone, Lindsay C. Sidak-Loftis, Jason W. Sahl, Adam J. Vazquez, Kristin B. Wiggins, John D. Gillece, Nathan D. Hicks, James M. Schupp, Joseph D. Busch, Paul Keim, David M. Wagner

Published: October 10, 2016 / http://dx.doi.org/10.1371/journal.pone.0164504

 

Abstract

Nosocomial acquisition of Clostridium difficile is well documented, yet recent studies have highlighted the importance of community acquired infections and identified community associated reservoirs for this pathogen. Multiple studies have implicated companion pets and farm animals as possible sources of community acquired C. difficile infections in humans. To explore the potential role of pet dogs in human C. difficile infections we systematically collected canine fecal samples (n = 197) in Flagstaff, AZ. Additionally, nineteen fecal samples were collected at a local veterinary clinic from diarrheic dogs. We used these combined samples to investigate important questions regarding C. difficile colonization in pet canines: 1) What is the prevalence and diversity of C. difficile in this companion pet population, and 2) Do C. difficile isolates collected from canines genetically overlap with isolates that cause disease in humans? We used a two-step sequence typing approach, including multilocus sequence typing to determine the overall genetic diversity of C. difficile present in Flagstaff canines, and whole-genome sequencing to assess the fine-scale diversity patterns within identical multilocus sequence types from isolates obtained within and among multiple canine hosts. We detected C. difficile in 17% of the canine fecal samples with 10% containing toxigenic strains that are known to cause human disease. Sequencing analyses revealed similar genotypes in dogs and humans. These findings suggest that companion pets are a potential source of community acquired C. difficile infections in humans.

_____

Citation: Stone NE, Sidak-Loftis LC, Sahl JW, Vazquez AJ, Wiggins KB, Gillece JD, et al. (2016) More than 50% of Clostridium difficile Isolates from Pet Dogs in Flagstaff, USA, Carry Toxigenic Genotypes. PLoS ONE 11(10): e0164504. doi:10.1371/journal.pone.0164504

Editor: Hsin-Chih Lai, Chang Gung University, TAIWAN

Received: July 26, 2016; Accepted: September 26, 2016; Published: October 10, 2016

Copyright: © 2016 Stone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All whole genome sequencing reads generated during this study have been deposited in NCBI BioProject database under accession #PRJNA309189. The associated SRA numbers for these 54 isolates are sequentially assigned beginning with #SRR3115454 and ending with #SRR3115507. Multilocus sequence types for one representative of the 44 unique isolates discovered during this study have been deposited in the isolate database of http://www.pubmlst.org/cdifficile.

Funding: This project was funded by the Northern Arizona University Technology & Research Initiative Fund (TRIF) and the Flinn Foundation, https://nau.edu/research/funding/technology-research-initiative-fund/, http://www.flinn.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Clostridium Difficile; Dogs; Human; USA; Arizona.

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