Comparative efficacy of #treatments for #Clostridium difficile #infection: a systematic review and network meta-analysis (Lancet Infect Dis., abstract)

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

Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis

Tumas Beinortas, MBBCh†, Nicholas E Burr, MBBS†, Prof Mark H Wilcox, MD

†Contributed equally

Published: 16 July 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30285-8

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Several new treatments for Clostridium difficile infections have been investigated. We aimed to compare and rank treatments for non-multiply recurrent infections with C difficile in adults.

Methods

We did a random effects network meta-analysis within a frequentist setting to obtain direct and indirect comparisons of trials. We searched MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for published and unpublished trials from the creation of these databases until June 30, 2017. We included randomised controlled trials of treatments for non-multiply recurrent infections with confirmed C difficile in adults (at least 18 years) that reported both primary cure and recurrence rates, and we used the Cochrane Risk of Bias tool to appraise trial methods. For our analysis, we extracted the total numbers of patients with primary cure and recurrence from published and unpublished reports. The primary outcome was sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death.

Findings

Of 23 004 studies screened, 24 trials, which comprised 5361 patients and 13 different treatments, were included in the analysis. The overall quality of evidence was rated as moderate to low. For sustained symptomatic cure, fidaxomicin (odds ratio 0·67, 95% CI 0·55–0·82) and teicoplanin (0·37, 0·14–0·94) were significantly better than vancomycin. Teicoplanin (0·27, 0·10–0·70), ridinilazole (0·41, 0·19–0·88), fidaxomicin (0·49, 0·35–0·68), surotomycin (0·66, 0·45–0·97), and vancomycin (0·73, 0·56–0·95) were better than metronidazole. Bacitracin was inferior to teicoplanin (0·22, 0·06–0·77) and fidaxomicin (0·40, 0·17–0·94), and tolevamer was inferior to all drugs except for LFF571 (0·50, 0·18–1·39) and bacitracin (0·67, 0·28–1·58). Global heterogeneity of the entire network was low (Cochran’s Q=15·70; p=0·47).

Interpretation

Among the treatments for non-multiply recurrent infections by C difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C difficile.

Funding

None.

Keywords: Clostridium difficile; Antibiotics; Fidaxomicin; Vancomycin; Metronidazole.

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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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