#Vancomycin #resistance #gene cluster, vanC, in the #gut #microbiome of acute #leukemia #patients undergoing intensive #chemotherapy (PLoS One, abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Vancomycin-resistance gene cluster, vanC, in the gut microbiome of acute leukemia patients undergoing intensive chemotherapy

Armin Rashidi , Zhigang Zhu, Thomas Kaiser, Dawn A. Manias, Shernan G. Holtan, Tauseef Ur Rehman, Daniel J. Weisdorf, Alexander Khoruts, Gary M. Dunny, Christopher Staley

Published: October 10, 2019 / DOI: https://doi.org/10.1371/journal.pone.0223890

 

Abstract

Two recent reports suggested that the less common, less virulent enterococcal species, Enterococcus gallinarum and E. casseliflavus, with low-level vancomycin resistance due to chromosomally encoded vanC1 and vanC2/3, may influence host immunity. We reported that peri-transplant gut colonization with E. gallinarum and E. casseliflavus is associated with lower mortality after allogeneic hematopoietic cell transplantation (HCT). Because most acute leukemia patients undergoing HCT have received intensive chemotherapy (usually requiring prolonged hospitalization) for their underlying disease before HCT, we hypothesized that some may have acquired vanC-positive enterococci during chemotherapy. Therefore, we evaluated the presence of the vanC gene cluster using vanC1 and vanC2/3 qPCR in thrice-weekly collected stool samples from 20 acute leukemia patients undergoing intensive chemotherapy. We found that an unexpectedly large proportion of patients have detectable vanC1 and vanC2/3 (15% and 35%, respectively) in at least one stool sample. Comparing qPCR results with 16S rRNA gene sequencing results suggested that E. gallinarum may reach high abundances, potentially persisting into HCT and influencing transplant outcomes.

___

Citation: Rashidi A, Zhu Z, Kaiser T, Manias DA, Holtan SG, Rehman TU, et al. (2019) Vancomycin-resistance gene cluster, vanC, in the gut microbiome of acute leukemia patients undergoing intensive chemotherapy. PLoS ONE 14(10): e0223890. https://doi.org/10.1371/journal.pone.0223890

Editor: Senthilnathan Palaniyandi, University of Kentucky, UNITED STATES

Received: July 26, 2019; Accepted: October 1, 2019; Published: October 10, 2019

Copyright: © 2019 Rashidi 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: Raw sequencing data are deposited under accession number SRP141394 at the NCBI SRA.

Funding: This work was supported by grants from the University of Minnesota (Medical School Innovation award and Foundation grant for new faculty) to AR. In addition, funding from Achieving Cures Together and Hubbard Broadcasting Foundation supported this research. TK received partial support from the Masonic Cancer Center at the University of Minnesota. 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: Antibiotics; Drugs Resistance; Vancomycin; Enterococci; Enterococcus gallinarum; Cancer; Leukemia.

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#Enterococcal #bacteremia in febrile #neutropenic #children and adolescents with underlying #malignancies, and clinical #impact of #vancomycin resistance (Infection, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Infection. 2019 Jun;47(3):417-424. doi: 10.1007/s15010-018-1260-z. Epub 2018 Dec 19.

Enterococcal bacteremia in febrile neutropenic children and adolescents with underlying malignancies, and clinical impact of vancomycin resistance.

Bae KS1,2, Shin JA1, Kim SK1,3, Han SB4,5, Lee JW1,3, Lee DG2,3,6, Chung NG1,3, Cho B1,3, Jeong DC1,2, Kang JH1,2.

Author information: 1 Department of Pediatrics, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. 2 The Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 3 The Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 4 Department of Pediatrics, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. beomsid@catholic.ac.kr. 5 The Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. beomsid@catholic.ac.kr. 6 Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

 

Abstract

PURPOSE:

Enterococci are a common cause of bacteremia in immunocompromised patients. Although the increase of vancomycin-resistant enterococci (VRE) makes appropriate antibiotic therapy difficult, clinical characteristics of enterococcal bacteremia and the impact of VRE infection on outcomes have rarely been reported in immunocompromised children.

METHODS:

We enrolled children and adolescents (< 19 years of age) with underlying malignancies who were diagnosed with enterococcal bacteremia during febrile neutropenia between 2010 and 2017. Medical records of the enrolled children were retrospectively reviewed to evaluate the clinical characteristics of enterococcal bacteremia and impact of VRE infection on outcomes.

RESULTS:

Thirty-six episodes of enterococcal bacteremia were identified in 30 patients. VRE infection was identified in 11 episodes (30.6%); the 7- and 30-day mortalities were 27.8% and 44.4%, respectively. Acute lymphoblastic leukemia (50.0%) and acute myeloid leukemia (30.6%) were the most common underlying disorders. Three (8.3%) of the patients were in complete remission, and palliative and reinduction chemotherapies were administered in 47.2% and 36.1% of episodes, respectively. Empirical antibiotic therapy was appropriate in 64.0% of patients with vancomycin-susceptible enterococcal infection and in none of the VRE-infected patients (p = 0.001). However, the 30-day mortality was not significantly different between the two patient groups (44.0% vs. 45.5%, p = 1.000).

CONCLUSIONS:

Most episodes of enterococcal bacteremia occurred in advanced stages of underlying malignancies, and still showed high mortality. The prognosis seemed to be related to the underlying disease condition rather than vancomycin resistance of the isolated enterococci, although the number of enrolled patients was small.

KEYWORDS: Child; Enterococcus; Neutropenia; Vancomycin resistance

PMID: 30565009 DOI: 10.1007/s15010-018-1260-z [Indexed for MEDLINE]

Keywords: Enterococci; Bacteremia; Cancer; Antibiotics; Drugs Resistance; Vancomycin.

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Therapeutic Effects of Intravitreously Administered #Bacteriophage in a Mouse Model of #Endophthalmitis Caused by #Vancomycin-Sensitive or -Resistant #Enterococcus faecalis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis

Tatsuma Kishimoto, Waka Ishida, Ken Fukuda, Isana Nakajima, Takashi Suzuki, Jumpei Uchiyama, Shigenobu Matsuzaki, Daisuke Todokoro, Masanori Daibata, Atsuki Fukushima

DOI: 10.1128/AAC.01088-19

 

ABSTRACT

Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have now demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis. Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis–related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 colony forming units and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Enterococcus faecalis; Endophthalmitis; Bacteriophages.

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#Microbiota-derived #lantibiotic restores resistance against #vancomycin-resistant #Enterococcus (Nature, abstract)

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

Microbiota-derived lantibiotic restores resistance against vancomycin-resistant Enterococcus

Sohn G. Kim, Simone Becattini, […] Eric G. Pamer

Nature (2019)

 

Abstract

Intestinal commensal bacteria can inhibit dense colonization of the gut by vancomycin-resistant Enterococcus faecium (VRE), a leading cause of hospital-acquired infections1,2. A four-strained consortium of commensal bacteria that contains Blautia producta BPSCSK can reverse antibiotic-induced susceptibility to VRE infection3. Here we show that BPSCSK reduces growth of VRE by secreting a lantibiotic that is similar to the nisin-A produced by Lactococcus lactis. Although the growth of VRE is inhibited by BPSCSK and L. lactis in vitro, only BPSCSK colonizes the colon and reduces VRE density in vivo. In comparison to nisin-A, the BPSCSK lantibiotic has reduced activity against intestinal commensal bacteria. In patients at high risk of VRE infection, high abundance of the lantibiotic gene is associated with reduced density of E. faecium. In germ-free mice transplanted with patient-derived faeces, resistance to VRE colonization correlates with abundance of the lantibiotic gene. Lantibiotic-producing commensal strains of the gastrointestinal tract reduce colonization by VRE and represent potential probiotic agents to re-establish resistance to VRE.

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Enterococcus faecium; Lantibiotics; Microbiota.

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#Shock and Early #Death in #Hematologic Patients with Febrile #Neutropenia (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Shock and Early Death in Hematologic Patients with Febrile Neutropenia

Mariana Guarana, Marcio Nucci, Simone A. Nouér

DOI: 10.1128/AAC.01250-19

 

ABSTRACT

Empiric antibiotic therapy with a betalactam is standard of care in febrile neutropenia (FN), and is given to prevent early death. The addition of vancomycin is recommended in certain circumstances but the quality of evidence is low, reflecting the lack of clinical data. In order to characterize the epidemiology of early death and shock in FN, we reviewed all episodes of FN from 2003 to 2017 at University Hospital, Federal University of Rio de Janeiro, and looked at factors associated with shock at first fever and early death (within 3 days from first fever) by univariate and multivariate analyses. Among 1305 episodes of FN, shock occurred in 42 episodes (3.2%) and early death in 15 (1.1%). Predictors of shock were bacteremia due to Escherichia coli (odds ratio [OR] 8.47, 95% confidence interval [95% CI] 4.08 – 17.55, p<0.001), Enterobacter sp. (OR 7.53, 95% CI 1.60 – 35.33, p=0.01), and Acinetobacter sp. (OR 6.95, 95% CI 1.49 – 32.36, p=0.01). Factors associated with early death were non-Hodgkin lymphoma (OR 3.57, 95% CI 1.18-10.73, p=0.02), pneumonia (OR 21.36, 95% CI 5.72-79.72, p<0.001), shock (OR 11.64, 95% CI 2.77-48.86, p=0.01) and bacteremia due to Klebsiella pneumoniae (OR 5.91, 95% CI 1.11-31.47, p=0.03). Adequate empiric antibiotic therapy was protective (OR 0.23, 95% CI 0.07 – 0.81, p=0.02). Shock or early death was not associated with Gram-positive bacteremia, catheter-related, skin or soft tissue infection, or inadequate Gram-positive coverage. These data challenge guidelines recommendations for the empiric use of vancomycin at first fever in neutropenic patients.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Vancomycin; Sepsis; Bacteremia; Enterobacteriaceae.

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High #prevalence of a globally disseminated #hypervirulent clone, #Staphylococcus aureus CC121, with reduced #vancomycin susceptibility in community settings in #China (J Antimicrob Chemother., abstract)

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

High prevalence of a globally disseminated hypervirulent clone, Staphylococcus aureus CC121, with reduced vancomycin susceptibility in community settings in China

Ping Shen, Kai Zhou, Yu Wang, Jingjie Song, Yang Liu, Yanzi Zhou, Yonghong Xiao

Journal of Antimicrobial Chemotherapy, dkz232, https://doi.org/10.1093/jac/dkz232

Published: 15 June 2019

 

Abstract

Objectives

Most vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are derived from hospital-associated MRSA due to treatment failure; however, the prevalence of hVISA/VISA in community settings remains unclear.

Methods

Four hundred and seventy-six community-associated isolates were collected between 2010 and 2011 during national surveillance for antimicrobial resistance in 31 county hospitals across China. Drug susceptibility evaluation and mecAdetection were performed by using broth microdilution and PCR analysis, respectively. hVISA/VISA were identified by using macro-Etest and a modified population analysis profile (PAP)-AUC method. The genetic features of all hVISA/VISA isolates were genotyped.

Results

Among 476 isolates, MRSA and MSSA accounted for 19.7% (n = 94) and 80.3% (n = 382), respectively. Two VISA and 36 hVISA isolates were identified by PAP-AUC testing. The VISA isolates and 29 of the hVISA isolates were MRSA. The proportion of hVISA/VISA was significantly higher in MRSA (30.9%) than in MSSA (1.8%). The hVISA/VISA isolates were assigned to 18 STs classified into seven clonal complexes (CCs). CC121 (n = 12) followed by ST239 (n = 11) was the most prevalent hVISA/VISA clone. All ST239-hVISA/VISA were MRSA, while 12 CC121-hVISA isolates included 6 MSSA and 6 MRSA isolates. SCCmec III was predominant among MRSA-hVISA/VISA isolates. agr I and agr IV were detected in ST239 and CC121, respectively. All except two strains were positive for Panton–Valentine leucocidin genes.

Conclusions

To the best of our knowledge, this is the first report of CC121 as a prevalent hVISA clone in community settings, highlighting the necessity of surveillance and stricter infection control measures for this globally disseminated lineage.

Topic: polymerase chain reaction – vancomycin – staphylococcus aureus – heterogeneity – china – clone cells – drug resistance, microbial – genes – hospitals, county – ichthyosis, x-linked – infectious disease prevention / control – sequence tagged sites – treatment failure – genetics – sodium thiosulfate – surveillance, medical – methicillin-resistant  staphylococcus aureus – methicillin-susceptible staphylococcus aureus – community – complex – vancomycin intermediate staphylococcus aureus

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Staphylococcus aureus; China.

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#Intestinal #Bile Acids Induce a Morphotype Switch in #Vancomycin-Resistant #Enterococcus that Facilitates Intestinal Colonization (Cell Host Microbe, abstract)

[Source: Cell, Host & Microbe, full page: (LINK). Abstract, edited.]

Intestinal Bile Acids Induce a Morphotype Switch in Vancomycin-Resistant Enterococcus that Facilitates Intestinal Colonization

Peter T. McKenney, Jinyuan Yan, Julien Vaubourgeix 8, Simone Becattini, Nina Lampen, Andrew Motzer, Peter J. Larson, Daniel Dannaoui, Sho Fujisawa, Joao B. Xavier, Eric G. Pamer 9

Published: April 25, 2019 / DOI: https://doi.org/10.1016/j.chom.2019.03.008

 

Highlights

  • VRE forms long chains and biofilms in physiological concentrations of bile acids
  • This morphotype switch is reversed by cations
  • Selection against chaining is linked to sensitivity to the antibiotic daptomycin
  • Chaining-deficient VRE mutants exhibit reduced persistence in the gut

 

Summary

Vancomycin-resistant Enterococcus (VRE) are highly antibiotic-resistant and readily transmissible pathogens that cause severe infections in hospitalized patients. We discovered that lithocholic acid (LCA), a secondary bile acid prevalent in the cecum and colon of mice and humans, impairs separation of growing VRE diplococci, causing the formation of long chains and increased biofilm formation. Divalent cations reversed this LCA-induced switch to chaining and biofilm formation. Experimental evolution in the presence of LCA yielded mutations in the essential two-component kinase yycG/walK and three-component response regulator liaR that locked VRE in diplococcal mode, impaired biofilm formation, and increased susceptibility to the antibiotic daptomycin. These mutant VRE strains were deficient in host colonization because of their inability to compete with intestinal microbiota. This morphotype switch presents a potential non-bactericidal therapeutic target that may help clear VRE from the intestines of dominated patients, as occurs frequently during hematopoietic stem cell transplantation.

Keywords: Enterococcus – VRE – bile – microbiota – morphotype – faecium – faecalis – colonization resistance

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Daptomycin; Enterococcus.

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#WGS of 1058 #Enterococcus faecium from Copenhagen, #Denmark, reveals rapid clonal expansion of #vancomycin-resistant clone ST80 combined with widespread dissemination of a vanA-containing #plasmid and acquisition of a heterogeneous accessory genome (J Antimicrob Chemother., abstract9

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

WGS of 1058 Enterococcus faecium from Copenhagen, Denmark, reveals rapid clonal expansion of vancomycin-resistant clone ST80 combined with widespread dissemination of a vanA-containing plasmid and acquisition of a heterogeneous accessory genome

Mette Pinholt, Sion C Bayliss, Heidi Gumpert, Peder Worning, Veronika V S Jensen, Michael Pedersen, Edward J Feil, Henrik Westh

Journal of Antimicrobial Chemotherapy, dkz118, https://doi.org/10.1093/jac/dkz118

Published: 30 March 2019

 

Abstract

Objectives

From 2012 to 2015, a sudden significant increase in vancomycin-resistant (vanA) Enterococcus faecium (VREfm) was observed in the Capital Region of Denmark. Clonal relatedness of VREfm and vancomycin-susceptible E. faecium(VSEfm) was investigated, transmission events between hospitals were identified and the pan-genome and plasmids from the largest VREfm clonal group were characterized.

Methods

WGS of 1058 E. faecium isolates was carried out on the Illumina platform to perform SNP analysis and to identify the pan-genome. One isolate was also sequenced on the PacBio platform to close the genome. Epidemiological data were collected from laboratory information systems.

Results

Phylogeny of 892 VREfm and 166 VSEfm revealed a polyclonal structure, with a single clonal group (ST80) accounting for 40% of the VREfm isolates. VREfm and VSEfm co-occurred within many clonal groups; however, no VSEfm were related to the dominant VREfm group. A similar vanA plasmid was identified in ≥99% of isolates belonging to the dominant group and 69% of the remaining VREfm. Ten plasmids were identified in the completed genome, and ∼29% of this genome consisted of dispensable accessory genes. The size of the pan-genome among isolates in the dominant group was 5905 genes.

Conclusions

Most probably, VREfm emerged owing to importation of a successful VREfm clone which rapidly transmitted to the majority of hospitals in the region whilst simultaneously disseminating a vanA plasmid to pre-existing VSEfm. Acquisition of a heterogeneous accessory genome may account for the success of this clone by facilitating adaptation to new environmental challenges.

Topic: vancomycin – plasmids – heterogeneity – clone cells – denmark – enterococcus  faecium – genes – genome – whole genome sequencing

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Denmark.

——

Expansion of #Vancomycin-resistant #Enterococcus faecium in an academic tertiary #hospital in Southwest #Germany: a large-scale whole genome-based #outbreak investigation (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Expansion of Vancomycin-resistant Enterococcus faecium in an academic tertiary hospital in Southwest Germany: a large-scale whole genome-based outbreak investigation

Jan Liese, Leonard Schüle, Philipp Oberhettinger, Leonie Tschörner, Tran Nguyen, Daniela Dörfel, Wichard Vogel, Matthias Marschal, Ingo Autenrieth, Matthias Willmann, Silke Peter

DOI: 10.1128/AAC.01978-18

 

ABSTRACT

Background:

Vancomycin-resistant Enterococcus faecium (VREfm) is a frequent cause of nosocomial outbreaks. In the second half of 2015 a sharp increase in the incidence of VREfmwas observed at our university medical center. Next-generation sequencing (NGS) was used to analyze the first isolates of VREfm recovered from patients between 2010 and 2016 (n=773) in order to decipher epidemiological change, outbreak dynamics, and possible transmission routes.

Materials and methods:

VREfm isolates were analyzed using whole genome sequencing followed by sequence type extraction, and phylogenetic analysis. We examined epidemiological data, room occupancy data, and patient transferals and calculated an intensity score for patient-to-patient contact.

Results:

Phylogenetic analysis revealed the presence of 38 NGS clusters and 110 single clones. The increase of VREfm was mainly caused by the expansion of two newly introduced NGS clusters, comprising VanB-type strains of the MLST sequence type (ST)80 and ST117. Combining phylogenetic information with epidemiological data, intra-hospital transmission could be demonstrated, however to a lesser extent than initially expected based solely on epidemiological data. The outbreak clones were continuously imported from other hospitals, suggesting a change of the epidemiological situation at a regional scale. Tracking intra-hospital patient transferals, two major axes could be identified that contributed to the spread of VREfmwithin the hospital.

Conclusions:

NGS-based outbreak analysis revealed a dramatic change in the local and regional epidemiology of VREfm, emphasizing the role of healthcare networks in the spread of VREfm.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs resistance; Enterococcus faecium; Nosocomial outbreaks; Germany.

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#Cadazolid for the #treatment of #Clostridium difficile #infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials (Lancet, abstract)

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

Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials

Dale N Gerding, MD, Prof Oliver A Cornely, MD, Simon Grill, PhD, Hilke Kracker, PhD, Anne Claire Marrast, MD, Prof Carl Erik Nord, PhD, et al.

Published: January 29, 2019 / DOI: https://doi.org/10.1016/S1473-3099(18)30614-5

 

Summary

Background

Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection.

Methods

IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficileinfection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin −10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2).

Findings

Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: −1·4 [95% CI −7·2 to 4·3] for modified intention to treat and −4·1 [–9·2 to 1·0] for per protocol; IMPACT 2: −4·7 [–10·7 to 1·3] for modified intention to treat and −4·9 [–10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar.

Interpretation

Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely.

Funding

Actelion Pharmaceuticals.

Keywords: Antibiotics; Vancomycin; Cadazolid; Clostridium difficile.

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