#Azidothymidine [#AZT] produces synergistic #activity in combination with #colistin against #antibiotic-resistant #Enterobacteriaceae (Antimicrob Agents Chemother., abstract)

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

Azidothymidine produces synergistic activity in combination with colistin against antibiotic-resistant Enterobacteriaceae

Yanmin Hu, Yingjun Liu, Anthony Coates

DOI: 10.1128/AAC.01630-18

 

ABSTRACT

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae is prevalent and extremely difficult to treat. Reusing existing drugs and rejuvenating the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here we investigated in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae including extended-spectrum beta-lactamase (ESBL), New Delhi metallo-beta-lactamase 1 (NDM) or the mobilized colistin resistance (mcr-1) producing strains. Minimum inhibitory concentration was determined using the broth microdilution method. The combinatory effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. Fractional inhibitory concentration index from checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae, respectively, 100% of NDM-1-producing strains and 92% of mcr-1 producing E. coli. Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In the murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. AZT and colistin combination poses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antivirals; Antibiotics; Drugs Resistance; Colistin; AZT; MCR1; Enterobacteriaceae.

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Novel partners with #colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin #resistance in #NDM- and #MCR-co-producing #Ecoli in a murine infection model (J Antimicrob Chemother., abstract)

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

Novel partners with colistin to increase its in vivotherapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model

Yang Yu, Timothy R Walsh, Run-Shi Yang, Mei Zheng, Meng-Chao Wei, Jonathan M Tyrrell, Yang Wang, Xiao-Ping Liao, Jian Sun, Ya-Hong Liu

Journal of Antimicrobial Chemotherapy, dky413, https://doi.org/10.1093/jac/dky413

Published: 20 October 2018

 

Abstract

Objectives

The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes.

Methods

To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose–response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs).

Results

Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs.

Conclusions

The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. 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: Research; Abstracts; Antibiotics; Drugs Resistance; Colistin; E. Coli; Rifampicin; Rifabutin; Minocycline; MCR; NDM.

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#Synergistic antimicrobial #activity of #colistin in combination with #rifampin and #azithromycin against #Escherichia coli producing #MCR-1 (Antimicrob Agents Chemother., abstract)

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

Synergistic antimicrobial activity of colistin in combination with rifampin and azithromycin against Escherichia coli producing MCR-1

Yanqin Li, Xiaohuan Lin, Xuan Yao, Yan Huang, Wenguang Liu, Tao Ma, Binghu Fang

DOI: 10.1128/AAC.01631-18

 

ABSTRACT

The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli that produces colistin-resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli, including colistin-resistant isolate MZ1501R, HE1704R that produces MCR-1, and colistin-susceptible isolate MZ1509S. Experiments were conducted at a medium inoculum of ∼107 CFU/mL over 48 h. Subsequently, the in vivo therapeutic effect was investigated using a neutropenic thigh-infected mouse model. Almost all monotherapies showed unsatisfactory antibacterial activity against E. coli isolates producing MCR-1. By contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in bacterial burden, albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. In vivo treatments confirmed these findings where a mean decrease of 0.38 to 0.90 log10 CFU and 1.27 to 1.78 log10 CFU was noted after 24 h and 48 h of treatment, respectively, against colistin-resistant E. coli strains when 5 mg/kg colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against E. coli producing MCR-1.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; E. Coli; MCR1; Azithromycin; Rifampin; Animal models.

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Rapid #detection and discrimination of chromosome- and #MCR-plasmid-mediated #resistance to #polymyxins by MALDI-TOF MS in #Escherichia coli: the MALDIxin test (J Antimicrob Chemother., abstract)

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

Rapid detection and discrimination of chromosome- and MCR-plasmid-mediated resistance to polymyxins by MALDI-TOF MS in Escherichia coli: the MALDIxin test

Laurent Dortet, Remy A Bonnin, Ivana Pennisi, Lauraine Gauthier, Agnès B Jousset, Laura Dabos, R Christopher, D Furniss, Despoina A I Mavridou, Pierre Bogaerts, Youri Glupczynski, Anais Potron, Patrick Plesiat, Racha Beyrouthy, Frédéric Robin, Richard Bonnet, Thierry Naas, Alain Filloux, Gerald Larrouy-Maumus

Journal of Antimicrobial Chemotherapy, dky330, https://doi.org/10.1093/jac/dky330

Published: 01 September 2018

 

Abstract

Background

Polymyxins are currently considered a last-resort treatment for infections caused by MDR Gram-negative bacteria. Recently, the emergence of carbapenemase-producing Enterobacteriaceae has accelerated the use of polymyxins in the clinic, resulting in an increase in polymyxin-resistant bacteria. Polymyxin resistance arises through modification of lipid A, such as the addition of phosphoethanolamine (pETN). The underlying mechanisms involve numerous chromosome-encoded genes or, more worryingly, a plasmid-encoded pETN transferase named MCR. Currently, detection of polymyxin resistance is difficult and time consuming.

Objectives

To develop a rapid diagnostic test that can identify polymyxin resistance and at the same time differentiate between chromosome- and plasmid-encoded resistances.

Methods

We developed a MALDI-TOF MS-based method, named the MALDIxin test, which allows the detection of polymyxin resistance-related modifications to lipid A (i.e. pETN addition), on intact bacteria, in <15 min.

Results

Using a characterized collection of polymyxin-susceptible and -resistant Escherichia coli, we demonstrated that our method is able to identify polymyxin-resistant isolates in 15 min whilst simultaneously discriminating between chromosome- and plasmid-encoded resistance. We validated the MALDIxin test on different media, using fresh and aged colonies and show that it successfully detects all MCR-1 producers in a blindly analysed set of carbapenemase-producing E. coli strains.

Conclusions

The MALDIxin test is an accurate, rapid, cost-effective and scalable method that represents a major advance in the diagnosis of polymyxin resistance by directly assessing lipid A modifications in intact bacteria.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. 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; Polymyxin; MCRx; Diagnostic Tests; E. Coli.

——

Molecular #epidemiology of isolates with multiple #mcr #plasmids from a #pig #farm in #GB: the effects of #colistin withdrawal in the short and long term (J Antimicrob Chemother., abstract)

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

Molecular epidemiology of isolates with multiple mcr plasmids from a pig farm in Great Britain: the effects of colistin withdrawal in the short and long term

Nicholas A Duggett, Luke P Randall, Robert A Horton, Fabrizio Lemma, Miranda Kirchner, Javier Nunez-Garcia, Camilla Brena, Susanna M Williamson, Christopher Teale, Muna F Anjum

Journal of Antimicrobial Chemotherapy, dky292, https://doi.org/10.1093/jac/dky292

Published: 14 August 2018

 

Abstract

Background

The environment, including farms, might act as a reservoir for mobile colistin resistance (mcr) genes, which has led to calls for reduction of usage in livestock of colistin, an antibiotic of last resort for humans.

Objectives

To establish the molecular epidemiology of mcr Enterobacteriaceae from faeces of two cohorts of pigs, where one group had initially been treated with colistin and the other not, over a 5 month period following stoppage of colistin usage on a farm in Great Britain; faecal samples were also taken at ∼20 months.

Methods

mcr-1 Enterobacteriaceae were isolated from positive faeces and was WGS performed; conjugation was performed on selected Escherichia coli and colistin MICs were determined.

Results

E. coli of diverse ST harbouring mcr-1 and multiple resistance genes were isolated over 5 months from both cohorts. Two STs, from treated cohorts, contained both mcr-1 and mcr-3 plasmids, with some isolates also harbouring multiple copies of mcr-1 on different plasmids. The mcr-1 plasmids grouped into four Inc types (X4, pO111, I2 and HI2), with mcr-3 found in IncP. Multiple copies of mcr plasmids did not have a noticeable effect on colistin MIC, but they could be transferred simultaneously to a Salmonella host in vitro. Neither mcr-1nor mcr-3 was detected in samples collected ∼20 months after colistin cessation.

Conclusions

We report for the first known time on the presence in Great Britain of mcr-3from MDR Enterobacteriaceae, which might concurrently harbour multiple copies of mcr-1 on different plasmids. However, control measures, including stoppage of colistin, can successfully mitigate long-term on-farm persistence.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Colistin; MCR1; MCR3; UK; Pigs; Enterobacteriaceae.

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Spread of #mcr-1–Driven #Colistin #Resistance on #Hospital #Surfaces, #Italy (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 24, Number 9—September 2018 / Research Letter

Spread of mcr-1–Driven Colistin Resistance on Hospital Surfaces, Italy

Elisabetta Caselli  , Maria D’Accolti, Irene Soffritti, Micol Piffanelli, and Sante Mazzacane

Author affiliations: Università Degli Studi di Ferrara, Ferrara, Italy

 

Abstract

Plasmid-mediated colistin resistance driven by the mcr-1 gene is of great clinical concern. Its diffusion in the hospital environment is unknown. We detected mcr-1–driven resistance in 8.3% of Enterobacteriaceae isolates from hospital surfaces in Italy, which might represent a reservoir of threatening nosocomial pathogens.

Keywords: Antibiotics; Drugs Resistance; MCR1; Enterobacteriaceae; Nosocomial Outbreaks; Italy.

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#Prevalence and molecular characterization of #Escherichia coli clinical isolates carrying #mcr1 in a #Chinese teaching #hospital from 2002 to 2016 (Antimicrob Agents Chemother., abstract)

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

Prevalence and molecular characterization of Escherichia coli clinical isolates carrying mcr-1 in a Chinese teaching hospital from 2002 to 2016

Hong Lu1, Chong Wang1, Guofeng Dong2, Chunquan Xu1, Xiaoxiao Zhang1,Haiyang Liu1, Majun Zhang1, Jianming Cao2* and Tieli Zhou1*

Author Affiliations: 1 Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. 2 Department of Medical Lab Science, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.

 

ABSTRACT

Colistin will be gradually banned from animal feeds in China and switched to clinical human therapy in the near future (1).…

 

FOOTNOTES

*Corresponding author: Jianming Cao. School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province, China., Tel: +86-0577-88069595; E-mail: wzcjming@163.com

*Corresponding author: Tieli Zhou. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China., Tel: +86-0577-86699370; E-mail: wyztli@163.com

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; E. Coli; China; Nosocomial Outbreaks; MCR1.

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