Presence of #NDM in non-E. coli #Enterobacteriaceae in the #poultry #production #environment (J Antimicrob Chemother., abstract)

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

Presence of NDM in non-E. coli Enterobacteriaceae in the poultry production environment

Rongmin Zhang, Jiyun Li, Yang Wang, Jianzhong Shen, Zhangqi Shen, Shaolin Wang

Journal of Antimicrobial Chemotherapy, dkz193,

Published: 18 May 2019




Characterization of non-Escherichia coli NDM-carrying Enterobacteriaceae in the poultry production environment.


A total of 36 NDM-positive Enterobacteriaceae (22 Klebsiella pneumoniae, 13 Enterobacter cloacae and 1 Salmonella enterica) were isolated from a chicken farm and WGS was conducted using Illumina Hiseq2500. The genomic characterization of the isolates acquired through WGS analysis included the genomic context-flanking blaNDM genes, MLST, the antibiotic resistance genes (ARGs) and replicon types of plasmids. WGS information for another 73 K. pneumoniae isolates from different sources was retrieved from GenBank and then combined with isolates in this study for comparative genomic and phylogenetic analysis.


Three types of genetic environment carrying blaNDM were identified in 36 non-E. coli Enterobacteriaceae isolates. Sequence comparison analysis indicated these genetic environments were completely identical to our previous findings. WGS further revealed three major types of plasmids (IncFIB, IncX3 and IncFII) from these isolates and the phylogenetic analysis suggested several K. pneumoniae isolates with ST11, ST37 and ST147 from the commercial chicken farm that were closely related to isolates of human origin.


The blaNDM-harbouring genetic contexts were identified not only in E. coli, but also in K. pneumoniae, E. cloacae and S. enterica, which may indicate that blaNDM has been widely disseminated to non-E. coli Enterobacteriaceae species in animal farms. The close relationship of K. pneumoniae isolates from different origins suggests they could serve as a key vehicle for the transfer of ARGs between humans and food animal production environments.


© 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:

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; NDM; Poultry; Food Safety.



Identification of Novel Mobilized #Colistin #Resistance #Gene #mcr9 in a #MDR, Colistin-Susceptible #Salmonella enterica Serotype #Typhimurium Isolate (mBio, abstract)

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

Identification of Novel Mobilized Colistin Resistance Gene mcr-9 in a Multidrug-Resistant, Colistin-Susceptible Salmonella enterica Serotype Typhimurium Isolate

Laura M. Carroll, Ahmed Gaballa, Claudia Guldimann, Genevieve Sullivan, Lory O. Henderson, Martin Wiedmann

Mark S. Turner, Editor

DOI: 10.1128/mBio.00853-19



Mobilized colistin resistance (mcr) genes are plasmid-borne genes that confer resistance to colistin, an antibiotic used to treat severe bacterial infections. To date, eight known mcrhomologues have been described (mcr-1 to -8). Here, we describe mcr-9, a novel mcrhomologue detected during routine in silico screening of sequenced Salmonella genomes for antimicrobial resistance genes. The amino acid sequence of mcr-9, detected in a multidrug-resistant (MDR) Salmonella enterica serotype Typhimurium (S. Typhimurium) strain isolated from a human patient in Washington State in 2010, most closely resembled mcr-3, aligning with 64.5% amino acid identity and 99.5% coverage using Translated Nucleotide BLAST (tblastn). The S. Typhimurium strain was tested for phenotypic resistance to colistin and was found to be sensitive at the 2-mg/liter European Committee on Antimicrobial Susceptibility Testing breakpoint under the tested conditions. mcr-9 was cloned in colistin-susceptible Escherichia coliNEB5α under an IPTG (isopropyl-β-d-thiogalactopyranoside)-induced promoter to determine whether it was capable of conferring resistance to colistin when expressed in a heterologous host. Expression of mcr-9 conferred resistance to colistin in E. coli NEB5α at 1, 2, and 2.5 mg/liter colistin, albeit at a lower level than mcr-3. Pairwise comparisons of the predicted protein structures associated with all nine mcr homologues (Mcr-1 to -9) revealed that Mcr-9, Mcr-3, Mcr-4, and Mcr-7 share a high degree of similarity at the structural level. Our results indicate that mcr-9 is capable of conferring phenotypic resistance to colistin in Enterobacteriaceae and should be immediately considered when monitoring plasmid-mediated colistin resistance.



Colistin is a last-resort antibiotic that is used to treat severe infections caused by MDR and extensively drug-resistant (XDR) bacteria. The World Health Organization (WHO) has designated colistin as a “highest priority critically important antimicrobial for human medicine” (WHO, Critically Important Antimicrobials for Human Medicine, 5th revision, 2017,, as it is often one of the only therapies available for treating serious bacterial infections in critically ill patients. Plasmid-borne mcr genes that confer resistance to colistin pose a threat to public health at an international scale, as they can be transmitted via horizontal gene transfer and have the potential to spread globally. Therefore, the establishment of a complete reference of mcr genes that can be used to screen for plasmid-mediated colistin resistance is essential for developing effective control strategies.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Salmonella enterica; MCR9; MCR3; Colistin; USA; Plasmids.


Effect of #carbapenem #resistance on outcomes of #bloodstream #infection caused by #Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study (Lancet Infect Dis., abstract)

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

Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study

Andrew J Stewardson, MBBS  †, Kalisvar Marimuthu, MBBS †, Sharmila Sengupta, MD, Arthur Allignol, PhD, Maisra El-Bouseary, PhD, Maria J Carvalho, PhD, Brekhna Hassan, PhD, Monica A Delgado-Ramirez, MD, Anita Arora, MD, Ruchika Bagga, MD, Alex K Owusu-Ofori, MD, Joseph O Ovosi, MBBS, Shamsudin Aliyu, MBBS, Hala Saad, MD, Prof Souha S Kanj, MD, Prof Basudha Khanal, MD, Prof Balkrishna Bhattarai, MD, Samir K Saha, PhD, Jamal Uddin, MPH, Purabi Barman, MD, Latika Sharma, MD, Tarek El-Banna, PhD, Rabaab Zahra, PhD, Mansab Ali Saleemi, MPhil, Amarjeet Kaur, MD, Kenneth Iregbu, FWACP, Nkolika SC Uwaezuoke, FWACP, Pierre Abi Hanna, MD, Rita Feghali, MD, Prof Ana L Correa, MD, Maria I Munera, MD, Thi Anh Thu Le, MD, Thi Thanh Nga Tran, MD, Chimanjita Phukan, MD, Chiranjita Phukan, MD, Sandra L Valderrama-Beltrán, MD, Prof Carlos Alvarez-Moreno, MD, Prof Timothy R Walsh, DSc, Prof Stephan Harbarth, MD

Published: April 29, 2019 / DOI:




Low-income and middle-income countries (LMICs) are under-represented in reports on the burden of antimicrobial resistance. We aimed to quantify the clinical effect of carbapenem resistance on mortality and length of hospital stay among inpatients in LMICs with a bloodstream infection due to Enterobacteriaceae.


The PANORAMA study was a multinational prospective cohort study at tertiary hospitals in Bangladesh, Colombia, Egypt, Ghana, India, Lebanon, Nepal, Nigeria, Pakistan, and Vietnam, recruiting consecutively diagnosed patients with carbapenem-susceptible Enterobacteriaceae (CSE) and carbapenem-resistant Entero-bacteriaceae (CRE) bloodstream infections. We excluded patients who had previously been enrolled in the study and those not treated with curative intent at the time of bloodstream infection onset. There were no age restrictions. Central laboratories in India and the UK did confirmatory testing and molecular characterisation, including strain typing. We applied proportional subdistribution hazard models with inverse probability weighting to estimate the effect of carbapenem resistance on probability of discharge alive and in-hospital death, and multistate modelling for excess length of stay in hospital. All patients were included in the analysis.


Between Aug 1, 2014, and June 30, 2015, we recruited 297 patients from 16 sites in ten countries: 174 with CSE bloodstream infection and 123 with CRE bloodstream infection. Median age was 46 years (IQR 15–61). Crude mortality was 20% (35 of 174 patients) for patients with CSE bloodstream infection and 35% (43 of 123 patients) for patients with CRE bloodstream infection. Carbapenem resistance was associated with an increased length of hospital stay (3·7 days, 95% CI 0·3–6·9), increased probability of in-hospital mortality (adjusted subdistribution hazard ratio 1·75, 95% CI 1·04–2·94), and decreased probability of discharge alive (0·61, 0·45–0·83). Multilocus sequence typing showed various clades, with marginal overlap between strains in the CRE and CSE clades.


Carbapenem resistance is associated with increased length of hospital stay and mortality in patients with bloodstream infections in LMICs. These data will inform global estimates of the burden of antimicrobial resistance and reinforce the need for better strategies to prevent, diagnose, and treat CRE infections in LMICs.



Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Bacteremia.


#Synergistic effect of #colistin combined with PFK-158 against colistin-resistant #Enterobacteriaceae (Antimicrob Agents Chemother., abstract)

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

Synergistic effect of colistin combined with PFK-158 against colistin-resistant Enterobacteriaceae

Youwen Zhang, Xiukun Wang, Xue Li, Limin Dong, Xinxin Hu, Tongying Nie, Yun Lu, Xi Lu, Jing Pang, Guoqing Li, Xinyi Yang, Congran Li, Xuefu You

DOI: 10.1128/AAC.00271-19



As increasing numbers of colistin-resistant bacteria emerge, new therapies are urgently needed to treat infections caused by these pathogens. The discovery of new combination therapies is one important way to solve such problems. Herein, we report that the antitumor drug PFK-158 and its analogs PFK-015 and 3PO can exert synergistic effects with colistin against colistin-resistant Enterobacteriaceae, including mcr-1 positive or high-level colistin resistant (HLCR) isolates, as shown by a checkerboard assay. The results of a time-killing assay revealed that colistin combined with PFK-158 continuously eliminated colistin-resistant Escherichia coli 13-43, Klebsiella pneumoniae H04 and Enterobacter cloacae D01 in 24 h. Images from scanning electron microscopy (SEM) 5 h post-inoculation confirmed the killing effect of the combination. Finally, the in vivo treatment showed that PFK-158 had a better synergistic effect than its analogs. Compared to the corresponding rates after colistin monotherapy, the survival rates of systemically infected mice were significantly increased 30% or 60% when the mice received an intravenous injection of colistin in combination with 15 mg/kg PFK-158. These results have important implications for repurposing PFK-158 to combat colistin resistance.

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

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


In vitro activity of #cefepime-#enmetazobactam against #Gramnegative isolates collected from #USA & #European #hospitals during 2014-2015 (Antimicrob Agents Chemother., abstract)

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

In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from United States and European hospitals during 2014-2015

Ian Morrissey, Sophie Magnet, Stephen Hawser, Stuart Shapiro, Philipp Knechtle

DOI: 10.1128/AAC.00514-19



Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase inhibitor. The combination of enmetazobactam with cefepime has entered clinical trials to assess safety and efficacy in patients with complicated urinary tract infections. Here, the in vitro activity of cefepime-enmetazobactam was determined for 1,993 clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa collected in the US and Europe during 2014 and 2015. Enmetazobactam at a fixed concentration of 8 μg/ml lowered the cefepime MIC90from 16 to 0.12 μg/ml for Escherichia coli, >64 to 0.5 μg/ml for Klebsiella pneumoniae, 16 to 1 μg/ml for Enterobacter cloacae, and 0.5 to 0.25 μg/ml for Enterobacter aerogenes. Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa. Applying the CLSI ‘susceptible-dose dependent’ (SDD) breakpoint of 8 μg/ml to cefepime-enmetazobactam for comparative purposes resulted in cumulative inhibitions of 99.9% for E. coli, 96.4% for K. pneumoniae, 97.0% for E. cloacae, 100% for E. aerogenes, 98.1% for all Enterobacteriaceae surveilled, and 82.8% for P. aeruginosa. Comparator susceptibilities for all Enterobacteriaceae were 99.7% for ceftazidime-avibactam, 96.2% for meropenem, 90.7% for ceftolozane-tazobactam, 87% for cefepime (SDD breakpoint), 85.7% for piperacillin-tazobactam, and 81.2% for ceftazidime. For the subset of ESBL-producing K. pneumoniae isolates, addition of 8 μg/ml enmetazobactam to cefepime lowered the MIC90 from >64 to 1 μg/ml, whereas the shift for 8 μg/ml tazobactam was from >64 to 8 μg/ml. Cefepime-enmetazobactam may represent a novel carbapenem-sparing option for empiric treatment of serious Gram-negative infections in settings where ESBL-producing Enterobacteriaceae are expected.

Copyright © 2019 Morrissey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Cefepime; Enmetazobactam.


Worsening #epidemiological #situation of #carbapenemase-producing #Enterobacteriaceae in #Europe, #assessment by national experts from 37 countries, July 2018 (Euro Surveill., abstract)

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

Worsening epidemiological situation of carbapenemase-producing Enterobacteriaceae in Europe, assessment by national experts from 37 countries, July 2018

Alma Brolund1,2, Nina Lagerqvist1,2,3, Sara Byfors1, Marc J Struelens4, Dominique L Monnet4, Barbara Albiger4, Anke Kohlenberg4, European Antimicrobial Resistance Genes Surveillance Network (EURGen-Net) capacity survey group5

Affiliations: 1 Public Health Agency of Sweden, Solna, Sweden; 2 These authors contributed equally to this work; 3 European Public Health Microbiology Training Programme (EUPHEM), European Centre for Disease Prevention and Control, Stockholm, Sweden; 4 European Centre for Disease Prevention and Control, Stockholm, Sweden; 5 The members of the capacity survey group are listed at the end of this article

Correspondence:  AnkeKohlenberg

Citation style for this article: Brolund Alma, Lagerqvist Nina, Byfors Sara, Struelens Marc J, Monnet Dominique L, Albiger Barbara, Kohlenberg Anke, European Antimicrobial Resistance Genes Surveillance Network (EURGen-Net) capacity survey group. Worsening epidemiological situation of carbapenemase-producing Enterobacteriaceae in Europe, assessment by national experts from 37 countries, July 2018. Euro Surveill. 2019;24(9):pii=1900123.

Received: 15 Feb 2019;   Accepted: 28 Feb 2019



A survey on the epidemiological situation, surveillance and containment activities for carbapenemase-producing Enterobacteriaceae (CPE) was conducted in European countries in 2018. All 37 participating countries reported CPE cases. Since 2015, the epidemiological stage of CPE expansion has increased in 11 countries. Reference laboratory capability, dedicated surveillance and a specific national containment plan are in existence in 33, 27 and 14 countries, respectively. Enhanced control efforts are needed for CPE containment in Europe.

© This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Antibiotics; Drugs Resistance; Carbapene; Enterobacteriaceae; European Region.


Dynamics of #resistance #plasmids in #ESBL-producing #Enterobacteriaceae during post-infection #colonization (Antimicrob Agents Chemother., abstract)

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

Dynamics of resistance plasmids in extended spectrum β-lactamase-producing Enterobacteriaceae during post-infection colonization

Alma Brolund, Fredrika Rajer, Christian G Giske, Öjar Melefors, Emilia Titelman, Linus Sandegren

DOI: 10.1128/AAC.02201-18



Extended spectrum β-lactamase-producing Enterobacteriaceae (EPE) are a major cause of bloodstream infections and the colonization rate of EPE in the gut microbiota of individuals lacking prior hospitalization or comorbidities is increasing. In this study we performed an in-depth investigation of the temporal dynamics of EPE and their plasmids during one year by collecting fecal samples from three patients initially seeking medical care for urinary tract infections. In two of the patients the same strain that caused the UTI was found at all consecutive samplings from the gut microbiota and no other EPEs were detected, while in the third patient the UTI strain was only found in the initial UTI sample. Instead, this patient presented a complex situation where a mixed microbiota of different EPE strain types, including three different E. coli ST131 variants, as well as different bacterial species was identified over the course of the study. Different plasmid dynamics were displayed in each of the patients including spread of plasmids between different strain types over time, transposition of blaCTX-M-15 from the chromosome to a plasmid followed by subsequent loss through homologous recombination. Small cryptic plasmids were found in all isolates from all patients and they appear to move frequently between different strains in the microbiota. In conclusion, we could demonstrate an extensive variation of EPE strain types, plasmid composition, rearrangements and horizontal gene transfer of genetic material illustrating the high dynamics nature and interactive environment of the gut microbiota during post UTI carriage.

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

Keywords: Antibiotics; Drugs Resistance; Beta-lactams; E. Coli; Enterobacteriaceae; Bacteremia.