Proactive Efforts by U.S. Federal Agencies Enable Early Detection of New
Antibiotic Resistance
May 26, 2016
By: U.S. Department of Health and Human Services (HHS)
Summary:
Our three departments take the emergence of this resistance gene very
seriously. A coordinated response is underway to try to prevent its spread.
Just over a year ago, President Obama released a National Action Plan for
Combating Antibiotic Resistant Bacteria. As part of that plan, he also charged
the Department of Defense (DoD), Department of Agriculture (USDA) and Department
of Health and Human Services (HHS) with co-chairing a Presidential Advisory
Council on Combating Antibiotic-Resistant Bacteria (Advisory Council). In the
past year, our three agencies and the Council have held numerous stakeholder
meetings, made new discoveries, and undertaken new research to preserve the
effectiveness of antibiotics.
In recent weeks, our three agencies have made some important discoveries
regarding antibiotic resistance in the United States. Earlier this week, the
Department of Defense notified stakeholders that its Multidrug-resistant
Organism Repository and Surveillance Network (MRSN) at the Walter Reed Institute
of Research had identified the first colistin-resistant mcr-1 E. coli in a
person in the United States. A USDA and HHS search for colistin-resistant
bacteria in food animals, retail meats and people also has found
colistin-resistant E. coli in a single sample from a pig intestine.
These discoveries are of concern because colistin is used as a last-resort
drug to treat patients with multi-drug resistant infections. Finding
colistin-resistant bacteria in the United States is important, as it was only
last November that scientists in China first reported that the mcr-1 gene in
bacteria confers colistin resistance. Following the revelation in China,
scientists across the globe began searching for other bacteria containing the
mcr-1 gene, and the bacteria have since been discovered in Europe and Canada.
The mcr-1 gene exists on a plasmid, a small piece of DNA that is not a part of a
bacterium’s chromosome. Plasmids are capable of moving from one bacterium to
another, spreading antibiotic resistance between bacterial species.
The patient with colistin-resistant E. coli was treated in an outpatient
military treatment facility in Pennsylvania. Biologic samples were sent to the
Walter Reed National Military Medical Center for initial testing and then to
MRSN for genetic sequencing to identify the mcr-1 gene.
Our three departments take the emergence of this resistance gene very
seriously. A coordinated public health response is underway to try to prevent
its spread.
For example, to respond to the DoD finding of mcr-1 in a human isolate,
HHS’s Centers for Disease Control and Prevention is working with DoD, the
Pennsylvania Department of Health, local health departments, and others to
identify close contacts, including household and healthcare contacts, of the
Pennsylvania patient to determine whether any of them may have been at risk for
transmission of the bacteria containing the mcr-1 gene. Similarly, USDA is
conducting traceback work to determine the sampled pig's farm of origin.
At the same time, the National Antimicrobial Resistance Monitoring System
(NARMS) is continuing its search for evidence of colistin-resistant bacteria in
the United States. For the past 20 years, NARMS has detected emerging resistance
to clinically important antibiotics. NARMS is a partnership between HHS and
USDA, as well as state and local public health departments, dedicated to
tracking changes in the antimicrobial susceptibility of intestinal bacteria
found in ill people, in retail meats, and in food animals.
After the detections in China, the NARMS teams began a two-pronged approach
to search for evidence of colistin-resistant bacteria caused by mcr-1 in the
United States. First, USDA’s Agricultural Research Service (ARS) scientists took
on a proactive study that used a modified technique to look for bacteria with
the mcr-1 gene, employing a targeted and extremely sensitive method to examine
whole bacterial populations found in intestinal samples from food-producing
animals. In the still-ongoing study, USDA scientists analyzed the samples by
first exposing them to colistin at a concentration that would kill sensitive
bacteria and allow any bacteria carrying mcr-1 to survive. Out of 949 animal
samples screened so far, one strain of colistin-resistant E. coli was found in a
pig intestinal sample. The DNA sequence of this isolate revealed that the strain
contained the mcr-1 gene on a plasmid. The scientists also determined that the
mcr-1 carrying colistin-resistant E. coli is resistant to other antibiotics
including ampicillin, streptomycin, sulfisoxazole, and tetracycline.
Second, HHS’ Centers for Disease Control and Prevention (CDC) and the Food
and Drug Administration used whole genome sequencing technology to search for
the gene in Salmonella, E. coli and Klebsiella taken from human and retail meat
sources. As of April 2016, more than 44,000 Salmonella and 9,000 E.
coli/Shigella isolates from NARMS as well as the National Center for
Biotechnology Information genomic database did not show the presence of the
mcr-1 gene.
Although the findings suggest that mcr-1-mediated colistin resistance might
be rare, HHS and USDA remind consumers that cooking all meat, poultry and fish
to its proper internal temperature kills bacteria, viruses and other foodborne
pathogens, whether or not they are antibiotic-resistant.
The NARMS partners will continue to study the newly isolated E. coli strain
to better understand the mcr-1 gene, as well as continue to analyze the
remaining food animal samples for the presence of colistin resistance. Once
USDA’s ARS completes this study, the findings could help determine any
additional steps necessary to further understand the mechanisms and
dissemination of mcr-1 and associated genes.
Beginning in fall 2016, CDC’s Antibiotic Resistance lab network will
provide the infrastructure and lab capacity for seven to eight regional labs,
and labs in all states and seven major cities/territories, to detect and respond
to resistant organisms recovered from human samples. State labs will be able to
detect new forms of antibiotic resistance—including mutations that allow
bacteria to survive the effects of the last-resort drugs like colistin—and
report these findings to CDC in near real-time. With this comprehensive lab
capacity, state health labs and regional labs that are part of the network will
be able to investigate emerging resistance in ways currently unavailable,
generating better data for stronger infection control among patients to prevent
and combat future resistance threats.
And consistent with the National Action Plan for Combating Antibiotic
Resistant Bacteria, CDC, FDA, USDA, DOD and other government agencies will
continue efforts to track, slow and respond to the emergence of antibiotic
resistance.
The two detections of the mcr-1 gene in the U.S. provide a new clue into
the antibiotic resistance landscape, and it also highlights how much we still do
not understand. Colistin is rarely used in human medicine compared to other
antibiotics. It is often used to treat multi-drug resistant infections and its
use is increasing. It is not used in animals in this country. As such, the new
detection underscores the urgent need for more research in this area, and that’s
why the President’s 2017 budget request also calls for Congress to fund the
Agriculture and Food Research Initiative at its full level, allowing our
nation’s best and brightest scientists to help the NARMS partners get ahead of
the fight to keep antibiotics effective and available. Earlier this month, USDA
announced that it is seeking applications for $6 million in research funding to
address antibiotic resistance through this program, but currently USDA must
leave nine in ten applications for AFRI grants unfunded, keeping meaningful
projects off the table.
David J. Smith, M.D., is the Deputy Assistant Secretary of Defense for
Health Readiness Policy and Oversight.
Cathie Woteki, Ph. D., is USDA Under Secretary for Research, Education
& Economics.
Beth P. Bell, MD MPH, is Director of CDC’s National Center for Emerging and
Zoonotic Infectious Diseases
Posted In: Public Health and Safety
Tagged: antibiotic resistance
Discovery of first mcr-1 gene in E. coli bacteria found in a human in
United States
MCR-1 causes resistance to colistin, a last-resort drug for treating
resistant infections
Media Statement
For Immediate Release: Tuesday, May 31, 2016 Contact: Media Relations,
(404) 639-3286 The Centers for Disease Control and Prevention is part of a
coordinated public health response after the Department of Defense (DoD)
announced the discovery of the first mcr-1 gene found in bacteria in a human in
the United States. CDC is working with DoD, the Pennsylvania Department of
Health, local health departments, and others to identify people who have had
contact with the patient and take action to prevent local spread.
E. coli bacteria carrying the MCR-1 gene was found in a urine sample from a
Pennsylvania woman with no recent travel outside of the U.S. The mcr-1 gene
makes bacteria resistant to the antibiotic colistin, which is used as a
last-resort drug to treat patients with multi-drug-resistant infections,
including carbapenem-resistant Enterobacteriaceae (CRE). The mcr-1 gene exists
on a plasmid, a small piece of DNA that is capable of moving from one bacterium
to another, spreading antibiotic resistance among bacterial species. The CDC and
federal partners have been hunting for this gene in the U.S. ever since its
emergence in China in 2015.
Despite some media reports, the Pennsylvania State Health Department
investigation has determined that the woman did not have CRE and the bacteria
identified is not resistant to all antibiotics (referred to as a pan-resistant
infection). The presence of the mcr-1 gene, however, and its ability to share
its colistin resistance with other bacteria such as CRE raise the risk that
pan-resistant bacteria could develop.
The investigation is currently focused on identifying close contacts,
including household and healthcare contacts, of the Pennsylvania patient to
determine whether any of them may have been at risk for transmission of the
bacteria containing the mcr-1 gene.
Beginning in fall 2016, CDC’s Antibiotic Resistance Lab Network will
provide the infrastructure and lab capacity for seven to eight regional labs,
and labs in all states and seven major cities/territories, to detect and respond
to resistant organisms recovered from human samples . State labs will be able to
detect new forms of antibiotic resistance—including mutations that allow
bacteria to survive the effects of the last-resort drugs like colistin—and
report these findings to CDC. With this comprehensive lab capacity, state health
labs and regional labs that are part of the network will be able to investigate
emerging resistance faster and more effectively, generating better data for
stronger infection control among patients to prevent and combat future
resistance threats. CDC will also provide new resources to state health
departments to support their efforts to stop antibiotic-resistant outbreaks and
prevent the spread of antibiotic-resistant pathogens across communities.
Consistent with the National Action Plan for Combating Antibiotic-Resistant
Bacteria, CDC and other government agencies will continue efforts to track, slow
and respond to the emergence of antibiotic resistance.
For more information on the mcr-1 discovery, see http://www.hhs.gov/blog/2016/05/26/early-detection-new-antibiotic-resistance.html.
### U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in
animals and human beings in China: a microbiological and molecular biological
study
Yi-Yun Liu
x
Yi-Yun Liu
snip...
Affiliations
Beijing Advanced Innovation Center for Food Nutrition and Human Health,
College of Veterinary Medicine, China Agricultural University, Beijing,
China
Correspondence
Prof Jianzhong Shen, Beijing Advanced Innovation Center for Food Nutrition
and Human Health, College of Veterinary Medicine, China Agricultural University,
Beijing 100094, China
, PhDcorrespondence
Correspondence
Prof Jianzhong Shen, Beijing Advanced Innovation Center for Food Nutrition
and Human Health, College of Veterinary Medicine, China Agricultural University,
Beijing 100094, China
email
†Contributed equally
Published Online: 18 November 2015
Article has an altmetric score of 1630 DOI: http://dx.doi.org/10.1016/S1473-3099(15)00424-7
Publication History
Published Online: 18 November 2015
© 2016 Elsevier Ltd. All rights reserved.
This article can be found in the following collections: Anti-infective
therapy; Healthcare-associated infections; Infectious diseases-other
To view the full text, please login as a subscribed user or purchase a
subscription. Click here to view the full text on ScienceDirect.
Figures
Figure 1
Map of China
Figure 2
Structure of plasmid pHNSHP45 carrying mcr-1 from Escherichia coli strain
SHP45
Figure 3
Hydropathy plot predicting five transmembrane α-helices in the N-terminal
200 aminoacids of MCR-1 (A) and i-Tasser homology modelling analysis of MCR-1
based on models from LptA (Neisseria meningitidis; Protein Data Bank ID 4KAY)
and EptC (Campylobacter jejuni; Protein Data Bank ID 4TNO; B)
Figure 4
In-vivo effects of colistin treatment (7·5 mg/kg of colistin sulfate per 12
h) in a murine thigh model showing 106 CFU infection with Escherichia coli with
mcr-1 (363R, red circles) and without mcr-1 (363S, blue circles)
p value calculated by a two-sample t test for the log difference in CFUs
between 363S and 363R after treatment was also indicated. CFU=colony forming
unit.
Summary
Background
Until now, polymyxin resistance has involved chromosomal mutations but has
never been reported via horizontal gene transfer. During a routine surveillance
project on antimicrobial resistance in commensal Escherichia coli from food
animals in China, a major increase of colistin resistance was observed. When an
E coli strain, SHP45, possessing colistin resistance that could be transferred
to another strain, was isolated from a pig, we conducted further analysis of
possible plasmid-mediated polymyxin resistance. Herein, we report the emergence
of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in
Enterobacteriaceae.
Methods
The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid
sequencing and subcloning. MCR-1 mechanistic studies were done with sequence
comparisons, homology modelling, and electrospray ionisation mass spectrometry.
The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae
strains collected from five provinces between April, 2011, and November, 2014.
The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a
murine thigh model.
Findings
Polymyxin resistance was shown to be singularly due to the plasmid-mediated
mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a
frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and
maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model,
production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the
phosphoethanolamine transferase enzyme family, with expression in E coli
resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1
carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat
and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from
inpatients with infection.
Interpretation
The emergence of MCR-1 heralds the breach of the last group of antibiotics,
polymyxins, by plasmid-mediated resistance. Although currently confined to
China, MCR-1 is likely to emulate other global resistance mechanisms such as
NDM-1. Our findings emphasise the urgent need for coordinated global action in
the fight against pan-drug-resistant Gram-negative bacteria.
Funding
Ministry of Science and Technology of China, National Natural Science
Foundation of China.
Tuesday, September 17, 2013
Antibiotic resistance threats in the United States, 2013 THREAT REPORT
MRSA
Terry S. Singeltary Sr.
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