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[Echo20]

Radcliff

Great post.

Also:

antibiotic resistance as global health threat worsens

By Steven Ross Johnson  | September 20, 2016

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A rise in antimicrobial-resistant infections is in the global spotlight as world leaders on Wednesday will discuss the growing threat of a post-antibiotic world.

The one day meeting of the United Nations General Assembly marks only the fourth time the group has met to discuss a health crisis. 

The move marks a new era of heightened urgency regarding antibiotic resistance. Health experts warned for years that overprescribing and prioritizing development of more lucrative drugs over cheap antibiotics led to an increase in “superbug” infections that are resistant to one or multiple antibiotics.

Wednesday's meeting is the first toward developing a coordinated global plan that focuses on reducing antibiotic use while creating ways to give companies incentives to develop new drugs. 

Efforts to encourage improved antibiotic stewardship within the healthcare field has led to some successes among a number of providers.

“In a sense, this U.N. meeting will allow the world to see just how dangerous a problem this is,” said Dr. Amesh Adalja, infectious disease expert and senior associate at the UPMC Center for Health Security. 

An estimated 700,000 people around the world die every year from antimicrobial-resistant infections, with more than 23,000 deaths and 2 million illnesses occurring within the U.S., according to the Centers for Disease Control and Prevention.

But the problem of overuse remains a huge concern. An analysis of U.S. acute-care hospitals found a little more than one-third had stewardship programs that met all seven of the CDC's recommended elements for best practices. 

A study published in May in JAMA found 1 in 3 antibiotic prescriptions written in the U.S. was considered unnecessary for the conditions they are used to treat. 

A more recent analysis of more than 300 hospitals published Tuesday inJAMA Internal Medicine found that between 2006 and 2012, the rate of antibiotic use had not changed much over the time studied. Perhaps more disturbing was that there was a significant increase in the use of broad-spectrum antibiotics, which are considered the drugs of last resort for the worst infections.

Adalja said that if stewardship falters, or there's not enough leadership buy-in by hospital administrators, the task will be impossible. "Every new antibiotic we discover is invariably going to be met with resistance,” he said. “It's very easy to do compared to developing new antibiotics. This is something that every hospital can do now, today.” 

But recent moves by the Joint Commission as well as the CMS aim to develop standards of practice for prescribing antibiotics. In July, the Joint Commission released a document entitled New Antimicrobial Stewardship Standard, which goes into effect Jan. 1 for acute-care and critical-access hospitals, as well as nursing-care centers, ambulatory-care organizations and office-base surgical practices. 

In June, the CMS issued a proposed rule for Medicare and Medicaid participants requiring them to have an antibiotic stewardship program in place and designate qualified infectious disease personnel to lead those programs.

“Those two key activities that have really come down in less than the last six months have really made everyone stand at attention to ask what do they have in place for antibiotic stewardship, what do they need to get in place, and how can they be prepared for both the Joint Commission and CMS,” said Kristi Kuper, senior clinical manager of infectious disease for member-owned healthcare company Vizient.

But reducing antibiotic prescribing within healthcare only solves part of the problem. Antibiotics, some of which are medically important to humans, continue to be fed to livestock to cure and stave off disease, or in some instances, they are used to promote weight gain in livestock without having to increase the animals' food intake.

A report released in December 2015 by the Food and Drug Administration found that despite efforts in recent years to limit the use of antibiotics in food-producing animals, sales of such drugs for livestock increased by 3% between 2013 and 2014. 

For years, health officials have called for a multisector, multigovernmental approach to combating antimicrobial resistance. At the World Economic Forum in January, a number of the world's largest drug manufacturers signed a declaration pledging to work with governments on promoting greater antibiotic stewardship. 

But even with such commitments, the pipeline for new antibiotics remains low. An estimated 37 new antibiotics with the potential to treat serious bacterial infections are in clinical development for the U.S. market as of March, according to an analysis from the Pew Charitable Trusts. 

Only seven currently in Phase 3 trials are expected to work against gram-negative pathogens, which are multidrug resistant and considered to be among the toughest to treat. An estimated 1 out of 5 drugs that reach Phase 1 human testing win approval for use.

But drugmakers find little incentive to develop new antibiotics.

“I think it's an important context to remember that it costs about $1 billion to bring a drug to market,” UPMC's Adalja said. “When drugmakers try to look at what the revenue stream is from an antibiotic, if it's only going to be used for the most drug-resistant organisms, that's not very appealing to a company because it isn't something that they're going to be able to easily recoup their $1 billion investment on.

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Echo20

[farrell90]

Colistin resistant superbug described as crisis situation in August 2016 Journal of American Medical Association

This recognition should lead to more funding for antibiotic research including Brilacidin and other HDP.

Good luck Farrell


Medical News & Perspectives
Infectious Disease Expert Sees Threat
From Colistin-Resistant Superbug
Jennifer Abbasi
Scientists at theWalter Reed Army Institute
of Research (WRAIR) and the
Walter Reed National Military MedicalCenterrecentlypublishedatroublingfinding:
Escherichia coli carrying a gene conferring
resistance to the antibiotic colistin in the
urine of a Pennsylvania woman (McGann P
et al. Antimicrob Agents Chemother. 2016;
60[7]:4420-4421). It was the first time the
gene, mcr-1, had been found in ahumanbacterial
infection in the United States.
Mcr-1 thwarts colistin, a 1950s-era antibiotic
called out of retirement to treat
multi-drug-resistant infections including
carbapenem-resistant Enterobacteriaceae.
Evenmoreconcerning, the gene is carried
on a plasmid, a short, circular strand of
nonchromosomal DNA that can transfer to
other types of bacteria, spreading its potentially
lethal resistance.
Scientists reported the discovery of the
geneinChinajustlastyear(LiuYYetal.Lancet
Infect Dis.2016;16[2]:161-168).Bythen, itwas
already widespread in E coli and Klebsiella
pneumoniae, two species of Enterobacteriaceae,
foundinanumberofpigsandpatientsin
SouthChina.Enterobacteriaceaeisafamilyof
gram-negativebacteria that also includes Salmonella,
Shigella,andYersiniapestis (plague).
Thegenehasnowbeendetected in livestock,
meat, and people on most continents
(SkovR,MonnetD.Euro Surveill.2016;21[9]:
1-6). In July, a second case of E coli with the
mcr-1 genewas reported in a human patient
inNewYork (CastanheiraMet al. Antimicrob
AgentsChemother.doi:10.1128/AAC.01267-16
[published online July 11, 2016]).
NewsofthesuperbuginUSpatientscame
asnosurprisetoBarbaraE.Murray,MD,director
of the division of infectious diseasesat the
University of Texas Health Science Center at
Houstonandaninternationallyrecognizedexpertonantibioticresistance.“
Once[resistance
has] appeared somewhere, you knowit’s goingtoappearotherplaces,
soitwasjustamatteroftime,”
saidMurray,apastpresidentofthe
Infectious Diseases Society of America. “I’ve
beenworking on antibiotic resistance for 30
years, and it always happens [thisway].”
Theemergenceof themcr-1genecomes
at a time when federal agencies are steppingupsurveillance
todetect antibiotic resistance,
Murraysaid.ThePennsylvaniacasewas
confirmed by the Department of Defense’s
Multidrug-resistantOrganismRepositoryand
Surveillance Network at WRAIR, a program
that is being formalized by the “National Action
Plan for Combating Antibiotic-Resistant
Bacteria,” introduced in 2015. Inthe past few
months,theNationalAntimicrobialResistance
Monitoring System—a joint effort between
theUSDepartmentofHealthandHumanServices
and the US Department of Agriculture
(USDA)—foundcolistin-resistantEcoliin2pigs
from slaughterhouses in South Carolina and
Illinois, a USDA spokesperson confirmed.
Recently, Murray spoke with JAMA
about the challenges posed by mcr-1 and
antibiotic-resistant bugs.The following is an
edited version of the interview.
JAMA: Whatwasyourinitial responseto the
news that the colistin-resistant gene, mcr-1,
had been discovered in E coli bacteria cultured
from a patient in the United States?
DR MURRAY: The Chin[ese] report was the
real surprise because [before the report] I
didn’tknowthatcolistinwasbeingusedinanimals.
Thereaction [totheUSreport]was kind
ofliketheothershoedropped.Weareinthese
situationswherewereallydon’thaveanything
to treatsomepatients. It’s closinginonusand
you can just kind of feel it constricting, constricting,
constricting what our options are.
And I’ve been through this before with other
resistancecyclesandit’sveryworrisomeforpatientsbecauseyouseetheseexamplesandit’s
like,“Wellgosh,there’snothingelsewecando.”
JAMA: Can you tell us a little bit about the
mcr-1 gene?Howwas it discovered and how
does it give rise to antibiotic resistance?
DR MURRAY: It was discovered because
they were seeing a lot of colistin resistance
[in China] and they knew colistinwas being
used a lot in animal feeds. They did wholegenome
sequencing on the bacterium
[samples from pigs] and saw a gene that
looked like it might be involved in modifying
lipid A. Lipid A is a component of the
outer membrane of gram-negative bacteria
and is the target for the drug colistin.
JAMA: Sowhy is the colistin-resistant gene
so concerning to infectious disease experts?
DR MURRAY: Colistin has become the last
go-to antibiotic for some of our multidrugresistant
bacteria. Colistin’s been around for
at least 50 years, [but] it wasn’t used very
much because it was toxic and other [less
toxic] agents were developed. What’s happening
[now] is [that] we have these infections
where the bacterium is resistant to almost
everything, and we’ve gone back and
started using colistin. When you’re left with
only one drug and now you see resistance
developing to it, it’s very concerning.
The [Pennsylvania] patient sounded
like a healthy person [who] was not in the
hospital, and there were still options for
therapy. But the sicker the patient, themore
likely [he or she] is to have these multidrugresistant
bacteria. Organ transplant patients,
bonemarrowtransplant patients,and
very sick ICU [Intensive Care Unit] patients
[who] have been in the hospital a long time
and keep getting recurrent infections—you
treatthemfirst with a simpler drug and then
you move it up to the extended-spectrum
ß-lactamases. And then something infects
them and it’s resistant. Youmove to the carbapenemsand
then resistancedevelops. It’s
this sequential development of this resistance
thatwe often see.Andyou’re left with
colistin being the only therapeutic option.
JAMA: And there’s some concern that the
gene could be transferred to other types of
bacteria? How could that occur—and what
would the worst-case scenario be?
DR MURRAY: Absolutely. There are certain
plasmids that can transfer from bacterium to
bacterium.Someofthemcantransfer widely,
to whole different species and genre of bacteria.
Wecallthisconjugationorbacterialmatingbecause
it’s spreadingDNA.Ecoli can frequently
genetically communicate with all
sorts of other bacteria like Salmonella,
Shigella—thosearediarrheagerms—andother
kinds of bacteria that cause infections in
hospitals, like Klebsiella,Enterobacter.These
plasmid-mediatedthingscanspreadlikewildfire,
andtheycanspreadfromspecies tospecies,
to all of the moderately related types of
bacteria. Then they have their own resistances,
which just makes the problem exponentiallyworse.
JAMA: Physicians often say they feel pressured
by patients to dole out antibiotics.
What would you say to them?
DR MURRAY: I think that’s tough. The big
pressure in an outpatient setting is for respiratory
infections—colds, sore throats,andsinusitis—
andthe vast majorityof those are viral.
I think we just have to tell patients that
this is a virus.Andit’s not good for you or the
world to put you on antibiotics for a viral infection
against which antibioticsdon’twork.
JAMA: Would restricting colistin use in agriculture
help?
DRMURRAY: Absolutely. China isoneof the
world’s highest users of colistin in agriculture.
In France, 90% of farms in the pig industry
report using colistin during the
postweaningperiod. Belgium, Spain,Austria,
Sweden, Germany, Vietnam, the Netherlands.
It’s used all over the world in animal
food. Iwas really surprised to read that itwas
in products going to animals in the European
Union because they had banned a lot
of antibiotic use already in animals because
of their prior experience with vancomycinresistant
enterococci.
I think people thought colistinwas kind
of a dead drug for humans because it had
been supplanted by a whole bunch of differentonesandthereforewasn’t
going tobe
used in man. So my guess is that it was
thought tobeokay to use in animal feeds because
it was not going to conflict, not realizing
that in the next 20 years we were going
to need it in humans as well.
LikeSalmonella withyour chickens,you
couldcomein contact with these bacteriaon
the meat products and then ingest them. If
it’s inanimals, it’s goingtogetonanimalmeat
because there’snoway they can butcher animals
and not have them contaminated to
some extent with what’s in their intestinal
tract. We could consume the bacteria that
has the resistance genes.Andit could either
just lie dormant in us or it could spread to
other bacteria.
JAMA: There’sbeena lot of public attention
around antibiotic resistance for many years
now.Whatare the biggest barriersyou’veencountered
to curbing antibiotic resistance?
DR MURRAY: There are efforts being made
todecreasetheuseof antibiotics, todecrease
thespreadof resistanceonceit occurs,andto
stimulate the industry tomakenewantibiotics,
but it’s a very tough problem.
Therehavebeencampaignsin thecommunity,
particularlyamongpediatricians,totry
not to use antibioticswhennot needed.And
inhospitals,thegoaloftheantibioticstewardship
programis to try to reduce unnecessary
use of antibiotics. But when you’re dealing
with a very sick patient in the hospital, you’re
not thinkingof the public health implications,
you’re just thinking of that patient. As clinicians,
wetend to just keepchangingantibioticsandaddingnewantibiotics.
AndIcan’t say
that’s wrong. But at the same time, it does
drive the selective pressure for resistance.
The other aspect is how quickly resistancespreads.
Therewasastudyawhileback
that if every ICU nursewashed her hands every
time it was indicated, she would spend
somethinglike22minutesonthe hourwashing
hands. The medical system just will not
takethat.It’sverydifficulttokeepthingsfrom
spreadinginthehospital,andthat’swherethe
realdanger is. In the hospital setting, the bacteria
thatmay acquire the mcr-1 genemay already
be resistant to everything else.
Finally, major pharma has gotten out of
theantimicrobial industrybecausetheydon’t
make money from it.
JAMA: The federal government is addressing
the issue with initiatives including
an executive order, a national strategy, and
the “National Action Plan for Combating
Antibiotic-Resistant Bacteria” (http://1.usa
.gov/28NYmNM).Haveweseenanytangible
results of these initiatives?
DR MURRAY: It’s quite early. There’s certainly
some increased funding for surveillance
and I think that will trickle down to increased
funding for investigator-initiated
studies. The Generating Antibiotics Incentives
Now(GAIN) Act is prolonging the patent
life on certain antibiotics. The FDA [US
Food and Drug Administration] now has a
rapid pathway for agents that fill an unmet
need.TheFDAhas also gotten the signal that
when it’s a crisis situation, [it] may need to
considerapprovingagents with smaller studies.
Because you don’t have hundreds and
hundreds of patients out there—thank
goodness—[who] are infected with these
multidrug-resistant organisms.
News & Analysis
jama.com (Reprinted) JAMA August 23/30, 2016 Volume 316, Number 8