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Major pharmaceutical companies like Novartis dropping antibiotics projects and future tools against superbugs

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antibiotic resistance bacteria multi drug resistant microbes laboratory testing cdc
A
researcher tests bacteria’s ability to growth in the presence of
antibiotics.


CDC


  • Novartis
    in July
    became the latest pharmaceutical company to shut
    down its antibiotics research projects.
  • The move comes as FDA commissioner Scott Gottlieb has
    expressed concern over the growing epidemic around
    antimicrobial resistance, which is when bacteria grow resistant
    to available medications.
  • New options to combat the resistant bacteria include
    antibiotic-combination therapy and bacteriophage
    therapy.

Just two years after Novartis announced it would embrace the
challenge of searching for cures for life-threatening infections
known as superbugs, the drugmaker said last week it would exit
antibacterial and antiviral research.

Novartis’ retreat follows a growing trend of big pharmaceutical
companies — including AstraZeneca, Sanofi, and Allergan — that
are exiting from this type of research because of a lack of
profit.

That leaves Merck, Roche, GlaxoSmithKline, and Pfizer as the
remaining pharmaceutical companies with active antibiotic
programs, according to Nature
Biotechnology
. Only 12 antibiotics have been approved since
2000.

Ever since the invention of penicillin, antibiotic development
has been a treadmill. Patients who took too little of too much
antibiotics would evolutionarily select for stronger strains by
killing off only the sensitive bacteria. Antibiotics were once a

lucrative business
before inventing new drugs to catch up
with the evolution of resistant strains became exhausting.

Dr. Jean Patel, science team lead of antibiotic strategy and
coordination unit at the CDC, said a fair number of active
antibiotics used against bacteria actually come from small,
startup-sized companies, that usually later get acquired by big
pharma, which provides the infrastructure to complete clinical
trials and market the drug. But with increasing numbers of big
pharma firms backing out of antibiotic pursuits, it decreases the
variety of new drugs that can be brought to market.

“The costs to develop a new antibiotic drug are no less expensive
compared to development of drugs for other therapeutic areas, yet
the commercial potential and return on investment for companies
developing new antibiotics are significantly lower than drugs to
treat chronic conditions such as diabetes or heart disease,” said
Gary Disbrow, deputy director of the Biomedical
Advanced Research and Development Authority, which sits within
the U.S. Department of Health and Human Services. 

The lack of research from big pharma companies is a problem. Each
year in the US at least 2 million people become infected with
antibiotic-resistant bacteria, according to Centers for Disease
Control and Prevention, and 23,000 people die each year as a
direct result of these infections.

It’s estimated that as many as 10 million people could die
annually from superbugs by 2050 if nothing is done, according to
a report commissioned by the UK.

The superbug supercrisis

The public threat from antibiotic-resistant superbugs is growing.
Doctors
recently warned that an emerging sexually transmitted
infection
could become an antibiotic-resistant superbug and
lead to pelvic inflammatory disease, and ultimately infertility
in women. A woman
died in 2017
because she contracted a bug that resisted 26
different antibiotics — every antibiotic available in the US.

Antibiotic-resistant strains were also reported to be
found in a huge portion of supermarket meats, which the World
Health Organization says is a threat to food safety and security.

Why is there a rise in superbugs?


The overuse of prescription drugs
and antibiotics in both
humans and agriculture is one culprit, as is rise of antimicrobial
chemicals
in household products. Climate change may also be

contributing to
growing antibiotic resistance.

Certain
lifestyle
factors like constantly using hand sanitizer and
other antiseptics may decrease the body’s microbial diversity.
With fewer good bacteria in the body as defense, humans are more
likely to become susceptible to bad, resistant ones. And the
antibiotics one person takes can affect everyone because it’s not
the person who becomes immune; it’s the strain of bacteria.

Antibiotic resistance appeared almost immediately after the
advent of antibiotics. To companies, that didn’t matter for
a lot of years because there were always new antibiotics in the
pipeline. But that slowed down and almost came to a stop starting
about 15 years ago. Unlike almost every area of drug development,
antibiotics will all eventually lose their effectiveness, because
bacteria is good at evolving ways to defeat them. 

The US is trying to do its part to combat these superbugs.

To encourage the costly development of new antibacterial drugs,
FDA Commissioner Scott Gottlieb has mentioned the possibility of
a reimbursement model for antibiotics that met certain criteria,
primarily their ability to target dangerous, multi-drug resistant
infections.

Both the CDC and the National Institute of Allergy and Infectious
Diseases have developed
strategic plans
and
solutions initiatives
to fight antimicrobial resistance.

Congress increased CDC’s funding to combat antibiotic resistance
in 2018 to $168 million, a $5 million increase over last fiscal
year, and tasked it with the effort to contain, protect and
prevent superbug spread. But prevention is just one aspect of the
crisis. The CDC also tries to monitor new drugs that become
active to ensure they are not underused or overused.

“We try to hold on to new drugs that come into market and use
them prudently so they can remain active for longer,” said the
CDC’s Patel. “This antibiotic stewardship is good for public
health but not good for drug companies trying to turn a profit on
their initial investment.”

Patel said that because of this there’s a need for novel types of
therapeutics, and also for diagnostic companies that can detect
resistance early on so that it can be contained and eradicated
before it spreads.

What’s in the pipeline for antibiotics

There are two ways researchers are hoping to tackle antibiotic
resistance. While there’s a hefty research force dedicated to
product development of therapeutic treatments, there’s also a
good chunk of research dedicated to understanding the mechanisms
of resistance, including how it happens and how it spreads.

In early July, researchers at the European Molecular Biology
Laboratory in Germany
combined different antibiotics
to take out drug-resistant
strains and found sweet spots where certain combinations worked
perfectly without damaging healthy bacteria. However, sometimes,
combinations would actually make both drugs less effective. Ana
Rita Brochado, an author of the study, said that what happens is
that some bacteria have protective systems that become activated
with the addition of the second drug, which shields them against
the antibiotics. 

The drug combinations that worked well together were very species
specific, meaning they only worked for certain strains of
resistant bacteria and were not all-encompassing. “I think
there’s a lot of potential for using combinations, but we do need
to understand a lot more about mechanisms behind antibiotic
action so we can fully understand why they are different from
bacteria to bacteria and what each antibiotic is doing to the
bacteria’s defense, not just the drug target,” said Brochado.

The treatment is being tested out in mice and bacteria extracted
from humans. 

Researchers have even gone as far as to revive a 100-year-old,
discontinued method to battle bacteria: bacteriophage
therapy
.

“It’s a back-to-the-future kind of remedy,” said Steffanie
Strathdee, chief of the division of global public health in the
department of medicine at University of California at San Diego.
“It’s tapping into the body’s own microbial arms race.”

Strathdee’s husband contracted an infection while on vacation in
2015 and fell into a coma after the gut-superbug resisted
multiple antibiotics. In a case study now made famous, Strathdee
dug up buried research on so-called phages, which are viruses
that infect bacteria, in search of a cure. After finding a phage
that matched up with the resistant bacteria and injecting it into
his bloodstream, Strathdee’s husband woke up from the coma.

Since then, phage therapy has been used successfully to treat
five other patients. After the discovery of the antibiotics in
the 1920s, phages were relegated to the back burner. The
trickiest part lies in finding the matching phage, characterizing
it and purifying it so that it’s safe for patient use.

Phage therapy is an experimental treatment used by doctors at UC
San Diego Health and the demand has been so high that they’ve
opened a
new center
. Since it’s not yet approved in the US, patients
need approval from the FDA for emergency use to access it.

Strathdee and her team of scientists at UCSD have partnered with
two startups,
AmpliPhi Biosciences
and Adaptive Phage Therapeutics, to
compile a phage library and create personalized phage cocktails
for patients. They noticed that bacteria became resensitized and
started responding to antibiotics after interacting with phages,
said Strathdee.

Understanding the science and makeup of bacteria can also help
scientists devise new ways to destroy it. To stay ahead of the
mutation, many scientists are sequencing
the genomes
of resistant microbes to track their evolution
and spread.

There are also external funds from CARB-X and BARDA
a part of the Department of Health and Human Services — to
encourage development of new therapeutic agents and encourage
drugs to come to market.

On the front end of drug development, there’s a lot of work being
done. Dr. John Farley, deputy director of the office of
antimicrobial products at the Food and Drug Administration, says
the agency teams up with small and midsize companies to study
bacteria pathways and develop drugs.

There has been government-wide response to seek funding to move
drugs into clinical trials and advance them through the approval
process. Programs like
Generating Antibiotic Incentives Now
 and
LPAD
also aim to attract external investment for the back end
of drug development. 

“I don’t think anyone thinks the pipeline is as strong as it
needs to be,” said Farley. “There are economic challenges that
still remain that’s at the heart of all of this.”

In the
antibiotic clinical pipeline
, one new drug application has
been submitted to the FDA for clinical approval and two new drugs
have been approved. In clinical development, there are 16 drugs
in phase 1, 14 in phase 2, and 15 in phase 3, according to a
report by PEW. But medical experts say the number of drugs in
development aren’t nearly enough to address superbugs.

“There’s relatively little in the
pipeline that actually tackles the most serious resistant
organisms that are out there today,” said Allan Coukell, senior
director of drugs and medical devices at the Pew Charitable
Trusts.


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