[Pharmwaste] Are We Running Out of Antibiotics?

[DeBiasi, Deborah (DEQ)]

http://www.newsweek.com/2010/12/07/are-we-running-out-of-antibiotics.htm
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Are We Running Out of Antibiotics?

As more bacteria become resistant to the most powerful drugs in our
arsenal, new weapons are getting harder and harder to find. Why we need
to change the way we think about treating infection.

by Jeneen InterlandiDecember 07, 2010 


 Dennis Kunkel Microscopy, Inc. / Visuals Unlimited-Corbis

Penicillium mold, the source of the antibiotic, penicillin. 

Hardly any doctors still practicing can remember life before
antibiotics, when people were routinely hospitalized for common
infections, and the threat of deadly Staphylococcus shadowed even the
simplest surgery. But infectious-disease specialists like Brad Spellberg
of UCLA's David Geffen School of Medicine have been reading up on those
days because of a growing fear they are not all in the past. Wealthy
countries take for granted the triumph of science over bacteria, but
increasingly doctors are coming up against infections that can be
quelled only by the most powerful antibiotics known to medicine-or by
none of them. "It's already happening," says Spellberg, to the tune of
roughly 100,000 deaths a year from antibiotic-resistant infections in
the United States alone. "But it's going to become much more common."
Imagine a world in which antibiotics resemble chemotherapy
drugs-producing toxic side effects and unpredictable outcomes instead of
the guaranteed cures we have come to expect-and you can understand what
keeps Spellberg awake at night.

Breakthroughs and Breakdown In the future, historians of science may
debate whether victory over bacteria was ever within our grasp. But it
seems almost certain that the 60 or so years after penicillin came to
market will eventually be viewed as just an interlude in the eternal war
between us and them. We are multicelled animals of astonishing
complexity and delicacy, moving through a world in which they vastly
outnumber us. They are single-celled organisms so primitive they lack
even a nucleus, marvelously adapted to multiply inside us-under the
right circumstances, to consume our flesh and poison us with their
waste. For a few decades we gained the upper hand through the use of
antibiotics, natural substances that are as toxic to germs as germs are
to us. But our ingenuity is in a desperate race against their ability to
reproduce. More and more strains of bacteria are developing biological
countermeasures to antibiotics-cell membranes that won't let them in,
tiny pumps that push them back out, biochemical tweaks that make them
harmless. Evolution is a process that has been at work on earth for
hundreds of millions of years; modern biological science has been around
for less than a century and a half. Which would you bet on?

We have handicapped ourselves in this race, partly through carelessness
and partly as an outcome of the complex politics and economics of drug
policy. We've squandered our antibiotics through overuse-in animal feed,
or on diseases they can't cure, such as influenza-and, paradoxically, by
under-use. Particularly among the poor and illiterate, it's not uncommon
for patients to stop taking antibiotics as soon as they feel
better-leaving behind a residual population of resistant bacteria to
multiply and spread.

For a while this didn't matter, because there were always new
antibiotics being discovered. Beginning in the 1940s, when penicillin
first hit pharmacy shelves, humanity embarked on a decades-long quest to
collect as many soil samples as possible and probe them for potential
miracle cures. Allied soldiers scooped up dirt from the African front,
the National Geographic Society collected samples from the top of the
Himalayas, and schoolchildren everywhere dug up shovelfuls from parks
and fields. Pharmaceutical companies led the charge in harvesting this
vast collection, ultimately producing some 200 new drugs in a mere three
decades.

But by the mid-1980s, the discoveries had slowed to a trickle. "It's a
bit like oil," says Spellberg, author of the book Rising Plague.
"There's still a lot out there, but we've harvested all the easy gets.
There are very few places left where you can just tap the ground and
find some bountiful reserve." For a time, scientists thought the
molecular wizardry of modern drug design-small molecules, high
throughput screening, and the like-might reinvigorate our war against
bacteria, the same way it reinvigorated our war against cancer. No such
luck. "There are a set of rules that chemists follow when looking for
new drugs," says AstraZeneca medical director John Rex. "To make an
antibiotic, you have to break those rules. They are different from
anything else we make because they are designed to kill a living
organism inside another living organism."

That is not to say that there are no more wonder drugs left to find.
Indeed, oceanographers have turned up hundreds of thousands of
previously unknown organisms in a single cubic centimeter of deep-sea
mud. Bacteriophages-viruses that infect and kill bacteria-remain a vast
untapped source of potential anti-microbial medications, and the same
soils that gave us some of the first and most successful antibiotics are
just waiting to be reexamined with newer technology.

Video muted: click volume for sound Immigrating Can Be Bad for Your
Health For some immigrant populations, the United States is more than
just "the Land of Opportunity." Moving to America has presented a long
history of health challenges for America's immigrants. 
But the researchers best equipped to do that examining have long since
abandoned antibiotics. According to the Infectious Disease Society of
America, only five of the 13 biggest pharmaceutical companies are still
looking at all. Medications that treat cancer or chronic conditions like
diabetes, heart disease, or even baldness are simply much more
lucrative. That's because a single course of the most expensive
antibiotics (linezolid and daptomycin) runs just seven days and sells
for $1,000 to $2,000, while a single course of, say, any given cancer
treatment runs for weeks to months and costs from 10 to 20 times as
much. Chronic-disease medications, which a patient typically takes for
the rest of his or her life, yield even higher returns. It doesn't
matter that bacterial infections are infinitely more common than cancer
or even heart disease; antibiotics are still less profitable, in part
because we undervalue them. "We expect antibiotics to be not only safe
and highly effective, but cheap too," says Princeton University health
economist Ramanan Laxminarayan. "We see them as like a God-given right."
Case in point: in 2009 several large chain pharmacies began giving away
free generic antibiotics in an effort to lure more customers.

Even when an antibiotic is highly prized, the twin forces of drug
resistance and patent law still conspire against it in the marketplace.
To prevent resistance from developing, doctors are encouraged to
conserve the newest, most powerful antibiotics, using them only in the
direst of circumstances. While this preserves the drug's value as a
treatment option, it also means that sales will be slowest when a
compound is new, and will pick up only toward the end of its patent
life, when it can easily be supplanted by cheaper generic brands. "It's
a huge disincentive to develop anything new," says Rex, whose company is
one of the few still developing new antibiotics.

Of course, those economic conundrums pale in comparison to the unique
regulatory uncertainty that antibiotics face. To test any compound
against any infection, one first needs to find a group of patients. This
is easy enough for cancer or chronic diseases, or any fatal condition
where prospective study participants have some time to consider their
options. It's a bit trickier with infectious diseases, especially those
that are drug-resistant. "You pretty much need to wait for an outbreak
to occur," Rex says. "And there's no way of knowing when or where that
will happen." To test a compound against vancomycin-resistant
Enterococcus (VRE), a super-bug that infects the digestive system and
urinary tract, one pharmaceutical company opened 54 different testing
sites for two full years. Only three patients enrolled in the study. A
second attempt secured just 45 patients in 18 months, thanks largely to
an outbreak at one testing site. Both studies were closed due to
insufficient enrollment. Five years later, the drug remains stuck in
clinical-trial limbo. That is not to say that VRE isn't a significant
problem. According to the Centers for Disease Control and Prevention,
this particular super-bug infects some 26,000 hospital patients each
year. But so far, no one has a good way to match those patients to
trials.

When drugmakers do manage to cobble together a decent-size group of
study participants, they need to test their prospective drug against a
proven medication. If the experimental drug is as good as or better than
the existing treatment, it gets a green light. Sounds simple, but it
isn't. The problem is that many antibiotics were tested and approved
before there was any such thing as the FDA or double-blind
placebo-controlled clinical trials. And that has left clinicians and
statisticians at odds over how to measure success. "The clinical
evidence that has guided antibiotic therapy for decades means nothing to
the statisticians," says Paul Ambrose, president of the Institute for
Clinical Pharmacodynamics in New York. "This is part of a larger
FDA-wide crisis over how to measure drug effectiveness. But antibiotics
have it the worst because they have no placebo-controlled data to begin
with."

For just one example of how sticky this can get, take skin infections.
Last year the FDA issued guidelines for companies seeking to develop new
antibiotics to treat this condition. Its definition of a successful
drug? One that stopped skin lesions from spreading, even if it didn't
make the lesions disappear. "So if you come to me with skin lesions, and
I give you a drug, and in three days the lesions are exactly the same,
that counts as a success," Ambrose explains. "How did they come up with
this?" It turns out that the FDA based its proposed rules on just two
studies, both published in 1937, which compared an antibiotic to UV-lamp
therapy. The UV therapy was so ineffective-and skin infections were so
fatal at the time-that investigators were thrilled just to have patients
not get worse. So they counted that as a success.

The FDA has spent the past year working with would-be antibiotic
manufacturers to develop a clear path around such issues, but critics
say that in that time, the level of uncertainty has only increased.
"There are viable solutions, but we need fresh voices," Ambrose says.
"It's one or two statisticians, and a handful of clinicians arguing back
and forth and back again over the same few points." In the meantime,
without clear guidance on how to get new antibiotics approved,
pharmaceutical companies aren't going to invest the money to find and
develop them.

Neither, it seems, is anyone else. In 2009 the National Institute of
Allergy and Infectious Diseases spent $94 million on research into
treatments for potential, albeit exceedingly rare, bioterrorism agents
like anthrax and plague, and only $16 million on developing new
medications to treat drug-resistant pathogens. Likewise, Project
Bioshield, enacted after the 2001 anthrax attacks, spurred volumes of
research on the most worrisome bioterrorism agents. By promising to
purchase any successful products, the federal government ensured that
drugs to treat anthrax, plague, and Ebola would be profitable, despite
the rarity of those conditions. But that legislation included no such
guarantee for antibiotics to treat much more common drug-resistant
infections. An analogous plan to combat antimicrobial resistance was
launched around the same time, but critics say that it was grossly
underfunded and thus never quite put into action.

Policymakers are, at last, working to change this. One bill floating
through Congress, the Generating Antibiotic Incentives Now Act, would
extend the patents on certain types of antibiotics by five years to
protect them from generic competition. Other proposals include tax
breaks, liability protection, and the same guaranteed government
purchases that have been so successful in spurring bioterrorism
research.

Of course, as critics point out, market-based incentives are no
substitute for more judicious use of existing antibiotics. "Its like
saying, 'We're running out of oil because we are doing a terrible job at
conserving it, and the only solution is to find more oil,'?" says
Laxminarayan. "If we just keep developing new drugs, and then overusing
them, we aren't going to solve anything." The trick, he says, is to
start talking about antibiotics in the same terms that we use to discuss
other nonrenewable natural resources-namely, conservation and
sustainable use.

That would certainly mark a paradigm shift. The CDC estimates that as
much as 50 percent of all antibiotic use is unnecessary. Doctors
routinely prescribe antibiotics as a precautionary measure, to ward off
infections that have not yet occurred, or to appease patients worried
about falling ill while on the road. And for patients who are infected,
the approach is hardly more sophisticated. Most diagnostic methods
pre-date penicillin, which is to say they are slow, cumbersome, and
unreliable. This means doctors often have no way of knowing which bug a
patient is infected with, or which drugs that bug might be susceptible
to. Rather than waste time and money trying to answer those basic
questions, they often prescribe a couple of antibiotics at once and then
just cross their fingers. This approach is cheaper, and in the short
term it works, but it also contributes to overuse and thus allows
resistance to grow and spread.

The future will almost certainly be different. Antibiotics will cost
more and do less. They will also be less readily available than we are
accustomed to. No more fast cures, free giveaways, or "just in case"
prescriptions. But if we act quickly-and if we're lucky-it's still
possible that we won't have to know a world without them.




Deborah L. DeBiasi 
Email:   Deborah.DeBiasi at deq.virginia.gov (NEW!)
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Virginia Department of Environmental Quality 
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