-
Bacteria race ahead of drugs.
Deadly infections
increasingly able to beat antibiotics.
Sabin Russell -
Sunday, January 20, 2008
At a busy microbiology lab in San
Francisco, bad bugs are brewing inside vials of
human blood, or sprouting inside petri dishes, all
in preparation for a battery of tests.These tests
will tell doctors at UCSF Medical Center which
kinds of bacteria are infecting their patients,
and which antibiotics have the best chance to
knock those infections down.
With disturbing regularity, the
list of available options is short, and it is
getting shorter.
Dr. Jeff Brooks has been director
of the UCSF lab for 29 years, and has watched with
a mixture of fascination and dread how bacteria
once tamed by antibiotics evolve rapidly into
forms that practically no drug can treat. "These
organisms are very small," he said, "but they are
still smarter than we are."
Among the most alarming
of these is MRSA, or methicillin-resistant
Staphylococcus aureus, a bug that used to be
confined to vulnerable hospital patients, but now
is infecting otherwise healthy people in schools,
gymnasiums and the home. As MRSA continues its
natural evolution, even more drug-resistant
strains are emerging. The most aggressive of these
is one called USA300.
Last week, doctors at San
Francisco General Hospital reported that a variant
of that strain, resistant to six important
antibiotics normally used to treat staph, may be
transmitted by sexual contact and is spreading
among gay men in San Francisco, Boston, New York
and Los Angeles.
Yet the problem goes far beyond
one bug and a handful of drugs. Entire classes of
mainstay antibiotics are being threatened with
obsolescence, and bugs far more dangerous than
staph are evolving in ominous ways. "We are on the
verge of losing control of the situation,
particularly in the hospitals," said Dr. Chip
Chambers, chief of infectious disease at San
Francisco General Hospital.
The reasons
for increasing drug resistance are well known:
- Overuse of antibiotics, which
speeds the natural evolution of bacteria,
promoting new mutant strains resistant to those
drugs.
- Careless prescribing of antibiotics that
aren't effective for the malady in question,
such as a viral infection.
- Patient demand for antibiotics when they
aren't needed.
- Heavy use of antibiotics in poultry and
livestock feed, which can breed resistance to
similar drugs for people.
- Germ strains that interbreed at hospitals,
where infection controls as simple as
hand-washing are lax.
All this is
happening while the supply of new antibiotics from drug company
laboratories is running dry.
Since commercial production of
penicillin began in the 1940s, antibiotics have
been the miracle drugs of modern medicine,
suppressing infectious diseases that have
afflicted human beings for thousands of years. But
today, as a generation of Baby Boomers begins to
enter a phase of life marked by the ailments of
aging, we are running out of miracles.
Top
infectious disease doctors are saying that
lawmakers and the public at large do not realize the
grave implications of this trend.
"Within just a few
years, we could be seeing that most of our
microorganisms are resistant to most of our
antibiotics," said Dr. Jack Edwards, chief of
infectious diseases at Harbor-UCLA Medical Center.
At Brooks' microbiology
laboratory, the evolutionary struggle of bacteria
versus antibiotics is on display every day. He
grabbed a clear plastic dish that grew golden-hued
MRSA germs taken from a patient a few days
earlier. Inside were seven paper dots, each
impregnated with a different drug.
If the antibiotic worked, the dot
had a clear ring around it - a zone where no germs
could grow. No ring meant the drug had failed.
This test was typical. Three drugs worked, four
had failed.
The strategy for nearly 70 years
has been to stay a step ahead of resistance by
developing new antibiotics. In the past decade,
however, major drugmakers have been dropping out
of the field.
The number of new antibiotics in
development has plummeted. During the five-year
period ended in 1987, the FDA licensed 16 novel
antibiotics. In the most recent five-year period,
only five were approved.
For
drugmakers, the economics are simple: An
antibiotic can cure an infection in a matter of
days. There is much more money in finding drugs,
that must be taken for a lifetime.
Toll of
antibiotic resistance.
With antibiotic research
lagging, the bugs are catching up, and infections
are taking a terrible toll.
The CDC
estimates that each year 99,000
Americans die of various bacterial infections
that they pick up while hospitalized - more than
double the number killed every year in
automobile accidents.
Of the
1.7 million hospital-acquired infections that
occur each year, studies show, 70
percent are resistant to at least one
antibiotic.
Drug-resistant staph is rapidly
becoming a major public health menace. Last fall,
the CDC estimated that MRSA alone has killed
19,000 Americans. Most of these patients picked up
the bug in the hospital, but it is now spreading
in urban and suburban neighborhoods across the
nation.
Peg
McQueary's struggle to survive:
"MRSA is killing people. It almost
killed me," said Peg McQueary, whose life was
upended when she nicked her leg with a razor three
years ago. Within days, her leg was grotesquely
swollen, red from foot to knee.
Her husband wheeled her into a
Kaiser medical office, where her doctor took one
look and rushed her to an isolation room. She was
placed on intravenous vancomycin, a drug reserved
for the most serious cases of MRSA.
Since that frightening week, the
42-year-old Roseville woman has spent much of her
life in and out of hospitals, and she's learned
just how difficult these infections can be to
treat. McQueary has burned through drug after
drug, but the staph keeps coming back.
She's been hooked up at her home
to bags of vancomycin and swallowed doses of
linezolid, clindamycin and a half a dozen other
antibiotics with barely pronounceable names and
limited effect.
One of the newest antibiotics,
intravenous daptomycin - approved by the Food and
Drug Administration in 2003 - seems to work the
best, but it has not prevented recurrences. "It's
just a struggle to do everyday things," she said.
"I am ready to scream about it."
Today, she moderates a Web site,
MRSA Resources Support Forum, swapping stories
with other sufferers. "Giving them a place to vent
is some sort of healing for me," she said.
McQueary's travails are becoming
an all-too-familiar American experience. As
bacteria evolve new ways to sidestep antibiotics,
doctors treating infections find themselves with a
dwindling list of options. Old-line drugs are
losing their punch, while the newer ones are both
costly and laden with side effects.
Drugs' weakening grip.
Dr. Joseph Guglielmo, chairman of
the Department of Clinical Pharmacy at UCSF,
closely tracks the effectiveness of dozens of
antibiotics against different infectious bacteria.
Laminated color-coded cards called antibiograms
are printed up for hospital physicians each year.
They chart the success rate of each antibiotic
against at least 12 major pathogens.
These charts show how antibiotics,
like tires slowly leaking air, are losing strength
year by year.
As head of the hospital pharmacy,
Guglielmo oversees a small warehouse at the
medical center that stores millions of dollars
worth of prescription drugs that are used every
day to treat patients there. Strolling down the
aisles that houses bins of antibiotics, he reached
for a bottle of imipenem, and cradled the little
vial in the palm of his hand. "This one is the
last line of defense," he said.
Imipenem was approved by
the FDA in 1985. A powerful member of the
carbapenem family - the latest in a long line of
penicillin-like drugs - it is frequently used in
hospitals today because it can still defeat a wide
variety of germs that have outwitted the
earlier-generation antibiotics.
But at a cost of about
$60 a day, and with a safety profile that includes
risk of seizure, it is a "Big Gun" drug that must
be used carefully. As soon as doctors discover
that a lesser antibiotic will work, they will stop
prescribing imipenem, like soldiers conserving
their last remaining stores of ammunition.
Now, there
are signs of trouble.
Imipenem has been the
antibiotic of choice for doctors treating
Klebsiella, a vigorous microbe that causes
pneumonia in hospitalized patients.
In June 2005, New York
City doctors reported in the journal Archives of
Internal Medicine outbreaks of imipenem-resistant
Klebsiella. Fifty-nine such cases were logged at
just two hospitals.
The death rate among
those whose infections entered their bloodstreams
was 47 percent. Last year, Israeli doctors battled
an outbreak of carbapenem-resistant Klebsiella
that has killed more than 400 patients.
Cipro's
dramatic decline.
The antibiotic Cipro, approved by
the Food and Drug Administration in 1987, is
familiar to millions of Americans because it is
widely prescribed for pneumonia, urinary tract
infections and sexually transmitted diseases. It
was the drug used to treat victims of the anthrax
mailings that followed the Sept. 11 attacks.
Unlike most antibiotics, which
originated from natural toxins produced by
bacteria, Cipro came from tinkering with a
chemical compound used to fight malaria. The
German drug giant Bayer patented Cipro's active
ingredient in 1983, and it subsequently became the
most widely sold antibiotic in the world.
At hospitals across the country,
however, clinicians have witnessed a remarkable
drop-off in the utility of Cipro against more
commonly encountered germs. Antibiograms from the
UCSF lab highlight the alarming erosion: As
recently as 1999, Cipro was effective against 95
percent of specimens of E. coli - bacteria
responsible for the most common hospital-acquired
infections in the United States.
By 2006, Cipro would work
against only 60 percent of samples tested.
The bacterial evolution that has
so quickly sapped Cipro has also reduced the
effectiveness of the entire family of related
antibiotics called fluoroquinolones - drugs such
as Levaquin, Floxin, and Noroxin. "If there is
ever a group of drugs that has taken a beating, it
is these," said UCSF pharmacy chief Guglielmo.
Against Acinetobacter -
a bug responsible for rising numbers of
bloodstream and lung infections in intensive care
units, as well as among combat casualties in Iraq
- Cipro's effectiveness fell from 80 percent in
1999 to 10 percent just four years later.
Cipro has also lost
ground against Pseudomonas aeruginosa, a common
cause of pneumonia in hospitalized patients.
Nearly 80 percent of the bugs tested were
susceptible to Cipro in 1999. That fell to 65
percent by 2004.
At UCSF, doctors carefully monitor
the trends in drug resistance and modify their
prescribing patterns accordingly. As a result,
they have been able to nudge some of these
resistance levels down. Cipro's effectiveness
against Acinetobacter crept up to 40 percent last
year, for example, but the overall trend remains
alarming.
Although MRSA infections have been
capturing headlines, bugs such as Acinetobacter,
Klebsiella and Pseudomonas are keeping doctors
awake at night. They come from a class of
pathogens called Gram-negative bacteria, which
typically have an extra layer of microbial skin to
ward off antibiotics, and internal pumps that
literally drive out antibiotics that penetrate.
Gram-negative infections have
always been difficult to treat, and few new drugs
are in development. Some researchers believe that
the pipeline for new antibiotics is drying up
because it is simply getting more difficult to
outwit the bugs.
"It may be that we've already
found all the good antibiotics," warned Chambers,
San Francisco General Hospital's infectious disease
chief. "If that is so, then we've really got to be
careful how we use the ones we have."
Bacteria's
natural evolution.
Terry Hazen, senior scientist at
Lawrence Berkeley National Laboratory and director
of its ecology program, is not at all surprised by
the tenacity of our bacterial foes. "We are
talking about 3.5 billion years of evolution," he
said. "They are the dominant life on Earth."
Bacteria have invaded virtually
every ecological niche on the planet. Human
explorers of extreme environments such as deep
wells and mines are still finding new bacterial
species.
"As you go deeper into the
subsurface, thousands and thousands of feet, you
find bacteria that have been isolated for millions
of years - and you find multiple antibiotic
resistance," Hazen said.
In his view, when bacteria develop
resistance to modern antibiotics, they are merely
rolling out old tricks they mastered eons ago in
their struggle to live in harsh environments in
competition with similarly resilient species.
Drug industry economics are also a
factor. "It takes a hell of a lot of effort to
find the next really good drug," said Steven
Projan, vice president of New Jersey
pharmaceutical giant Wyeth Inc. The costs of
bringing a new drug to market are hotly debated. A
Tufts University study estimated $802 million; the
consumer group Public Citizen pegs it at $110
million. Either way, the investment is huge.
By
1990, according to the Infectious Diseases Society
of America, half the major drugmakers in Japan and
the United States had cut back or halted antibiotic
research. Since 2000, some of the biggest names in
pharmaceutical development - Roche, Bristol-Myers
Squibb, Abbott Laboratories, Eli Lilly, Aventis and
Procter & Gamble - had joined the exodus.
By common measures used
to gauge the profit potential of new drugs,
antibiotics fall way behind, Projan explained. For
every $100 million that a new antibiotic might
yield, after projected revenue and expenses are
tallied, a new cancer drug will generate $300
million. A new drug for arthritis, by this same
analysis, brings in $1.1 billion. Investors have
been placing their bets accordingly.
In 2002, Wyeth had sharply
curtailed its own antibiotic drug discovery
programs. "We tried to get out of the field, but
one of the reasons we did not get out altogether
is we feel we have a public responsibility to fund
more research," said Projan.
Wyeth's decision to keep some
antibiotic research alive eventually paid off. In
June 2005, the FDA licensed Tygacil, an intravenous
antibiotic for complicated skin diseases such as
drug-resistant staph infection. Only one new
antibiotic for oral or intravenous use has won FDA
approval since.
Pointing a finger at doctors.
The waning of antibiotics in the
arsenal of modern medicine has been going on for
so long that some doctors fear a kind of
complacency has set in. Increasingly, the medical
profession is pointing a finger at itself.
"We have behaved very badly," said
Dr. Louis Rice, a Harvard-educated,
Columbia-trained specialist in infectious
diseases. "We have made a lot of stupid choices."
His words brought a nervous silence to thousands
of his colleagues, as he delivered a keynote
speech in 2006 for the American Society for
Microbiology's annual conference in San Francisco.
Rice, a professor at Cleveland's
Case Western Reserve University, said doctors and
drug companies alike are responsible for breeding
resistance by "the indiscriminate dumping of
antibiotics into our human patients."
Drug-resistant germs contaminate
the bedrails, the catheter lines, the blood
pressure cuffs and even the unwashed hands of
doctors, nurses and orderlies. The germs keep
evolving, swapping drug-resistance traits with
other microbes. He likened American intensive-care
units - the high-tech enclaves where the most
seriously ill patients are treated - to "toxic
waste dumps."
Drug companies, he said, have a
responsibility to refill the nation's depleted
medicine chest. He suggested that a tax - similar to
a Superfund tax placed on polluters to clean up
toxic waste sites - be imposed on companies that
have dropped antibiotic research. It would support
drugmakers that are still in the game. "Your
products that you've made billions and billions and
billions and billions of dollars on have created
this problem, and you can't just walk away," he
said.
Rice has stressed that the
existing arsenal of antibiotics should be used
wisely, and that often means sparingly.
During a
half century of antibiotic use, he said, there is scant research on how
short a course of drugs is actually needed to
cure a patient. Instead,
doctors routinely prescribe a week to 10-day
course of drugs recommended by manufacturers.
If patients are taking antibiotics
after their infections are truly gone, they are
creating conditions that breed resistance. Indeed,
a Dutch study showed that one kind of pneumonia
can be treated just as successfully with three
days of amoxicillin as with the traditional eight.
Since drug companies cannot be
expected to spend money on research that could
trim sales of their products, federally funded
agencies such as the National Institutes of Health
should do the job, Rice said in a recent
interview.
He also took his
own specialty to task for failing to protect the
most important weapons its arsenal. Infectious
disease experts at hospitals must find the
"backbone" to stop other doctors from
prescribing antibiotics unnecessarily, Rice
said. He argued they should assert their
authority to control antibiotic usage, just as
cancer specialists have a say in which
chemotherapy drugs are prescribed by surgeons.
And all health care professionals, he added,
"have to wash their damn hands." - www.sfgate.com
So how do we stay healthy?
Checklist
Begin by removing these toxins from your home.
Drug resistance to antibiotics is
failing.
