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#285: TB Fights Back (fwd)
From: Anne Russell <email@example.com>
TB Fights Back
Misuse of antibiotics is prompting outbreaks of tuberculosis that don't
respond to standard treatment. Why drug resistant infections are everyone's
-- from The Washington Post
Tuesday, August 17, 1999; Page Z10
Paul Farmer, an American doctor working in a small hospital in Haiti, found
one of his tuberculosis patients weeping one day a few months ago. The
woman, Roseleine Pierre, 27, was sick with a strain of TB bacteria that had
already destroyed her left lung and part of her right, even though she had
faithfully completed two rounds of treatment with a drug regimen recommended
by the World Health Organization (WHO).
Pierre's lung infection was resistant to those drugs. She'd lost her baby
several weeks earlier -- probably to TB. Soon, despite the new medicines
Farmer was trying, she, too, might die. She was crying, she told Farmer,
because she couldn't repay the money she had borrowed to pay for her
Stories like Pierre's are common, according to Farmer, a TB specialist and
assistant professor of social medicine at Harvard Medical School. Cases of
TB caused by strains of bacteria resistant to standard drugs are showing up
with increasing frequency in many regions of the world, from Eastern Europe
and Asia to North and South America.
The growing threat of drug-resistant TB is an ironic twist in the story of
mankind's battle with this ancient disease, which first became curable with
antibiotics just a few decades ago. The discovery of drugs that would kill
disease-causing bacteria was one of the greatest medical achievements of the
20th century and led many to hope that tuberculosis, along with a number of
other infections, would soon become a distant memory.
But TB bacteria, like many other kinds of microbes, are fighting back.
Widespread use of antibiotics has triggered the evolution of new strains
that can't be killed by the standard drugs used to treat the disease,
raising concerns that TB--still a major killer worldwide--could be on the
verge of a comeback here and in other developed countries.
The problem is not confined to TB. Many kinds of bacteria are becoming more
resistant to antibiotics, including common microbes that cause pneumonia,
ear infections, wound abscesses and blood poisoning.
Health officials view the rise of drug-resistant TB with particular alarm.
Tuberculosis is the world's second-deadliest infectious disease, killing
between 1.5 million and 2 million people per year--almost as many as AIDS.
Public health experts warn that without an international effort to find and
treat drug-resistant cases, the new strains of bacteria will spread widely.
Drug-resistant TB strains migrate with the people who carry them and can be
spread whenever an infected person coughs them into the air. Hospital
patients can spread them to doctors and nurses, school bus drivers can pass
them along to students, airline passengers to their fellow travelers on a
Though most cases are concentrated in poor communities and developing
countries, drug-resistant TB may be "coming soon to your neighborhood,"
Farmer said. "If we can stop arguing about this now and just move forward .
. . we can alter the face of this epidemic in the future."
Making Matters Worse
People who are infected with drug-resistant strains often endure repeated
rounds of ineffective treatment with standard antibiotics that leave them
sick while making the highly contagious infection in their lungs even more
difficult to cure.
In a study published last year, the WHO surveyed 35 countries and found that
among TB patients who had never been treated before, 10 percent of bacterial
strains causing the disease were resistant to at least one drug. Hot spots
for drug-resistant TB include Russia (where experts say an epidemic in
prisons is spreading to surrounding communities), parts of Eastern Europe,
the Dominican Republic, Argentina and the Ivory Coast.
Because testing for drug resistance is complex, expensive and unavailable in
many developing countries, people who are sick with drug-resistant TB often
are treated repeatedly in clinics with standardized regimens sanctioned by
WHO. But in many cases, those medicines can't cure their illness. Instead,
each course of inadequate therapy only encourages the bacteria to evolve
built-in protections against additional drugs. Soon, a strain that was once
resistant to two drugs can become resistant to four or five.
That's what had happened to Pierre, Farmer's patient. If such patients don't
die, Farmer said, they continue to cough--thereby spreading their
hard-to-treat TB to family members, acquaintances, other patients and health
care workers. "When you lose them, you lose them slowly and they're
spreading resistant organisms," he said.
For now, most strains of TB that are resistant to standard medicines can be
successfully treated with second-line or third-line regimens, but the drugs
used in those regimens are much more expensive and have more side effects.
The standard regimen costs about $20 per patient, the second-line regimen
$35 and the third-line regimen about $2,000.
In New York, where an outbreak of drug-resistant TB occurred in the early
1990s, all patients are now tested for their response to antibiotics and
prescribed more potent drugs if necessary.
But TB programs in most developing countries can't afford the costly
third-line therapy needed for cases resistant to multiple drugs, nor can
many individual patients. But Farmer argues that if the global community
isn't willing to pay now to treat drug-resistant TB, it will pay more dearly
later as the microbes become even harder to kill and spread more widely.
The spread of a TB strain resistant to all current treatments could turn
back the clock to the pre-antibiotic era, when tuberculosis was incurable,
said Kenneth Castro, director of the division of tuberculosis elimination at
the federal Centers for Disease Control and Prevention. In the early 1950s,
before effective drugs became widely available, at least 20,000 Americans
died of the disease each year.
Many doctors, researchers and health officials fighting TB say the WHO's
longtime focus on a single strategy to combat the disease has delayed action
on the problem of drug resistance and may have contributed to the slow
progress of research on new treatments and a better vaccine.
The WHO's primary weapon against TB is called DOTS--short for Direct
Observation Treatment, Short-course. Most patients take four anti-TB drugs
for two months, then two drugs for four more months. A health worker or
someone else watches each patient take the medicines daily. TB control
programs must have a consistent drug supply as well as reliable laboratory
methods--usually microscopic examination of mucus samples coughed up by
patients--for monitoring whether treatment is working. To implement the DOTS
strategy, the WHO urges governments to establish national TB control
programs that employ standard, approved combinations of drugs. Arata Kochi,
the WHO's director of communicable disease prevention and control, said
health departments in developing countries don't have the money to provide
individually tailored treatment to patients with drug-resistant TB, as
Farmer and his co-workers are doing on a small scale in clinics in Peru and
Haiti. The WHO, which spends between $25 million and $30 million annually to
provide technical assistance on TB control, is strengthening a network of
laboratories that conducts surveillance for resistant strains, and recently
initiated studies in Russia to test regimens, nicknamed "DOTS-PLUS," which
are designed for cases of tuberculosis that are resistant to multiple drugs.
If the new DOTS-PLUS treatment regimens work, setting up national programs
to make them widely available to patients with drug-resistant TB is likely
to be both challenging and enormously expensive, noted the WHO's Mario
Raviglione. Most patients infected with such strains will need to take
medicines continuously for 18 to 24 months, he added, and those caring for
them must "guarantee that these drugs are administered . . . under strict
supervision, so that they are not lost for the future by the creation of
further multidrug resistance."
Currently, most of the global cost of TB control, which Kochi estimated at
$2 billion annually, is borne by individual countries. About $70 million per
year comes from foreign aid provided by the United States and other donors.
The WHO's first priority, Kochi said, remains improving the track record of
national TB control programs in treating strains of the disease that respond
to first-line drugs, which can cure up to 95 percent of people with
drug-sensitive TB. If a country doesn't have a good program for treating
drug-sensitive TB, he said, "it's no use to start introducing regimens" for
treating it. "How could you expect good results?"
Kochi acknowledged the importance of research, particularly to develop a
better vaccine to immunize people against TB, but added, "We don't want
competition of resources. The tuberculosis research pie should be much
bigger, as well as the tuberculosis control pie."
Other TB experts emphasized that the DOTS approach, while a vital part of an
overall strategy for fighting TB, will not stem the growth of drug-resistant
strains of bacteria. They applauded the WHO's recent establishment of the
"DOTS-PLUS" initiative for finding and treating resistant cases.
"The current DOTS program is not going to make drug-resistant tuberculosis
go away, and it will continue to increase if it's not addressed," said Mary
Wilson, a professor of medicine at Harvard Medical School.
Seeking the Ideal Vaccine
Developing new drugs to treat TB and a better vaccine to prevent it should
also be part of the international health agenda, said Gilla Kaplan, an
associate professor of immunology at Rockefeller University in New York.
"There's never been a disease that's been eliminated with antibiotics," she
said. "DOTS should definitely be a priority but I would like to see . . . a
very vigorous vaccine development program and a serious drug development
program. If they force us to choose, it's an outrage."
Kaplan and her team of researchers are studying how the body fights off a
tuberculosis infection. They infect mice or rabbits with various TB strains
and then test them to find out which components of the immune system's
response are important in controlling the infection and which ones
contribute to the organ damage produced by the disease.
Ninety percent of people who become infected with TB bacteria never get
sick, probably because the immune system successfully walls off the microbes
in a tiny area of the lung. In the 10 percent who do fall ill, much of the
damage is triggered by inflammation associated with chemicals produced by
the immune system, particularly one called tumor necrosis factor alpha, or
TNF alpha, Kaplan said.
One new treatment for TB-associated tissue damage, currently being tested by
Kaplan and colleagues in South Africa, is the drug thalidomide, a sedative
once removed from the international market because it can cause birth
defects. Thalidomide, which is now being used as a treatment for leprosy and
for some cancers, reduces TNF alpha production by the immune system, thereby
limiting tissue damage associated with TB. It also stimulates T cells, the
specialized white blood cells that fight the infection.
Treatments that improve the immune response to tuberculosis could be
particularly helpful for patients with drug-resistant TB, whose immune
systems are their chief weapon against the disease, Kaplan said.
The ideal vaccine for tuberculosis might be made from a strain of weakened
TB bacteria that provokes a strong, protective immune response but doesn't
stimulate too much production of TNF alpha and other inflammatory factors,
Kaplan suggested. But researchers don't yet have a clear enough
understanding of how the immune system handles the infection to identify
that perfect strain or to predict how well an experimental vaccine is likely
A TB vaccine known as BCG, made from a weakened bacterial strain and
currently used in many countries, protects against the most severe forms of
childhood tuberculosis but doesn't prevent infection or protect against the
most common form of TB, which destroys the lungs of adults.
"We have over 100 candidate vaccines out there . . . that would be
potentially as good or better than BCG," Kaplan said. "However, we don't
know how to test them in humans besides designing an enormous clinical trial
with 100,000 people that would last for 10 years."
The National Institutes of Health has increased its funding for TB research
during the 1990s, and the Clinton administration's proposed budget for the
year 2000 includes about $50 million for TB research, said Anthony M. Fauci,
director of the National Institute of Allergy and Infectious Disease
But few pharmaceutical companies have shown interest in developing new drugs
or a new vaccine for TB, said Barry Bloom, dean of the Harvard School of
Public Health. "They feel there's no market," he said.
Rifapentine, approved last year, was the first new TB drug to be marketed in
the United States in 25 years. Researchers say it is not a major therapeutic
advance. It is chemically similar to rifampin, one of the standard
Fauci said the U.S. Department of Health and Human Services has adopted a
20-year plan for developing and testing a new TB vaccine. Initially, money
to test candidate vaccines in animals will come from NIAID's annual research
Fauci said that eventually, a few of the most promising vaccines will have
to be tested in large, expensive trials enrolling tens of thousands of
people, probably in developing countries. Even with huge studies, it may
take many years to determine whether a new vaccine is effective.
But with tuberculosis bacteria rapidly becoming resistant to the existing
treatments, finding a more effective vaccine may offer the best long-term
hope of vanquishing the disease. "You have to assume we're going to run out
of TB drugs," Bloom said.
In U.S., Patients Play Role in Antibiotic Resistance
You have a scratchy throat and plugged-up sinuses--worse than a cold, you
think. You go to the doctor and plead for a prescription for antibiotics. In
a few days, when you feel better, you stop taking the drug.
That common scenario is a major reason why infectious agents are
increasingly able to fight off the miracle drugs designed to conquer them.
The rise in cases of drug-resistant tuberculosis in countries around the
world is one alarming aspect of a more general global problem: the emergence
of antibiotic resistance in many kinds of disease-causing bacteria.
Streptococcus pneumoniae, a common cause of pneumonia and childhood ear
infections, used to be exquisitely sensitive to penicillin and chemically
related antibiotics. But now many strains have become harder to kill,
requiring patients to take much higher doses. Some hospital strains of
staphylococcus, the culprit in many skin and wound infections, have become
resistant to vancomycin, a powerful antibiotic that doctors have long relied
on to work in such cases when all else failed.
The development of resistance to antibiotics isn't some conscious, malicious
plot hatched by germs. Instead, the new strains evolve in large part because
doctors and patients are misusing these valuable drugs. Resistant bacteria
arise through a process called natural selection. When bacteria are
repeatedly exposed to powerful antibiotics that kill large numbers of them,
the few that possess the genetic capacity to survive are "selected." They
eventually multiply until they predominate, creating a new strain of
bacteria that aren't responsive to standard drugs.
This process works the same way in bacteria that cause tuberculosis and in
those that cause other diseases. It's also the reason some strains of the
human immunodeficiency virus (HIV) are developing resistance to drugs used
to treat AIDS.
Used properly, antibiotics work so well against bacterial infections that
the results often seem miraculous. But that very effectiveness makes
patients demand them and leads some doctors to prescribe them
indiscriminately. The result is widespread overuse here and in other
countries. Researchers at the federal Centers for Disease Control and
Prevention (CDC) estimate that as many as a third of the approximately 150
million courses of antibiotic treatment prescribed in the United States each
year may be unnecessary.
Illnesses that shouldn't be treated with antibiotics (but often trigger a
prescription anyway) include the common cold, sore throats not caused by
"strep" bacteria, most cases of bronchitis, sinus congestion not accompanied
by the severe pain and fever that signal an acute infection, and fluid
behind the eardrum of a child who isn't having fever and earache.
Most colds, coughs, sore throats and stuffy noses, as well as many childhood
ear infections, are caused by viruses--and most viruses that invade the
upper respiratory tract can't be killed by drugs. (One exception is the
influenza virus, for which new antiviral drugs are becoming available, but
CDC experts say they probably won't be needed in the majority of "flu"
"One of the things we're really trying to get across to the public is the
difference between a bacterial infection that may be cured by antibiotics
and viral infections that cannot be cured by antibiotics," said Richard
Besser, a pediatrician and medical epidemiologist at the CDC.
Taking antibiotics when they're not needed isn't merely wasteful; it can be
dangerous for the patient and for the community. All drugs have potential
side effects. For example, many antibiotics kill off various species of
bacteria that normally live in the digestive tract, sometimes leading to the
overgrowth of one type, Clostridium difficile, that can produce diarrhea and
Since the human body harbors millions of bacteria at all times, taking
antibiotics also exposes those resident bacteria to natural selection,
contributing to the evolution of resistant strains that might produce an
infection or be passed to someone else. Some types of resistant bacteria can
live on the skin or in the nose, throat or digestive tract without producing
any symptoms, but may cause illness if transmitted to a vulnerable person--a
newborn baby, a surgical patient or someone with a weakened immune system.
Once resistant strains of bacteria become common in a community or in a
hospital, anyone may become infected--not just people who have taken many
antibiotics in the past. Someone who develops drug-resistant TB, for
instance, can transmit it to healthy family members, friends or health care
"It's clear that communities that use more antibiotics will have more
resistant infections than communities that do not," says Besser. And within
each community--whether it's a town, a school or a day-care center--people
who have taken antibiotics recently are the ones most at risk for developing
a drug-resistant infection.
Another form of behavior that promotes the development of
antibiotic-resistant microbes is not taking the drugs as prescribed.
Although you shouldn't take antibiotics needlessly, when these drugs are
required to treat an infection, it's important to take each dose and to
finish the prescription. Don't share antibiotics with anyone else or save a
few pills in case of future need. Doctors prescribe an antibiotic for a
certain number of days because they have reason to believe (based on studies
or accepted guidelines) that this length of treatment is necessary to cure
If a patient stops taking an antibiotic early because the symptoms are gone,
or neglects to take doses regularly, the bacteria causing the infection may
not all be killed--and the ones that survive will be more likely to have
genetic traits that have rendered them partially resistant to the drug.
Incomplete treatment of an infection with antibiotics--whether it's TB or a
child's ear infection--is one of the surest ways to produce
In focus groups conducted by CDC researchers, most doctors admit they
sometimes prescribe antibiotics when the drugs aren't needed because they
think patients (or patients' parents) expect it.
Besser says the CDC is working hard to change attitudes of both physicians
and patients. The campaign includes brochures, posters and videos in
doctors' waiting rooms, as well as efforts to teach practitioners and
medical students how to explain to patients why an antibiotic isn't always a
To make sure antibiotics will keep working, everyone needs to use them with
care. Instead of asking your doctor, "Can I have an antibiotic?" Besser
suggests you say, "Do I really need an antibiotic?
"I think that's an important question for patients to ask."
-- Susan Okie
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