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#285: TB Fights Back (fwd)

From: Anne Russell <avrussell@hotmail.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 
unsuccessful treatment.
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.
WHO's Strategy
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 
to work.
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 
intestinal inflammation.
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 
the infection.
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 
antibiotic-resistant strains.
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 
good idea.
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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