Tuberculosis
Liz Highleyman
Tuberculosis (TB) is one of the most feared diseases known to humanity. An estimated
one-third of the world's population is infected with TB. Although drugs began to bring the
disease under control in the late 1940s, TB still kills more people worldwide than any
other infectious disease.
TB infection is not the same as active TB disease. Nine out of ten people with healthy
immune systems who are infected with TB bacteria do not develop active disease; this rate
is 100 times higher in people with HIV. People with TB infection feel well, have no
symptoms, and cannot spread TB to others. In some cases, however, the immune system can no
longer control TB and active disease develops.
History
Humans have been plagued with TB since prehistoric times. Egyptian and Peruvian mummies
have been found that show signs of TB. In 17th century Europe, most of the population was
TB-infected and a quarter of deaths were attributable to the disease. The bacterium that
causes TB was discovered by Robert Koch in 1882.
TB was previously known as consumption because people with the disease experienced slow
wasting. Before the development of anti-TB drugs, people with TB were often sent to
sanitoria to recuperate with fresh air, rest, and a healthy diet, and to prevent the
transmission of the disease to others. In the pre-drug era, progressive TB disease was
often fatal.
In the late 1800s, chest X-rays began to be used to monitor TB, and two French
scientists developed an anti-TB vaccine known as Bacille Calmette-Guérin, or BCG. In
1944, streptomycin was the first antibiotic to be successfully used to treat a person with
advanced TB disease. Soon, however, drug-resistant TB strains evolved, making clear the
need for combination therapy.
Epidemiology
In the U.S., the rate of TB began to increase in the mid-1980s after declining for
three decades. TB incidence increased 15% between 1984 and 1991. This increase has been
attributed to a combination of HIV/AIDS, increased immigration, and the dismantling of the
public health infrastructure. The resurgence served as a wake-up call, and health
departments began devoting more resources to TB control.
Following a peak in 1992, the TB rate among U.S.-born persons has declined for five
years. A total of 19,855 cases of active TB disease were reported in 1997 (a rate of 7.4
per 100,000 people). The rate of active disease in San Francisco is twice the California
rate and four times the national rate. An estimated 10-15 million people in the U.S. are
infected with TB but do not have active disease.
TB incidence continues to hold steady in foreign-born U.S. residents. Nearly 40% of
TB-infected people in the U.S. are foreign-born, many of whom were infected in their
countries of origin. The TB rate among foreign-born people is 4-5 times higher than that
of U.S.-born people.
Globally, TB is most common in developing countries, especially in Africa, Asia, Latin
America and, increasingly, in Eastern Europe. There are an estimated 8-10 million new
cases of TB disease and three million deaths due to TB each year. The World Bank estimated
in August that TB accounts for more than 25% of avoidable adult deaths worldwide. In
March, the World Health Organization (WHO) reported that global efforts to control and
eliminate TB are stalled in several countries.
TB incidence varies by race, age, and sex. People of color (including those born in the
U.S.) have a higher risk than whites of becoming infected with TB and of developing active
TB disease. The U.S. Centers for Disease Control and Prevention (CDC) estimates that TB
rates are ten times higher in Asians, eight times higher in African-Americans, and five
times higher in Hispanics and Native Americans, compared to whites. Researchers think that
different racial/ethnic groups may have varying genetic susceptibilities to TB, but the
differences are also due to socioeconomic factors.
TB is more common in young children and the elderly, who tend to have weaker immune
systems. Among middle-aged people, statistics indicate that women are more likely to
develop active TB disease than men, possibly due to hormonal influences; development of
active disease is also more likely during pregnancy.
Several medical and socioeconomic factors predict a higher risk of TB infection and
disease, including diabetes, silicosis (a lung disease), chronic kidney failure,
malnutrition, cancer chemotherapy, alcoholism, injection drug use, poverty, and residence
in communal living settings such as homeless shelters, prisons, and long-term healthcare
facilities.
Multidrug-Resistant TB
Beginning in 1990, epidemiologists began to see new strains of TB that were resistant
to more than one of the drugs commonly used to treat the disease, usually isoniazid and
rifampin. These strains are known as multidrug-resistant TB (MDRTB). Several outbreaks of
MDRTB occurred in 1990-91 in hospitals and prisons in New York City and Florida. Many of
the people affected were HIV positive.
MDRTB develops when the TB bacteria mutate in such a way that they lose their
susceptibility to drugs. This is often caused by failure to take a full course of anti-TB
treatment. The CDC reports that in 1997, over 7% of TB strains tested for drug
susceptibility were resistant to at least isoniazid, and 1.3% were resistant to at least
isoniazid and rifampin. MDRTB has been seen in over 40 U.S. states and 30 countries. The
WHO recently reported on several MDRTB "hot zones" in countries including
Russia, India, Argentina, and Côte d'Ivoire.
Treatment of MDRTB is typically longer and more expensive than treatment of
drug-susceptible strains, and the fatality rate is higher. The development of
multidrug-resistant strains points to the need for continual development of new anti-TB
drugs.
Tuberculosis and HIV
The epidemics of TB and HIV are closely intertwined. HIV infection is among the
strongest risk factors for the development of active TB disease. The HIV epidemic is
increasingly affecting the same populations (people of color, the homeless, substance
users, low income people) that have the highest rates of TB. And strategies for HIV
treatment have increasingly come to resemble those established for the treatment of TB.
TB and HIV: Some
Similarities in Treatment
- Use a combination regimen of three, four, or more drugs
- Monotherapy can rapidly lead to resistance
- Do not add a single new drug to a failing regimen
- Resistance testing can help guide therapy
- Consult an expert in the case of treatment failure
- Adherence is the key to successful therapy
Diane Bennett, MD, of the CDC, reported at the 12th World AIDS Conference in July that
the U.S. rate of TB among people with HIV is more than 40 times greater than the rate in
the general population. Worldwide, TB is the leading cause of death of people with
HIV/AIDS. In 1993, TB was added to the CDC's list of AIDS-defining conditions. The rate of
HIV in people with active TB disease is also high; in one recent study of 118 TB patients
in Atlanta, over 40% had undiagnosed HIV infection.
In people previously infected with TB, HIV infection increases the risk of developing
active TB disease by an estimated 100-fold. TB-infected HIV positive people have a 1 in 10
chance per year of developing active TB disease, compared to a 1 in 10 chance in a
lifetime for TB-infected HIV negative people. People with HIV may experience a more rapid
progression of TB disease; this is thought to be related to impaired T-cell activity.
Several promising studies suggest that combination anti-HIV therapy (HAART) can lead to
clinical improvement of TB disease in people co-infected with TB and HIV. A report
presented at the July AIDS conference showed that HAART reduced the rate of TB disease by
50% in São Paolo, Brazil in 1997. TB also appears to accelerate the progression of HIV
disease, possibly due to increased production of cytokines and the stimulation of HIV
replication.
In addition, TB may manifest differently in HIV positive people. HIV-infected people
are at higher risk for TB outside the lungs (extrapulmonary TB). Mary Reichler, MD,
presented results of a study of over 7,000 people with TB and HIV at the July conference.
She found that HIV positive people were almost twice as likely to have combined
pulmonary/extrapulmonary TB as HIV negative people (55% vs 29%). She also found that HIV
positive people were more likely to be infected with MDRTB. Other researchers at the
conference reported increased occurrence of TB meningitis (infection of the membranes
surrounding the brain) and TB pericarditis (heart infection) in people with HIV.
Fortunately, TB prevention and treatment of active TB disease using standard first-line
regimens are effective in HIV positive as well as HIV negative people. In the past, many
experts recommended a longer course of therapy for people with HIV, but recent trials have
demonstrated that a shorter course of therapy is adequate in most cases. In general, the
same drugs are used for HIV positive and HIV negative people; the exception is that people
taking protease inhibitors should substitute rifabutin for rifampin (see section on drug
side effects and interactions).
Pathogenesis of TB Disease
Tuberculosis is caused by Mycobacterium tuberculosis, a rod-shaped aerobic
bacteria that is described as acid-fast because it remains stained when washed in an acid
bath.
Primary infection is the initial entry of TB into the body. In most cases, TB remains
inactive in the lungs. Reactivation, or recrudescence, occurs when the immune system can
no longer keep TB under control. Active disease is most likely to develop within the first
two years after infection.
After TB bacteria are inhaled, they settle in tiny air sacs deep in the lungs called
alveoli. Here, the bacteria are engulfed by alveolar macrophages, a type of immune system
white blood cell. As macrophages die, the released bacteria are engulfed by other immune
system cells such as neutrophils and monocytes, which are called to the site by chemical
messengers called cytokines. The body usually begins to mount a cell-mediated immune
response within 2-4 weeks. This immune response depends on functioning T-cells, and is
reduced in people with HIV.
Over time, the immune system walls off the TB bacteria in a defense structure called a
tubercle or granuloma, which consists of a core of TB-containing giant cells surrounded by
epithelioid cells, lymphocytes, and macrophages. Once the tubercle forms, the cells within
it die, a process known as caseous necrosis. Tubercles may burst, releasing bacteria and
leaving a hole or cavity in the lung. This process may eventually result in scars and
calcium deposits which can harbor inactive bacteria and provide a source for later
reactivation.
Immune cells containing TB bacteria may migrate to regional lymph nodes. If the immune
system is too weak or the number of bacteria is too high, tubercle formulation may not
adequately control the bacteria, which can enter the bloodstream, a condition known as
disseminated TB. In miliary TB, infection becomes established at multiple locations
throughout the body.
TB affects the lungs 85% of the time (pulmonary TB), but can affect almost any part of
the body, including the liver and kidneys, the stomach and intestines, the bones, and the
brain and spinal cord. Extrapulmonary TB is more common in children and people with
weakened immune systems.
A person who has been infected with TB and received either preventive therapy or
treatment for active disease can become infected again with a different TB strain, but
this is uncommon since past infection does confer some protective immunity.
TB Symptoms
A person who has TB infection but not active disease typically does not have any
symptoms. Symptoms of active TB disease in the lungs include a cough lasting longer than
two weeks, expulsion of (possibly bloody) lung fluid, and chest pain. People with active
TB disease in any part of their body may experience fatigue, weakness, malaise, loss of
appetite, weight loss, and fever and/or chills (including night sweats). Untreated TB may
lead to severe wasting and death.
If TB spreads through the bloodstream, a person may develop TB meningitis. Symptoms
include headache, nausea, drowsiness, and eventually coma. TB in the lymph nodes can lead
to inflammation and swelling called lymphadenitis. TB that infects the bone marrow may
lead to anemia and other blood cell deficiencies. TB of the vertebrae is called Pott's
disease, and may result in back pain and paralysis. Infants infected perinatally may have
TB in multiple organs, with symptoms including respiratory distress, liver and spleen
enlargement, and failure to thrive.
Several symptoms of TB disease are similar to those of other diseases such as HIV
disease, toxoplasmosis, and Mycobacterium avium complex (a disease caused by a
bacterium related to the one that causes TB). TB should be considered as a possibility
when making a differential diagnosis.
Preventing TB Transmission
TB bacteria are spread from person to person through the air in droplets of sputum,
which is fluid from deep within the lungs; transmission by ingestion or through a wound
may occur, but is much less common. Droplets are carried through the air when a person
with active TB disease coughs, sneezes, or spits. Droplets can remain suspended in the air
for many hours, and TB bacteria can live in dried sputum for several days or weeks.
It usually takes an extended period of time for TB transmission to occur. Family
members and others sharing a residence are most at risk. Occasional exposures to people
with active TB disease usually do not lead to infection. The National Institutes of
Allergy and Infectious Disease estimates that for people with healthy immune systems there
is about a 50% chance of infection from spending eight hours a day over six months, or 24
hours a day over two months, with a person with active TB disease. Perinatal TB
transmission from mother to fetus can occur, but it is more common for transmission to
occur due to close contact between a TB-infected mother and her infant after birth.
A person who is TB-infected but does not have active disease usually cannot spread TB,
and people who only have extrapulmonary (outside the lungs) TB are rarely infectious. Most
people with active TB disease are no longer infectious after about three weeks of
treatment.
Environmental
Precautions
Precautions can be taken to prevent a person with active TB disease from transmitting
the bacteria to others. People who are suspected of having or are being treated for active
TB disease should be isolated from others until they are no longer infectious, and should
cover their nose and mouth when they cough. Those who must be around people with active
disease, such as healthcare workers, can use a disposable personal respirator (which
resembles a surgical mask).
Engineering measures can remove or inactivate infectious bacteria. Isolation rooms
should have a negative pressure, meaning that air tends to flow inward rather than
outward. Proper ventilation mixes contaminated air and fresh air, thus reducing the number
of infectious droplets; a ventilation system should vent contaminated air directly outside
rather than recirculating it. High-efficiency particulate air (HEPA) filters can extract
infectious droplets from the air, and ultraviolet light can kill TB bacteria.
TB Vaccines
The BCG vaccine, made from a weakened strain of Mycobacterium bovis -- a
closely related bacteria that infects cattle -- is used in several countries for TB
prevention, but is uncommon in the U.S. BCG is not highly effective in preventing TB, with
estimates of efficacy ranging from 0-80%. The vaccine may, however, reduce the risk of
serious complications due to TB. In the U.S., the CDC recommends BCG vaccination only for
certain high-risk children. BCG should not be given to people with suppressed
immune systems.
The mapping of the Mycobacterium tuberculosis genome, completed in 1997, offers
new opportunities for genetically engineering a more effective vaccine. Several antigens
of Mycobacterium tuberculosis have been identified that can stimulate an immune
response. In the June 1998 issue of Infection and Immunity, researchers from
Colorado State University, Merck and Company, and the Pasteur Institute reported on two
vaccine candidates based on pieces of the Mycobacterium tuberculosis bacteria. The
vaccines significantly lowered the risk of TB infection in animals, and the researchers
are currently preparing to conduct human trials.
In late August, the federal Advisory Council for the Elimination of Tuberculosis issued
a national call to develop an anti-TB vaccine. The organization recommends focusing on a
post-infection vaccine that will prevent TB-infected people from developing active TB
disease. The CDC has urged a "nationwide push" to develop a new vaccine, and
predicts that several candidates should be available for human testing in the next few
years.
Diagnosing TB
Skin Test
for TB Infection
People who are infected with TB typically develop a hypersensitivity reaction which can
be measured using a skin test called the Mantoux test. A small amount of a liquid purified
protein derivative (PPD) of tuberculin is injected beneath the skin of the forearm. After
48-72 hours, a healthcare worker reads the test. A hard swelling (induration) at the
injection site indicates that the person has been infected with TB. A swelling larger than
10 mm is considered a positive reaction for most at-risk people. For people with HIV or
close contacts of people with active TB disease, a smaller cut-off of 5 mm is used.
It may take 10-12 weeks after infection before a hypersensitivity reaction develops,
and a TB skin test may not be accurate during this "window period." People who
have received the BCG vaccine may show a positive reaction on a TB skin test even if they
are not TB-infected. This may also occur if a person is infected with a related species of
mycobacteria such as Mycobacterium avium.
Some people with weakened immune systems do not produce a reaction when given a TB skin
test, even if they are in fact infected. This condition is known as anergy. An anergy test
uses control substances to measure cell-mediated immunity in order to determine whether a
person is capable of mounting an immune response to common antigens. Anergy testing was
once commonly used when skin-testing HIV positive people, and some experts still recommend
it in individual cases; however, as of 1997 the CDC no longer recommends routine anergy
testing for people with HIV.
Skin testing is recommended for people at risk of becoming infected with TB. Healthcare
workers and others at risk of occupational exposure should be tested annually. HIV
positive people should be tested when they are diagnosed with HIV, then annually
thereafter. A conversion from a negative to a positive skin test indicates a recent
infection. Skin test screening, in which large numbers of people are tested, is
recommended for certain high-risk populations; screening of low-risk groups is not
recommended by the CDC.
A positive TB skin test only indicates that a person has been infected with the TB
bacteria; it does not mean that he or she has active TB disease.
Tests for
Active TB Disease
Different tests are used to determine whether a person who has a positive skin test has
active TB disease.
Chest X-rays are used to detect active disease and to gauge the extent of lung damage.
People with active TB disease (or who have had active disease in the past) will typically
show tubercles, cavities, and/or scars in their lungs. In people with HIV, however, chest
X-rays are often atypical. Chest X-rays are not adequate to diagnose TB, but they may help
rule out active disease.
A TB smear involves looking at a sample of sputum under a microscope to see if
acid-fast bacteria are present. This type of test takes a few hours. The smear test cannot
distinguish between TB and related species of mycobacteria such as Mycobacterium avium.
Culture tests are done to confirm that a person harbors active TB bacteria. In this
test, a specimen of sputum (or another fluid such as urine, gastric juices, or
cerebrospinal fluid in the case of extrapulmonary TB) is cultured in a laboratory. TB
grows more slowly than most bacteria; it can take anywhere from 10-14 days to six weeks
before bacterial growth is seen, depending on the culture medium used. More rapid tests
that measure TB genetic material, including the polymerase chain reaction (PCR) test and
the amplified Mycobacterium tuberculosis direct test (MTD), have recently been
developed.
Regardless of what type of test is used for initial diagnosis, a culture is required
for drug resistance testing. A test called restriction fragment length polymorphism (RFLP)
can identify specific TB strains, and is used to track transmission during outbreaks.
Treatment of TB
In most cases, TB can be successfully prevented or treated. Drugs can prevent the
development of active disease in people already infected with TB, and can halt disease
progression in people with active disease.
Preventive
Therapy
People who have been infected with TB usually feel well, but are at risk for
reactivation of TB as they age or if their immune system becomes weakened. Treatment of
TB-infected people can prevent the development of active disease. Preventive therapy is
recommended for at-risk people with positive TB skin tests; in certain cases, people at
high risk of developing active TB disease may be given preventive therapy even if they do
not have a positive skin test. Preventive therapy should not be given until the
possibility of active TB disease has been ruled out.
The usual preventive therapy is isoniazid (INH), a well-tolerated and inexpensive drug.
Isoniazid is typically taken daily or twice weekly for six months; nine months of therapy
is recommended for children. Some experts recommend a longer course of therapy for people
with HIV, but recent research suggests that six months is adequate in the majority of
cases. Isoniazid is not known to cause fetal abnormalities, but still some experts
recommend that TB-infected pregnant women without active disease should wait until after
delivery to start preventive therapy. Isoniazid is highly effective; in various studies it
has been shown to reduce the rate of active TB disease by 30-90% (depending on adherence).
Side effects of isoniazid are discussed later.
Recent research suggests that a shorter course of preventive therapy may be as
effective and easier to adhere to. Fred Gordin, MD, reported at the 5th Conference on
Retroviruses and Opportunistic Infections in February 1998 that in 1,583 people
co-infected with HIV and TB, a 2-month course of rifampin plus pyrazinamide was as
effective in preventing active disease as a 12-month course of isoniazid alone (see Research Notes, BETA, April 1998).
An alternative preventive regimen is rifampin taken daily for 12 months, which is used
if a person is suspected of being infected with an isoniazid-resistant strain of TB. If
the TB strain is resistant to both isoniazid and rifampin, preventive therapy may be
difficult. Possible regimens for MDRTB preventive therapy include pyrazinamide plus
ethambutol daily for six months, and pyrazinamide plus ofloxacin or ciprofloxacin for six
months.
Consistent adherence to the full prescribed preventive regimen is necessary to
ensure that all TB bacteria are killed and that drug resistance does not develop. This
is sometimes accomplished through directly observed therapy (described later). People
should be monitored at least monthly while receiving therapy to ensure that it is working
properly.
Treatment
of Active TB Disease
Like HIV, TB bacteria can mutate rapidly to resist drugs, and effective treatment of
active TB disease requires combination therapy. The standard first-line treatment for
active TB disease is a 4-drug regimen that includes isoniazid, rifampin, and pyrazinamide,
plus either ethambutol or streptomycin while drug resistance testing is being done;
ethambutol is generally preferred because it is an oral drug, while streptomycin must be
injected. If the TB strain is shown to be susceptible to isoniazid and rifampin, the
ethambutol or streptomycin can be discontinued.
The currently favored short-course regimen involves an intensive 2-month, 4-drug
induction phase followed by a continuation phase consisting of four additional months of
just isoniazid plus rifampin. This regimen is highly effective in both HIV positive and
HIV negative people. The same regimen is used for the treatment of extrapulmonary TB,
although disseminated TB may require longer treatment.
The standard regimen may be modified to allow for intermittent rather than daily
dosing, which can make directly observed therapy much more practical. Effective
intermittent regimens include:
- the standard 4-drug regimen daily for two months, then isoniazid plus rifampin
two or three times per week for four months
- the standard 4-drug regimen daily for two weeks, then the same four drugs two
or three times per week for six weeks, then isoniazid plus rifampin two times per
week for four months
- the standard 4-drug regimen three times per week for six months.
Doses of isoniazid, pyrazinamide, and ethambutol should be increased if given two or
three times per week rather than daily. An alternative regimen, if a person cannot take
pyrazinamide, is a 9-month course of isoniazid plus rifampin.
The same standard 4-drug regimen is used to treat children with TB. However, in young
children side effects may have to be managed differently, and ethambutol is not
recommended. Isoniazid, rifampin, and ethambutol have not been shown to cause fetal damage
and may be used by pregnant women. Streptomycin is not recommended for use during
pregnancy because it can harm the fetus; pryazinamide has not been adequately tested for
this indication. Pregnant women with active disease should be treated as soon as possible.
The preferred regimen is isoniazid/rifampin/ethambutol for nine months.
Because TB was in decline for many years, minimal resources were devoted to developing
new anti-TB drugs. Most of the drugs used today were developed in the 1950s and 1960s. In
June, the FDA approved the first new TB drug in over 25 years. Rifapentine (brand name
Priftin), made by Hoechst Marion Roussel, is a long-acting formulation of rifampin that
can be taken twice weekly during the induction period and then once weekly for the
continuation period.
Symptoms of active TB disease usually improve after 3-4 weeks of treatment, and most
people are no longer infectious after about three weeks. A person is definitively
considered to be non-infectious when they produce three negative sputum smears; smears
typically become negative within 2-3 months. However, it is important that people
continue to take their full prescribed course of drugs in order to kill all bacteria and
to prevent a relapse or the development of drug resistance.
Regular follow-up (at least monthly) with sputum smears or cultures tests should be
done to ensure that treatment is working. If a person still has symptoms or a positive
culture after three months of treatment, drug resistance or nonadherence is likely, and
re-evaluation and more extensive resistance testing should be done.
Treating
Drug-Resistant TB
Treatment of drug-resistant TB is more difficult, takes longer and costs much more than
treatment of drug-susceptible TB. In-hospital treatment for MDRTB may cost as much as
$250,000. More drugs are required, they must be taken for longer periods, and they have
more serious side effects.
TB strains are routinely tested for drug resistance. Use of the BACTEC system can
determine resistance to the five most commonly used anti-TB drugs in about three weeks.
For TB strains that are resistant to isoniazid alone, the standard 4-drug regimen
remains effective. If the TB strain is resistant to isoniazid and rifampin, at least three
new drugs to which the TB strain is susceptible should be added, and treatment duration
should be extended for up to 24 months. Sometimes seven or more drugs may be necessary. As
is the case with combination anti-HIV therapy, a single drug should not be added to a
failing regimen. It may be valuable to consult an expert when dealing with MDRTB.
Many drugs have been tried for TB treatment. The first-line drugs were chosen for their
combination of tolerability and effectiveness. Some of the other drugs sometimes used are
more toxic or must be given by injection. Others are in various stages of testing. The
emergence of MDRTB has renewed the use of older drugs, encouraged the use of alternative
drugs, and refocused efforts on the development of new drugs.
Drugs that may be tried as part of a combination regimen for MDRTB include
aminoglycosides (e.g., amikacin, capreomycin, kanamycin), fluoroquinolones (e.g.,
ciprofloxacin, ofloxacin), cycloserine, ethionamide, clofazimine, and para-aminosalicylic
acid. Rifamycin derivatives other than rifampin (for example, rifabutin) are also
sometimes used. Macrolide antibiotics such as clarithromycin, which are effective against Mycobacterium
avium, are not very active against Mycobacterium tuberculosis.
In some advanced, treatment-resistant cases of TB, surgery may be done. This involves
removing part of the lung to excise the infected tissue. Sometimes corticosteroids are
used to reduce inflammation and control tissue damage, especially when TB affects the
brain.
Side Effects and Interactions of Anti-TB Drugs
The side effects of isoniazid are usually mild, and may include lack of appetite,
nausea, vomiting, abdominal cramps, and central nervous system symptoms. The most
worrisome side effect is liver toxicity leading to hepatitis. This is most likely in
people over age 35 and those with existing liver damage. People should not drink alcohol
when taking isoniazid, and liver enzyme levels should be monitored regularly. Another
possible side effect is peripheral neuropathy, characterized by pain and tingling in the
feet and hands. The risk of peripheral neuropathy may be reduced by using pyridoxine
(vitamin B6) along with isoniazid.
Rifampin side effects include gastrointestinal upset, malaise, skin rash, sensitivity
to sunlight and, less often, platelet deficiencies characterized by easy bleeding. The
drug turns urine, tears, and saliva orange.
Because rifampin is metabolized by the CP450 enzyme system in the liver, it interacts
with many other drugs that also use the same enzymes. This may result in undesirably high
or low blood levels of the drugs. People on methadone maintenance taking rifampin often
report withdrawal symptoms; this can be countered by increasing the methadone dose.
Rifampin may make birth control pills and other hormonal contraceptives less effective.
The protease inhibitor drugs are also metabolized by the CP450 enzyme system. Taking
rifampin and a protease inhibitor together may lead to subtherapeutic levels of the
protease inhibitor and increased rifampin-related side effects (see Protease Inhibitor Drug Interactions, BETA,
September 1997). If a person has not yet started combination anti-HIV therapy, some
experts recommend waiting if possible until after TB treatment is completed.
If a person is taking a protease inhibitor, most experts recommend that they should not
stop in order to take rifampin, as this could lead to the development of drug-resistant
HIV. Instead, they should take rifabutin. This drug has anti-TB activity comparable to
rifampin, but a lesser effect on the CP450 enzymes. Carol Dukes Hamilton, MD, of Duke
University Medical Center, recommends that if a co-infected person requires both anti-TB
treatment and protease inhibitor therapy, the best protease inhibitors to use are
indinavir (Crixivan) or nelfinavir (Viracept), because they interact with rifabutin less
than saquinavir (Fortovase) or ritonavir (Norvir). Doses of both rifabutin and the
protease inhibitor may have to be adjusted. According to Vertex Pharmaceuticals, rifampin
should not be used with amprenavir (Agenerase), and doses should be adjusted when
combining rifabutin and amprenavir.
Among the other first-line drugs, pyrazinamide can lead to liver toxicity,
gastrointestinal upset, joint pain, skin rash, and high blood levels of uric acid. The
most serious side effect of ethambutol is damage to the optic nerve, which can lead to
visual impairment and color blindness. Visual acuity should be checked regularly in people
taking this drug, and it is not recommended for children too young to report visual
changes. Streptomycin can cause damage to the inner ears, possibly leading to vertigo
(dizziness and balance problems) and hearing loss. Auditory acuity should be monitored in
people taking this drug, and it should be stopped if a person experiences ringing in the
ears or any hearing loss. The aminoglycosides may also cause inner ear damage. Side
effects of other drugs used to treat TB tend to be more serious, and these drugs are not
favored except in cases of drug-resistant TB.
Major Drugs Used to Prevent and Treat Tuberculosis
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