GMHC Treatment Issues 1991 Nov; 5(8): 1
Mycobacterium avium complex, or MAC, is a disease made up of
different strains of mycobacteria found in AIDS patients, which
together form a "complex." M. avium, the most common strain,
and M. intracellulare, previously gave the disease its name,
MAI (or Mycobacterium avium intracellulare). The new name, MAC,
came about when researchers discovered that the illness is
actually caused by up to ten different strains of bacteria,
which makes the infection notably difficult to treat. The
organisms which cause MAC occur naturally in food, water, and
soil -- as well as in hospital water supplies. The most
common strains found in PWA's are particularly associated with
heated water supplies. Avoiding exposure remains difficult
Before the AIDS epidemic, illness caused by MAC was rare in
humans. In fact, in 1980, only 24 cases had ever been reported
in medical literature. In 1982, however, reports of MAC
infection increased dramatically, and the infection began to be
recognized as an AIDS-related illness. In the early days of
AIDS, MAC infection was usually identified only at autopsy.
Most PWA's dies of other causes, such as PCP, which can now
usually be prevented. At that time, doctors and researchers
believed that MAC bacteria caused infection in the late stages
of HIV disease, but did not cause serious illness, since the
bacteria was found at autopsy in people who had dies of other
causes. Since then, studies have shown that MAC infection,
which spreads to numerous parts of the body (disseminated
infection), can cause both illness and death in PWA's. By
December 31, 1990, 12,202 cases of disseminated MAC infection
were reported in persons with AIDS. This number comprises 7.6%
of all AIDS cases reported to the Centers for Disease Control
In clinical studies, 76% - 90% of MAC infections come late in
the course of HIV, well after AIDS has first been diagnosed.
Current estimates indicate that between 15% - 24% of PWA's have
symptomatic MAC disease. Applying this ratio to the number
of actual reported cases, disseminated MAC infection may affect
between 30,000 - 49,000 people with AIDS in the U.S.
According to a report from Florence, MAC and other atypical
mycobacterial infections occur in women twice as often as they
occur in men. At the National Conference on Women and HIV
Infection, similar studies were reported from the Bronx, New
York, and Newark, New Jersey, which point to the possibility
that MAC may have a different pattern in women than in men.
This possibility requires immediate investigation.
Symptoms of MAC usually include fevers, chills, weakness,
abdominal pains, night sweats, diarrhea, anemia, and weight
loss. MAC is a major cause of "wasting syndrome." Though very
uncommon, the infection can produce non-specific symptoms,
making diagnosis difficult. As people with AIDS live longer,
MAC illness continues to occur relatively late. Data indicate
that it occurs on average 7 to 15 months after AIDS is
diagnosed. Additionally, MAC seems to be associated with
advanced immune dysfunction. In fact, the majority of patients
with MAC disease seem to have T4 cell counts below 60.
MAC remains a challenge to diagnose in PWA's. As with most
bacterial infections, people with immunosuppression are often
not capable of producing antibody responses to MAC
infection. When MAC involves the lungs, pulmonary symptoms
may appear, but new studies show that symptoms don't occur in
about 4% of PWA's. Chest x-rays may be insufficient to diagnose
the illness. Microscopic examination of phlegm with a special
acid-fast method of detection is another way do diagnose MAC.
However, a positive result could represent other types of
mycobacteria and may not be conclusive. Additionally, although
lungs may become infected, recent research shows that bacteria
first enter the gastrointestinal (GI) tract. In the GI
tract, MAC invades the wall of the intestine, liver, and
spleen, causing diarrhea and abdominal pain, swelling and often
abnormal liver function tests.
Since most PWA's have disseminated disease, it is best to
diagnose MAC by blood cultures. Blood culture is a process by
which blood is removed from the body and placed in an
atmosphere where bacteria, if present, will grow in large
numbers for easy detection. Two consecutive blood cultures are
usually adequate to make a diagnosis. New techniques are
leading to faster blood culturing for MAC. For instance, a
French group reported using a 2-step polymerase chain reaction
(PCR) test to diagnose MAC in less than 4 hours. Studies
have also shown that liver biopsies and bone marrow
examinations are rapid ways of diagnosing MAC; however, they
are more invasive procedures.
PROMISING MULTI-DRUG THERAPIES
Early studies of therapies for disseminated MAC were
discouraging. Recently, studies have shown relief of symptoms
in most patients with some treatments. The most effective MAC
therapies have been shown to be multiple drug combinations of
3-7 drugs. Fever, night sweats, and malaise may respond to
combination therapies within two to eight weeks. Diarrhea and
weight loss are still difficult to control, and improvement in
survival has been modest.
Several studies have demonstrated that combinations of three or
more antibiotics can be effective in improving symptoms and
clearing bacteria from the blood, although many patients still
display MAC in tissue at autopsy. One study, reported in San
Francisco last year by Dr. Potage and others, evaluated the
response of 20 AIDS patients with disseminated MAC.
Patients were treated with a regimen consisting of intravenous
amikacin, oral clofazimine, firampin, and ethambutol. Amikacin
was given intravenously for 30 days or until a dose-limiting
toxicity occurred. Nineteen of the 20 patients had a favorable
response with lab blood tests showing clearance of mycobacteria
from tissue. One patient's bacterial recurred when amikacin was
stopped. Amikacin caused hearing loss in some patients who had
been taking it for more than 60 days. The frequency of such
hearing loss is significantly diminished when amikacin is used
for no longer than 4 weeks. Irreversible ear damage may occur
with longer-term use.
In Florence, a study from Sweden was presented in which 31
patients with MAC were treated with the combination therapy:
amikacin, ethambutol, and rifabutin. After an average of 14
days of therapy, 71% of patients had improvement in symptoms,
including fever, diarrhea and a new sense of well-being.
Two other published studies have reported similar successes
with combination therapies.
Azithromycin, an antibiotic made by Pfizer, is an experimental
option for toxoplasmosis and MAC. The drug penetrates well into
tissues with very little toxicity in both animals and humans. A
four-week azithromycin study using mice resulted in 95%
survival and a significant decrease in bacteria in the blood,
liver, and spleen. A phase I human pilot study treated 16
patients with AIDS and MAC bacteria with azithromycin (500 mg
per day). Of the 16 patients treated for 20 or 30 days, 14
had improvement of such symptoms as fever, night sweats,
fatigue, and weight loss. Blood tests showed a reduction of
bacteria. The main side effect was diarrhea.
Azithromycin is available under compassionate use from Pfizer
as treatment for toxoplasmosis and MAC. Unfortunately,
according to Pfizer, only 20 patients have used the drug
through compassionate use for MAC, since advertisement efforts
have been minimal. A representative from the company did reveal
that plans to get the word out are under way. Additionally, the
PWA Health Group sells the drug for $43.00 per six pills at 250
Rifabutin, an antibiotic similar to rifampin (used to treat
tuberculosis), has been studied as a treatment for MAC for
several years. It was originally available from the CDC and
from Adria Pharmaceuticals for compassionate use.
One study presented in San Francisco by Dr. Fred Siegal from
New York, assessed rifabutin (300-900 mg/day) in 20 PWA's.
Compared to an historical control group of 184 patients who did
not receive rifabutin, the patients taking the drug for less
than 30 days had an improvement in MAC-free survival. In
Florence, investigators from Adria Pharmaceuticals presented
data on 90 patients with AIDS and MAC treated with rifabutin in
a combination regimen. Fever and night sweats resolved in
72% of patients, although there was a minimal decrease in
diarrhea. Average survival time was 207 days.
Side effects of Rifabutin include low white blood cell counts,
low platelet counts, and rashes. Rifabutin is presently being
studied in a large placebo-controlled trial sponsored by Adria
for treatment of MAC in combination with ethambutol and
clofazimine. In addition, it is being studied for preventing
initial MAC infection in patients with T4 cell counts under
200. For more information on these trials in the New York area,
patients can call 1-800-TRIALS-A.
Clarithromycin is a broad-spectrum antibiotic approved for use
in 20 countries to treat respiratory, skin, and
gastrointestinal infections. Until now, the drug has been
imported from Europe, and costs about $600-$750 per month for
six weeks of acute treatment. for maintenance therapy, it costs
about $200 per month. It continues to be a hot item at buyers'
clubs, such as the PWA Health Group.
Experience using clarithromycin in AIDS patients is limited.
One recent study compared a group of patients taking
clarithromycin, isoniazid, ethambutol, and clofazimine to a
group of patients taking placebo, isoniazid, ethambutol, and
clofazimine for six weeks. Then all patients received
clarithromycin and combination therapy with rifabutin for an
additional six months and finally received clarithromycin alone
as therapy to prevent relapse. All patients receiving
clarithromycin in combination showed that bacteria cleared from
the blood, compared to only two patients of the five receiving
placebo and combination therapy. Of six patients receiving
clarithromycin alone to prevent recurrence of disease, only 1
in 5 had a relapse.
Early data from Abbott Laboratories, developer of
clarithromycin, indicate that the drug reduces blood levels of
AZT by 15%-25%, but the significance of this reduction is not
The prevention of MAC with clarithromycin is controversial.
Abbott Laboratories has put on hold until early 1992 a
prophylaxis study using clarithromycin. The company claims to
be uncertain as to the dose that should be used for
prophylaxis. Since prophylaxis usually employs a lower dose
than the dose used for treatment of disease, some physicians
are recommending clarithromycin for prophylaxis, using doses in
a lower range: 250 or 500 mg/day. It should be noted that
mycobacteria are known to develop resistance quite easily.
Therefore, there is concern that an inadequate dose might
promote resistance, making the drug useless for prophylaxis and
treatment. The problem is that if MAC becomes resistant to
clarithromycin, it may well become resistant to other similar
antibiotics, thus erasing treatment options. Since there is
much at risk, it is important to consult with physicians and
other experts before deciding to prophylax against MAC.
CLARITHROMYCIN EXPANDED ACCESS
Abbott Laboratories announced in April the establishment of an
expanded access study of clarithromycin for disseminated MAC
infection. This study does not enroll patients who have
previously used clarithromycin. However, a second expanded
access study was recently announced for patients who have taken
clarithromycin before. These patients do not have to test
positive for MAC. One obstacle to both of these programs is the
amount of paperwork required, which inhibits many physicians
from obtaining the drug for patients.
Another problem may be single-agent therapy. Despite the fact
that there are more data supporting combination therapy, the
Abbott-sponsored expanded access studies use clarithromycin
alone. Patients with acute MAC are taking the drug for 12
weeks, and are randomized to receive either 500 mg or 1000 mg,
each twice per day. Upon the first follow-up visit in the
fourth week of using clarithromycin alone, a physician can add
additional drugs if the patient is declining. All additional
drugs used thereafter must be reported to Abbott with
Expanded access is intended to offer earlier treatment to those
patients without other options while at the same time
collecting data that reflect "real world" use. Current trends
indicate that clarithromycin in combination with other drugs is
akin to "real world" use and, most importantly, is more
beneficial for the patient. A formal clinical study with a
control group, rather than an expanded access program, may be a
better option for collecting complex data about such use of
A new antibiotic called sparfloxacin is about to be tested at
12 sites nationwide. Sparfloxacin is more active in the
test tube against MAC than older drugs of its class (called
quinolones), including ciprofloxacin. The new studies, to be
headed by Dr. Lowell Young, will determine the safety of the
drug and, to a lesser degree, its efficacy. Sparfloxacin has
been tested extensively in Japan to treat gynecological skin,
respiratory, and urinary tract infections. The major side
effect associated with the drug is skin sensitivity to sun or
Five sites in Denver, CO; Irvine, CA; Orange, CA; Portland, OR,
and San Francisco, CA are ready to enroll. Other sites will be
announced. Parke-Davis is the only U.S. commercial developer of
sparfloxacin for the Japanese pharmaceutical company,
Disseminated MAC infection is increasingly recognized as a
significant illness in PWA's. Combined drug therapies can now
lead to symptomatic improvement and are becoming more widely
used. As always, there is much yet to learn about optimal
therapies for treatment and prevention of MAC. Optimal study
designs continue to be explored, since studying combination
therapy is more complex than studying single agent therapy.
Current experimental studies offer eligible patients some,
though not many, alternatives to the handful of drugs currently
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