MAC: Results Emerging from Long-Term Research

New drugs and drug combinations are providing some serious
ammunition for treating an infection that was once counted
among the most elusive of opportunistic diseases, Mycobacterium
avium complex (MAC).

MAC is an umbrella description of a number of strains of
mycobacteria that many people with low CD4 cell counts can
expect to be troubled with. It causes symptoms typical of many
AIDS-related infections, such as fevers, fatigue and wasting.

Current Prophylaxis, Treatment

Like Pneumocystis carinii, MAC organisms are almost impossible
to avoid in the environment, and everyone is assumed to have
been exposed to them. But it may be possible to prevent latent,
asymptomatic infections from progressing to active,
disseminated disease. This is called MAC prophylaxis, and
earlier this year, the Food and Drug Administration approved
the drug rifabutin for exactly that purpose.

A number of older drugs which were tried in the past to treat
active MAC gave tepid results. These drugs included amikacin,
ciprofloxacin, clofazimine, ethambutol and rifampin.
Unfortunately, as in the treatment of tuberculosis, one or more
of the strains of mycobacteria often develop resistance when
these drugs have been used alone. Consequently, a solid
consensus in the researcher/physician community holds that
active MAC cannot be effectively treated with a single agent,
that a combination of drugs is necessary. The same might become
true for prophylaxis.

Two relatively new antibiotics, clarithromycin and a related
drug, azithromycin, are widely used for treating MAC, and might
also be useful in prevention. They happen to be approved for
various non-AIDS related conditions, so they are already
available. Clarithromycin is expected soon to be approved by
the FDA specifically to treat active MAC.

In the September issue of PAAC NOTES (a monthly news journal of
the Physicians Association for AIDS Care, in Chicago), Richard
E. Chaisson, M.D., offered an overview of current MAC
prophylaxis and treatment. Interested persons can order that
issue by calling PAAC at 312/222-1326. Dr. Chaisson's
recommendation for prophylaxis involves the use of rifabutin,
300 mg daily, with clarithromycin or azithromycin on hand as an
alternative. For treatment, Dr. Chaisson combines
clarithromycin (500 to 1000 mg twice daily) or azithromycin
(500 to 1000 once daily), with two of the five older drugs
mentioned above.

This approach is very close to that used by several other
physicians we recently spoke with, including Michael Gottlieb,
M.D., Medical Director of the Immune Suppressed Unit at Sherman
Oaks Community Hospital in Southern California. Dr. Gottlieb
initially offers his patients with active MAC clarithromycin,
but it so frequently causes gastrointestinal upsets that he
often switches to azithromycin, 500 mg once or twice a day. To
this he adds ethambutol, 400 mg twice a day, ciprofloxacin, 500
mg twice a day, and clofazimine 100 mg once a day.

Since taking these drugs all together can cause nausea, even
without the clarithromycin, Dr. Gottlieb recommends staggering
them throughout the day. And if these oral drugs do not resolve
at least the fevers associated with MAC, he gives amikacin,
which is administered intravenously. Amikacin is an
aminoglycoside, a class of drugs that can cause irreversible
ototoxicity (damage to the organs of hearing and balance) or
kidney toxicity. Dr. Gottlieb explains this to patients, and
makes sure that "peak and trough" levels of the drug are
monitored to minimize this danger.

Experimental Approaches

There are a number of new drugs under study in laboratory or
clinical trials (or both) for the treatment of MAC; many of
them were discussed at the annual Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC) held last month
in New Orleans. (Because MAC is related to the organisms that
cause tuberculosis and leprosy, researchers often approach test
tube experiments on the three infections with the same drugs.
People with HIV must be concerned about tuberculosis as well as
MAC, and so will benefit from mycobacterial research in
general.) For interested researchers and activists, we list
those drugs below, followed by the numbers of the relevant
abstracts.

In addition to azithromycin (abstract numbers 284, 1351) and
clarithromycin (abstracts 76, 286, 287, 288, 658, 1344, 1349),
we noted roxithromycin, (abstract 1343), gangamicin (abstract
77), isepamicin (abstracts 76, 1351), sparfloxacin (abstracts
1344, 1351), ofloxacin (abstracts 79, 1343), levofoxacin
(abstract 1498), trifluoperazine (abstract 1345), several code-
named agents -- BAYy3118 (abstracts 75, 76), CI-960 (abstract
79), DU6859a (abstracts 79, 80), VUF 8514 and VUF 8842
(abstract 74), and KRM 1648 (abstracts 69, 70) -- and liposomal
preparations of two older drugs, capreomycin (abstract 285) and
gentamicin (also known as TLC G65, abstract 1078).

Many abstracts also discussed the use of older MAC drugs,
largely for the purpose of comparing their effectiveness to the
newer agents. There are too many of those citations to be
listed here, with one interesting exception. Dapsone, a drug
long used to treat leprosy, and more recently to prevent
pneumocystis, was twice discussed as a possible prophylaxis
against MAC. In a mouse study, dapsone was added to
clarithromycin (abstract 287) with beneficial effects on the
reduction of bacteremia. And in a study of pneumocystis
prophylaxis, dapsone combined with pyrimethamine (abstract
1080) seemed to reduce the overall incidence of mycobacterial
infections, compared to the patients receiving aerosolized
pentamidine.

Only an expert can distinguish the truly promising agents under
study from those that are just mildly interesting, and so we
asked infectious disease researcher Luiz Bermudez, M.D., to
share his impressions of the new possibilities. Dr. Bermudez is
a senior scientist at the Kuzell Institute in San Francisco,
and he coauthored several reports presented at ICAAC.

Dr. Bermudez surmised that sparfloxacin is probably not potent
enough to treat active MAC, but it may prove adequate as
prophylaxis, when a weaker drug would ostensibly suffice.
Sparfloxacin is now in phase I clinical trials. He also said
that ofloxacin and levofloxacin are not very convincing in MAC
studies, but might be more useful for tuberculosis.

[The TB research at ICAAC was also interesting, and warrants a
separate review. But we want to point out an especially
intriguing report describing the "promising" activity of
paromomycin (by injection) against multi-drug resistant
Mycobacterium tuberculosis in laboratory mice. The report
(abstract 290) is relatively surprising, considering that
paromomycin (trade name Humatin) is a very common, well-
established drug long used to treat intestinal parasites.
Paromomycin made a similar splash over three years ago at the
Sixth International Conference on AIDS, where doctors from
Houston reported good results using it to treat
cryptosporidiosis, an opportunistic infection that had defied a
number of newer, more exotic treatments (see AIDS TREATMENT
NEWS #111, September 21, 1990).]

Most of the research presented at ICAAC was done in the test-
tube or with animals, and so is not immediately useful to
physicians and patients. Furthermore, much of the research
relevant to MAC was presented by scientists from France, Japan
and Italy, and some of the agents they studied may not be
easily accessible to U.S. researchers or clinicians. Of those
new potential anti-MAC agents under study in the U.S., Dr.
Bermudez felt, in fact, that only two appear to be really worth
pursuing as therapies for active MAC -- liposomal gentamicin,
which is an aminoglycoside like amikacin, and KRM 1648, a
rifamycin like rifabutin. His lab is working with the latter
drug in animal studies, and liposomal gentamicin is now in
phase I and II clinical trials.

The liposomal gentamicin must be administered intravenously,
which has disadvantages, except in two aspects. For one, the
effectiveness of oral MAC drugs is often hampered by the poor
gastrointestinal absorption common in persons with this
illness. Additionally, the nature of liposomes may allow one
dose to last for a week or more, minimizing the inconvenience
of IV administration. [Note: Liposomes are microscopic spheres
of fat, designed to target the drug they contain to where it is
needed in the body.]

Interestingly, Dr. Bermudez said that a liposomal formulation
of amikacin is probably even stronger than gentamicin, but has
not yet entered clinical trials for treating MAC. We contacted
the developer of liposomal amikacin, Vestar Inc., in San Dimas,
California, to determine the progress of this promising
treatment. Michael Ross, Executive Vice President of Medical
Regulatory Affairs, told us that a phase I dose-ranging study
of liposomal amikacin (Mikasome), conducted in Brussels, showed
the formulation to be safely tolerated in volunteers who had
HIV but were not experiencing symptomatic MAC. He said Vestar
is now planning phase II (efficacy) trials of Mikasome for the
treatment of various bacterial infections, probably including
MAC, and probably to be conducted in the U.S. Mr. Ross also
thinks it could be a good candidate to test against
tuberculosis. He pointed out that small changes in the lipid
structure can make a very large difference in biological
activity.

As mentioned above, one of the problems with the standard
versions of aminoglycosides has been potentially serious side
effects following long-term use. But when drugs are
encapsulated in liposomes, the active agents can be transported
to the interior of targeted cells, rather than simply drenching
the entire body; many side effects that once limited the
practicality of a drug can be a lesser problem. Obviously,
liposomes could be a very dynamic technology for improving AIDS
therapies. Vestar, for example, is also studying liposomal
formulations of amphotericin and daunorubicin.

Of the drugs now available for treating active MAC, Dr.
Bermudez would use clarithromycin or azithromycin combined with
ethambutol, and perhaps clofazimine if a third drug is
warranted. He sees less value in the use of ciprofloxacin or
rifampin. Dr. Bermudez also noted that GM-CSF (granulocyte-
macrophage colony stimulating factor, a growth factor that
increases the number and function of these cells), may become a
useful adjunct to current MAC treatment. GM-CSF, combined with
azithromycin, is being studied in clinical trials for this
purpose. It is already FDA-approved to treat people recovering
from bone-marrow transplants.

In sum, physicians have a number of drugs available to them for
the treatment and the prophylaxis of MAC, with several more in
clinical trials. Dr. Gottlieb suggests that physicians and
their patients be flexible with MAC therapy: certain
combinations may work for some individuals and not for others.
There may not yet be a "standard of care" for MAC as concrete
as that for PCP or CMV disease, but neither is there cause for
the pessimism that once made MAC one of the "untreatable"
infections.