AIDS TREATMENT NEWS #188, December 3, 1993
Denny Smith

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.

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