Roxithromycin and Azithromycin: Toxoplasmosis, Cryptosporidiosis Experimental Treatments (Not in USA)

Roxithromycin is an antibiotic approved as a prescription drug in France; azithromycin, a similar drug, has been approved in Yugoslavia. They might be useful in treating toxoplasmosis, cryptosporidiosis, isospora (an infection which, like cryptos- poridiosis, causes severe diarrhea), and possibly MAI.


Despite the need for better treatments for these conditions, we could find nothing being done or planned in the United States to learn whether these drugs might be useful. (We have heard that a trial for toxoplasmosis may start soon in France.) We pub- lish this article to bring attention to these treatment possibilities, so that others can investigate further and organize clinical trials to determine whether these drugs are valuable for treating AIDS-related infections.

Background: Toxoplasmosis

Toxoplasmosis is typically a brain infection caused by the protozoan Toxoplasma Gondii (which can also affect the eye and other organs). Many healthy people are infected with the parasite, which is commonly present in cats, but usually the immune system keeps the organism controlled. At present, toxo- plasmosis is becoming an increasing problem because of AIDS, and also because of wider use of immunosuppressive drugs, for example by organ-transplant patients. Toxoplasmosis is also a threat to the fetus and newborn infant, even in healthy persons without immune suppression.


Toxoplasmosis is usually treated with a combination of pyrimethamine and sulfadiazine (leucovorin must be given with the pyrimethamine). While the drugs are effective, they do not kill cysts of the parasite, so the treatment must be continued as a maintenance dose; often toxicity forces discontinuation of the drug, and relapses result. The statistics are not good, with reported death rates of about 70 percent and median survival of four months, although some people remain alive and healthy for many years after diagnosis. If pyrimethamine and sulfadiazine cannot be used, other drugs such as clindamycin or spiramycin may be used instead. It is important to start treatment early.

One recent study found that one-year survival rates were greatly improved (58 percent vs 12.5 percent) in patients who were given AZT after starting the maintenance dose (Clumeck and others, 1988). But another paper presented at the same confer- ence reported that AZT interfered with the action of pyrimetham- ine and greatly reduced survival from toxoplasmosis in mice (Israelski and others, 1988). Possibly the important difference is that in the human study, the AZT was not used until after the acute therapy for toxoplasmosis had been successfully completed.

A year ago (January 28, 1988) AIDS Treatment News mentioned the case of one person diagnosed with toxoplasmosis who rejected conventional treatments and used large amounts of garlic instead--despite a physician's warning that failure to use the drugs would almost certainly result in death. This patient is still alive today. While rejecting the conventional drugs would seem to be extremely dangerous, this case suggests that there might be some value in using garlic in addition to the treatments recommended by physicians.

It is clear that better treatments are needed.

Note: due to publication deadlines we were unable to review all relevant articles before writing the background summary above.

Roxithromycin and Azithromycin: Animal and Laboratory Studies

At first glance, roxithromycin looks mediocre in animal studies of toxoplasmosis (see discussion below). This appearance, which may be deceptive, may have discouraged wider interest in the drug.

Several published studies have suggested that these drugs are worth trying for treating toxoplasmosis. Our review of these studies is in order by publication date, starting with the most recent.

"Azithromycin, a Macrolide Antibiotic with Potent Activity against Toxoplasma Gondii" (Araujo and others, 1988) reported an experiment in which 10 days of treatment with azithromycin protected mice after their brains were infected with Toxoplasma Gondii. Eight of ten of the treated mice were alive and well on day 30 after infection, while nine of the ten untreated mice were dead by the 14th day and the survivor remained ill. The researchers pointed out that compared to roxithromycin, azithro- mycin seemed effective in smaller doses. The authors concluded that azithromycin should be studied as an alternative treatment for toxoplasmosis.

"Effect of Roxithromycin on Acute Toxoplasmosis in Mice" (Chang and Pechere, 1987) studied roxithromycin and other drugs, including the conventional treatments for toxoplasmosis, in mice given 500 times the 100 percent fatal dose of Toxoplasma gondii. The conventional treatment (pyrimethamine-sulfadiazine) worked well, protecting up to 100 percent of the mice, depending on the number of doses given. Roxithromycin worked less well, but it also protected up to 100 percent of the mice, depending on the dose. For spiramycin, however, only a 50 percent dose could be determined, because the mice died from toxicity of the drug before a 100 percent protective dose was reached. The authors concluded that roxithromycin might be useful for treating toxo- plasmosis, but that clinical studies would be necessary to see how it compared with other drugs.

"Activity of Roxithromycin (RU 28965), a Macrolide, against Toxoplasma gondii Infection in Mice" (Chan and Luft, 1986) found that roxithromycin was effective in mice, but less so than the standard treatment, pyrimethamine and sulfadiazine. The authors suggested that roxithromycin might be a safe and effective alter- native treatment for toxoplasmosis--presumably for use when the standard treatments fail or cannot be used because of toxicity.

"In Vitro Effects of Four Macrolides (Roxithromycin, Spiramycin, Azithromycin [CP-62,993], and A-56268) on Toxoplasma gondii" (Chang and Pechere, 1988) tested the drugs in cell cultures in the laboratory. Roxithromycin was the most powerful, spiramycin the least. The authors suggested clinical studies of roxithromycin and other drugs.


Human Experience with Roxithromycin (Not AIDS Related)

Recently the British Journal of Clinical Practice published a special issue on roxithromycin (volume 42, supplement 55, 1988). This issue included several short reports of clinical trials or experience, mostly for lower respiratory tract infec-
tions. These reports, from France, Austria, and Argentina, all found the drug effective.

Roxithromycin is a "macrolide"--an antibiotic in the same class as erythromycin, a prescription drug widely used in the
U.S. and elsewhere for atypical pneumonias and certain other infections. Roxithromycin is believed to have about the same antimicrobial activity as erythromycin, but better bioavailability--correcting an important shortcoming of other macrolides. Macrolides are considered one of safest classes of antibiotics (Neu, 1988).

Human Experience Relevant to AIDS

In a study presented at the October 1988 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), roxithromycin was found to reach very high concentrations in the human brain (Manuel and others, 1988). Researchers in France and Switzerland, noting that roxithromycin had been effective in treating toxoplasmosis in mice, gave the antibiotic to volunteers who were scheduled to undergo brain surgery, so that levels in brain tissue could be determined. (These volunteers did not have toxoplasmosis or AIDS.) The four patients for whom concentra- tions were measured had much higher roxithromycin concentrations in brain tissue than in blood plasma; two had brain concentrations seven times as high, the other two had fifty times or more roxithromycin in brain tissue than in blood. These measurements were taken 12 hours after the last roxithromycin dose; since blood levels are known to remain high for 12 hours or more, the comparison is a fair one.

This study suggests that roxithromycin is extremely effective in crossing the blood-brain barrier. No other macrolides
are known to behave similarly.

In comparable tests in rats, roxithromycin was found not to penetrate well into brain tissue--suggesting that the drug may be even more effective in humans than it was in the mouse studies cited above. The potential value for humans might have been missed.


Another human study presented at the same conference (Kazmierczak and others, 1988) found that roxithromycin had much better blood concentrations, 12 and 24 hours after a single dose, than the two other drugs which were compared (spiramycin and trolandomycin).

Taken together, these studies show that roxithromycin, a drug known to be effective against toxoplasmosis in mice, reaches a high concentration in human blood, and a much higher concentration yet in the human brain, where it is needed for treating the disease.

The obvious next step would be to test roxithromycin as a treatment for toxoplasmosis. We have only heard of one case where it has been tried. The physician thought that the drug (brand name "Rulid" in France) had been beneficial, but was not sure, pending study of before and after brain images.

We have heard that a clinical trial of roxithromycin or azithromycin for toxoplasmosis is about to start in France, but we do not have any further information at this time.


Other Opportunistic Infections

A letter in the Journal of Infectious Diseases (Musey and others, 1988) reported that roxithromycin cured one case of Isospora belli infection, after several other treatments had failed. This infection causes severe diarrhea; the patient had had chronic diarrhea for two years.

Isospora belli is closely related to Toxoplasma gondii, the organism which causes toxoplasmosis. Both are also related to the organism which causes cryptosporidiosis. Isospora is easier to treat, however, and often bactrim is effective.

We heard two anecdotal reports of treatment of cryptosporidiosis with azithromycin, a drug approved in Yugoslavia which is closely related to roxithromycin. In one, we talked to a U.S. physician who was convinced that the treatment had worked very well. In the other, we heard from a Project Inform hotline volunteer that a patient had called and said that azithromycin seemed to make his cryptosporidiosis worse; this patient did not leave his name or any way to contact him, so Project Inform cannot investigate further.


It is possible that roxithromycin or azithromycin may also be useful for treating MAI, in combination with other drugs. Physicians are interested because these new macrolide antibiotics penetrate well into monocytes; MAI is often found inside these cells.

FDA Roxithromycin Controversy

On December 15, 1988, The Alternative, a Baltimore gay paper which often publishes important, original investigative stories on AIDS treatment research and public policy, reported that a major drug company had applied to the FDA for an IND (Investigational New Drug approval) to study roxithromycin and azithromycin in clinical trials, but that the FDA had rejected the application due to lack of adequate animal studies--even though roxithromycin was already approved and in human use in France. (Roxithromycin was later mentioned in U. S. News and World Report, February 13, 1989, page 82.)

We called the FDA and the drug company (Roussel, a French company which also has offices in New Jersey), and found that the agency and the company had different understandings of the facts of this case. The misunderstanding, which came to light by accident, may have helped cause the proposed research to be cancelled.

Both agree that the company did apply for an IND (Investigational New Drug approval, meaning permission to test the drug on humans), and that the FDA asked for animal studies. The IND application was to study roxithromycin for AIDS-related cryptosporidiosis and isospora -- not toxoplasmosis. The animal studies were to answer certain questions concerning the rationale of the treatment--not to test roxithromycin as if it were a new chemical which had never before been given to humans.

The question at issue is whether the drug was rejected because animal tests showed it was unpromising for cryptosporidiosis and isospora--or whether it was dropped without any tests because of the expense or impossibility of obtaining the information requested.

The FDA spokesperson we talked to believed that the company did do the studies, and based on the results decided it was unlikely that the drug would be effective, and therefore decided not to pursue human trials. He suggested a person at Roussel whom we could call for further information.


We called that person, who needed to check further, as we had called asking about toxoplasmosis, but he had been prepared to reply about cryptosporidiosis and isospora. Our concern was that people were starting to use the drug, and if animal studies had suggested that it would be ineffective, it was urgent that the information be known.

After checking with other people in the company, the Roussel spokesperson called us back and told us that no such animal studies had been done. Instead, after the FDA asked for those studies to confirm the activity of the drug, the researchers at Roussel found no good animal models to answer the questions asked, so the company decided not to pursue the project. The spokesperson also confirmed that the IND application had not concerned toxoplasmosis.

Today we know of no plans in the U.S. to study roxithromycin for any AIDS-related condition. There may be a toxoplasmosis study soon in France.

Roxithromycin--the Next Step

As many as 31,000 persons with AIDS may develop toxoplasmosis by 1991 (Potasman and others, 1988); with conventional treatments only, most of them will die. Obviously clinical trials of promising treatments like roxithromycin are needed.

Physicians, scientists, and regulatory officials may have missed the importance of roxithromycin, thinking that it could not be a major advance because in the test tube and in animals it is no more effective than the conventional treatment for toxoplasmosis, and perhaps somewhat less effective. The implication that roxithromycin is therefore unimportant is probably erroneous, for two reasons.

First, it overlooks the strikingly high concentration of roxithromycin in brain tissue, where toxoplasmosis is located. This very good penetration into the human brain is not found in the rat, so animal experiments would not be expected to show the benefits which might be found in humans. The study (cited above) which found the high concentrations in human brain tissue was presented as a poster session at the ICAAC conference last October, and may not be widely known.

Second, the comparative efficacy against Toxoplasma gondii is not the important question here. Both roxithromycin and pyrimethamine/sulfadiazine (the conventional treatment) are clearly effective, though neither kills Toxoplasma entirely. The problem with pyrimethamine/sulfadiazine is that toxicity develops, preventing long-term use and resulting in relapse when the drugs can no longer be used. Roxithromycin has very little toxicity, so it could probably be used for a long time.

At the very least, roxithromycin should be tried in cases when there is no other option.

The central problem seems to be that no one is making sure that even the most obvious and fundamental interests of persons with AIDS or at risk for AIDS are considered when drug- development decisions are made. We need leadership from the medical community, as well as from patient-advocacy groups.

Until trials can be arranged, the second best option is to obtain roxithromycin from France, or send patients there, and
collect anecdotal information. The PWA Health Group recently listed roxithromycin as one of the prescription drugs it wants to make available (see "AIDS Group Organizing Imports of Drugs Not Approved by F.D.A.", The New York Times, March 6, 1989, page 1).


References

Araujo, FG and others. Azithromycin, a macrolide antibiotic with potent activity against Toxoplasma gondii. Antimicrobial Agents and Chemotherapy, volume 32 number 5, pages 755- 757, May 1988.

Chan, J and Luft, BJ. Activity of roxithromycin (RU 28965), a macrolide, against Toxoplasma gondii infection in mice. Antimicrobial agents and chemotherapy, volume 30 number 2, pages 323- 324, August 1986.

Chang, HR and Pechere JF. Effect of roxithromycin on acute toxoplasmosis in mice. Antimicrobial Agents and Chemotherapy, volume 31 number 7, pages 1147-1149, July 1987.

Chang, HR and Pechere JF. In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin [CP-62,993] and A-56268) on Toxoplasma gondii. Antimicrobial Agents and Chemotherapy, volume 32 number 4, pages 524-529, April 1988.

Clumeck, N. and others. The benefit of zidovudine on the longterm survival of AIDS patients with CNS toxoplasmosis.Program and

Abstracts of the Twenty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract number 1474, Los Angeles, 23-26 October 1988.

Holliman, RE. Toxoplasmosis and the acquired immune deficiency syndrome. J. Infect., volume 16 number 2, pages 121-128, March 1988.

Israelski, DM and others. AZT antagonizes pyrimethamine in experimental infection with Toxoplasma gondii. Program and Abstracts of the Twenty-Eighth Interscience Conference on Antimcrobial Agents and Chemotherapy, abstract number 349, Los Angeles, 23-26 October 1988.

Kazmierczak, A and others. Roxithromycin pharmacokinetic compared with those of spiramycin and trolandomycin after a single oral dose. Program and Abstracts of the Twenty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract number 137, Los Angeles, 23-26 October 1988.

Manuel, C and others. Penetration of roxithromycin into brain tissue. Program and Abstracts of the Twenty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract number 1224, Los Angeles, 23-26 October 1988.

Musey, KL and others. Effectiveness of roxithromycin for treating Isospora belli infection. The Journal of Infectious
Diseases, volume 158 number 3, page 646, September 1988.

Neu, HC. Roxithromycin--an overview. The British Journal of Clinical Practice, volume 42 supplement 55, pages 1-3, 1988.

Potasman, I and others. Intrathecal production of antibodies against Toxoplasma gondii in patients with toxoplasmic encephalitis and the acquired immunodeficiency syndrome (AIDS). Annals of Internal Medicine, volume 108, pages 49-51, 1988.

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