AIDS TREATMENT NEWS No. 111 - September 21, 1991
Denny Smith

Diclazuril, Related Developments

Diclazuril is a veterinary drug used to treat parasites in chickens, and over a year ago was found to help some people with cryptosporidiosis. Contrary to what we implied in our previous articles, diclazuril is not marketed to U.S. veterinarians, although a number of people have acquired personal supplies from other countries.

A version redesigned by the manufacturer, Janssen Pharmaceutica, for human use was tested in recent clinical trials in New York. Rosemary Soave, M.D., reported the results thus far at the Sixth International Conference on AIDS in June. She tested daily doses from 200 mg to 600 mg, and saw the best responses at the higher doses.

Even though cryptosporidiosis is usually not a problem outside the gastrointestinal tract, Dr. Soave said that those people who experienced the best response to diclazuril also showed higher levels of the drug in their bloodstream. So Janssen is again reformulating diclazuril to improve absorbability. Trials of the improved compounds are planned, but details have not been released. Meanwhile, Janssen has applied to the Food and Drug Administration for permission to provide compassionate use access to diclazuril.

On a speculative note, a pharmacist told us that a close chemical relative of diclazuril, called toltrazuril, is also used for treating parasites in animals. Toltrazuril, a product of Bayer (under the trade name Baycox), is a broad-spectrum anti-protozoal used to treat sheep, poultry, and fish. Like diclazuril (trade name Clinicox), it is marketed in some Latin American countries for veterinary use. We were told that in animal studies, toltrazuril was as safe as diclazuril, and that it is formulated in a liquid more concentrated than the diclazuril powder mixed with poultry feed. However, we know of no human experience with toltrazuril nor of any laboratory data testing it against Cryptosporidium. A veterinarian friend of ours is looking further into toltrazuril, as well as other veterinary drugs which might be able to treat infections in humans.

Humatin Success?

One of the studies of cryptosporidiosis presented at the Sixth International Conference was a hospital chart review of patients treated with the common anti-parasite drug paromomycin (brand name Humatin); the study found good results (see AIDS TREATMENT NEWS #107, July 20, 1990, page 5). Surprised that an ordinary, available medicine was found useful after years of research into numerous possibilities, we contacted the author of the abstract, Joseph Gathe, M.D., at Park Plaza Hospital in Houston. Dr. Gathe said that he continues to see very good responses to paromomycin in about 90% of his patients with cryptosporidiosis. The improvements include a substantial decrease in the quantity and frequency of diarrhea, and often a decrease in stool counts of the parasite's cysts.

This drug is an intraluminal agent, which means it passes through the gastrointestinal tract with little absorption into the bloodstream. Dr. Gathe explained that this characteristic is an advantage for controlling toxicity (none was seen in his patients), but would make the drug useless for treating infections which have disseminated to other body systems. However, drug handbooks caution that if this drug should reach the bloodstream, such as through intestinal ulcers or blockage, it could lead to hearing loss or kidney toxicity or other side effects attributed to large or extended doses of aminoglycoside antibiotics.

We consulted three other physicians who have tried paromomycin in the past to treat cryptosporidiosis: two of them had not seen any response. One of the two pointed out that chart reviews can be unreliable methods of drawing conclusions about a treatment because they analyze data retrospectively, without control over variables which a prospective clinical study would eliminate or at least manage.

The third was Paula Sparti, M.D., a respected HIV physician in Miami. She has tried paromomycin with her patients diagnosed with cryptosporidiosis, sometimes without any results. But one of her patients responded dramatically within 36 hours after starting paromomycin, at 500 mg given four times daily. His profuse diarrhea completely cleared, and related abdominal pain subsided. Shortly after, a patient treated by an associate of Dr. Sparti's responded similarly to the drug.

Dr. Sparti's assessment is that some people, not all, may benefit from paromomycin. She feels that since it is available and safe, people with cryptosporidiosis should be offered a trial. If there is no improvement within 7 to 10 days, the drug can be discontinued.

It is possible that some of the differences in response to the drug may result from the difficulty in diagnosing intestinal infections. In the search for a cause of diarrhea or malabsorption, several organisms capable of causing illness might be identified in stool specimens. Other microbes may not be readily found in the specimens, yet be present and causing problems in the intestinal tract. Given these uncertainties, the treatment for diarrhea and resulting weight loss can be hit and miss. If symptoms begin to clear up during the administration of a given drug, such as paromomycin, it might not always be possible to know which organism the drug acted upon, if any.

Macrolide Antibiotics?

Two other drugs tried so far to treat this infection are spiramycin and clindamycin; there have been positive, but limited, results. Clindamycin is already approved to treat certain infections; spiramycin is an investigational macrolide antibiotic, available through compassionate use. A related drug called azithromycin, approved in Yugoslavia, has strong laboratory activity against another protozoal infection, toxoplasmosis. Human trials to test azithromycin against toxoplasmosis are long overdue. A pilot study testing the drug in MAI infections is already in progress. The manufacturer, Pfizer, Inc., is now working toward FDA approval as a treatment for certain respiratory infections and chlamydia. We have heard that some buyer's clubs are investigating how to increase access to azithromycin in this country.

Given azithromycin's broad potential, we wondered about trying it for cryptosporidial infections. We spoke to Shelley Gordon, M.D., an infectious disease specialist in San Francisco who usually tries clindamycin with primaquine to treat cryptosporidiosis, with some success. She noted that her patients with higher helper cells tend to have the best results. We asked her about the logic of trying azithromycin, and she agreed that it is worth considering. A spokesperson for Pfizer told us that they were not aware of any studies suggesting that azithromycin has activity against Cryptosporidium.

The safety and availability of paromomycin suggest that it is worth trying for cryptosporidiosis. Diclazuril and its future analogs appear promising, and speedy development could spare many people from resorting to veterinary versions. Azithromycin is a speculative possibility, but it warrants research attention. These drugs, like clindamycin, spiramycin, and hyperimmune milk, may work for some people some of the time. Until one is proven consistently effective, we support aggressive experiments with the reasonable choices at hand.

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