Aerosol Pentamidine: New PCP Prophylaxis and Treatment

Published in SAN FRANCISCO SENTINEL, January 16, 1987 Also published in AIDS TREATMENT NEWS, same date

The SENTINEL has learned of a new treatment which may be a major advance in preventing pneumocystis in persons with AIDS.
About 100 patients in New York and 30 in San Francisco are now using this experimental therapy, but so far there has been little
publicity and most physicians are unfamiliar with it. Until the current trials are finished, the treatment must be considered
unproved; but so far it appears to be close to 100 percent effective in preventing pneumocystis, with few if any side effects.

(Meanwhile, a completely separate study in San Francisco is now enrolling patients for aerosol pentamidine treatment after pneumocystis has already been diagnosed. For more information, see below. It is important to start this treatment early.)

The new prevention procedure was developed by Edward Bernard, M.D., and other investigators; he is a researcher in infectious diseases at the Memorial Sloan-Kettering Cancer Center in New York, where the aerosol pentamidine prophylactic treatment has been used for about 11 months. Due to the great demand and a huge waiting list to get into the study, the Sloan-Kettering team has provided information to other physicians who are interested.

In San Francisco, Pacific Presbyterian Medical Center is treating about 30 patients with the aerosol pentamidine
prophylaxis. While the treatment is not generally available at this time, physicians can probably find ways to obtain it for
their patients when necessary.


Rationale of Aerosol Pentamidine

Pentamidine has been used for over 40 years as an anti-parasite drug. In Africa, it was learned that one treatment
every six months could prevent sleeping sickness. Ten million people have used the drug; due to the duration of its effect, it has been called "the chemical vaccine". The reason for the long-lasting protection is that pentamidine stays in the tissues and is eliminated very slowly.

Pentamidine is effective against pneumocystis, but when sufficient amounts are given in the conventional way, by IM or IV injection, it can cause severe side effects. Studies have shown that only a very small portion of the injected drug reaches the lungs. Much more of it goes to the liver, kidney, spleen, and other organs, where it is useless for preventing pneumocystis and may cause toxicity.

To deliver the medicine more selectively to where it is needed, researchers tried administering it by a very fine aerosol spray which could be inhaled deeply into the lungs. They tested the treatment with animals first, because the drug had never before been given in that way, and there is little experience with using aerosols for any infection. Aerosol pentamidine did reach effective levels in the lungs, and very little went to other organs. Even ten times the effective dose showed no evidence of harmful effects in the animals. The half-life of the medicine in the lungs -- the time required for half of it to disappear -- was 35 days, meaning that one treatment every two weeks could maintain a reasonably constant drug level.


How Is the Preventive Treatment Used?

Every two weeks, patients come to the clinic and inhale the medicine from a machine called a nebulizer, which produces a very fine spray. Sloan-Kettering uses an ultrasonic, hand-held model; it is known in the clinic as "the green machine". For safety, the Sloan-Kettering team provides a separate machine for each patient; it imports them from West Germany for investigational use. Patients administer the medicine at their own pace. The treatment takes 15 to 30 minutes.

For the first month, treatment is used once a week, to build up protection quickly.

How safe and effective is the preventive use of aerosol pentamidine? In the Sloan-Kettering study with about 100
patients so far, a few mild cases of pneumocystis occurred in the early stages of treatment, before the researchers began starting patients on a once a week schedule for the first month to build protective levels quickly. After the change to the new schedule, there have been no cases at all in anyone on the treatment. And as far as we know there have been no side effects.

Of course this treatment has no effect on the underlying AIDS infection or immune deficiency, so for continued protection it must be used indefinitely. Also, the aerosol treatment cannot protect against other opportunistic infections which are not in the lung, a factor which should be considered before other preventive treatments are discontinued.

What Happens Next?

The Sloan-Kettering team wants above all to get this treatment thoroughly tested and approved, so that any physician
can prescribe it; they are working with the U.S. Food and Drug Administration toward this end. But usually it is necessary to do a double-blind placebo trial as part of the approval process. The Sloan-Kettering researchers do not want to use a placebo, and have not done so. To get approval without a placebo trial requires a much stronger showing than usual. The researchers are trying to prove that the treatment is at least 95 percent effective in preventing pneumocystis. Getting conclusive proof of safety and effectiveness is especially complicated because many of the patients have other opportunistic infections or KS, and many are also using other treatments such as AZT.


For More Information On Prevention

Because this treatment is experimental, some researchers at least don't think it is quite ready for routine use in
physicians' offices, and instead prefer to see it used at a medical center or university hospital, where institutional review
boards provide additional protection for patients.

In San Francisco, a number of pulmonary specialists are familiar with the aerosol pentamidine treatment. Other
physicians can consult with them about where to obtain it for their patients.

Almost nothing about this treatment has appeared in print, except for two brief references in the abstracts of the Paris
AIDS conference last June (poster sessions number 300 and 294). In three months, a medical journal will report on the early animal studies at Sloan-Kettering. The team presented the earliest report of its work at a March, 1986 meeting of the American Society for Microbiology. It issued a press release at the time, but apparently nobody picked it up.

The researchers at Sloan-Kettering are willing to answer questions from physicians, but they cannot handle a large volume of calls. Also, they do not have lists of physicians or hospitals currently using the treatment in other areas. But if physicians cannot find out locally about aerosol pentamidine , they can call this writer 800-TREAT-1-2, for the phone number of the research team at Sloan-Kettering.


Aerosol Pentamidine To Treat Pneumocystis

A completely separate group of researchers has developed an aerosol pentamidine treatment for use after pneumocystis has already been diagnosed. Two hospitals in San Francisco are now ready to accept patients. As far as we know, the treatment is not yet available outside of San Francisco.

Some of the researchers at Sloan-Kettering doubt that aerosol pentamidine would be effective after pneumocystis has developed; they fear that congestion would prevent the medicine from reaching the parts of the lung where it is most needed. However, a team of researchers at the University of California San Francisco Medical Center carried out numerous animal studies and found that aerosol pentamidine could be highly effective if pneumocystis was present but in its less severe forms. Some of the animal results were published in the January 1987 Antimicrobial Agents and Chemotherapy. Although these studies used rats, the results are likely to apply also to humans, because in previous experiments, the effects of new treatments on pneumocystis in the rat have been highly predictive of their effects in humans.

Robert Debs, M.D., the principal investigator in the animal studies, calls pneumocystis the perfect disease to treat by
aerosol, because the infection is in the air spaces at the end of the airways, where the medicine goes, and ordinarily it does not occur outside of the lung.

Two hospitals within the University of California San Francisco system have received approval from the U.S. Food and Drug Administration and are currently enrolling patients with established pneumocystis pneumonia for treatment with aerosol pentamidine. Treatment will be given once a day for fourteen days; each administration takes about half an hour. There is no control group; everyone enrolled will receive the drug, and the results will be compared with recent studies of IV pentamidine or septra. Physicians may contact either Bruce Montgomery, M.D., at San Francisco General, or Jeffrey Golden, M.D., at Moffitt. If physicians suspect that pneumocystis is present, it is important to enroll the patient early for this treatment.


Acknowledgements

We wish to thank Edward Bernard, M.D., of Memorial Sloan-Kettering Cancer Center in New York, Robert Debs, M.D., of University of California San Francisco Medical Center, Robert Fallat, M.D., of Pacific Presbyterian Medical Center, San Francisco, and two patients who must remain nameless, for their assistance with this article.