Fluconazole: A Major Advance for Cryptococcal Meningitis and Other Systemic Fungal Infections?

Fluconazole is an experimental broad-spectrum antifungal taken orally once per day. About 150 persons have received this drug for serious or life-threatening systemic fungal infections related to AIDS; over a thousand others (mostly in Europe) have used smaller doses orally for less serious fungal infections. But despite this widespread and successful use, most physicians know little about fluconazole. They can often obtain the drug if necessary in an emergency, but they have not known to ask for it.

Fluconazole appears to be effective for cryptococcal meningitis, other systemic cryptococcal infections, systemic
candidiasis, histoplasmosis, coccidioidomycosis (also called valley fever or San Joaquin fever), and other fungal
infections.

We first heard of fluconazole several weeks ago, when a friend of a person with cryptococcal meningitis called to urge us to look into it. He told us it had been a wonder drug, giving all the benefit of the standard treatment, amphotericin
B, without the side effects. The patient no longer had to spend half of each day for months or longer in the hospital for
the hours-long intravenous infusion of amphotericin B (often called "amphoterrible" by patients); instead he took the
fluconazole capsules once per day.

We asked two leading AIDS physicians about the drug; both had heard of it and knew what it was used for, but neither had much more information. A computer database search found several animal studies. We couldn't find more until last week, when a personal friend happened to mention that he knew someone with cryptococcal meningitis, and we told him about fluconazole. Our friend has contacts at medical research centers, and he was able to learn that the physicians working with the drug are enthusiastic about it. They are hoping for cure of cryptococcal meningitis, not only control, as they have been unable to find the organism in the cerebrospinal fluid after treatment in some cases, although other patients still have the disease-causing organism and continue to require preventive or maintenance medication. There has been little if any trouble with side effects. And preventive use simply requires taking the capsules once a day or less, not the repeated trips to the hospital for amphotericin B.

Most importantly, many people have been unable to tolerate enough amphotericin B to treat cryptococcal meningitis
successfully. As a result, the disease has had a high fatality rate despite the standard treatment. Many of these deaths may be avoidable if a less toxic treatment can be used.

Another computer search found the only report yet published on human use of fluconazole: a letter from two
physicians at the Pasteur Institute in Paris (Dupont and Drouhet, 1987) reporting successful treatment of cryptococcal
meningitis. We also found published statements from the chairman of the manufacturer, Pfizer Inc., to financial
analysts. Then we interviewed a spokesperson for Pfizer Central Research in Groton, Connecticut, to complete the
research for this article.


Background

Fluconazole is known chemically as an azole compound, in the same class as ketoconazole (Nizoral), an antifungal in common use. It differs from ketoconazole in crossing the blood-brain barrier, and also in being effective in far smaller
doses. In some animal studies, doses ten to a hundred times less the ketoconazole dose had the same antifungal effect. Typical human doses are 200 to 400 mg for ketoconazole and 100 to 150 mg or possibly more for fluconazole. Most of the fluconazole taken is excreted unchanged in the urine.

No human studies comparing fluconazole with amphotericin B have yet been done; these should begin soon. Animal studies have given varying results (see references). Sometimes amphotericin B has been more effective, sometimes fluconazole has been, and sometimes they have been equivalent.

In the U.S., the main interest in fluconazole is for major, life-threatening fungal infections usually resulting
from AIDS or other immune deficiencies. In Europe, a different branch of Pfizer Central Research, in Sandwich, England, has studied fluconazole mainly for less serious infections such as vaginal candidiasis or fungal skin infections. In Europe the drug is better known and more widely used than in the U.S.

The only published report of human use, at least for the serious systemic infections, is the letter in the May 1987
Annals of Internal Medicine from physicians at the Pasteur Institute (Dupont and Drouhet, 1987). An HIV positive patient
with cryptococcal meningitis had been treated for two and a half months with amphotericin B and flucytosine, but toxic
effects required that the treatment be stopped.

Several months later the meningitis returned, and because of the previous toxicity with standard treatments, the
physicians tried fluconazole. Temperature decreased by the fourth day, and by the tenth day the headache was gone and the patient was able to walk around in his bedroom. In one month, the organism could not be cultured from cerebrospinal fluid. Still the physicians are keeping the patient on the long-term maintenance recommended for persons with AIDS; they are using 150 mg of fluconazole twice per week.

The two physicians summarized the results as follows: "The patient is being followed at regular intervals and is
asymptomatic and in excellent general condition five months after the end of daily treatment. Clinical tolerance of
fluconazole is excellent; hematologic, renal, and hepatic characteristics show no abnormalities."

This letter reported only one case. For more information, we called the press office at Pfizer Inc., which referred us to
one of Pfizer's researchers. He told us that fluconazole has been used with an estimated 150 to 200 patients with serious
systemic fungal infections (as well as many others with less serious conditions). They have not seen any serious toxicity
with fluconazole; very few side effects have either been definitely related to the drug, or serious enough to cause treatment to be interrupted. Side effects may be similar to those of ketoconazole, which in rare cases can cause serious
liver toxicity, so the physicians conducting the clinical trials are carefully testing for any liver problems.

The researcher we spoke with explained that early trials have emphasized cryptococcal meningitis because it is
immediately life-threatening, much more common with AIDS than most other fungal infections, and easily diagnosed from the cerebrospinal fluid, allowing a quick test to determine how well the drug is working. But he explained that other
infections are expected to increase as AIDS moves into areas of the country where these fungal diseases are endemic, such as coccidioidomycosis in the Southwest and histoplasmosis in the Midwest. Pfizer plans to watch for increases in these infections and design new trials for them. Some trials have already accepted patients with serious fungal infections other than cryptococcal meningitis.


Public Policy Concerns -- And Three Recommendations

The example of fluconazole illustrates serious problems in the drug-development system in the United States. Lives have been lost and are continuing to be lost unnecessarily, because the system fails to deliver medical care in the best interest of the patients.

We should point out that Pfizer Inc. has handled fluconazole much better than many other companies have
typically handled AIDS treatments entrusted to their care. Pfizer has made a serious effort to develop and test
fluconazole, an effort costing several million dollars already. By contrast, many companies appear to be using their potential AIDS treatments for stock manipulation--although it is almost impossible to get proof as we cannot know the intentions of their directors. Other companies have apparently engaged in speculation, buying the rights or options to promising but unproven substances on the cheap and holding these rights in case they become hot later, meanwhile neither developing the drugs nor letting anyone else do so.

Pfizer has also been open to compassionate use of fluconazole in emergencies; many others have not. This
compassionate policy, however, has only affected those whose physicians have heard about fluconazole and are willing to try an experimental, non-approved treatment. While exact figures are not known, the available numbers suggest that most of those whose cryptococcal meningitis or other severe fungal infections cannot be treated successfully with standard therapies have been left to die without fluconazole being tried or considered.

Most of all, the example of fluconazole illustrates a lack of communication among physicians and others concerned with AIDS treatments. By the end of last year, 1986, over two thousand people had used fluconazole orally as an antifungal-- mostly in Europe and in the smaller 50 mg doses and for less serious infections. Yet now in September 1987, few U.S. physicians even among AIDS specialists know enough about fluconazole to consider using it.

What should be done to correct this problem for the future? In our opinion, three things need to happen:

* Medical ethicists must examine the barriers to treatment development and to professional communication, and speak out when necessary. With fluconazole the biggest problem may have been requirements of professional secrecy. The protocols describing the clinical trials are trade secrets of the manufacturer. The results of the trials belong to the researchers, who will publish them, but medical journals usually insist that they not be published elsewhere first. Peer-reviewed journals often take months or longer between receipt and publication of an article; some have greatly reduced this time for AIDS studies. But researchers themselves are busy, and naturally they want their articles to be perfect before they are submitted to journals, because once published an article remains public forever and cannot be changed. Usually researchers will share vital information with other physicians before publication, but these physicians must first know to ask.

Other AIDS treatments have suffered worse problems, such as being used primarily for stock manipulation or for
speculation; companies have acquired the rights and then sat on these drugs, allowing essentially no research to proceed.

There is no legal recourse in these cases, because U.S. law allows a corporation to acquire exclusive proprietary
rights to a drug and then refuse to develop it or allow anyone else to do so, for any reason or no reason as it sees fit. But
medical ethics is becoming a small industry in this country. If ethicists would investigate these problems and speak out
about them, then at least the most grievous abuses could become universally unacceptable in the professional community. Few companies would ignore such a consensus.

* Practicing physicians seldom have time to keep up with research. Many learn about new treatments primarily from drug- company salespersons--who are forbidden to say anything about drugs or uses of drugs not already approved by the FDA. Such approval often lags several years behind the time researchers are confident that the treatment is valuable. And the expense of U.S. new-drug approval, usually estimated at about 80 million dollars per drug, deters many companies from ever starting the process in the first place.

Physicians who specialize in complex diseases like AIDS or cancer might consider doing what a few in private practice have already done: have a research person on their staff. This person, perhaps a research nurse, can spend full time keeping up with the published literature, as well as telephoning researchers to learn what is and is not working, in order to keep the physician informed on current developments. In addition, this information can help the physician evaluate drug-company claims.

* AIDS organizations need to pay attention to treatments and develop in-house expertise, in order to advocate in the
interests of their clients. If service organizations put as much effort into making sure promising treatments were properly
researched and made available as they now put into teaching people to die, much of the dying would be unnecessary.
Organizations should consider hiring a research nurse or physician to follow research full time and keep them informed.

Effective patient advocacy could force ethicists and other professionals to re-examine the whole issue of medical
decisions which are not in the interest of the patient, but instead serve the purposes of drug companies or other organized professionals. We need a new look at widely and unthinkingly accepted procedures, such as withholding access to unapproved treatments in order to force patients into clinical trials, or requiring those in trials to give up all other treatments or otherwise accept substandard care which gets them sicker faster, reducing the cost of conducting the trials and proving efficacy. Even double-blind trials can and should be designed so that patients do not need to be desperate to accept them.

Whenever patients and their physicians are removed from decision making about their own care, we can reasonably suspect that someone else's interests are being served. No one can stop powerful forces such as the pharmaceutical industry or the Federal drug bureaucracy from acting in their own behalf. But let's stop pretending that they represent the patient's interest too.


Information for Physicians

Physicians can obtain fluconazole for compassionate use in an emergency, if amphotericin B has failed or cannot be used because of toxicity. For more information, physicians only should call Pfizer Central Research, Groton, Connecticut, (203) 441-4112.

Pfizer Inc. plans to increase its clinical testing of fluconazole, adding several hundred more patients. The National Institutes of Health through its AIDS Treatment Evaluation Units plans to begin its own study soon on cryptococcal meningitis and expects to enroll 200 patients. Trials will take place in many cities, including San Francisco, New York, Los Angeles, and Miami, but none of these trials is recruiting at this time (September 1987). They may begin doing
so in the coming weeks. Many of these studies will be double blind, comparing fluconazole with amphotericin B (no placebo will be used), so patients cannot enter if any condition would rule out their use of amphotericin B. Those patients should qualify for compassionate use instead.

Pfizer does not expect to be able to apply for permission to market fluconazole as a prescription drug in the United
States until 1989. At that time Pfizer will present its data to the U.S. Food and Drug Administration, which must then make
its decision. No one knows when fluconazole will become generally available. But physicians can obtain it now for
life-threatening infections, when standard treatments cannot be used.


References

B Dupont, M.D., and E Drouhet, M.D. Cryptococcal Meningitis and Fluconazole. Annals of Internal Medicine,
volume 106 number 5, page 778, May 1987.

Seventeen other technical references, mostly animal and laboratory studies, can be found by a Medline computer search. The European database Excerpta Medica contains 25 references at this time.


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