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The following is based largely on The Fungus Fighters: Two Women Scientists and Their Discovery, written by Richard Baldwin in 1981. The book chronicles the discovery of nystatin, and it develops how fungi have come to be largely ignored by the world of medicine, despite the many cases and studies that document their role in causing disease. Elizabeth Hazen and Rachel Brown teamed up in the late 1940s to develop a safe, effective antifungal for use in medicine. Hazen had already had a long career as a microbiologist and as a mycologist, or fungi specialist, while Brown specialized in organic chemistry. Their research was funded by the New York State Division of Laboratories and by the N.Y. Health Department. The two scientists tested the effectiveness of a wide variety of agents against two, particularly dangerous fungi: Cryptococcus neoformans and Candida albicans.
By 1949, Brown and Hazen had discovered nystatin. The agent worked not only against the targeted microbes, but against fourteen other fungi, as well. The second part of this last statement is important, because it counts as one of many incidences in which nystatin has been shown to work as a broad-spectrum antifungal. Unfortunately, the FDA has only approved the drug for use in treating Candida found in the mouth (thrush) or on the skin. Clearly, that approval should be broadened.p.78 Even if it never is, however, the FDA’s stance is not much of an obstacle. Remember, once a drug is approved for use in treating one disease, doctors have license to use it to treat other conditions as they see fit.
Nystatin is produced by the fungus, Streptomyces noursei. The drug is named after the organization that funded Hazen and Brown’s research – NY State. Although it is, in fact, a mycotoxin, it has yet to demonstrate any of the harmful side effects, including cancer and atherosclerosis, found in the mycotoxins produced by other fungi. Hazen and Brown found that for efficient, mass production of nystatin, peanut meal turned out to be the ideal substance for growing Strptomyces noursei.p.14 This is hardly surprising today – even peanuts grown for human consumption are notorious for fungal contamination. Among other contaminants, the nuts have to be frequently screened for a mycotoxin called aflatoxin.
The two scientists presented their findings at the National Academy of Sciences regional meeting in Schenectady in the fall of 1950.p.79 Squibb Inc. – now known as Bristol-Myers Squibb – got the nod for further testing and the eventual production and marketing of the drug. Four years later, the FDA approved Squibb’s Mycostatin oral tablets. Doctors began writing their patients prescriptions for the drug within a month. Nystatin was described as “the first broadly effective antifungal antibiotic available to the medical profession.” It was recommended for the prevention and treatment of intestinal moniliasis, or candidiasis, especially for patients taking oral antibacterial antibiotics for prolonged periods. It was also recommended for prevention of intestinal moniliasis in intestinal surgery. Researchers reported that Mycostatin could clear up established yeast infections in patients’ digestive tracts within one to two days; a full course of treatment typically lasted 21-30 days.
Hazen and Brown created a nonprofit organization to receive their share of the royalties from the sale of nystatin, which over the span of their 16-year patent eventually came to almost $7 million. The Brown-Hazen grants program became the United States’ largest, single source of non-federal funding for research and training in combatting fungal disease.p.103 Hazen and Brown accepted not even a dime for their personal use. Today, nystatin is widely available in both as a brand name and as a generic drug. According to Bristol-Myers Squibb’s website, worldwide sales through 2001 of the pharmaceutical company’s Mycostatin alone totaled $15.3 billion.
Squibb later combined nystatin with the antibiotic, tetracycline. The new drug, Mysteclin, was designed to offset the yeast overgrowth that often happens from taking antibiotics. Other manufacturers followed suit. The host of combination drugs that arose were later banned by the FDA for “lack of proof of efficacy,” though they continue to be sold in other countries. In its decision, it seems that the FDA may have ignored a number of studies in the 1950s and 1960s that clearly documented not only that antibiotic administration often leads to the overgrowth of intestinal yeast, but that combining nystatin with antibiotics could stop such growth in its tracks.2
In 1960, Squibb came out with a more soluble antifungal called Fungizone (amphotericin B) that could be administered both orally and through an I.V.p.124 Amphotericin-B was also combined with antibiotics by various drug manufacturers – one such combination, Mysteclin F, can still be found overseas. Unfortunately, even though it proved safe when taken in pill form, amphotericin turned out to have harmful side effects over the long term when administered intravenously. Today, although safer, systemic antifungals have been developed, amphotericin remains a key drug used to treat a number of life-threatening, fungal infections.
The Prevalence and Seriousness of Fungal Diseases Hazen and Brown’s work was sparked by their awareness of the growing danger of fungal illnesses. Remember, however, that then, as now, doctors have not been required to report fungal diseases, which makes an exact quantification of the true extent of fungi-caused disease impossible.
That said, the National Health Survey performed by the U.S. Public Health Service showed that by the early 1970s, 8 percent, or 16 million Americans, were suffering from skin conditions caused by fungi.p.24 These numbers qualify such infections as an unofficial epidemic. The same health service reported that “unknown numbers of people, regardless of occupation or location, have contracted one or another of the most serious of the fungus diseases – the deep, systemic mycoses – which can disable and kill.” This number remains unknown not just because doctors are not required to report fungal disease, but also because such infections are often misdiagnosed as other diseases.p.25
The ability of some of the more serious, fungal diseases to mimic other, common diseases encountered in medicine is no small problem. Indeed, some scientists believe that fungal pathogens account for more upper respiratory infections than bacteria and viruses combined. Fungi can cause all of the symptoms associated with low-grade, upper respiratory infections, such as mild fever and cough, chills, sweating, and headache. Examination of more serious, fungal infections often leads to mistaken diagnoses of pneumonia, tuberculosis, meningitis, rheumatoid arthritis or even brain tumors.
Although fungi lie at the root of the problem, physicians base their treatments upon the inaccurate diagnoses, addressing the symptoms instead of the actual cause of the disease at hand. In cases in which antifungal measures are finally applied as a last resort, the point at which such an approach would have been most effective has often long since passed. Health care professionals often rush their patients into medicinal or surgical treatments in order to control rapidly worsening conditions in time. We should remember that such haste could increase the chance of a wrong diagnosis, which then makes the quickly delivered treatment worse than meaningless.
Wilhelm R. Rosenblatt of the Tuberculosis Control Program, New Mexico Health and Environment Department, echoes this point. He comments that physicians often mistake coccidioidomycosis and histoplasmosis of the lungs for tuberculosis. He adds that when patients suffering from fungal, lung infections have inadvertently been sent to tuberculosis hospitals, they often contracted tuberculosis in addition to their already-misdiagnosed fungal lung infection.p.30
Several studies supported by the Brown-Hazen grants have centered on the fungus Histoplasma capsulatum, the agent responsible for the tuberculosis-mimicking histoplasmosis. Many of these studies have concluded that, when doctors treat their patients as though they had contracted tuberculosis, the underlying cases of histoplasmosis often worsen as a result of secondary effects of the antibiotics used to treat tuberculosis.p.140 This happens all too often today, when physicians prescribe antibiotics to treat other conditions, such as chronic sinusitis, which is typically caused by fungi and not bacteria. The antibiotics only assure the chronicity of the underlying, fungal problem.
So, how do we contract histoplasmosis, and how could it possibly be mistaken for tuberculosis? As it turns out, although most people in areas where H. capsulatum is widespread breathe the fungi’s spores with no apparent damage, others suffer harm for reasons still not fully understood. The pathogenic fungi thrive in their lungs, where they form lesions that calcify. These calcified lesions leave a pattern that, when X-rayed, is almost impossible for doctors to distinguish from tuberculosis and its own, calcium formations.p.145
Histoplasmosis is sometimes missed to the point that the fungal infection behind it ends up killing the patient. Even then, the real cause of death is often still overlooked. This happens because, unless a fungal infection is suspected initially, pathologists tend not to test for them. Autopsies end up fingering tuberculosis, pneumonia or even cancer as the cause of death, and not the fungus that was actually the problem.p.29 Given this tendency to misdiagnose, it’s worth taking a closer look at some of the more common, fungal diseases.
Cryptococcosis is a frequent cause of secondary disease in AIDS patients. It is not isolated to any one specific, geographic area. In fact, according to one authority, it can be found wherever there are laboratories equipped to test for it!p.26 The disease coccidioidomycosis occurs mostly in the Southwestern United States’ more arid regions, including southwestern Texas, southern New Mexico, Arizona, and parts of California, especially the San Joaquin Valley. A soil fungus called Coccidioides immitis causes the disease. When people breathe contaminated dust kicked up by the wind, the fungus infects their lungs. Coccidioides immitis is apparently so hardy and so widespread that even flying over the above mentioned areas can expose airline passengers to its spores!p.158
Most victims of coccidioidomycosis come down with mild cases that involve cough, fever, and chest pain, all of which clear up on their own, given time. The more severe, progressive variety of the disease spreads from the lungs throughout the body, impregnating skin, bones, and vital organs. At that point, if not treated the disease becomes highly malignant, with a death rate of close to 50 percent.P.158 The North Central and Southeastern United States are home to the disease blastomycosis, while the central Mississippi and Ohio River valleys have histoplasmosis to contend with-as does anyone who works around or with birds, as the fungus is commonly found in bird droppings. Aspergillus is another, common species of fungi capable of infecting both the healthy and the sick. Aspergillus spores can be found airborne virtually everywhere, including hospitals and environmentally controlled, clinical laboratories.p.28,197
Fungi Forgotten Despite the growing threat to public health, scientists, physicians and many of their patients continue to display a surprising lack of knowledge and interest in fungi. Ironically, the use of drugs against other illnesses, including antibiotics, has only increased the dangers we face.p.23 Since the 1940s, dependence upon broad-spectrum antibiotics has led to an increase in the number of patients suffering from fungal diseases.p.44 Corticosteriods have been overprescribed, as well, in that doctors often use them to control symptoms such as inflammation without investigating what caused such symptoms in the first place. Used correctly, antibiotics and corticosteroids such as prednisone can bring a person back from close to death. When they are given with no thought to the causes of a given illness, they can set the stage for fungi to take over.
Libero Ajello was director of the Mycology Division, Laboratory Bureau, of the CDC in Atlanta in the early 1970s He echoes our frustration with medicine’s inability to quantify fungal diseases because doctors are not required to report cases they treat.p.30 The Centers for Disease Control (CDC) did try to bridge this information gap back in 1969. Administrators began gathering, organizing, and publishing data on fungal diseases voluntarily supplied by physicians and investigators around the country who had maintained their own records. Four years on, the program ended when funds for the CDC were slashed. Additionally, the CDC was forced to close its Kansas City field station – an outstanding center for research and training physicians to recognize and treat fungal diseases – and a number of similar programs in place at other institutions.p.31
Ajello has also noted that, about the same time the effort to collect information maintained voluntarily was launched, the 2nd National Conference on Histoplasmosis passed a resolution recommending that the CDC require doctors to report fungal diseases. Despite this, histoplasmosis remains a non-reported disease even today. Other, scattered attempts at defining the true scope of diseases caused by fungi were made throughout the 1970s. In 1974, the Commission on Professional and Hospital Activities reported that 2,192 patients in the United States had developed fungal diseases. They based their figure on stats provided by a third of the United States’ non-federal, acute-care hospitals.p.32 In 1978, 27 states combined to report 2,119 cases of fungal infections requiring hospitalization – twice the number they’d reported the prior year.p.33 Deaths from candidiasis and aspergillosis accounted for slightly more than half of these numbers, more than doubling over a ten year period. Aspergillosis deaths alone jumped dramatically between 1976 and 1977.
To put things in perspective, the 688 deaths from fungal infections reported to the CDC by these few hospitals in 1977 dwarfed the number of deaths ascribed to such reportable diseases as hepatitis, meningococcal infections, encephalitis, and rheumatic fever. Meanwhile, Brown and Hazen continued to work to educate health care professionals about fungi. The research fund they established fueled a program begun in 1970, designed to train more physicians in medical mycology.p.133 High on the program’s needs list were physicians who could correctly diagnose fungal diseases, and lab techs who could identify disease-causing fungi in specimens sent to them for analysis.p.135 Back then, many medical schools did not include lectures in Medical Mycology, while others might cover Mycology in two or three lectures during required courses in Microbiology. As a result, most med techs and microbiologists knew nothing about fungi’s role in disease. Even biologists specializing in mycology continued to study fungi from a botanical standpoint, as a subject separate from medicine.
Samuel B. Guze is a former vice chancellor for medical affairs at Washington University’s School of Medicine. In 1973, he wrote that many of the frustrations patients and physicians experience with medical care could be solved by better training.p.140 Sadly, more than 30 years later, fungi remain excluded from most medical school curriculums – just check the course schedule of any major medical school. Of course, classes on fungal mycotoxins-the harmful, chemical byproducts produced by fungi-are practically nonexistent. Finally, most laboratories remain incapable of performing rapid, accurate diagnostic tests for fungal diseases. The Brown-Hazen program was eventually cancelled. Absent its replacement, today the U.S. Department of Health and Human Services’ National Institute of Allergy and Infectious Disease (NIAID) has become virtually the sole provider of funds for work in mycology at universities, hospitals, and other nongovernmental institutions.p.193
NIAID has made two, major grants to fund centers for medical mycology – UCLA and Washington University at St. Louis.194 The American Society of Microbiology greeted the grants with enthusiasm. “The creation of these units reflects recognition,” it said, “that fungal infections have become an increasingly important cause of disability and death in this country. The emergence of this problem reflects the darker side of new treatments for malignant or immunological disorders [such as antibiotics and chemotherapy drugs]; such treatments often appear to weaken the defense mechanisms that ordinarily prevent such infections.”
Despite such recognition, neither the program at UCLA nor its counterpart at Washington University would last very long. Their cancellations were not the losses they might have been – NIAID had specified that none of the funds it provided could be used to actually train physicians. How could paying scientists to analyze mushrooms in the lab benefit med students and doctors, let alone the outside world? What’s more, funding levels had been a joke. In fact, NIAID devoted less than 2 percent of its yearly budgets to mycology, despite the billions spent to research viruses and bacteria. Does this mean that fungi are not the threat the Brown and Hazen believed them to be? Not necessarily.
Late in 1977, a dust storm occurred over California’s San Joaquin Valley. As we’ve mentioned, the disease coccidioidomycosis is common there. The storm raised soil and fungal spores and carried them as far north as Sacramento, some 300 miles away.p.196 A year later, an epidemic of coccidioidomycosis broke out near where the clouds of soil had finally come to rest. Soon thereafter, Indianapolis experienced an outbreak of nearly 350 clinical cases of acute pulmonary histoplasmosis, from which 14 people died. Most cases during the epidemic were reported from neighborhoods located downwind from heavy construction. In other words, fungi liberated by digging equipment more than likely caused the infections.
Environmental disturbances – some caused by human activity – that spread fungi comprise the common denominator between incidences like those in California and Indianapolis. Remember this next time when you or someone you know gets sick. Time spent in or around construction sites could be to blame. While incidences such as those in California and Indianapolis added to the evidence that the fungal diseases required more attention, CDC investigators were working to get some measure as to how widespread the problem had actually become. The center’s report was published in the Journal of the American Medical Association (JAMA) in late 1979, paraphrased below.p.197
From 1970 to 1976, studies of a third of American hospitals showed that the number of candidiasis cases had risen 9 percent, while Aspergillus had risen 158 percent. Contributing factors in the rise of cases of coccidioidomycosis, cryptococcosis, and aspergillosis included the use of immune-system suppressing drugs, population increases in areas where fungal infections had become endemic, and simple aging. Histoplasmosis and coccidioidomycosis combined to cause more than 75 percent of all reported cases of systemic fungal disease, while aspergillosis, candidiasis, and cryptococcosis caused the longest duration of hospitalization and the highest death rates. The total cost of these fungal diseases was estimated at $27 million in 1976.p.198 Clearly, fungal diseases were out of control. Given this, the small number of antifungal drugs developed since then and the ever growing use of antibiotics, the situation has not improved to date.
Although doctors are key in any effort to generate better data as to the impact of fungal diseases, federal law continues to exempt them from reporting such diseases to the CDC. What’s more, when the states write their own laws as to which diseases require reporting to state-based disease organizations, they exclude fungi, as well.p.199. It appears that the United States does not stand alone with regard to this problem. Speaking before a Biological Conference in Israel in 1976, the CDC’s Ajello maintained that fungal diseases remained unreported worldwide.
Why is it important to require that fungal diseases be reported? Moreover, why has the study of viruses and bacteria received so much funding, while fungi remain virtually ignored? The answer is that, without proper stats, increased funding for training and diagnostic centers, as well as research, is difficult if not impossible to obtain. Researchers who study fungi must compete for the limited funds available for disease research in general. In this they are at a disadvantage. While scientists who study bacteria and viruses can point to convincing, up-to-date, concrete data on sickness and death rates, until fungal diseases are changed to reportable status, scientists who study fungi are forced to use old data and anecdotes that may or may not still be relevant.
NIAID put together a fact sheet in September of 1996. “Although still outnumbered by their bacterial and viral counterparts,” the sheet states, “fungal pathogens are responsible for an increasing number of emerging infectious diseases.” The fact sheet goes on to say that between 1985 and 1995, NIAID more than doubled the number of fungal disease research grants and contracts it supports from 42 to 95. It also more than quadrupled funding for such research, from $6.5 to almost $29 million. The increase in spending is encouraging. And yet, at least according to the 1996 Fact Sheet, the objectives of NIAID funded research appear to remain unchanged since the 1970s. Rather than focus upon training physicians how to recognize fungal diseases, it would seem that NIAID has chosen to continue its focus on laboratory research. The question is, what is the focus of this research? Are they studying fungi that attack insects and plants, or are they truly addressing the human pathogens? NIAID’s 1996 Fact Sheet fails to answer this question.
Finally, though the millions of dollars spent on fungal research may sound generous, again, it is still dwarfed by the billions spent studying bacterial and viral pathogens. We have outlined in this book how fungi cause catastrophic diseases such as diabetes and heart disease. We look forward to the scientific community’s response. We challenge scientists to perform the vital research necessary to prove to us we are wrong. We believe that in the process, our position will only be strengthened, and that all of humanity will come closer to winning its fight against the fungi.
1.Baldwin, Richard S. The Fungus Fighters: Two Women Scientists and Their Discovery. Cornell University Press. Ithaca and London. 1981. 2.Tewari, S.N., Fletcher, R. The Efficacy of Mysteclin and Tetracycline. The British Journal of Clinical Practice. Vol. 20 No 12. Dec. 1966.