Why Physicians No Longer Know About Fungi: An exposé on Nystatin

[Guest guest]

http://www.knowthecause.com/sciencefungus.html

 

By: Doug A. Kaufmann

 

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 -

N.Y. 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.