Antibiotics Losing Ground:

The Truth About Infectious Diseases

Americans used to have a germ fetish. From scalding rinse water for the dinner dishes to orange-hued methylate, which stained our clothes as it swabbed our cuts, the war on unseen microbes was tedious, time-consuming and relentless. And with good reason.

Before World War II, there were few drugs to fight infection of any kind. Viruses, bacteria, fungi, protozoa, even intestinal worms were a real and accepted threat and the diseases they caused, from pneumonia to pertussis, an unhappy consequence of normal life.

With the discovery of antibiotics and the rapid-fire development of vaccines for such viral scourges as polio and small pox, most Americans traded the vigilance of their parents and grandparents for a relaxed sense of security. It is, after all, easier to take a pill than drain a swamp and simpler to forget than to worry.

Today that sense of certainty is evaporating under the ual onslaught of new and mysterious infectious gents, such as the Ebola virus, and the drug resistance of some very old ones, including malaria and tuberculosis. That 12,000 Americans are dying each year because their drug-resistant strains of disease are untreatable - and that many of these deaths occur in hospitals among surgery and immunocompromised patients - feeds the insecurity.

But is the fear justified? Are new "killer bugs" nature's revenge on a profligate and plundering race? Or is the recent spate of books, articles and movies about deadly diseases merely the latest adrenaline fix for the thrill-addicted masses? There is no easy answer. But infectious disease specialists at UCSF and elsewhere all agree that human behavior - from dam building to air travel- is the key ingredient in the emergence and spread of infectious diseases and that clean water, good sanitation, strong public health systems and civil peace are the chief weapons of control.

That none of these is in abundant supply around the world should give us pause. So should the recent and sudden appearance in America of Lyme disease, its more fatal cousin, human granulocytic ehrlichiosis, Legionnaire's disease, hantavirus and cryptosporidiosis. This is not to mention E. coli disease, spread by contaminated food, which according to CDC [U.S. Center for Disease Control], estimates now is killing hundreds of young children and elderly people each year.

There is another truth as well. Most of the world's major infectious diseases - malaria, hepatitis, cholera and tuberculosis - barely register on Americans'empathy scale because most Americans are not perceived to be at risk. (HIV is the one obvious exception but here, too, there are signs of limited interest among the public at large. See UCSF Magazine, "AIDS - 10 Years After," February 1994) Nor are the world's major pharmaceutical companies very interested in "developing-world" diseases, because drugs that work in poor countries have to be cheap and easy to administer, reducing profits. As a result, funding for research into the causes and control of such diseases, research of potential benefit to tens of millions, is paltry when compared to that for the more common diseases of their developed world, such as cancer and atherosclerosis.

Infectious disease research also takes place almost exclusively at universities, far from the public eye and often on a precarious financial shoestring. Yet even when threats to public health do strike close to home, multiple drug-resistant tuberculosis being a case in point, the money spigots do not gush. Indeed, critics have charged that the attempt to save money by reducing public health budgets in the 1980s contributed mightily to the resurgence of TB in the U.S.

The good news is that the public, for whatever reason, now seems to be paying more attention. And a revived public interest in infectious disease could fuel a new awareness of prudent precautions - some of which, like the simple washing of hands, need to be dusted off and re-enshrined as canon in homes and hospitals.

The University of California Medical Center in San Francisco has recently become home to a federally funded Tropical Disease Research Unit that combines the talents of parasitologists, crystallographers, and specialists in recombinant protein production, enzyme mutagenesis and drug design. Such innovative efforts presage what could soon be the norm in the battle against infectious diseases - a battle that as recently as 30 years ago, many assumed was over.

As the following review of infectious disease research reveals, that assumption was tragically wrong.

TB: Too Tough To Kill?

Chief among these warrior diseases is tuberculosis, which in the 100 years before 1950 killed an estimated 1 billion people. It still kills an estimated three million per year, despite the existence of antibiotic therapy widely available for the last four decades.

How can this be? For UCSF TB researcher Joel Ernst, the question has two answers - one that stems from decreased vigilance in fighting the disease and the other from the nature of the tuberculosis mycobacterium itself. "This is a very clever, very tough bacterium," says Ernst. "It grows slowly, spreads through coughing and has infected probably one-third of the world's population. And because it's been around for 10,000 years, it knows our immune defenses well and can hide for decades before causing any disease."

Moreover, the bacterium thrives with close and prolonged person- to-person contact. No wonder then that tuberculosis has always been associated with poverty, malnutrition and fearful crowding. That such conditions still exist, together with widespread drug addiction and such immuno-compromising diseases as AIDS, explain in part why TB has revived. But they still beg the question of how the mycobacterium outwits the human immune system and why in an otherwise healthy person, the infectious areas are sealed off in a kind of fibrous shell, rather than destroyed outright.

"This was a big mystery," Ernst explains. "Macrophages [the scavenger cells of the immune system] should kill it, but they obviously don't since the bacteria take up residence inside them. That led us to ask how the mycobacteria manage to survive." With the answer to that question as their objective, Ernst and his colleagues at San Francisco General Hospital began to examine exactly what happens at the cellular and molecular level when the TB bacteria first encounter a macrophage.

Their initial experiments were designed to learn whether the mycobacteria avoid being killed by entering the cell through receptors that do not activate it. They soon discovered that this was not true, that, in fact, the mycobacteria survive just as well regardless of which receptor they used to penetrate the macrophage. To test the next theory, Ernst infected human macrophages both with TB bacteria and the parasite toxoplasma. He then treated them with gamma interferon, an immune-system substance that activates macrophages. Clearly, if the gamma interferon treatment resulted in the death of the toxoplasma (the normal result) but not the TB bacteria, then the latter's "too- tough-to-kill" status would have been substantiated.

To Ernst's relief, that did not happen. "Because neither infectious agent was killed, we concluded that the TB bacteria somehow disarmed the macrophage's ability to respond to gamma interferon." And to disarm so successfully means that there must be a biochemical trail to follow. Ernst and colleagues now are searching for that trail with the new tools and techniques of molecular biology. In time, they hope to discover the signaling malfunction that is responsible for disarming the macrophages. Understanding that malfunction might unlock the weapon that would not merely control TB, but destroy it. That is, Ernst cautions, if research funding does not dry up first.

According to SFGH pulmonary specialist Philip Hopewell, "We as a country have always had our heads in the sand about TB. We abandoned TB control in the 1980s to save money and look what happened, multiple drug-resistant strains and high infection rates in many cities around the country, especially among those with HIV." Now there is talk of turning what federal funding there is left into block grants to the states. Hopewell is unimpressed. "That happened once before in the late 1 970s and the money for TB just dried up. Now we need huge amounts just to put the lid back on the disease."

Perhaps the best example of how spending on prevention can pay off is the SFGH TB Clinic's Directly Observed Therapy (DOT) program. Tuberculosis remains a treatable disease, thanks to a combination of up to four different drugs, usually given over six months. Because treatment is lengthy, compliance can be a problem. And if treatment is begun and not completed, the infection will reignite with mutant bacteria that are resistant to the drugs the next time around. It is just such haphazard therapy that has allowed a few strains of TB to develop resistance to as many as 11 different drugs.

Complicating matters, at least in San Francisco, is the fact that about 60 percent of the TB Clinic patients are foreign-born. Many are recent arrivals, may not speak English (clinic staff are fluent in 12 different languages, including sign language), and may not be familiar with TB control practices. Other patients may be homeless, drug addicted, at risk for or already diagnosed with HIV.

The DOT program identifies those patients with active TB cases who, for whatever reason, seem unlikely to comply with the daily drug regimen. These patients are asked to come to the clinic daily to take their medicine. If that proves too difficult, TB control field workers instead deliver the medicine to the patient's home, work site or "hang out" anywhere in the city. Using a free sandwich as enticement, the field workers watch to ensure that the patient takes the medicine.

"It is because of this enforcement program that multiple drug- resistant tuberculosis has not become a big problem in San Francisco," says Richard Locksley, head of the Division of Infectious Diseases. "And the credit for that must go the people at SFGH and in the Public Health Department who refused to let the infrastructure disintegrate to the point it has in places like New York City and Miami."

Will the Bad Old Days Return?

The signs - multiple antibiotic resistance - are everywhere to be seen, from hard-to-fight ear and throat infections to pneumonia and tuberculosis. Indeed, as Richard Duma, executive director of the National Foundation for Infectious Diseases, explains, "Americans may find themselves reliving the 1930s when deaths from pneumococcal infections [pneumonia] were extremely common."

Are such experts being alarmist? "Not at all," contends Merle Sande, Chief of Medical Services at SFGH, who spoke to a full session of the California State Senate in July about the dangers posed by resurgent infectious disease. "Drug resistance is a huge and growing problem and the public is completely unprepared."

Streptococcus pneumonia, for example, is one of the leading cause of illness in the U.S. It causes 3,000 cases of meningitis, 50,000 cases of bacteremia (or blood infection), 500,000 cases of pneumonia and more than seven million cases of otitis media (or ear infection) each year. Of these, an estimated 25,000 to 50,000 die. Fatalities worldwide are more than 4 million annually. Once controlled by penicillin, the organism is rapidly developing partial or total resistance.

In fact, in some American communities, according to unpublished data from the Centers for Disease Control, more than 30 percent of the strains gathered and studied in 1994 were unfazed by the drug. For those affected, the results can be prolonged discomfort and the risk of serious illness should a resistant strain evade immediate detection. There also is the possibility of what clinicians who practiced in the 1930s and early 1940s routinely call the return of the "crisis."

"When a patient caught pneumonia in those days," recalls Moses Grossman, professor emeritus of pediatrics, "you couldn't do anything but wring your hands and await the crisis." The treatment advice found in clinical practice manuals of the day suggests the desperation: liquid diet, tepid baths to control delirium, morphine for chest pain, caffeine to stimulate circulation, rectal tubes to expel accumulated gas, soapsuds enemas and blankets.

"The mortality from pneumonia was high," adds Grossman. And although deaths from pneumonia today tend to cluster among the very young and very old, healthy, young adults usually have been spared thanks to the success of antibiotics. But that margin of safety may be evaporating, at least for those unlucky individuals who happen to become infected with a resistant strain.

From gram-negative bacilli and shigellosis to enterococci and tuberculosis, the trends are all the same - emerging resistance due to enzymatic action, alterations in the bacterial cell membrane, alteration in molecular structure, permeability changes that allow bacteria to pump out the antibiotics and the transfer of resistance to other species. "It can make you panicky some days," says Marilyn Jordan, nurse epidemiologist in the Medical Center's Infection Control Unit. "But then you realize that prevention, precaution and containment still are the best weapons and that they still work."

This remains true even though, as Sande explains, "Viruses and bacteria outnumber us by totals we cannot imagine. In reality, whatever we do to try to stop them, they will always be one step ahead." Still, he insists, there is time to regain our balance and our previous, if always precarious, edge. "We misuse antibiotics at an incredible rate, so we can start solving the problem by refusing to ask for them - and by discouraging doctors from prescribing them - when they won't do any good." Chambers concurs. "The golden age of antibiotics is passing. To be successful in the future, we will have to develop a much better understanding of the biology and ecology of all infectious organisms."

Original publication date: October, 1995

Excerpted from UCSF Magazine
U.C. San Francisco

Reprinted by permission.

See also:
Report on the Tuberculosis Epidemic, 1995
From the World Health Organization.