MUENCHHAUSEN

AN ELECTRONIC NEWSLETTER ABOUT ENVIRONMENT,
RENEWABLE RESOURCE TECHNOLOGY,
AND RELATED TOPICS

By BOOTSTRAP PRESS, INC.
BETHESDA, MD
GREENBARON@CSI.COM

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FEBRUARY 25, 2004
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WELCOME!

The Green Baron welcomes one and all who take the time to read Muenchhausen. He aims to “tell it like it is” as much as possible, and avoid advocacy and ideological positions. There are enough of those to go around in other publications.

DEDICATION

This issue of Muenchhausen is dedicated to the scientists and their supporters who study the alarming tendency of many pathogenic microorganisms to develop resistance (“R”) against antibiotics. It also is dedicated to those of the National Foundation for Infectious Diseases (NFID, Bethesda, MD) and other experts in the field who are trying to carry the warning about overuse and misuse of antibiotics and the way these factors contribute to the phenomenon of “R”. In addition, the Green Baron expresses his gratitude to NFID for inviting him to their various press conferences and meetings so that he may become more familiar with “R” and its disturbing ramifications.

WAS THE ENEMY INDEED FLUNG BACK. . .

. . . Or is the enemy flinging humanity back? During the 1920s, Alexander Fleming noticed that bacteria growing in the vicinity of colonies of the mold Penicillium notatum died. This phenomenon could easily have escaped notice, but Dr. Fleming, who was working on another project at the time, serendipitously decided to investigate the matter of bacterial death in the presence of P. notatum. “The rest is history,” as the hackneyed quotation has it; from Fleming’s research came penicillin (“the wonder drug”) and, later, additional medicinal drugs derived from other molds and other such organisms, such as streptomycin, amoxicillin, erythromycin, ciprofloxacin, vancomycin—the list goes on and on. Fleming was awarded the Nobel Prize in Physiology or Medicine for his discovery of penicillin, the first of a family of drugs that came to be known as “antibiotics”.

As Gregory Benford, professor of physics at the University of California Irvine put it, “At the time [for example, the late 1940s], it seemed that an old enemy was flung back.” But was the enemy indeed flung back? For a while, yes. But Benford reminded his readers that nature has its way of fighting back, and soon enough, pathogenic bacteria began to develop resistance or “R” against antibiotics. The process was slow, but it was inexorable. Here, the Green Baron should note that he found Benford’s commentary in The Magazine of Fantasy and Science Fiction (F&SF). F&SF, however, normally makes it a practice to include an article on actual science, written by an expert, or at least, one highly knowledgeable in his or her field. Benford suggested to his readers that should “R” prevail and antibiotics become ineffectual, medicine could well be flung back to the way it was during the 19th century.

A SCARY HEADLINE

“Supergerms” loom,” screams the headline. The subhead warns, “Antibiotic resistance soars with Chinese overuse” (1). The Green Baron sits in his living room on that Friday morning, reading Julie Chao’s article and starting to feel disquieted.

Yes, the Green Baron acknowledges that the headline is a bit sensational. Nevertheless, several points in Chao’s story bear repeating.

According to Chao, a Mr. Ye Zhiming goes to a drugstore and buys antibiotics whenever his throat feels scratchy. He can buy, without prescription, a box of 24 capsules of spiramycin for the equivalent of 60 cents. “Buying any of a range of powerful antibiotics in China is as easy as buying aspirin—not that a doctor would have refused [Mr. Ye] a prescription. Up to 90% of people who visit hospitals in China are given some type of antibiotic.

“The overuse of antibiotics has resulted in a new generation of drug-resistant ‘supergerms’ in the world’s most populous country.” Chao goes on to say that rates of drug resistance “that took decades to develop in the United States have been surpassed in China in just 10 years.”

DRUG-RESISTANT MICROBES IN THE COMMUNITY

What concerns the Green Baron even more than the evolution of drug-resistant bacteria is the near-certainty that such microbes will get out into the community, and not be confined to hospitals. This spread of such resistant pathogens is an ongoing topic of discussion at meetings and press conferences sponsored by such organizations as the NFID, some of which the Green Baron attended in person.

“Microbial resistance first showed up in hospitals, but now, drug-resistant bacteria have migrated into the community. We are all at risk of infection from multi-drug-resistant [MDR] bacteria,” Stuart Levy, Professor of Medicine, Molecular Biology, and Microbiology at the Tufts University School of Medicine (Boston, MA), warned nearly two years ago (2). As he put it fancifully, “[Drug] resistance [“R”] is propagated in animals and food crops and is cultivated by antibiotics—Darwinism at its best.”

The misuse and overuse of antibiotics during past decades helped contribute to the outward spread of “R”. Since the mid-1940s, for example, physicians often prescribed antibiotics to treat such ailments as viral influenza or even the common cold, against which these drugs are ineffective. (Some doctors explained that the strategy was to kill other pathogens so that the body’s immune system could concentrate on the viruses.) Also, with diminishing disease symptoms, patients often would stop their courses of medicines, even though their prescriptions called for using up all of the drugs. These practices have not yet stopped.

Levy listed other factors that contribute to the spread of pathogens, including “R” and even MDR pathogens beyond the hospital setting. One is that patients are moved out of hospitals more quickly than they were in past years; resistant bacteria go with them. Another factor is international travel, in which aircraft passengers are exhaling “R” microbes into confined, recirculated air that is not well cleansed of contaminants.

A major factor, however, is that antibiotics have become “societal,” as Levy put it. He discussed a study in the UK, according to which antibiotics administered to chickens found their way to humans—“an ecological effect.” In addition, antibiotics go out to the environment in human and farm-animal waste. These waste-contained drugs help bacteria select genetically to enhance “R”. Examples include Escherichia coli and Campylobacter.

“We should not be surprised that large amounts of antibiotics spill out to the environment,” said Richard Duma, a practicing epidemiologist in Flagler County, FL, and former NFID president. “In animal husbandry, we use 10—100 times the antibiotics than we use on humans; we use them by the ton. These large doses … are being used to suppress disease—at which they are increasingly failing—and to accelerate livestock growth (3). This heavy use of antibiotics in livestock has led to bacterial resistance to all classes of these pharmaceuticals, all of which (with one exception) are used in human medicine. Such resistant bacteria could migrate into surrounding air, surface water, groundwater, and soil, and could threaten the food supply.

Remember the anthrax scare of autumn 2001? Large amounts of ciprofloxacin (“cipro”), an antibiotic of the fluoroquinolone class, were made available. Cipro was chosen because it worked well in animals. Other drugs could have worked, but cipro was selected also “because it was listed first alphabetically,” Levy remarked. He added that a woman was able to obtain cipro via the Internet “to treat ‘recurring urinary infections’; she got six refills for $256. Other people self-medicate with cipro or other antibiotics ‘because it’s in the medicine closet.’” Levy expects that the development of “R” in Bacillus anthracis (the cause of anthrax) and other currently cipro-susceptible bacteria will happen within a few years. In 1998, he published a table of several drug-resistant bacteria and the years that “R” was first observed (4).

Not only can antibiotics be obtained over the counter and without prescription in China (1). Levy showed a picture of a pharmacy in Hanoi, Vietnam, that posted a “menu” board and price list. Indeed, some antibiotics may be so obtained in food stores along the U.S.—Mexican border.

THE “CULTIVATION” OF RESISTANCE

The development of microbial resistance was an unintended result of the wide use of advanced pharmaceutical technology. “If humanity had intended to ‘cultivate’ resistance, [however], it couldn’t have done better,” Levy told the NFID press conference (2). “Bacteria have been around for millions [perhaps more like billions] of years, and they’ve learned more than a few clever tricks in that considerable amount of time” (5).

How do microbes develop “R”? “One trick is straightforward ‘Darwinism,’ Levy observed (2). Some bacteria simply inherit genes from their forebears that happen to confer resistance to a given antibiotic—“the survival of the fittest.” In other cases, bacteria will undergo genetic mutations—common among microbes—that will produce a new resistance trait or strengthen an already existing one. In yet other instances, bacteria will receive resistance genes from other bacteria in their vicinity (gene transfer via packages known as plasmids). Levy explains, “The exchange is so pervasive that the entire bacterial world can be thought of as one huge multicellular organism in which the cells exchange their genes with ease” (4).

Roberto Kolter and Richard Losick of Harvard’s microbiology and molecular biology departments, respectively, describe some such “multicellular organisms” in terms of biofilms. In a clinical setting, these biofilms can be deadly, particularly when they form on catheters or medical implants. The infections they cause are “extremely difficult to control because biofilm bacteria, for reasons that remain largely unknown, are extremely resistant to the action of antimicrobial agents” (6). Perhaps with more catheterized and medically implanted patients now at home, such resistant microbes also could have migrated into the community.

Here are some more “tricks”: A virus can take up a resistance gene and inject it into another bacterial cell. Moreover, bacteria can even scavenge gene-bearing packets of DNA from dead cells in their vicinity. Such genes will persist in their new “owner” if they become incorporated stably into the recipient’s chromosome or into a plasmid (4). Possibly, many such genetic changes and resistance enhancements take place in biofilms.

DEFEATING ANTIBIOTICS

Antibiotics inhibit bacterial growth, which gives a host’s immune defenses “a chance to outflank the ‘bugs’ that remain.” Generally, the drugs enter the microbes and interfere with the production of components needed for reproduction. For example, tetracycline binds to ribosomes, thereby impairing protein manufacture; penicillin and vancomycin impede proper synthesis of the bacterial cell wall (4).

One way microbes defeat antibiotics is an efflux mechanism, by which the bacteria essentially eject the antibiotic(s). Benjamin Estrada, professor of pediatrics at the University of South Alabama (Mobile), lists several species of Streptococcus that commonly affect children and that via efflux, resist macrolides such as azithromycin, clarithromycin, and erythromycin (7). Another mechanism associated with macrolide resistance is an erythromycin ribosomal methylase enzyme linked to the ermAM gene (which degrades the drug); in this case, in S. pneumoniae (8, 9).

S. pneumoniae provides one example of a microbe’s using genes that can allow it to alter, degrade, inactivate, or replace biochemically molecules that are normally bound by an antibiotic. In essence, the microbe eliminates the drug’s targets within the cell. Another example is the enzyme penicillinase, which enables Neisseria gonorrhoeae to resist penicillin by breaking it down chemically. In other cases, resistance expresses itself in the microbe’s being able to close entry ports for the drugs (4).

FORGET THAT RARE BURGER!

To say that counteracting resistance is a formidable task that will take many years of intensive research is a great understatement. Peter Rudd, professor of internal medicine at Stanford University Medical Center (Palo Alto, CA) (and a cousin of the Green Baron), put it this way: “The problem is well recognized, even if recast for spicy headlines. The ‘solution’ is more difficult because it rests on changing expectations and habits for healthy people, patients, health professionals, and regulators. No quick fixes are possible” (personal communication with author via e-mail, July 23, 2002).

Still, we must start somewhere; Levy shares Rudd’s view and has set forth several steps the public can take now. One is to improve livestock hygiene. That step could help reduce the need for veterinary antibiotics and the amount of resistant bacteria migrating to food and the environment. Veterinarian Robert Whitney, president of Earthspan (Steilacom, WA), suggested to the NFID Duma press conference that veterinarians are having second thoughts about heavy antibiotic use. Duma observed that in Sweden, where antibiotics were banned for livestock, drug-susceptible bacteria have begun to reappear. (The Green Baron’s pessimistic assessment is that even should antibiotic use be sufficiently reduced that susceptible bacteria come back in large numbers, resistant bacteria never will be at the low baseline proportion to susceptibles as in pre-antibiotic days.)

Consumers should wash raw fruits and vegetables thoroughly to clear off resistant bacteria and antibiotic residues (the latter could enhance microbial resistance among bacteria within the consumer’s body). They should avoid raw eggs and undercooked meat, especially ground meat; in essence, forget about that rare burger. Soaps and detergents with antibacterial chemicals should be used only when a sick person whose defenses are weakened needs to be protected; otherwise, regular soap and detergent should remove most microbes.

If a patient must have a prescription for antibiotics, he or she should complete the entire course of therapy to ensure that all of the target bacteria die. Pills should never be saved for future use. Patients should not ask for antibiotics to treat colds and other viral infections or conditions such as acne.

If a patient demands an antibiotic that is not indicated, the physician must firmly refuse to issue the prescription. The physician also should try to identify the pathogen that causes an infection before therapy begins. The aim would be to prescribe an antibiotic specific for the given microbe, rather than a broad-spectrum pharmaceutical. Moreover—and this is frequently neglected—the physician should wash hands thoroughly after seeing each patient. Hospitals should continue the practice of placing patients affected by infectious diseases in separate rooms and have them seen by health workers and visitors who are wearing appropriate gloves and gowns (4).

CAN “R” BE WEAPONIZED?

The Green Baron thought he’d finish this issue with this cheerful question: Can microbial resistance be weaponized? “Can pathogenic microbes be deliberately engineered or manipulated to become antibiotic-resistant with a view to using such bacteria as weapons?” the Green Baron asked Levy. He answered, “Yes, they can be modified in that way,” and suggested that some “bad guys” in this world might indeed be doing research to achieve such a goal. This becomes much more relevant in the wake of September 11, 2001 and the anthrax scare later that year.

ALLIANCE FOR THE PRUDENT USE OF ANTIBIOTICS (APUA)

Established in 1981, APUA is the only organization dedicated solely to strengthening society’s defenses against infectious disease through research and education on antibiotic use and microbial resistance. Its mission is to improve infectious disease treatment and control worldwide by promoting appropriate antibiotic access and use and reducing resistance to antibiotics. APUA participates in a network of scientists, clinicians, and public health professionals in more than 100 countries, and sponsors and cosponsors international symposia and special meetings. For more information concerning APUA, visit its Web site at www.APUA.org.

In a future issue of Muenchhausen, the Green Baron will look into possible ways of combating the mechanisms that help bacteria become resistant to drugs. Let us hope that research in this field will be successful. Otherwise, as Benford warned (1), if such research fails to bear positive fruit, the art and science of infectious-disease medicine might well march forward to where they were in the 19th century.

References:

1. Chao, J. (Cox News Service). “’Supergerms loom”. The Washington Times, Jan. 30, 2004, p. A15.

2. Levy, S. B, Presentation at the 7th Richard J. Duma/NFID Annual Press Conference and Symposium on Infections Diseases, Washington, DC, July 18, 2002.

3. Duma, R. J. Presentation at the 7th Richard J. Duma/NFID Annual Press Conference and Symposium on Infections Diseases, Washington, DC, July 18, 2002.

4. Levy, S. B. Scientific American 1998, 278(3), 32—39.

5. Bechtel, B., Associated Press. “Resistant Bacteria Bred with Antibiotics Overuse”. Washington Times, Jan. 2, 2002, p. A3.

6. Kolter, R.; Losick, R. Science 2002, 280(5361), 226.

7. Estrada, B. Infections in Medicine 2002, 19(8), 245.

8. Leclercq, R. Clin. Infect. Dis. 2002, 34, 482—92.

9. Gay, K. et al. J. Infect. Dis. 2000, 182, 1417—21.

WHAT IS BOOTSTRAP PRESS?

Bootstrap Press is a nonprofit organization founded in Bethesda, Maryland, U.S.A., to promote the development and management of technology and businesses based on renewable resources. We also encourage the preservation of our Earth's natural habitats and its plant and animal species. So do a lot of other organizations, and more power to them for doing so!

Bootstrap Press is different because its members believe that the development of renewable resources and the preservation of habitats and species are receiving far more lip service than the financial and technical support needed to achieve these goals. We also think they will continue to be subjects of more talk than action until someone can show how renewable resources and the diversity of biological species can be the basis for potentially profitable businesses as well as a matter of ethics. Bootstrap Press intends to provide a forum for the discussion of how to build up such business, and of related topics.

There's one more thing we should mention about Muenchhausen and Bootstrap Press. We try to present only the scientific and technical facts that are correct to the best of our knowledge, belief, and good faith. It is up to Muenchhausen's readers to draw their own conclusions and make their own judgments.

NOTE: The mention of a product or service in MUENCHHAUSEN is in no way to be regarded as an endorsement of that product or service by MUENCHHAUSEN, Bootstrap Press, The Green Baron, or any other contributor to MUENCHHAUSEN.