Who's to Blame When Antibiotics Don't Work?

Novelist Anne Bronte and poet John Keats died of tuberculosis. President William Henry Harrison died of pneumonia after falling ill at his inauguration only a month earlier. The threat of bacterial infection once hung, not simply over the heads of its more famous victims, but over every ordinary family.

Today we expect that infections can be quickly and effectively treated with antibiotics. Improvements in public sanitation, personal hygiene and nutrition made a huge difference in combating infectious disease. But it was the discovery and development of antibiotics in the 1930's that gave physicians effective tools against typhoid, pneumonia, meningitis, tuberculosis and other vicious infections.

Now the frightening reality is that the usefulness of these "wonder drugs" is seriously threatened by the growing problem of what to do when bacteria no longer respond to commonly used antibiotics. Penicillin, for example, can no longer fight 25% of infections caused by Streptococcus pneumoniae, the leading cause of bacterial pneumonia, meningitis and ear infections in the U.S., the U.S. Centers for Disease Control & Prevention (CDC) announced last month. In some regions of the country, resistance has reached 38%. And an antibiotic-resistant strain of Staphylococcus aureus, a common cause of serious infections in hospitals, has killed four children and sickened more than 200 people in South Dakota and Minnesota over the past two years, The New York Times reported on August 20, 1999.

"We are now entering a post-antibiotic era," says J. Glenn Morris, M.D., a professor of medicine at the University of Maryland. Overuse and misuse of antibiotics, by physicians, patients, farmers and hospitals, is creating resistance that can pass from human to human, animal to human. And resistant bacteria are spreading in the environment itself, in water and wildlife.

A Competitive Environment

Bacteria, microscopic one-celled organisms, live on and in the human body in astonishing numbers. Most are harmless or even helpful, such as the 400 different species in the colon that aid digestion and the immune system. To cause harm, disease-causing bacteria must penetrate a strong line of defenses, beginning with skin and mucous membranes. Pathogens may survive in the body without causing illness if there is enough competition from other bacteria to hold them in check. Serious exposure, however, can overwhelm the body's defenses.

In 1928, Sir Alexander Fleming, a British doctor, accidentally discovered a mold that killed Staph. Professor Howard Florey and Ernest Chain, M.D., developed the powerful drug penicillin from that mold in England during World War II. Since then, over 100 antibiotic drugs have been developed. They work by sabotaging the bacterial cell wall, stopping multiplication, or defusing cell functions in other ingenious ways. Broad-spectrum antibiotics, such as cephalosporins and penicillin derivatives, can topple a large number of bacterial species; others target particular organisms, as does Cortisporin for "swimmer's ear."

The most antibiotic-prescribed population in the U.S. are kids under age six, according to Drs. Paul A. Offit and Bonnie Fass-Offit, authors of Breaking the Antibiotic Habit. This makes children, especially those receiving decent medical care, more likely to be infected by antibiotic-resistant bacteria.

The Specter of Resistance

When a bacterium survives antibiotic treatment and multiplies after developing some defensive strategy for evading the action of the drug, resistance develops. Bacteria can also transfer resistance genes to one another and even other bacterial species. Use of broad-spectrum antibiotics can lead to serious trouble by wiping out microbial competition, leaving the strong, resistant bacteria behind to multiply unchecked.

Until the 1980's, new antibiotics steadily filled up space in the medicine cabinet. "Now that shelf is almost empty," according to Patricia B. Lieberman, Ph.D. and Margo G. Wootan, D.Sc., co-authors of a 1998 Center for Science in the Public Interest (CSPI) report, "Protecting the Crown Jewels of Medicine." The usefulness of these antibiotics is diminishing as more and more pathogenic bacteria are showing resistance to one, two and sometimes a whole range of antibiotics.

Tuberculosis, for one, was considered a disease of the past. But by 1992, 10% of TB cases were caused by new strains of multidrug-resistant tuberculosis (MDRTB), made worse by a relaxation of public health vigilance and an ever-increasing population of the immune-compromised. From 40% to 80% of MDRTB patients die, depending on their immune status, note Lieberman and Wootan.

At the same time, methicillin-resistant Staphylococcus aureus (MRSA) worried scientists who feared the strain might develop resistance to vancomycin, the antibiotic of last resort. (Methicillin is related to penicillin.) Today more than 90% of S. aureus are resistant to penicillin, and the incidence of MRSA increased from 2.4% to 29% between 1975 and 1991. What's worse, strains of vancomycin-resistant S. aureus have surfaced around the globe. "If untreatable Staph should emerge, it would certainly close down hospitals," says Fred Angulo, D.V.M., Ph.D., medical epidemiologist at CDC's National Center for Infectious Diseases.

Modern travel and trade mean that contact with a resistant pathogen is a handshake, an airplane ride, a hospital visit away. Antibiotic use on fruit trees -- up to 300,000 pounds per year in the U.S. -- may encourage the growth of resistant bacteria on fruit, which ultimately wind up in our stomachs.

Resistant bacteria are also flowing down major U.S. rivers, according to three studies presented at the 1999 American Society for Microbiology's annual meeting. At some test sites up to half the bacteria found were resistant to one or more commonly used antibiotics, such as ampicillin. Another study found that Canadian geese living year-round in the Chicago suburbs harbored multiple strains of bacteria resistant to a wide assortment of commonly used drugs, possibly picking up bacteria from contaminated water.

Who's Responsible?

Using antibiotics for livestock

A likely source of antibiotic resistance is drug overuse in livestock. Antibiotics added to feed or water deliver regular doses that prevent infections and promote faster growth. For foodborne pathogens such as Salmonella, Campylobacter and E. coli O157, "...the most likely source of most antimicrobial resistance is use of antimicrobials in food producing animals," reports a December 1998 Food & Drug Administration evaluation of antibiotic use in livestock. And antibiotics and resistant bacteria can enter waterways in manure runoff. Resistant pathogens may be transferred to those who handle or consume raw or undercooked animal products.

That's what happened to the Heyers, a dairy farm family in Vermont, in 1997. After drinking unpasteurized milk from a sick cow, they contracted Salmonella DT104, a strain resistant to five antibiotics, including ampicillin and tetracycline. Marjorie Heyer's adult daughter Cynthia Hawley nearly died when conventional antibiotic treatment failed. When the strain was properly identified, she was given Ofloxcin, a fluoroquinolone to which it was not resistant.

The fluoroquinolones, a newer class of antibiotics, are important in treating human disease. Despite evidence that their use in agriculture had led to the development of fluoroquinolone-resistant bacteria in the United Kingdom, they were approved by the FDA in 1995 for use in poultry drinking water. "Big mistake," says CSPI's Lieberman. Turkeys and chickens are now turning up in U.S. supermarkets harboring Campylobacter, the most common cause of foodborne disease in the U.S., resistant to fluoroquinolones, according to a report from the Minnesota State Department of Health. "Unfortunately, a lot of antibiotics are used in agriculture solely for economic (not health) reasons to promote the growth of animals," says Dr. Angulo. "The U.S. has the most liberal and uncontrolled drug use policy of any developed country," he adds.

"Antibiotics are added to livestock feed to counteract the effects of crowded living conditions and poor hygiene," says Richard Wood, executive director of Food Animal Concerns Trust (FACT). "If farmers provide cleaner barns, better feed, and more floor space per animal, they can reduce stress and illness while maintaining growth," he says.

Europeans are phasing out antibiotics used by humans as a regular animal feed ingredient amid strong protests and lawsuits from feed and drug companies. "But in the U.S., instead of reducing uses of antibiotics in livestock, we are still expanding into new uses," says Lieberman. In March 1999, CSPI and 40 other organizations filed a petition with the FDA asking that antibiotics important for treating humans, such as penicillin, tetracycline and erythromycin, be eliminated from "sub-therapeutic use" in animals, including growth promotion or disease prevention, echoing World Health Organization advice.

Antibiotic resistance concerns Stephen F. Sundlof, D.V.M., Ph.D., director of the Center for Veterinary Medicine at the FDA, who says the issue is his "first priority." He doesn't agree that a ban on certain antibiotics is necessary. "Judging antibiotics on a case-by-case basic would be more thorough," says Dr. Sundlof.

To complicate matters further, the FDA doesn't know how much of the antibiotics produced by drug companies actually go to animals. Most experts agree that agricultural use of antibiotics accounts for around 40% of the total. The FDA is seeking authority to get that information, currently considered proprietary by industry. Legislation might be needed, and restricting use in animals is likely to go slow. "The agriculture, drug and feed industries will try and stall endlessly," says Lieberman.

Meanwhile, the National Antimicrobial-Resistance Monitoring System is working with the CDC and the U.S. Department of Agriculture looking for resistance in the samples taken at slaughterhouses.

Overprescribing antibiotics for people

Misuse of antibiotics by humans is another major cause of resistance. Physicians hand out antibiotics too frequently, according to the CDC, which estimates that some 50 million of the 150 million outpatient prescriptions for antibiotics every year are unnecessary. "At a seminar I conducted, more than 80 percent of physicians present admitted to having written antibiotic prescriptions on demand against their better judgment," wrote Stuart Levy, M.D., director of Tufts University's Center for Adaptation Genetics and Drug Resistance, in the March 1998 issue of Scientific American. Patients often demand antibiotics for nonbacterial illnesses such as colds, caused by viruses on which antibiotics have no effect.

The CDC believes it can, through education of physicians and patients, have an impact on the way antibiotics are prescribed. In trials, physicians are promoting what they call "judicious treatment," such as culturing to identify the bacterial strain causing an infection and limiting use of broad-spectrum antibiotics.

Looking back, the great era of the antibiotic was tantalizingly brief. That ambitious notion that humans could control infectious diseases lasted a mere 30 years. Today, as nature bounces back from the antibiotic assault, there is no such complacency. Overuse, misuse and outright abuse may deprive us of one of the greatest achievements in medicine.

- Nicols Fox is an independent journalist and the author of two books on foodborne disease: Spoiled (Penguin, 1998, $14.95) and It Was Probably Something You Ate (Penguin, 1999, $12.95).