U.S. Food and Drug Administration

The Rise of Antibiotic-Resistant Infections
by Ricki Lewis, Ph.D.

When penicillin became widely available during the second world war, it was a medical miracle, rapidly vanquishing the
biggest wartime killer--infected wounds. Discovered initially by a French medical student, Ernest Duchesne, in 1896, and
then rediscovered by Scottish physician Alexander Fleming in 1928, the product of the soil mold Penicillium crippled
many types of disease-causing bacteria. But just four years after drug companies began mass-producing penicillin in
1943, microbes began appearing that could resist it.

The first bug to battle penicillin was Staphylococcus aureus. This bacterium is often a harmless passenger in the human
body, but it can cause illness, such as pneumonia or toxic shock syndrome, when it overgrows or produces a toxin.

In 1967, another type of penicillin-resistant pneumonia, caused by Streptococcus pneumoniae and called
pneumococcus, surfaced in a remote village in Papua New Guinea. At about the same time, American military personnel
in southeast Asia were acquiring penicillin-resistant gonorrhea from prostitutes. By 1976, when the soldiers had come
home, they brought the new strain of gonorrhea with them, and physicians had to find new drugs to treat it. In 1983, a
hospital-acquired intestinal infection caused by the bacterium Enterococcus faecium joined the list of bugs that outwit

Antibiotic resistance spreads fast. Between 1979 and 1987, for example, only 0.02 percent of pneumococcus strains
infecting a large number of patients surveyed by the national Centers for Disease Control and Prevention were
penicillin-resistant. CDC's survey included 13 hospitals in 12 states. Today, 6.6 percent of pneumococcus strains are
resistant, according to a report in the June 15, 1994, Journal of the American Medical Association by Robert F. Breiman,
M.D., and colleagues at CDC. The agency also reports that in 1992, 13,300 hospital patients died of bacterial infections
that were resistant to antibiotic treatment.

Why has this happened?

"There was complacency in the 1980s. The perception was that we had licked the bacterial infection problem. Drug
companies weren't working on new agents. They were concentrating on other areas, such as viral infections," says
Michael Blum, M.D., medical officer in the Food and Drug Administration's division of anti-infective drug products. "In the
meantime, resistance increased to a number of commonly used antibiotics, possibly related to overuse of antibiotics. In
the 1990s, we've come to a point for certain infections that we don't have agents available."

According to a report in the April 28, 1994, New England Journal of Medicine, researchers have identified bacteria in
patient samples that resist all currently available antibiotic drugs.

Survival of the Fittest

The increased prevalence of antibiotic resistance is an outcome of evolution. Any population of organisms, bacteria
included, naturally includes variants with unusual traits--in this case, the ability to withstand an antibiotic's attack on a
microbe. When a person takes an antibiotic, the drug kills the defenseless bacteria, leaving behind--or "selecting," in
biological terms--those that can resist it. These renegade bacteria then multiply, increasing their numbers a millionfold in
a day, becoming the predominant microorganism.

The antibiotic does not technically cause the resistance, but allows it to happen by creating a situation where an already
existing variant can flourish. "Whenever antibiotics are used, there is selective pressure for resistance to occur. It builds
upon itself. More and more organisms develop resistance to more and more drugs," says Joe Cranston, Ph.D., director
of the department of drug policy and standards at the American Medical Association in Chicago.

A patient can develop a drug-resistant infection either by contracting a resistant bug to begin with, or by having a
resistant microbe emerge in the body once antibiotic treatment begins. Drug-resistant infections increase risk of death,
and are often associated with prolonged hospital stays, and sometimes complications. These might necessitate
removing part of a ravaged lung, or replacing a damaged heart valve.

Bacterial Weaponry

Disease-causing microbes thwart antibiotics by interfering with their mechanism of action. For example, penicillin kills
bacteria by attaching to their cell walls, then destroying a key part of the wall. The wall falls apart, and the bacterium
dies. Resistant microbes, however, either alter their cell walls so penicillin can't bind or produce enzymes that dismantle
the antibiotic.

In another scenario, erythromycin attacks ribosomes, structures within a cell that enable it to make proteins. Resistant
bacteria have slightly altered ribosomes to which the drug cannot bind. The ribosomal route is also how bacteria
become resistant to the antibiotics tetracycline, streptomycin and gentamicin.

How Antibiotic Resistance Happens

Antibiotic resistance results from gene action. Bacteria acquire genes conferring resistance in any of three ways.

In spontaneous DNA mutation, bacterial DNA (genetic material) may mutate (change) spontaneously (indicated by
starburst). Drug-resistant tuberculosis arises this way.

In a form of microbial sex called transformation, one bacterium may take up DNA from another bacterium.
Pencillin-resistant gonorrhea results from transformation.

Most frightening, however, is resistance acquired from a small circle of DNA called a plasmid, that can flit from one type
of bacterium to another. A single plasmid can provide a slew of different resistances. In 1968, 12,500 people in
Guatemala died in an epidemic of Shigella diarrhea. The microbe harbored a plasmid carrying resistances to four

A Vicious Cycle: More Infections and Antibiotic Overuse

Though bacterial antibiotic resistance is a natural phenomenon, societal factors also contribute to the problem. These
factors include increased infection transmission, coupled with inappropriate antibiotic use.

More people are contracting infections. Sinusitis among adults is on the rise, as are ear infections in children. A report
by CDC's Linda F. McCaig and James M. Hughes, M.D., in the Jan. 18, 1995, Journal of the American Medical
Association, tracks antibiotic use in treating common illnesses. The report cites nearly 6 million antibiotic prescriptions
for sinusitis in 1985, and nearly 13 million in 1992. Similarly, for middle ear infections, the numbers are 15 million
prescriptions in 1985, and 23.6 million in 1992.

Causes for the increase in reported infections are diverse. Some studies correlate the doubling in doctor's office visits
for ear infections for preschoolers between 1975 and 1990 to increased use of day-care facilities. Homelessness
contributes to the spread of infection. Ironically, advances in modern medicine have made more people predisposed to
infection. People on chemotherapy and transplant recipients taking drugs to suppress their immune function are at
greater risk of infection.

"There are the number of immunocompromised patients, who wouldn't have survived in earlier times," says Cranston.
"Radical procedures produce patients who are in difficult shape in the hospital, and are prone to nosocomial
[hospital-acquired] infections. Also, the general aging of patients who live longer, get sicker, and die slower contributes
to the problem," he adds.

Though some people clearly need to be treated with antibiotics, many experts are concerned about the inappropriate
use of these powerful drugs. "Many consumers have an expectation that when they're ill, antibiotics are the answer.
They put pressure on the physician to prescribe them. Most of the time the illness is viral, and antibiotics are not the
answer. This large burden of antibiotics is certainly selecting resistant bacteria," says Blum.

Another much-publicized concern is use of antibiotics in livestock, where the drugs are used in well animals to prevent
disease, and the animals are later slaughtered for food. "If an animal gets a bacterial infection, growth is slowed and it
doesn't put on weight as fast," says Joe Madden, Ph.D., strategic manager of microbiology at FDA's Center for Food
Safety and Applied Nutrition. In addition, antibiotics are sometimes administered at low levels in feed for long durations
to increase the rate of weight gain and improve the efficiency of converting animal feed to units of animal production.

FDA's Center for Veterinary Medicine limits the amount of antibiotic residue in poultry and other meats, and the U.S.
Department of Agriculture monitors meats for drug residues. According to Margaret Miller, Ph.D., deputy division director
at the Center for Veterinary Medicine, the residue limits for antimicrobial animal drugs are set low enough to ensure that
the residues themselves do not select resistant bacteria in (human) gut flora.

FDA is investigating whether bacteria resistant to quinolone antibiotics can emerge in food animals and cause disease
in humans. Although thorough cooking sharply reduces the likelihood of antibiotic-resistant bacteria surviving in a meat
meal to infect a human, it could happen. Pathogens resistant to drugs other than fluoroquinolones have sporadically
been reported to survive in a meat meal to infect a human. In 1983, for example, 18 people in four midwestern states
developed multi-drug-resistant Salmonella food poisoning after eating beef from cows fed antibiotics. Eleven of the
people were hospitalized, and one died.

A study conducted by Alain Cometta, M.D., and his colleagues at the Centre Hospitalier Universitaire Vaudois in
Lausanne, Switzerland, and reported in the April 28, 1994, New England Journal of Medicine, showed that increase in
antibiotic resistance parallels increase in antibiotic use in humans. They examined a large group of cancer patients
given antibiotics called fluoroquinolones to prevent infection. The patients' white blood cell counts were very low as a
result of their cancer treatment, leaving them open to infection.

Between 1983 and 1993, the percentage of such patients receiving antibiotics rose from 1.4 to 45. During those years,
the researchers isolated Escherichia coli bacteria annually from the patients, and tested the microbes for resistance to
five types of fluoroquinolones. Between 1983 and 1990, all 92 E. coli strains tested were easily killed by the antibiotics.
But from 1991 to 1993, 11 of 40 tested strains (28 percent) were resistant to all five drugs.

Towards Solving the Problem

Antibiotic resistance is inevitable, say scientists, but there are measures we can take to slow it. Efforts are under way on
several fronts--improving infection control, developing new antibiotics, and using drugs more appropriately.

Barbara E. Murray, M.D., of the University of Texas Medical School at Houston writes in the April 28, 1994, New England
Journal of Medicine that simple improvements in public health measures can go a long way towards preventing infection.
Such approaches include more frequent hand washing by health-care workers, quick identification and isolation of
patients with drug-resistant infections, and improving sewage systems and water purity in developing nations.

Drug manufacturers are once again becoming interested in developing new antibiotics. These efforts have been
spurred both by the appearance of new bacterial illnesses, such as Lyme disease and Legionnaire's disease, and
resurgences of old foes, such as tuberculosis, due to drug resistance.

FDA is doing all it can to speed development and availability of new antibiotic drugs. "We can't identify new
agents--that's the job of the pharmaceutical industry. But once they have identified a promising new drug for resistant
infections, what we can do is to meet with the company very early and help design the development plan and clinical
trials," says Blum.

In addition, drugs in development can be used for patients with multi-drug-resistant infections on an "emergency IND
(compassionate use)" basis, if the physician requests this of FDA, Blum adds. This is done for people with AIDS or
cancer, for example.

No one really has a good idea of the extent of antibiotic resistance, because it hasn't been monitored in a coordinated
fashion. "Each hospital monitors its own resistance, but there is no good national system to test for antibiotic
resistance," says Blum.

This may soon change. CDC is encouraging local health officials to track resistance data, and the World Health
Organization has initiated a global computer database for physicians to report outbreaks of drug-resistant bacterial

Experts agree that antibiotics should be restricted to patients who can truly benefit from them--that is, people with
bacterial infections. Already this is being done in the hospital setting, where the routine use of antibiotics to prevent
infection in certain surgical patients is being reexamined.

"We have known since way back in the antibiotic era that these drugs have been used inappropriately in surgical
prophylaxis [preventing infections in surgical patients]. But there is more success [in limiting antibiotic use] in hospital
settings, where guidelines are established, than in the more typical outpatient settings," says Cranston.

Murray points out an example of antibiotic prophylaxis in the outpatient setting--children with recurrent ear infections
given extended antibiotic prescriptions to prevent future infections. (See "Protecting Little Pitchers' Ears" in the
December 1994 FDA Consumer.)

Another problem with antibiotic use is that patients often stop taking the drug too soon, because symptoms improve.
However, this merely encourages resistant microbes to proliferate. The infection returns a few weeks later, and this time
a different drug must be used to treat it.

Targeting TB

Stephen Weis and colleagues at the University of North Texas Health Science Center in Fort Worth reported in the April
28, 1994, New England Journal of Medicine on research they conducted in Tarrant County, Texas, that vividly illustrates
how helping patients to take the full course of their medication can actually lower resistance rates. The

TB is an infection that has experienced spectacular ups and downs. Drugs were developed to treat it, complacency set
in that it was beaten, and the disease resurged because patients stopped their medication too soon and infected others.
Today, one in seven new TB cases is resistant to the two drugs most commonly used to treat it (isoniazid and rifampin),
and 5 percent of these patients die.

In the Texas study, 407 patients from 1980 to 1986 were allowed to take their medication on their own. From 1986 until
the end of 1992, 581 patients were closely followed, with nurses observing them take their pills. By the end of the study,
the relapse rate--which reflects antibiotic resistance--fell from 20.9 to 5.5 percent. This trend is especially significant, the
researchers note, because it occurred as risk factors for spreading TB--including AIDS, intravenous drug use, and
homelessness--were increasing. The conclusion: Resistance can be slowed if patients take medications correctly.

Narrowing the Spectrum

Appropriate prescribing also means that physicians use "narrow spectrum" antibiotics--those that target only a few
bacterial types--whenever possible, so that resistances can be restricted. The only national survey of antibiotic
prescribing practices of office physicians, conducted by the National Center for Health Statistics, finds that the number
of prescriptions has not risen appreciably from 1980 to 1992, but there has been a shift to using costlier, broader
spectrum agents. This prescribing trend heightens the resistance problem, write McCaig and Hughes, because more
diverse bacteria are being exposed to antibiotics.

One way FDA can help physicians choose narrower spectrum antibiotics is to ensure that labeling keeps up with
evolving bacterial resistances. Blum hopes that the surveillance information on emerging antibiotic resistances from
CDC will enable FDA to require that product labels be updated with the most current surveillance information.

Many of us have come to take antibiotics for granted. A child develops strep throat or an ear infection, and soon a bottle
of "pink medicine" makes everything better. An adult suffers a sinus headache, and antibiotic pills quickly control it. But
infections can and do still kill. Because of a complex combination of factors, serious infections may be on the rise. While
awaiting the next "wonder drug," we must appreciate, and use correctly, the ones that we already have.


Big Difference
If this bacterium could be shown four times bigger, it would be the right relative size to the virus beneath it. (Both are
microscopic and are shown many times larger than life.)
Although bacteria are single-celled organisms, viruses are far simpler, consisting of one type of biochemical (a nucleic
acid, such as DNA or RNA) wrapped in another (protein). Most biologists do not consider viruses to be living things, but
instead, infectious particles. Antibiotic drugs attack bacteria, not viruses.


The Greatest Fear--Vancomycin Resistance
When microbes began resisting penicillin, medical researchers fought back with chemical cousins, such as methicillin
and oxacillin. By 1953, the antibiotic armamentarium included chloramphenicol, neomycin, terramycin, tetracycline, and
cephalosporins. But today, researchers fear that we may be nearing an end to the seemingly endless flow of
antimicrobial drugs.
At the center of current concern is the antibiotic vancomycin, which for many infections is literally the drug of "last
resort," says Michael Blum, M.D., medical officer in FDA's division of anti-infective drug products. Some
hospital-acquired staph infections are resistant to all antibiotics except vancomycin.

Now vancomycin resistance has turned up in another common hospital bug, enterococcus. And since bacteria swap
resistance genes like teenagers swap T-shirts, it is only a matter of time, many microbiologists believe, until
vancomycin-resistant staph infections appear. "Staph aureus may pick up vancomycin resistance from enterococci,
which are found in the normal human gut," says Madden. And the speed with which vancomycin resistance has spread
through enterococci has prompted researchers to use the word "crisis" when discussing the possibility of
vancomycin-resistant staph.

Vancomycin-resistant enterococci were first reported in England and France in 1987, and appeared in one New York
City hospital in 1989. By 1991, 38 hospitals in the United States reported the bug. By 1993, 14 percent of patients with
enterococcus in intensive-care units in some hospitals had vancomycin-resistant strains, a 20-fold increase from 1987.
A frightening report came in 1992, when a British researcher observed a transfer of a vancomycin-resistant gene from
enterococcus to Staph aureus in the laboratory. Alarmed, the researcher immediately destroyed the bacteria.

Ricki Lewis is a geneticist and textbook author.