The Risk of Antibiotic Resistance Explained

Antibiotic Resistance
from "RISK! A Practical Guide for Deciding What's Really Safe and What's Really Dangerous in the World Around You"

In 1941, when penicillin first became widely available, it was hailed as a wonder drug that could control several serious bacterial infections like staph and strep. Medical experts quickly predicted that infectious diseases would become a thing of the past. But within two years, doctors began reporting cases of a common bacterium, Staphylococcus aureus, which somehow could resist the effects of penicillin. Almost as soon as antibiotics became available, bacteria began developing ways to resist them. Ever since, we’ve been in a race between the development of new and more powerful antibiotics, and the ability of bacteria to adapt in ways that defeat those drugs. Many experts say the race is a dead heat. Some say the bacteria are winning.


The Hazard

All microscopic organisms – microbes – secrete a variety of chemicals. Some of these secretions kill or impair competitors. Antibiotics are based on these natural microbial secretions. Penicillin, for example, is based on a secretion from the mold Pencillium notatum which kills bacteria by destroying their ability to build a cell wall.
Antibiotics, also known as antimicrobials, bond to specific parts of specific bacteria, and either kill or impair them. Killing the bacteria outright, of course, eliminates the infection. But sometimes just impairing them can be enough, because that gives our natural immune system a chance to gain the upper hand in the battle against the bacteria and finish the fight. Most antibiotics bond with molecules that only occur on the surface of bacteria, which is why they don’t harm human cells and why they don’t kill viruses. And individual antibiotics only work on specific bacteria because their “attack” molecules only bond with specific molecules on those target bacteria. Think of the bonding as a kind of lock-and-key system. It takes a specific key (the right antibiotic molecule) to fit in a specific lock (the receptor molecule on the target bacterium).
But the bacterium that are under attack don’t just take this lying down. In the evolutionary competition between these attacking microbial secretions and the bacteria, the bacteria evolve ways of fighting back. They respond via the natural process of occasional changes to their DNA. These changes lead to the development of new traits, some of which allow the individual bacterium to counteract the effects of the antibiotic substance. A single bacterium that evolves a way of fighting off antibiotics has a survival advantage compared with it’s neighbors of the same species. It survives, and passes that resistance trait on to its offspring and they become the variation of the species that survives over time.
Bacteria are really good at this, for two reasons. First, they can undergo changes to their DNA in several different ways. They even have the ability to share sections of their DNA between species. So a resistance trait that arises in one bacterium can be passed to other types. Second, bacteria evolve quickly because they reproduce prolifically, as frequently as once every 20 minutes. If you put a single bacterium cell in an optimal growing environment, within twelve hours you can have as many as 68,719,476,736 copies of that original cell. That creates the likelihood of tens of thousands of mutations, each of which might produce a resistance trait that helps it fight off an antibiotic.
Over time, the resistant strains proliferate while the ones that can’t fight the drugs die off. And as they do they may spread their new, successful resistance trait to other strains within the same species, or even to other species of bacteria entirely.
The widespread use of antibiotics speeds up this process. When a microbial population of various organisms is exposed to an antibiotic, the bacteria susceptible to the antibiotic will be killed. Organisms that have some resistance survive. Without the other species around to compete for food and resources, the resistant strains find it easier to proliferate. Those strains then pass their resistance traits to their own offspring, or share their resistance genes with other bacteria. The result is that as antibiotics kill off the bacteria they work on, they increase the prevalence of strains that can resist them.
The most significant human contribution to this accelerated antibiotic resistance is the indiscriminate and often unnecessary use of antibiotic drugs. In the United States, between 160 and 260 million courses of antibiotics are prescribed each year. An estimated 75 percent of these are for respiratory infections, but between one third and one half are unnecessary, prescribed to people who have viral infections that aren’t treatable with antibacterial medication. Most doctors acknowledge they prescribe antibiotics to patients simply because the patients demand them. Since every application of antibiotics encourages the growth of resistant strains, mis-prescribed use of antibiotics accelerates the problem.
In addition, in hospitals, broad-spectrum antibiotics are often used when a more targeted drug that only kills the specific bacterium causing an infection would be enough. The advantage for the patient is that broad-spectrum antibiotics wipe out a wider range of susceptible species. But the downside is dthat this goes even further in clearing the playing field for the toughest, most resistant strains that are left behind.
Bacteria also get human help in developing antibiotic resistance when we fail to take the full course of a prescription of antibiotic medication. The weakest germs are killed within the first few days. Often, this eliminates the symptoms of the infection, so we stop taking the drugs. But the stronger bacteria that can resist the first few days of medication, survive. The full course of the medicine might have killed them off. Instead, these slightly more resistant bacteria survive and proliferate and spread the trait that helped them fight off the first few days of the drug.
Another way that humans are accelerating antimicrobial resistance is the use antibiotics in farm animals. As much as half of all the antibiotics produced for use in the United States are used on farm animals, mostly at low doses over a long period to encourage growth. But the low doses allow the more resistant strains of bacteria in animals to out-survive the weaker ones. Some of these resistant bacteria, like strains of salmonella, shigella, and E. Coli, can be transferred to people in improperly prepared foods. Then, when people develop bacterial illness, the strains of these bacteria are resistant to the drugs that used to control them.
Antibiotic resistance is also amplified in certain settings, like schools, hospitals, and chronic care facilities, environments where there are a lot of people with less effective immune systems carrying a lot of bacteria, so the chances of individual strains swapping their resistance genes is higher. And finally, bacterial resistance accelerates because of the global transportation system. People and goods spread microbes around the world. In many parts of the world, antibiotic drugs can be purchased without a prescription, and are often taken improperly. This can lead to resistant strains that then spread worldwide.



The Range of Consequences

In general, antibiotic resistance raises the likelihood that infections will have a more serious effect on a person’s health. It raises the likelihood that an otherwise treatable infection might turn lethal. In developed countries like the United States, with greater access to advanced medical care and pharmaceuticals, a frequent consequence of antibiotic resistance is that a second, third, or fourth type of drug has to be used when the principal agent against a particular bacterium no longer works. These backup drugs sometimes have more side effects. They are usually in shorter supply. And they are almost always much more expensive.
It is difficult to quantify the consequences of antibiotic resistance. Sometimes the drugs fail outright. Sometimes they merely don’t work quite as well as they used to, and a patient gets sicker and stays sick longer but then recovers. Often these effects occur outside a hospital, nursing home, or other facility where accurate surveillance records can be kept. But a pattern of chilling statistics comes from a number of sources.

* Staphylococcus aureus is a common bacterium. Most of us carry it in our noses or on our skin. It can cause minor infections, or life-threatening diseases like pneumonia. Penicillin used to kill it. But in the 1950’s, less than 10 years after penicillin hit the market, Staph aureus had become so resistant to penicillin that healthy people going to hospitals got sick and died. Many hospital maternity wards had to close. So drug companies developed methicillin in the 1960’s. By the 80’s, Staph aureus was resistant to methicillin. The CDC estimates that as many as 80,000 people a year get a methicillin-resistant Staph aureus infection after they enter the hospital. So doctors switched to the antibiotic vancomycin, a broad-spectrum drug widely thought of as the antibiotic of last resort. In 1997, the first cases of vancomycin-resistant Staph aureus showed up in three geographically separate locations. Many more have since been reported. In 2000, the first revolutionary new type of antibiotic to come out in 30 years, linezolid, was approved, offering promise in the fight against Staph aureus and other multi-drug resistant bacteria. It took less than a year for the first cases of linezolid-resistant Staph aureus to show up.
* According to the Centers for Disease Control, each year the bacteria Streptococcus pnuemoniae causes 100,000-135,000 hospitalizations for pneumonia, 6 million ear infections, and more than 60,00 cases of other invasive diseases, including 3,300 cases of meningitis. Of these, they estimate that at least 40 percent are caused by drug resistant strains of S. pneumoniae. Between 1993 and 1998, 45 states and the District of Columbia reported at least one case of tuberculosis that was multi-drug resistant. Health officials once thought tuberculosis had been all but wiped out in the U.S. Resistant strains threaten a comeback.
* The CDC estimates that 2 million people a year get infections after they enter the hospital, so-called nosocomial infections. Approximately 90,000 of these people will die because of these infections. It is not known how many of these fatal nosocomial infections are drug resistant, but it is believed that a significant number probably are. Between 1979 and 1987, only .02 percent of the pneumococcus strains infecting patients in 13 hospitals in 12 states sampled by the CDC were penicillin-resistant. By 1994, that number had risen to 6.6 percent.
* In a 1999 nationwide sampling of food borne bacteria by the National Antimicrobial Resistance Monitoring system (NARMS);
• 26 percent of the non-Typhimurium Salmonella samples were resistant to one or more antibiotics
• 49 percent of the Salmonella Typhimurium samples resisted one or more drugs
• 91 percent of the Shigella samples resisted one or more drugs.
• 10 percent of the E.coli samples resisted one or more antibiotic.
• 53 percent of the Campylobacter samples were resistant to one or more antibiotic.
* Food borne disease outbreaks are often caused by drug-resistant strains of bacteria. In 1998, 5,000 people in America fell ill from Campylobacter caused by contaminated chicken. The strains of bacteria found in the victims were multidrug-resistant. In 1968, 12,500 people in Guatemala died in an epidemic of Shigella-caused diarrhea, from a strain of the bacterium that was resistant to four antibiotics. A deadly drug resistant strain of Salmonella called DT104, more virulent than other strains, appeared in the late 90’s. It has killed people in Great Britain. 28 percent of the Salmonella Typhimurium samples tested by NARMS in 1999 had traits similar to DT104. (The Food and Drug Administration has approved a test kit for rapid detection of DT104.)
* Overseas, nearly every case of gonorrhea in Southeast Asia are multi-drug resistant. In 1990, cholera bacteria in India were susceptible to common antibiotics. Just ten years later, none of those drugs worked on cholera anymore. And our global world spreads some of these strains far and wide. Between 30,000 and 80,000 U.S. travelers returning from overseas suffer from a bacterial-caused diarrhea that is drug resistant. 2,500 travelers a year return with malaria that could not be prevented by prophylactic antibiotics that used to work. Investigators have documented the migration of one strain of multidrug-resistant Strep. Pneumoniae from Spain to the U.K., the U.S., South Africa, and elsewhere. Two cases of multidrug-resistant Staph. aureus were traced to Northern India. Most of the multidrug-resistant strains of typhoid found all over the world have been traced to six developing nations.
* Vancomycin-resistant enterococci, a normally harmless bacterium that lives in the human gut, were first detected in France and England in 1987. One appeared in New York in 1989. By 1993, 14 percent of patients in intensive care units in the U.S. had vancomycin-resistant enterococcus, a 20-fold increase in 6 years. Given the ready swapping of genes between different species of bacteria, the ability to resist vancomycin, currently the antibiotic given when others fail, could easily spread from enterococcus to other more harmful species.
One top U.S. health official said the ultimate consequence from the growing problem of antibiotic resistance “…could be a return to the days before antibiotics, when common diseases were often lethal.” “ We are skating on the edge of the ice,” he said.

The Range of Exposures

We are exposed to bacteria constantly. There is literally no setting in which potential exposure to drug resistant bacteria is not a concern. As mentioned above, people most at risk are those who have weakened immune systems. These include people already ill from something else, infants with still-developing immune systems, people taking steroidal medication, and the elderly, whose immune systems are no longer as effective as they used to be.
However, health officials are particularly worried about drug resistant bacteria in hospitals and nursing homes, places where a combination of factors raise the risk. A significant number of people who are hospitalized come in with weakened immune systems or undergo treatments such as chemotherapy that impair their immune response. These people are at risk of more serious illness, or death, from infections that neither they nor drugs can fight. In addition, a significant percentage of people who are hospitalized are elderly, with immune systems compromised simply by age. (This is one reason why exposure to drug resistant bacteria is also a concern in nursing homes and assisted-living facilities.) In addition surgical patients are more susceptible to any kind of bacterial infection simply because their skin has been opened. Open wounds, or healing wounds, are another potential route of nosocomial infection. Also, hospitals are, by definition, locations where a lot of people are carrying infections. They bring various strains of bacteria in with them. There are simply more infectious bacteria around in hospitals. Inadequate hygiene by people who work in hospitals, particularly something as simple as thorough and regular hand washing, allows drug resistant strains of bacteria to spread.
Another setting where exposure to drug resistant bacteria is a concern is day care centers, especially for infants. Here, a combination of children with still-developing immune systems, lots of direct contact between children and their care givers, and an environment where one or two people are frequently sick at any given time, increases the chances of spread of bacteria, accelerating the spread of resistance traits.


Reducing the Risk

There are several steps you can take to help slow the proliferation of antibiotic resistant bacteria.
* Don’t demand antibiotics any time you get sick. Remember, between one third and one half of antibiotics are mis-prescribed to patients that don’t really need them. Don’t automatically demand antibiotics for your children if they have what appears to be an ear infection. Medical authorities now think that mild cases may go away by themselves. And they say that not all ear infections are bacterial.
* Pay attention to simple hygiene. Cover your nose and mouth when you sneeze, to avoid spreading germs. Wash your hands frequently. Wash fruit and vegetables thoroughly. Cook meat, chicken pork, and fish well enough to kill any germs they may contain. And don’t forget that a piece of meat that you prepared on your kitchen counter might have contained a few germs. While you may kill those germs when you cook the meat, the germs are still there on the counter that you then use to prepare your salad. So wash your food preparation areas each time you finish working on one part of a meal.Sponges are a problem – throw them out or put them in the dishwasher.
* Diapers can be a source of bacteria. People handling diapers should be extra careful about washing their hands thoroughly.
* Finally, maintaining a good diet, getting half an hour of mildly aerobic exercise a few times a week, and other simple steps for staying healthy are good ways to avoid bacterial infection of any kind.
* FOLLOW THE INSTRUCTIONS FOR TAKING ANTIBIOTICS. DON’T STOP TAKING THEM AFTER YOU FEEL BETTER. SOME OF THE TARGETED BACTERIA MAY HAVE JUST ENOUGH RESISTANCE TO FIGHT OFF THE FIRST FEW DOSES. THEY MAY STILL BE LURKING, READY TO PASS ON THEIR RESISTANCE TRAITS. FINISHING THE FULL COURSE OF THE MEDICATION WILL HELP FINISH OFF THESE SLIGHTLY STRONGER GERMS.

For More Information

The Centers for Disease Control has a good website with basic information on this issue, and links to other sources.
http://www.cdc.gov/drugresistance/
You can call the CDC AT 1-800-311-3435

The Alliance for the Prudent Use of Antibiotics is a nonprofit organization working on this issue. Their website is
http://www.healthsci.tufts.edu/apua/apua.html
APUA
75 Kneeland Street
Boston, MA 02111-1901
617-636-0966

This chapter was reviewed by:
Marc Lipsitch, Assistant Professor of Epidemiology at the Harvard School of Public Health, who has done research on antibiotic resistance,
and by Dr. Don Goldman, Epidemiologist at The Children’s Hospital, Boston.