Bacterial Resistance to Antibiotics

Bacterial Resistance to Antibiotics - Rosacea-Ltd

U.S. Food and Drug Administration
FDA Consumer magazine
July-August 2002

The Battle of the Bugs: Fighting Antibiotic Resistance

by Linda Bren

Ever since antibiotics became widely available about 50 years ago, they have been hailed as miracle drugs--magic bullets able to destroy disease-causing bacteria.

But with each passing decade, bacteria that resist not only single, but multiple, antibiotics--making some diseases particularly hard to control--have become increasingly widespread. In fact, according to the Centers for Disease Control and Prevention (CDC), virtually all significant bacterial infections in the world are becoming resistant to the antibiotic treatment of choice.

For some of us, bacterial resistance could mean more visits to the doctor, a lengthier illness, and possibly more toxic drugs. For others, it could mean death. The CDC estimates that each year, nearly 2 million people in the United States acquire an infection while in a hospital, resulting in 90,000 deaths. More than 70 percent of the bacteria that cause these infections are resistant to at least one of the antibiotics commonly used to treat them.

Antibiotic resistance, also known as antimicrobial resistance, is not a new phenomenon. Just a few years after the first antibiotic, penicillin, became widely used in the late 1940s, penicillin-resistant infections emerged that were caused by the bacterium Staphylococcus aureus (S. aureus). These "staph" infections range from urinary tract infections to bacterial pneumonia. Methicillin, one of the strongest in the arsenal of drugs to treat staph infections, is no longer effective against some strains of S. aureus. Vancomycin, which is the most lethal drug against these resistant pathogens, may be in danger of losing its effectiveness.

Although resistant bacteria have been around a long time, the scenario today is different from even just 10 years ago, says Stuart Levy, M.D., president of the Alliance for the Prudent Use of Antibiotics. "The number of bacteria resistant to many different antibiotics has increased, in many cases, tenfold or more. Even new drugs that have been approved are confronting resistance, fortunately in small amounts, but we have to be careful how they're used. If used for extended periods of time, they too risk becoming ineffective early on."

How Resistance Occurs

Bacteria, which are organisms so small that they are not visible to the naked eye, live all around us--in drinking water, food, soil, plants, animals, and in humans. Most bacteria do not harm us, and some are even useful because they can help us digest food. But many bacteria are capable of causing severe infections.

The ability of antibiotics to stop an infection depends on killing or halting the growth of harmful bacteria. But some bacteria resist the effects of drugs and multiply and spread.

Some bacteria have developed resistance to antibiotics naturally, long before the development of commercial antibiotics. After testing bacteria found in an arctic glacier and estimated to be over 2,000 years old, scientists found several of them to be resistant against some antibiotics, most likely indicating naturally occurring resistance.

If they are not naturally resistant, bacteria can become resistant to drugs in a number of ways. They may develop resistance to certain drugs spontaneously through mutation. Mutations are changes that occur in the genetic material, or DNA, of the bacteria. These changes allow the bacteria to fight or inactivate the antibiotic.

Bacteria also can acquire resistant genes through exchanging genes with other bacteria. "Think of it as bacterial sex," says David White, Ph.D., a microbiologist in the Food and Drug Administration's Center for Veterinary Medicine. "It's a simple form of mating that allows bacteria to transfer genetic material." The bacteria reproduce rapidly, allowing resistant traits to quickly spread to future generations of bacteria. "The bacteria don't care what other bacteria they're giving their genes to," says White. This means that resistance can spread from one species of bacteria to other species, enabling them to develop multiple resistance to different classes of antibiotics.

Combating Resistance

In 1999, 10 federal agencies and departments, led by the Department of Health and Human Services, formed a task force to tackle the problem of antimicrobial resistance. Co-chaired by the CDC, the FDA, and the National Institutes of Health, the task force developed a plan of action. The success of this plan--issued in 2001 and known as the Public Health Action Plan to Combat Antimicrobial Resistance--will depend on the cooperation of many entities, such as state and local health agencies, universities, professional societies, pharmaceutical companies, health-care professionals, agricultural producers, and the public.

All of these groups must work together if the antibiotic resistance problem is to be remedied, says Mark Goldberger, M.D., director of the FDA's office responsible for reviewing antibiotic drugs. "This is a very serious problem. We need to do two things: facilitate the development of new antimicrobial therapy while at the same time preserve the usefulness of current and new drugs."

Preserving Antibiotics' Usefulness

Two main types of germs--bacteria and viruses--cause most infections, according to the CDC. But while antibiotics can kill bacteria, they do not work against viruses--and it is viruses that cause colds, the flu, and most sore throats. In fact, only 15 percent of sore throats are caused by the bacterium Streptococcus, which results in strep throat. In addition, it is viruses that cause most sinus infections, coughs, and bronchitis. And fluid in the middle ear, a common occurrence in children, does not usually warrant treatment with antibiotics unless there are other symptoms.

Nevertheless, "Every year, tens of millions of prescriptions for antibiotics are written to treat viral illnesses for which these antibiotics offer no benefits," says David Bell, M.D., the CDC's antimicrobial resistance coordinator. According to the CDC, antibiotic prescribing in outpatient settings could be reduced by more than 30 percent without adversely affecting patient health.

Reasons cited by doctors for over prescribing antibiotics include diagnostic uncertainty, time pressure on physicians, and patient demand. Physicians are pressured by patients to prescribe antibiotics, says Bell. "People don't want to miss work, or they have a sick child who kept the whole family up all night, and they're willing to try anything that might work." It may be easier for the physician pressed for time to write a prescription for an antibiotic than it is to explain why it might be better not to use one.

But by taking an antibiotic, a person may be doubly harmed, according to Bell. First, it offers no benefit for viral infections, and second, it increases the chance of a drug-resistant infection appearing at a later time.

"Antibiotic resistance is not just a problem for doctors and scientists," says Bell. "Everybody needs to help deal with this. An important way that people can help directly is to understand that common illnesses like colds and the flu do not benefit from antibiotics and to not request them to treat these illnesses."

Following the prescription exactly is also important, says Bell. People should not skip doses or stop taking an antibiotic as soon as they feel better; they should complete the full course of the medication. Otherwise, the drug may not kill all the infectious bacteria, allowing the remaining bacteria to possibly become resistant.

While some antibiotics must be taken for 10 days or more, others are FDA-approved for a shorter course of treatment. Some can be taken for as few as three days. "I would prefer the short course to the long course," says Levy. "Reservoirs of antibiotic resistance are not being stimulated as much. The shorter the course, theoretically, the less chance you'll have resistance emerging, and it gives susceptible strains a better chance to come back."

Another concern to some health experts is the escalating use of antibacterial soaps, detergents, lotions, and other household items. "There has never been evidence that they have a public health benefit," says Levy. "Good soap and water is sufficient in most cases." Antibacterial products should be reserved for the hospital setting, for sick people coming home from the hospital, and for those with compromised immune systems, says Levy.

To decrease both demand and over prescribing, the FDA and the CDC have launched antibiotic resistance campaigns aimed at health-care professionals and the public. A nationwide ad campaign developed by the FDA's Center for Drug Evaluation and Research emphasizes to health-care professionals the prudent use of antibiotics, and offers them an educational brochure to distribute to patients.

The FDA has also drafted a proposed labeling rule that would require specific language on antibiotic labels to encourage doctors to prescribe them only when truly necessary.

Upper Respiratory Infections and Antibiotics

Most upper respiratory infections are usually caused by viruses--germs that are not killed by antibiotics. Talk with your doctor about ways to feel better when you are sick. Ask what you should look for at home that might mean you are developing another infection for which antibiotics might be appropriate.

Illness	Usually caused by virus	Usually caused by bacteria	Antibiotic usually needed?
Cold			No
Flu			No
Chest Cold (in otherwise healthy children and adults)			No
Sore Throats (except strep)			No
Bronchitis (in otherwise healthy children and adults)			No
Runny Nose (with green or yellow mucus)			No
Fluid in the Middle Ear (otitis media with effusion)			No

Stimulating Drug Development

The FDA is working to encourage the development of new antibiotics and new classes of antibiotics and other antimicrobials.

"We would like to make it attractive for the development of new antibiotics, but we'd like people to use them less and only in the presence of bacterial infection," says Goldberger. This presents a challenge, he says. "Decreased use may result in sales going down, and drug companies may feel there are better places to put their resources."

Through such incentives as exclusivity rights, the FDA hopes to stimulate new antimicrobial drug development. Exclusivity protects a manufacturer's drug from generic drug competition for a specific length of time.

The FDA has a variety of existing regulatory tools to help developers of antimicrobial drugs. One of these is an accelerated approval process for drugs that treat severely debilitating or life-threatening diseases and for drugs that show meaningful benefit over existing prescription drugs to cure a disease.

The FDA is also investigating other approaches for speeding the antimicrobial approval process. One approach is to reduce the size of the clinical trial program. "We need to streamline the review process without compromising safety and effectiveness," says Goldberger. "One of the things that we are trying to look at now is how we can substitute quality for quantity in clinical studies." It has been difficult to test drugs for resistance in people, says Goldberger. "Although these resistant organisms are a problem, they are still not so common that it is very easy to accumulate patients."

From Farm to Fork

Although the inappropriate use of antibiotics in people is a major contributor to antibiotic resistance, it is not the only contributor. Another is the use of these drugs in agriculture. Antibiotics are used in agriculture when they are sprayed onto fruit trees and other food plants as a pesticide for disease control. In addition, antibiotics are used to treat and prevent diseases in food-producing animals and to improve their growth rate.

Scientists have found a link between antibiotic use in agriculture and antibiotic resistance in bacteria carried by humans. "There is a small, but very important, subset of resistant infections in humans that are caused by pathogens that animals carry inherently," says Linda Tollefson, D.V.M., M.P.H., deputy director of the FDA's Center for Veterinary Medicine (CVM). "These pathogens don't make the animal sick, but the animals are treated with antimicrobials for other diseases or to promote growth. These bacteria in the animal may then become resistant to the drug and cause resistant food borne infections in humans who consume products derived from the animals."

The resistant bacteria, which remain on the animal through the slaughtering and packaging process, make their way into home kitchens. The cooking process kills off many of the bacteria, but under cooked meat will still harbor some. In addition, if raw meat, poultry or fish comes in contact with other foods, bacteria can spread to these foods through cross-contamination.

Most people suffer only mild to moderate illness from these bacteria, but each year, thousands get severely ill and even die. People who do get sick may be treated with the same or a similar drug that is used in the animals and, because of the transfer of resistant bacteria, the drug may not be effective.

The human health impact of antibiotic use in food animals has long been debated. A 1999 National Academy of Sciences report concluded that there is "a link between the use of antibiotics in food animals, the development of bacterial resistance to these drugs, and human disease--although the incidence of such disease is very low."

However, a more recent report released by the Alliance for the Prudent Use of Antibiotics and published in the June 2002 issue of Clinical Infectious Diseases recommended eliminating the use of antibiotics for growth promotion in food-producing animals and limiting farm use of drugs that are critically important to humans. "There is a critical need for more timely action to ensure that antibiotics remain effective," says Levy. "Once the resistance in a bacterial population reaches a certain level, reversal becomes extremely difficult."

The Animal Health Institute (AHI), a national trade association representing manufacturers of animal health products, is also concerned about the possibility of antibiotics used in food animals causing resistant bacteria to develop. But stopping the use of antibiotics in animals is not the solution, says Ron Phillips, AHI spokesperson.

"The number one reason that antibiotic use in animals is important is to keep animals healthy; by keeping animals healthy, we increase food safety," says Phillips. "For farmers, it's an important production tool that contributes to the relatively low cost of our food supply."

The AHI recommends several actions to better manage human resistance. "The first thing we need to do is to be able to appropriately measure it so we can manage it," says Phillips. The AHI supports more and better surveillance of both human and animal resistance, and promoting to farmers and veterinarians better practice of "judicious use" principles regarding antibiotics.

"The FDA has done some good work in helping to promote those principles and ought to continue," says Phillips. But he urges the FDA to work even more closely with the livestock production and animal health communities in promoting judicious use principles. In addition, the AHI calls for "good, sound risk assessments that will yield us the kind of information necessary to make good management decisions."

Animal Drug Regulation

To reduce antibiotic resistance in humans caused by the use of antibiotic drugs in animals, the FDA is evaluating the animal drug pre-approval process, increasing surveillance, and expanding research.

CVM regulates drugs used in food-producing animals. One of CVM's major challenges is improving the way the FDA regulates antibiotics in livestock and poultry, says Stephen Sundlof, D.V.M., Ph.D., director of CVM. "Our main goal is to ensure that human antimicrobial therapies are not compromised or lost due to the use of antimicrobial drugs in animals. But we also have another important goal--to provide for the safe use of antimicrobial drugs in food-producing animals, because these drugs are valuable tools in livestock production and they provide one way of making sure that the food supply is safe."

To balance these two goals, CVM has presented suggested approaches for drug regulation in food animals. These approaches are included in CVM's 1998 publication known as the "Framework Document."

Based on feedback from public forums and advisory committee meetings, CVM is drafting guidance for drug sponsors to help them implement the suggested approaches in the Framework Document. A public meeting will follow the publication of this guidance, which is expected this summer, and the FDA will invite comments on any proposed new or amended rules before they are made final. CVM's approaches, designed to discover whether specific drugs might promote antibiotic resistance, include a more rigorous safety assessment for resistance prior to drug approval and categorizing antibiotic drugs based on their importance to human medicine.

"We decided that not all antibiotics are created equal," says Sundlof. "There are some antimicrobial drugs used in human medicine that are drugs of last resort for treating a life-threatening disease." Animal drugs similar to those used to treat a serious or life-threatening human disease that has no other effective alternative treatment would be subject to the strictest criteria for approval for animal use.

CVM's post-drug-approval approaches include monitoring the development of antimicrobial resistance and collecting data on drugs used in food animal production.

Surveillance

Strengthening the approval process for antibiotics in food animals is only one piece of CVM's multi-faceted approach to the resistance problem. Another important element is surveillance.

Researchers have already established a link between antibiotic use in food animals and human disease. But information regarding where antibiotic resistance emerges, the extent of the threat, and the trends of resistance over time was limited before the creation in 1996 of the largest monitoring system for resistance in the United States--the National Antimicrobial Resistance Monitoring System (NARMS).

Through NARMS, scientists monitor both human and animal bacterial resistance to a panel of antimicrobials selected for their importance in human and animal medicine. As part of this joint effort by the CDC, the FDA, and the U.S. Department of Agriculture (USDA), NARMS scientists collect specific intestinal bacteria samples from people with diarrheal illness and test these samples for antimicrobial resistance at the CDC's laboratory in Atlanta. The NARMS program was recently expanded to include samples provided by 28 state and local public health laboratories across the country. The program continues to expand and adapt by adding new collection sites and different species of bacteria and antimicrobial drugs for evaluation.

Animal specimens for NARMS are collected from federally inspected slaughter and processing facilities as well as from healthy and ill animals on farms. These samples are then tested for antimicrobial resistance at the USDA's lab in Athens, Ga. In 2001, retail meat samples were added to NARMS, and testing began at the CVM's lab in Laurel, Md. Testing of additional retail meat samples, as well as animal feed ingredients, is being conducted in 2002.

Data provided through NARMS can help support new treatment guidelines, determine the effects of drug usage practices and intervention strategies, and shape national policy regarding the use of antimicrobials in animals.

The high volume of international travel and food imports has intensified the risk of infectious agents and resistant pathogens crossing national borders. In a cooperative agreement with scientists in Mexico, the FDA is sharing its experience with NARMS to help establish a similar monitoring system in Mexico. This system will yield information that may one day be part of an international database, allowing comparison of trends among countries, enhanced food safety activities, improved detection of epidemics, and earlier responses to emerging pathogens on an international scale.

Research

Scientists and health professionals are generally in agreement that a way to decrease antibiotic resistance is through more cautious use of antibiotic drugs and through monitoring outbreaks of drug-resistant infections.

But research is also critical to help understand the various mechanisms that pathogens use to evade drugs. Understanding these mechanisms is important for the design of effective new drugs.

The FDA's National Center for Toxicological Research (NCTR) is studying the mechanisms of resistance to antibiotic agents among bacteria from the human gastrointestinal tract, which can cause serious infections.

In addition, the NCTR has studied the amount of antibiotic residues that people consume in food from food-producing animals and the effects of these residues on human intestinal bacteria. This information led to a new approach for assessing the safety of antibiotic drug residues in people, which may be adopted by the FDA to help review drugs for food animals.

For more information on antibiotic resistance, see the FDA's Web site at www.fda.gov/oc/opacom/hottopics/anti_resist.html, and the CDC's Web site at www.cdc.gov/drugresistance/.

Fluid in the Middle Ear

Fluid in the middle ear, also called otitis media with effusion, is a common condition in children. Fluid often accumulates in the ear, just like in the nose, when a child has a cold. In the absence of other symptoms, fluid in the middle ear usually doesn't bother children, and it almost always goes away on its own without treatment, says Janice Soreth, M.D., director of the FDA's Division of Anti-Infective Drug Products. "It usually does not need to be treated with antibiotics unless it is accompanied by additional signs or symptoms or it lasts a couple of months."

If your doctor does not prescribe an antibiotic for your child, do not insist on one. Taking an antibiotic when it is not necessary can be harmful. It increases the risk of getting an infection later that antibiotics cannot kill.

Instead, "observe your child," says Soreth. "If symptoms change, call your doctor to seek further help." Symptoms to watch for include fever, irritability, decreased appetite, trouble sleeping, tugging on the ear, or complaints of pain. "If symptoms occur, it doesn't mean the doctor misdiagnosed the condition," says Soreth. "What started out as a viral condition may have morphed into a bacterial infection several days later. If this happens, an antibiotic may be appropriate."

--L.B.

What You Can Do to Help Curb Antibiotic Resistance

Don't demand an antibiotic when your health-care provider determines one isn't appropriate. Ask about ways to help relieve your symptoms.
Never take an antibiotic for a viral infection such as a cold, a cough, or the flu.
Take medicine exactly as your health-care provider prescribes. If he or she prescribes an antibiotic, take it until it is gone, even if you're feeling better.
Don't take leftover antibiotics or antibiotics prescribed for someone else. These antibiotics may not be appropriate for your current symptoms. Taking the wrong medicine could delay getting correct treatment and allow bacteria to multiply.

Rosacea-Ltd III

Adapted from the Centers for Disease Control and Prevention.

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