Wednesday, November 30, 2005

Antibiotic Resistance - Part One

The Problem of Antibiotic Resistance


The triumph of antibiotics over disease-causing bacteria is one of modern medicine's greatest success stories. Since these drugs first became widely used in the World War II era, they have saved countless lives and blunted serious complications of many feared diseases and infections.

After more than 50 years of widespread use, however, many antibiotics don't pack the same punch they once did.

Over time, some bacteria have developed ways to outwit the effects of antibiotics. Widespread use of antibiotics is thought to have spurred evolutionary changes in bacteria that allow them to survive these powerful drugs. While antibiotic resistance benefits the microbes, it presents humans with two big problems: it makes it more difficult to purge infections from the body; and it heightens the risk of acquiring infections in a hospital.

Diseases such as tuberculosis, gonorrhea, malaria, and childhood ear infections are now more difficult to treat than they were decades ago. Drug resistance is an especially difficult problem for hospitals because they harbor critically ill patients who are more vulnerable to infections than the general population and therefore require more antibiotics. Heavy use of antibiotics in these patients hastens the mutations in bacteria that bring about drug resistance.

Unfortunately, this worsens the problem by producing bacteria with greater ability to survive even our strongest antibiotics. These even stronger drug-resistant bacteria continue to prey on vulnerable hospital patients.

To help curb this problem, the Centers for Disease Control and Prevention (CDC) provides hospitals with prevention strategies and educational materials to reduce antimicrobial resistance in health care settings. According to CDC statistics

Nearly two million patients in the United States get an infection in the hospital each year
Of those patients, about 90,000 die each year as a result of their infection-up from 13,300 patient deaths in 1992

More than 70 percent of the bacteria that cause hospital-acquired infections are resistant to at least one of the drugs most commonly used to treat them

Persons infected with drug-resistant organisms are more likely to have longer hospital stays and require treatment with second or third choice drugs that may be less effective, more toxic, and more expensive

In short, antimicrobial resistance is driving up health care costs, increasing the severity of disease, and increasing the death rates from certain infections.

Environment Forces Evolutionary Change

A key factor in the development of antibiotic resistance is the ability of infectious organisms to adapt quickly to new environmental conditions. Bacteria are single-celled creatures that, compared with higher life forms, have small numbers of genes. Therefore, even a single random gene mutation can greatly affect their ability to cause disease. And because most microbes reproduce by dividing every few hours, bacteria can evolve rapidly. A mutation that helps a microbe survive exposure to an antibiotic drug will quickly become dominant throughout the microbial population. Microbes also often acquire genes, including those that code for resistance, from each other.

The advantage microbes gain from their innate adaptability is augmented by the widespread and sometimes inappropriate use of antibiotics. A physician, wishing to placate an insistent patient ill with a cold or other viral condition, sometimes inappropriately prescribes antibiotics. Also when a patient does not finish taking a prescription for antibiotics, drug-resistant microbes not killed in the first days of treatment can proliferate. Hospitals also provide a fertile environment for drug-resistant germs as close contact among sick patients and extensive use of antibiotics force bacteria to develop resistance. Another controversial practice that some believe promotes drug resistance is adding antibiotics to agricultural feed.

A Growing Problem

For all these reasons, antibiotic resistance has been a problem for nearly as long as we've been using antibiotics. Not long after the introduction of penicillin, a bacterium known as Staphylococcus aureus began developing penicillin-resistant strains. Today, antibiotic-resistant strains of S. aureus bacteria as well as various enterococci-bacteria that colonize the intestines-are common and pose a global health problem in hospitals. More and more hospital-acquired infections are resistant to the most powerful antibiotics available, methicillin and vancomycin. These drugs are reserved to treat only the most intractable infections in order to slow development of resistance to them.

There are several signs that the problem is increasing:

In 2003, epidemiologists reported in The New England Journal of Medicine that 5 to 10 percent of patients admitted to hospitals acquire an infection during their stay, and that the risk for a hospital-acquired infection has risen steadily in recent decades.

Strains of S. aureus resistant to methicillin are endemic in hospitals and are increasing in non-hospital settings such as locker rooms. Since September 2000, outbreaks of methicillin-resistant S. aureus infections have been reported among high school football players and wrestlers in California, Indiana, and Pennsylvania, according to the CDC.

The first S. aureus infections resistant to vancomycin emerged in the United States in 2002, presenting physicians and patients with a serious problem. In July 2002, the CDC reported that a Michigan patient with diabetes, vascular disease, and chronic kidney failure had developed the first S. aureus infection completely resistant to vancomycin. A similar case was reported in Pennsylvania in September 2002.

Increasing reliance on vancomycin has led to the emergence of vancomycin-resistant enterococci infections. Prior to 1989, no U.S. hospital had reported any vancomycin resistant enterococci, but over the next decade, such microbes have become common in U.S. hospitals, according to CDC.

A 2003 study in The New England Journal of Medicine found that the incidence of blood and tissue infections known as sepsis almost tripled from 1979 to 2000.
NIAID Research

The National Institute of Allergy and Infectious Diseases (NIAID), part of the Department of Health and Human Services' National Institutes of Health (NIH), funds research, drug screening, and clinical trials to combat the problem of antimicrobial resistance. It manages a research portfolio of grants specifically aimed at the problem of antibiotic resistance among common bacteria responsible for hospital-acquired infections. These grants fund studies on the basic biology of resistant organisms; applied research on new diagnostic techniques, therapies, and preventive measures; as well as studies of how bacteria develop and share resistance genes. Other NIAID-funded research projects seek to identify natural antimicrobial peptides (small pieces of protein molecules) that could help stave off drug-resistant infections.

NIAID also funds the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA), a multidisciplinary international cadre of basic scientists, clinical microbiologists, and clinical investigators focused on combating drug-resistant S. aureus and related staphylococcal bacterial infections. The network maintains a repository of drug-resistant staph strains that scientists can request for use in their research. It also provides an Internet site with scientific presentations and a discussion forum to promote communication between researchers.

NIAID also supports a number of networks for clinical trials with the capacity to assess new antimicrobial drugs and vaccines against other drug-resistant infections. The AIDS Clinical Trials groups can evaluate drugs that combat the problem of the HIV virus developing resistance to standard antiretroviral treatments. The Bacteriology and Mycology Study Group, a network of academic and private research institutes, conducts clinical trials for improved treatments for fungal infections, particularly in people with weakened immune systems. In a similar fashion, the Collaborative Antiviral Study Group, made up of researchers at approximately 50 institutions, evaluates experimental therapies for viral infections. The Vaccine and Treatment Evaluation Units are a network of seven U.S. institutions that conduct clinical research on vaccines and therapeutics to speed development of new vaccines and therapies.
More details on these and other related projects can be found on the
NIAID Web site.

Other research projects-at NIH or funded by other components of NIH-are seeking new, molecular-level knowledge on the interactions of microbes and human cells as well as the tricks microbes use to outwit antibiotics. Another avenue of research is sleuthing the genomes of drug-resistant bacteria for vulnerabilities that could be attacked with new or existing drugs.

Antimicrobial Advances and Activities

NIAID-funded research grants and activities are yielding results that will help public health officials hold the line in our fight against drug-resistant microbes. For example
NIAID-funded researchers at the University of California Berkeley have documented the mechanics of how E. coli bacteria use pumps in the thin space between their membranes to expel antibiotic drugs. Their results, reported in the Journal of Bacteriology, serve as a model for how these molecular pumps work in bacteria responsible for hospital-acquired infections.
NIAID grantees at the Washington University School of Medicine in St. Louis have uncovered new information about how bacteria that cause urinary tract infections manufacture hair-like fibers to cling to the lining of the bladder. Their findings could lead to new drugs that would treat urinary tract infections by blocking formation of these protein fibers. Approximately half of all women experience urinary tract infections, and 20 to 40 percent of those will develop recurrent infections. The results were reported in the journal Cell.

An NIAID-funded project at The Institute for Genomic Research recently discovered that small pieces of DNA that can jump between chromosomes or organisms helped a strain of E. faecalis bacteria develop resistance to vancomycin. The researchers found that these "mobile elements" of DNA appear to contain a newly identified vancomycin resistance segment carrying vancomycin resistance genes. These results were published in the journal Science.

Partnerships and Interagency Collaborations

In addition to sponsoring research, NIAID co-chairs the Federal government's Interagency Task Force on Antimicrobial Resistance. This task force is made up of representatives from NIAID, CDC, the Food and Drug Administration, the Agency for Healthcare Research and Quality, the Department of Agriculture, the Department of Defense, the Department of Veterans Affairs, the Environmental Protection Agency, the Center for Medicaid and Medicare Services, and the Health Resources and Services Administration. The Task Force is working on implementing an antimicrobial resistance action plan that reflects a broad consensus of theses agencies with input from a variety of constituents and collaborators. The plan is available online

NIAID also co-sponsors the Annual Conference on Antimicrobial Resistance with the Infectious Disease Society of America and other government and not-for-profit agencies. The conference updates attendees on the science, prevention, and control of antimicrobial resistance and provides a forum for discussion of new methods of treatment and control.

Related Information

Other federal agencies are involved in combating the problem of drug-resistant microbes. See the links below for more information.

Prepared by:Office of Communications and Public Liaison

National Institutes of HealthBethesda, MD 20892
U.S. Department of Health and Human Services

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