Antimicrobial Resistance

Drug-resistant infectious agents – those that are not killed or inhibited by antimicrobial compounds – are an increasingly important public health concern. Tuberculosis, gonorrhea, malaria and childhood ear infections are just a few of the diseases that have become more difficult to treat due to the emergence of drug-resistant pathogens. Antimicrobial resistance is becoming a factor in virtually all hospital-acquired (nosocomial) infections. Many physicians are concerned that several bacterial infections soon may be untreatable.

In addition to its adverse effect on public health, antimicrobial resistance contributes to higher health care costs. Treating resistant infections often requires the use of more expensive or more toxic drugs and can result in longer hospital stays for infected patients. The Institute of Medicine, a part of the National Academy of Sciences, has estimated that the annual cost of treating antibiotic resistant infections in the United States may be as high as $30 billion.

A key factor in the development of antimicrobial resistance is the ability of infectious organisms to adapt quickly to new environmental conditions. Microbes generally are unicellular creatures that, compared with multicellular organisms, have a small number of genes. Even a single random gene mutation can have a large impact on their disease-causing properties; and since most microbes replicate very rapidly, they can evolve rapidly. Thus, a mutation that helps a microbe survive in the presence of an antibiotic drug will quickly become predominant throughout the microbial population. Microbes also commonly acquire genes, including those encoding for resistance, by direct transfer from members of their own species or from unrelated microbes.

The innate adaptability of microbes is complemented by the widespread and sometimes inappropriate use of antimicrobials. Ideal conditions for the emergence of drug-resistant microbes result when drugs are prescribed for the common cold and other conditions for which they are not indicated or when individuals do not complete their prescribed treatment regimen. Hospitals also provide a fertile environment for drug-resistant pathogens. Close contact among sick patients and extensive use of antimicrobials force pathogens to develop resistance.

Scope of the Problem

Antimicrobial resistance has been recognized since the introduction of penicillin nearly 50 years ago when penicillin-resistant infections caused by Staphylococcus aureus rapidly appeared. Today, hospitals worldwide are facing unprecedented crises from the rapid emergence and dissemination of other microbes resistant to one or more antimicrobial agents.

• Strains of Staphylococcus aureus resistant to methicillin and other antibiotics are endemic in hospitals. Infection with methicillin-resistant S. aureus (MRSA) strains may also be increasing in non-hospital settings. A limited number of drugs remain effective against these infections. S. aureus strains with reduced susceptibility to vancomycin have emerged recently in Japan and the United States. The emergence of vancomycin-resistant strains would present a serious problem for physicians and patients.

• Increasing reliance on vancomycin has led to the emergence of vancomycin-resistant enterococci (VRE), bacteria that infect wounds, the urinary tract and other sites. Until 1989, such resistance had not been reported in U.S. hospitals. By 1993, however, more than 10 percent of hospital-acquired enterococci infections reported to the CDC were resistant.

• Streptococcus pneumoniae causes thousands of cases of meningitis and pneumonia, and 7 million cases of ear infection in the United States each year. Currently, about 30 percent of S. pneumoniae isolates are resistant to penicillin, the primary drug used to treat this infection. Many penicillin-resistant strains are also resistant to other antimicrobial drugs.

• In sexually transmitted disease clinics that monitor outbreaks of drug-resistant infections, doctors have found that more than 30 percent of gonorrhea isolates are resistant to penicillin or tetracycline, or both.

• An estimated 300 to 500 million people worldwide are infected with the parasites that cause malaria. Resistance to chloroquine, once widely used and highly effective for preventing and treating malaria, has emerged in most parts of the world. Resistance to other antimalaria drugs also is widespread and growing.

• Strains of multidrug-resistant tuberculosis (MDR-TB) have emerged over the last decade and pose a particular threat to people infected with HIV. Drug-resistant strains are as contagious as those that are susceptible to drugs. MDR-TB is more difficult and vastly more expensive to treat, and patients may remain infectious longer due to inadequate treatment.

• Diarrheal diseases cause almost 3 million deaths a year – mostly in developing countries, where resistant strains of highly pathogenic bacteria such as Shigella dysenteriae, Campylobacter, Vibrio cholerae, Escherichia coli and Salmonella are emerging. Recent outbreaks of Salmonella food poisoning have occurred in the United States. A potentially dangerous "superbug" known as Salmonella typhimurium, resistant to ampicillin, sulfa, streptomycin, tetracycline and chloramphenicol, has caused illness in Europe, Canada and the United States.

• Fungal pathogens account for a growing proportion of nosocomial infections. Fungal diseases such as candidiasis and Pneumocystis carinii pneumonia are common among AIDS patients, and isolated outbreaks of other fungal diseases in people with normal immune systems have occurred recently in the United States. Scientists and clinicians are concerned that the increasing use of antifungal drugs will lead to drug-resistant fungi. In fact, recent studies have documented resistance of Candida species to fluconazole, a drug used widely to treat patients with systemic fungal diseases.

• Recent years have seen the introduction of powerful new drugs and drug combinations against HIV. Although treatments that combine new protease inhibitor drugs with other anti- HIV medications often effectively suppress HIV production in infected individuals, results from recent clinical studies suggest that many treatment failures occur due to the development of resistance by the virus.

NIAID Research

Scientists and health professionals agree that decreasing the incidence of antimicrobial resistance will require improved systems for monitoring outbreaks of drug-resistant infections and a more judicious use of antimicrobial drugs. They also recognize the critical role that basic research plays in responding to this problem. For example, studies of microbial physiology help scientists understand the biological processes that pathogens use to resist drug treatment. This knowledge can lead to the development of novel strategies to overcome or reverse these processes.

Investigations in molecular genetics and biochemistry identify critical pathways and functions in how microbes replicate. Rapid improvements in gene sequencing technology are making it faster and easier to pinpoint the actual molecules involved in these pathways, which in turn could serve as targets for new antimicrobial drugs. Basic research like this has already yielded practical results. For example, studies of the molecular basis of drug resistance in parasites have led to:

• the development of molecular tools to identify drug-resistant parasites;
• the identification of the genetic basis of resistance and resulting biochemical alterations in several parasite species;
• the identification of methods to reverse resistance; and
• the synthesis of drugs that are effective against drug-resistant strains of malaria.

NIAID funding for antimicrobial resistance research has risen dramatically in recent years, from $7.8 million in 1992 to an estimated $13.8 million in 1998, an increase of more than 75 percent. NIAID supports investigator-initiated research on the molecular mechanisms responsible for drug resistance, as well as research to develop and evaluate new or improved therapeutics for disease intervention and prevention. These efforts include epidemiologic research on major nosocomial pathogens such as Staphylococcus aureus, E. coli species associated with urinary tract infections, the enterococci, staphylococci and Streptococcus pyogenes. These studies seek to define how bacterial pathogens acquire, maintain and transfer antibiotic-resistance genes. In collaboration with investigators from malaria endemic areas, NIAID-supported investigators are conducting field studies on the distribution of drug-resistant malaria parasites.

In 1996, NIAID alerted the scientific community with a Program Announcement to encourage investigators to submit grant applications to support basic and applied research on emerging infectious diseases, including fungal diseases and those due to bacteria that are resistant to antibiotics. Last year, NIAID released a Program Announcement to encourage basic research on the molecular biology and genetics of resistance among bacteria and fungi, development of new tests for detecting resistance, identification of new classes of antimicrobial agents, and evaluation of alternative treatments of drug-resistant infections.

In conjunction with the National Aeronautics and Space Administration, the Defense Advanced Research Projects Agency and the University of Alabama, NIAID recently co-sponsored a meeting on emerging infections and antimicrobial resistance to examine rational approaches to drug design and stimulate research in these areas. Scientists discussed strategies for developing new drugs against bacteria, fungi, parasites and viruses.

NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis, malaria and other infectious diseases, as well as allergies and immunology.

Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services
June 2000

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