Antimicrobial (Drug) Resistance

Translating Basic Knowledge

Scientific discovery begins with basic research in the laboratory at "the bench." To improve human health, however, these discoveries must be translated into practical applications that reach the patient's "bedside." NIAID-supported research in antimicrobial (drug) research helps facilitate this translation of basic research discoveries from "bench to bedside."

Faster Diagnostic Tests

Tests that determine exactly which microbe is making a person sick can take a long time—sometimes several days—to get results. This is because many of today's tests are based on technology that requires laboratory staff to wait for the microbe to grow over a period of time before they can identify the cause of infection. As healthcare providers often cannot wait several days for that information before treating their patient, they may reach for a broad-acting drug they hope will kill whatever is infecting the patient. Unfortunately, the practice of using broad-spectrum drugs before the specific microbe is identified can accelerate the emergence of drug-resistant strains.

Healthcare providers need faster ways to diagnose infections and evaluate whether a certain strain of microbe is susceptible to antimicrobial drugs.

To meet this need for better, faster diagnostics, NIAID supports:

• Research on developing rapid diagnostics for a number of healthcare-associated bacterial infections that show signs of increased drug resistance. The microbes targeted in this program include Clostridium difficile, Pseudomonas, Acinetobacter, Enterobacter, and Klebsiella.
• A translational research program fostering the formation of collaborative partnerships among academic researchers from different disciplines or with industry to focus on developing new therapeutics or medical diagnostics for drug-resistant microbes.
• A program fostering collaboration between the mycology (fungus) research community and the innovative technology sector to identify novel targets and develop new clinical diagnostic tests for invasive aspergillosis and other invasive fungal diseases that attack immunocompromised or immunosuppressed patients.

Proper Dosage

Along with accurate diagnosis, healthcare providers need to prescribe the proper dose of a drug—one that is effective but limits the microbe's odds of developing resistance following prolonged or excessive exposure to the drug. The appropriate dosage requires a clear understanding of how the antimicrobial is broken down in the human body (the drug's pharmacokinetics) and how the drug affects the body (the drug's pharmacodynamics). To improve dosage recommendations, NIAID is supporting research proposals that incorporate drug dynamics and kinetics into studies on preventing antimicrobial resistance.

NIAID also supports efforts to collect data on the dynamics and kinetics of older antibiotics for which the most appropriate dosage information is not available. As situations arise where commonly used antibiotics are no longer effective, healthcare providers are resorting to some of the older antibiotics, such as Colistin. Though resistance to Colistin is still low, healthcare providers stopped using the drug because it was known to be toxic.

New Therapeutics

Recently, the number of new antimicrobial drugs has not kept pace with the rise of antimicrobial-resistant microbes. NIAID has a substantial research program to spur development of new therapeutics against disease-causing viruses, bacteria, parasites, and fungi.

NIAID supports university-based scientists and researchers at biotechnology companies, who are exploring new ways to treat infections with substances that make it difficult for microbes to develop resistance. For example, NIAID supported key foundational and preclinical studies of a novel monoclonal antibody for the treatment of Staphylococcus aureus. This therapeutic is now being tested for effectiveness in humans.

Other NIAID-supported efforts to develop new or improved drugs include:

• Partnership grants to support the development of antimicrobial-resistant bacteria and parasites. Awarded grants focus on the identification of novel targets, screens for new compounds with antimicrobial activity and pre-clinical development of novel classes of drugs, as well as the development of new members of existing drug classes.
• Research on new broad-spectrum antibiotics, including one to fight complicated skin infections and another that is now being tested as a treatment for community-acquired pneumonia.

To assist the research community, the NIAID Division of Microbiology and Infectious Diseases (DMID) has built a comprehensive set of product development services and research tools and technologies to facilitate efforts to develop the next generation of vaccines, diagnostics, and therapeutics. These services make needed expertise as well as standardized, high-quality research materials and state-of-the-art technologies available to eligible investigators worldwide at no charge. Information regarding these resources may be found at Microbiology and Infectious Diseases Resources

Clinical Trials: Data to Guide Treatment Decisions

The more an antibiotic is used, the more likely resistance to that drug becomes. In the presence of an antimicrobial, microbes are either killed or, if they carry resistance genes, survive. Through this process of selective pressure, drug-resistant survivors will replicate and their progeny will quickly become the dominant type throughout the microbial population. The selection of antimicrobial-resistant microbes can be reduced if the unnecessary use of these drugs is minimized. Well-designed clinical trials provide the data that healthcare providers need to make treatment decisions. This research will lead to better healthcare practices and more refined therapeutic approaches, such as shorter treatment duration or alternative therapies that do not require antimicrobials to minimize the emergence of antimicrobial resistance.

Examples of NIAID-supported clinical trials to examine ways to reduce the risk of antimicrobial resistance include:

• Antibiotics are commonly prescribed for children with acute ear infections (acute otitis media), despite the fact that many ear infections are viral, not bacterial, and thus not susceptible to antibiotics. Therefore, NIAID sponsored a trial to compare how long it takes for acute otitis media to resolve in children who received standard antibiotic treatment versus children who did not receive treatment. The trial showed that antibiotics are more effective than placebo in treating confirmed infections of the middle ear. A follow-up study is examining whether the course of antimicrobial treatment for acute otitis media can be shortened without reducing effectiveness.
• Skin and soft tissue infections caused by strains of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are a growing concern, but little is known about how to best treat uncomplicated forms of the infection. NIAID supports two clinical trials that are addressing the question of whether oral "first-line" antibiotics that are no longer under patent can effectively treat CA-MRSA and whether certain forms of disease can be managed medically without antibiotics (e.g., through drainage and wound care). If so, healthcare providers could use those drugs and avoid unnecessary use of last-resort antibiotics, which are critical for treating hospital-acquired MRSA.
• There is an initiative to target those infectious diseases most responsible for driving resistance to antimicrobials and to test the safety and efficacy of alternative therapeutic approaches. NIAID is funding clinical trials designed to preserve the effectiveness of existing antimicrobials by optimizing their use and thereby reducing the probability of the drug resistance. Two awards were made through this initiative in 2009: one to study shortened duration of therapy for urinary tract infections in children, and the other to study shortened duration of therapy for catheter-related bloodstream infections caused by Staphylococcus. Four additional contracts were awarded in 2010, focusing on acute otitis media, community-acquired pneumonia, and diseases caused by Gram-negative bacteria, which frequently are resistant to first-line antibiotics.
• The emergence and spread of drug-resistant malaria parasites has contributed to a reemergence of malaria, turning back the clock on control efforts. The National Institutes of Health is supporting a longitudinal study of chloroquine given by itself or in combination with artesunate, azithromycin, or atovaquone-proguanil to treat malaria in children in Blantyre, Malawi. These studies are needed to identify the pharmacokinetic and pharmacodynamic properties of drug combinations that will deter resistance and prolong the useful therapeutic life of the next generation of antimalarial drug combinations.

Vaccines Against Drug-resistant Microbes

The need for new drugs would be reduced if bacterial or other infections could be prevented with vaccines. NIAID supported preclinical studies of a vaccine that is protective against both drug resistant and susceptible S. aureus, the most common hospital-associated bacterial infection.

A NIAID-supported researcher who was testing an experimental vaccine in mice against the fungal infection caused by Candida albicans discovered that the vaccine also appeared to protect the animals against S. aureus. The discovery raises the possibility of developing a single vaccine against multiple microbes.

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