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) resistance 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 or weeks—to get results. This is because many of today's tests require the microbe to grow over a period of time before it can be identified. As patients often need treatment sooner, healthcare providers must provide drug coverage for a wide range of possible pathogens. They therefore may start with a combination of drugs, including broad-acting drugs that target multiple organisms. While this approach can effectively treat individual patients, using broad-spectrum therapies before the specific microbe is identified can contribute to drug resistance.
Multiple complementary strategies are needed to address the growing problem of antimicrobial resistance. For example, healthcare providers need faster ways to diagnose infections and evaluate whether a certain strain of microbe is susceptible to particular antimicrobial drugs. This information will help guide treatment decisions, including the use of narrow-spectrum drugs to effectively treat infection and minimize drug resistance.
To meet this need for better, faster diagnostics, NIAID supports research such as the following:
- Researchers are studying new ways to develop rapid diagnostics for a number of healthcare-associated bacterial infections that show signs of increased drug resistance. The microbes targeted in this initiative include Clostridium difficile, Pseudomonas, Acinetobacter, Enterobacter, and Klebsiella.
- NIAID has supported the development of a test to rapidly identify Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), including multidrug-resistant strains. The test, called the Xpert MTB/RIF, is simple to use and results can be provided in less than two hours, whereas traditional tests to determine drug resistance require weeks to generate results. Since its endorsement by the World Health Organization in 2010, Xpert MTB/RIF has been rolled out in over 65 countries. NIAID is supporting studies to understand how to best use the new test in different populations and how to expand it to other types of TB drug resistance.
- To advance new therapeutics and medical diagnostics for drug-resistant microbes, NIAID supports a translational research program fostering collaborative partnerships between academic researchers from different disciplines and between academia and industry.
- NIAID supports a program fostering collaboration between the 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.
Along with accurate diagnosis, healthcare providers need information that will help them to prescribe the proper dose of a drug—one that is effective but limits the microbe's odds of developing resistance following prolonged exposure to the drug. The appropriate dosage requires a clear understanding of how the antimicrobial drug is broken down in the human body (the drug's pharmacokinetics) and how the drug affects the microbe it is targeting (the drug's pharmacodynamics). NIAID is supporting research in these areas in order to improve dosage recommendations and limit the development of antimicrobial resistance. For example, NIAID supports projects studying the pharmacokinetics and pharmacodynamics of drugs commonly used to treat TB, influenza, and malaria, as well as hospital-acquired infections caused by Gram-negative bacteria.
NIAID also supports efforts to collect this information for older antibiotics for which the most appropriate dose is unclear. As situations arise where commonly used antibiotics are no longer effective, healthcare providers are returning to some of the older antibiotics, such as colistin. Though resistance to colistin is still low, healthcare providers stopped using the drug many years ago because of its toxicity. Information from NIAID-supported studies helps inform the best ways to dose colistin to maximize effectiveness while limiting toxicity. NIAID also supported research re-assessing the effectiveness of currently available drugs against TB to understand how drug resistance develops even when multiple drugs are used at the same time. These findings can help healthcare providers determine appropriate treatment strategies for TB.
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 drug-resistant 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.
Other NIAID-supported efforts to develop new or improved drugs include the following:
- Partnership grants support the development of new drugs for antimicrobial-resistant bacteria and parasites. Studies supported by these 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.
- NIAID supports research specifically targeting drug-resistant Gram-negative bacteria. Under this initiative, scientists are developing novel therapeutic approaches for these difficult-to-treat infections.
- NIAID is supporting the development of broad-spectrum therapeutics for biodefense and public health emergencies. Because of their ability to target multiple pathogens, broad-spectrum drugs are important and valuable tools, particularly before an infection has been diagnosed. The appropriate use of broad-spectrum therapeutics is critical for optimizing patient care while at the same time limiting drug resistance. Research is being conducted on new broad-spectrum antibiotics to fight complicated skin infections, community-acquired pneumonia, and possible bioterror threats.
- The safety, drug absorption, distribution, and best dosage of a novel narrow spectrum agent with activity against intestinal bacterium Clostridium difficile is currently being investigated. (Phase I study)
- NIAID-supported studies on new TB drugs and drug combinations have led to important advances in TB treatment. NIAID scientists were instrumental in discovering SQ109, a new compound to treat TB. With NIAID support, researchers studied the safety, drug absorption, distribution, and best dosage of single-daily doses of this experimental TB treatment. (Phase IB/C studies). Several studies are being planned to learn more about the safety and efficacy of SQ109.
- NIAID is sponsoring a Phase IIa clinical trial to evaluate an investigational TB drug in patients newly diagnosed with drug-sensitive pulmonary TB. Led by researchers at the Tuberculosis Research Unit at Case Western Reserve University, the study is being conducted in Cape Town, South Africa.
- NIAID-supported researchers are developing new methods to study TB drugs in the laboratory and animal models. These approaches will be used to identify new drug combinations and regimens that may be able to dramatically shorten the current six-month duration of treatment for TB.
- NIAID is committed to studying new ways to treat drug-resistant malaria. For example, NIAID-supported scientists identified an enzyme—known as Dihydroorotate Dehydrogenase (DHODase)—that is critical to the growth of malaria-causing Plasmodium parasites. Building on this research, NIAID is supporting the preclinical development of a new antimalarial drug, DSM265, that targets this enzyme. The public-private partnership Medicines for Malaria Venture named this work as their 2010 Project of the Year.
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 agent, microbes are either killed or, if they carry resistance genes, survive. Through this process, drug-resistant survivors will replicate and their progeny will quickly dominate the microbial population. The emergence and spread of antimicrobial-resistant microbes can be reduced by minimizing the unnecessary use of these drugs.
Well-designed clinical trials provide 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.
The following NIAID-supported clinical trials are examples of how NIAID is working to reduce the risk of antimicrobial resistance:
- 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. 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. Clinical evaluation to determine the likelihood of a bacterial infection is important for choosing appropriate treatment options and reducing unnecessary antibiotic use.
- 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—the first medicines used to treat people with CA-MRSA— that are no longer under patent can effectively treat the infection and whether certain forms of disease can be managed without antibiotics (e.g., through drainage and wound care). If so, healthcare providers could use those drugs and appropriate medical management to avoid the unnecessary use of last-resort antibiotics, which are critical for treating hospital-acquired MRSA.
- NIAID is funding clinical trials designed to preserve the effectiveness of existing antimicrobials by optimizing their use and thereby reducing the probability of drug resistance. Studies conducted through this initiative include
- Shortened duration of therapy for urinary tract infections in children and for acute otitis media
- Shortened duration of therapy for staphylococcal infections in the bloodstream
- Optimizing the use of colistin to treat Gram-negative bloodstream infections (e.g., Acinetobacter)
- The emergence and spread of drug-resistant malaria parasites have contributed to a re-emergence of malaria, turning back the clock on control efforts. Although chloroquine resistance has been widespread in Malawi, the prevalence of chloroquine-susceptible strains gradually increased when the drug was no longer used as the first-line treatment for malaria. NIAID-supported scientists conducted a clinical trial among children in Malawi to compare two treatment options for malaria: chloroquine given by itself or in combination with other antimalarials. This study found that chloroquine can be used to effectively treat the initial infection as well as repeated bouts of malaria. These findings support the possible re-introduction of combination antimalarial drug regimens containing chloroquine to prevent malaria in selected high-risk populations.
- Drug-resistant forms of gonorrhea, the second most commonly reported infectious disease in the United States, have begun to emerge in recent years. NIAID is studying new ways to treat these infections, including the use of two antibiotic therapies in combination (i.e., gentamicin and azithromycin vs. gemifloxacin and azithromycin).
Prevention Strategies and Vaccines Against Drug-Resistant Microbes
The need for new drugs would be reduced if bacterial or other infections could be prevented through effective interventions, including vaccines. NIAID supports a variety of studies on potential prevention strategies, including the following:
- An NIAID-supported researcher testing an experimental vaccine against the fungal infection Candidiasis discovered that the same vaccine also protects animals against Staphylococcus infection. Two early clinical trials found that the vaccine was safe and generated a strong immune response against Candida and S. aureus. These findings raise the possibility of developing a single vaccine against multiple microbes.
- Invasive Gram-negative blood infections can be life-threatening. Given the rise in antimicrobial resistance, there is a great need to develop new products to treat and prevent this infection. NIAID is supporting a study examining the safety and immune response generated by an experimental preventive vaccine for Gram-negative blood infection (Phase I study).
- Several studies are testing interventions to prevent healthcare-associated infections. Strategies include the decontamination of endotracheal tubes (Phase I study) and using a new topical agent to eliminate S. aureus in the nose (Phase I study).
- NIAID-supported researchers have developed promising new TB vaccine candidates, several of which have now entered human clinical trials.
Resources for Researchers
NIAID 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.
A variety of NIAID preclinical services are available to advance research related to drug-resistant pathogens, including
- Resources to support the preclinical development of new therapeutics, including manufacturing and formulation development, pharmacodynamics and pharmacokinetic studies, and toxicity testing
- Laboratory tests to screen novel compounds and therapies for activity against MRSA, vancomycin-resistant Enterococcus, M. tuberculosis, and drug-resistant Gram-negative bacteria
- Animal models to evaluate promising therapeutics for S. aureus, Escherichia coli, and Neisseria gonorrhoeae