Article

Duke-Led Research Network Addressing Antibacterial Resistance

Q&A with infectious disease specialist, co-principal investigator

Microscope Image of bacteria

The Antibacterial Resistance Leadership Group (ARLG), a research network facilitated by the Duke Clinical Research Institute, recently received a grant of $102.5 million from the National Institute of Allergy and Infectious Diseases, part of the NIH, to continue its work in reducing the public health threat from antibacterial resistance.

In this Q&A, Vance G. Fowler, MD, MHS, a Duke infectious disease specialist and ARLG’s co-principal investigator, discusses some of the factors that have led to antibiotic resistance and the group’s vision for improving clinical practice in treating infectious diseases.

Question: What are some of the factors that have led to antibacterial resistance?

Fowler: Antibiotic misuse and overuse is the primary cause of the antibacterial resistance that we now face. Traditionally, we in medicine have had the luxury of prescribing antibiotics freely, often without a second thought. Some antibiotic overuse is unavoidable. When treating critically ill patients with sepsis, specific data on the bacteria causing the life-threating infection is sometimes unavailable for several days, and physicians need to treat the patient immediately.  As a result, empiric antibiotic therapy is often broad until we have lab results and narrow the treatment accordingly.

Another cause of antibiotic overuse, particularly in the outpatient setting, is patient expectation. Patients or their parents frequently expect and request antibiotics of their providers, even when their infection is nonbacterial. For physicians in a busy clinic it’s sometimes easier to prescribe unneeded antibiotics because that’s what patients expect.

Finally, it’s important to remember that most antibiotics in the U.S. are not used in humans. Instead, they are used in the agricultural industry, often to promote growth or prevent infection in food animals.

Question: Why is antibacterial resistance considered a global health crisis?

Fowler:   Antibacterial resistance has the potential to affect every person on the planet. In May 2016, economist Jim O'Neill's now-famous report predicted that by 2050, without policies to stop its spread, antibacterial resistance would cause up to 10 million deaths annually and lead to a cumulative loss of global production of $100 trillion. As a result, WHO has identified antibacterial resistance as one of the world’s leading threats to human health.

Increasingly, antibiotics we have are not working. For example, I recently treated a patient at Duke who had developed osteomyelitis in a limb with a strain of Acinetobacter that was resistant to essentially all commercially available antibiotics.  Ultimately, we obtained FDA approval to treat the patient with an investigational antibiotic, and between that and multiple surgeries, the patient was able to avoid amputation.

And, the problem of antibacterial resistance is being made worse by the demise of the antibiotic pipeline. Just when we most need a robust portfolio of new antibiotic classes and compounds, pharmaceutical companies are abandoning the field of antibiotic development in droves. Since 2017, six companies have abandoned antibacterial development and three declared bankruptcy. Although it takes roughly the same cost (~ $1 billion) to develop a novel compound across any therapeutic area from pre-clinical discovery to FDA registration and commercialization, the pricing structure and prescribing patterns of antibiotics make it impossible for pharmaceutical companies to recoup those expenses. So for example, while drugs like antidepressants, or cholesterol-lowering agents, or antihypertensive drugs are generally used for years, most antibiotics are typically prescribed for only a few days. As a result, it’s much more difficult for the companies to be profitable with antibiotic development.

Against this backdrop, the NIH is responding to a public outcry from the medical community. That’s why it’s funding ARLG—to design, create, implement, and execute clinical research in antibiotic resistance.

Question: How will ARLG use the new federal funding to advance research?

Fowler: This renewal of our original grant will be focused on:

  • Gram-positive infection. The primary focus of this category is methicillin-resistant Staphylococcus aureus (MRSA).  It is one of the most common forms of drug-resistant bacteria.  The recent opioid epidemic has fueled rates of life-threatening MRSA endocarditis and bacteremia.
  • Gram-negative infection. Gram negative bacteria are the most important focus area for ARLG, and the most important pathogens in this category are the carbapenem-resistant Enterobacteriaceae (CRE). These bacteria are resistant to carbapenem, traditionally our last-resort class of antibiotics. CRE infections pose a growing threat to patients, especially in low- and middle-income countries.
  • Diagnostics. Diagnostics are also a key focus area for ARLG, because if we can more quickly identify what we’re treating and how best to treat it, we can avoid unnecessary antibiotic use altogether. An example of this is respiratory tract infections: There are between 30 and 50 million episodes of this in the U.S. annually. About 70% of these respiratory tract infections are viral, yet these infections are the largest indication for antibiotics—and they won’t help.

Duke researchers have played a significant role in ARLG’s development of a diagnostic platform that uses the host gene expression to differentiate whether a person is infected with a virus or bacteria. Because of the host immune response, the genes activated when someone is infected with bacteria are fundamentally different from the range of genes expressed when the same person is infected by a virus. We’re getting close to the prospect of a commercially available tool that can be used in EDs to identify the type of infection.

Question: What is ARLG’s vision to address this public health crisis?

Fowler: Our vision involves three broad areas:

  • Defining and informing providers on the best ways to use the antibiotics we have, because the numbers of new ones will progressively decline;
  • Improving diagnostic abilities, such as a program we’re working on to rapidly diagnose blood cultures to shorten the time needed to obtain accurate diagnostic data; and
  • Strengthening the pool of next-generation investigators. One casualty from the extinction of antibiotic development is a diminishing number of young scientists attracted to the field. Through fellowships, mentoring, and research, the best and brightest scientists and clinicians who are affiliated with ARLG are committed to addressing this critical issue.