[dropcap]T[/dropcap]he National Institutes of Health announced today that it has awarded a new six-year, $62 million federal grant to
Vance Fowler, MD, MHS, and a group of researchers at Duke and across the country that will allow them to form a national leadership group focused on antibacterial resistance.
Read the news announcement.
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Vance Fowler, MD, MHS[/caption]
Antibacterial resistance has been identified as one of the leading threats to human health worldwide because there is a dwindling pipeline of new antibiotics and, at the same time, bacterial resistance to drugs is growing, said Fowler, professor of medicine (Infectious Diseases) and molecular genetics and microbiology.
The National Institutes of Health has funded a number of efforts to address antibacterial resistance, some of which Duke has participated in.
This most recent effort, funded by the
National Institute of Allergy and Infectious Diseases, will establish an
Antibacterial Research Leadership Group (ARLG) that will be based at Duke. It will identify, prioritize, execute and publish research in antibacterial resistance. Fowler and Henry “Chip” Chambers, MD, professor of medicine at the University of California, San Francisco and chief of the Division of Infectious Diseases at San Francisco General Hospital, are the co-primary investigators on the grant and will lead the group.
Duke is uniquely qualified to house the ARLG, Fowler said, because of its track record as a home for other large research partnerships, the group of experts available to help lead the project and above all the
Duke Clinical Research Institute, which will work on clinical trials with ARLG researchers.
“You have to have the platform to conduct complex clinical trials over multiple countries, and perhaps more than any other institute in the country, the DCRI is poised to do that,” Fowler said. “The track record that DCRI brings to the table for NIH-funded networks is unprecedented."
The ARLG will act as a clearinghouse for research proposals that address one of four research areas in antibacterial resistance:
- gram-negative bacteria
- gram-positive bacteria
- stewardship and infection control, and
- devices and diagnostics.
Ideas for research projects will be submitted through a Web portal, which will be developed during the early stages of the grant. An idea about gram-negative bacteria, then, will undergo a review process within the gram-negative bacteria prioritization group. Each of the four areas will have an expert panel to review and prioritize proposals and decide which projects to fund and implement.
“Our goal is to undertake at least one pivotal trial for each of the four research areas, addressing key elements of antibacterial resistance,” Fowler said. “For example, there would be at least one transformative clinical trial in the area of gram-negative bacteria that would impact clinical medical care. That could include a new antibiotic, but it doesn’t limit our declaration of success to a new antibiotic. Identifying new ways to use existing antibiotics or better ways to use them is a win. As long as the ultimate deliverable benefits patient care, we would define that as a success.”
A complex problem
Antibacterial resistance is a problem with many facets. The ARLG is focusing on four main research areas to address it and improve patient care.
There are two types of resistant bacteria the ARLG will focus on. Fowler said gram-negative bacteria are a primary driver for researchers’ concern surrounding antibacterial resistance. This group of bacteria is particularly resistant to antibiotics and is associated with infections such as ventilator-associated pneumonia and meningitis, among others.
Gram-positive bacteria, on the other hand, are associated with antibiotic-resistant and highly contagious infections like methicillin-resistant Staphylococcus aureus and enterococci. Both are growing problems for hospitals.
Fowler identified stewardship and infection control as an area of focus because there is a growing need to protect increasingly precious antibiotic resources, he said. As bacteria have become resistant to antibiotics, it has become more important to prevent the spread of infection and to only use antibiotics when they are necessary.
Devices and diagnostics is the fourth research area of the grant and is particularly an important factor in patient care.
“Diagnosis can be difficult in the best of scenarios, but in the era of bacterial resistance, it is particularly challenging,” Fowler said. “It is made more challenging by the fact that the handful of drugs that retain utility against some of these bacteria are incredibly toxic, so there is potential for harm. One of the key approaches to undoing this Gordian knot is knowing what you are doing sooner.”
For an antibiotic that is not working, Fowler said, the challenge for physicians is knowing if that is because it was the wrong antibiotic or because the bacteria is not responding.
“The time to knowledge of what you’re actually treating can have a dual benefit of improving clinical care of that patient, and on a broader scale it can also serve to reduce the need for unnecessary antibiotic use,” he said.
Other areas of focus of the ARLG include pediatrics, pharmacokinetics and mentoring. Fowler said these areas were chosen because each adds a complicating layer to the overall problem of antibacterial resistance. He said fewer young investigators are coming into the field of antibacterial resistance and pathogenesis, so the ARLG includes a training component that will provide mentorship to the next generation of experts in the field.
“This project is complex because it is an attempt to respond to an incredibly complex problem, but there are some fundamental simplicities,” Fowler said. “There is a relatively small group that will be tasked with providing the leadership of this formidable group of investigators and scientists, and that is going to be housed at Duke Clinical Research Institute.”
Writing the grant
Fowler said he first heard about the possibility of funding for an antibiotic resistance network about a year before the RFA came out. That gave him time to consider how he’d respond when an RFA was posted. When that time came, he forged ahead.
“I felt this project needed to happen, and the convergence of the expertise that our leadership group was able to assemble, coupled with the expertise at the DCRI was a pretty powerful package,” Fowler said.
Fowler consulted with a number of people who provided leadership and ideas for the grant. He turned to
Daniel Benjamin, MD, PhD, MPH, professor of pediatrics and chair of the Pediatric Trials Network, housed at Duke Clinical Research Institute. Benjamin will work on the pediatrics piece of the project, and is, Fowler says, another asset that made Duke an attractive institutional candidate for this grant.
Fowler spent about six months writing the 550-page grant. Chambers, co-investigator on the grant, flew to Durham several times to discuss ideas, and Brenda Mickley, a business development associate with Duke Clinical Research Institute, worked with Fowler to prepare the grant and its supplemental materials.
“Brenda’s ability to help with these grants, the ideas that she can come up with, the infrastructure, the experiences that she’s had and that she brings forward from previous networks is an unbelievable asset that Duke has,” Fowler said.
Fowler used the
Center for HIV/AIDS Vaccine Immunology as a model for the ARLG. That group is an example of a response to an earlier medical challenge threatening human health that resulted in a number of discoveries that have led to success in treating, diagnosing and managing HIV/AIDS.
His approach to writing the grant was to come in early and stay late, he said. And planning also played a key role in his success.
“There was no point of gut-wrenching horror, when you are two-thirds through a grant and you’ve got two days before it’s due, and in many ways I’d like to think that our success with this grant reflected planning because many of the ideas came about through time and discussion,” Fowler said. “About halfway through, once I had a picture in my head of what the grant was going to look like, things felt reassuring because I knew where I was going.”
Now that the proposal has been funded by NIH, said Fowler, the real work begins.
The group already has a first round of ideas that have been vetted, and he hopes that research resulting from the grant will have some presence at 2014 scientific conferences.
“It’s a privilege to work on such a critically important national health issue with these resources; it is humbling,” Fowler said. “We just can’t have failure. We’ve got to win. This is just too important.”
Read Fowler's comments in a June 3, 2013, New York Times article about speeding up antibiotic development.
Fowler discusses the Antibacterial Research Leadership Group:
[youtube
http://www.youtube.com/watch?v=OUuo6mU95gk&w=560&h=315]
