“Urgent, ubiquitous, and long-term, this is a problem with many dimensions, all of which need to be dealt with simultaneously.” With these words, Dr. Harvey Fineberg, President of the Institute of Medicine (IOM), summarized a riveting discussion Tuesday evening at the IOM.
“Antimicrobial Resistance: A Problem without Borders” was the focus of Tuesday’s Rosenthal Symposium, the latest in an escalating series of high-profile working groups, events and initiatives addressing AMR, in non-profit, corporate and academic sectors as well as government, within and across the United States and around the globe.
AMR’s human and economic costs are staggering. In the U.S. alone, the Centers for Disease Control and Prevention (CDC) estimates 23,000 deaths annually from drug-resistant bacterial infections, $20 billion in direct health care costs, and $35 billion in lost productivity.
The worst could be yet to come. Last week, the World Health Organization called AMR a threat “so serious that it threatens the achievements of modern medicine,” requiring action across all sectors of government and society. Echoing similar pronouncements by CDC Director Dr. Tom Frieden and others, the WHO noted that “a post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century.”
The contributing factors and thus the prescriptions to address this problem have remained consistent over three decades (speaker Dr. Stuart Levy co-founded the Alliance for the Prudent Use of Antibiotics in 1981). What has failed to occur is sufficient implementation and action. The consistent theme of the IOM symposium was that what we’ve been doing is not working; instead we need to think disruptively. Instead of a focus on “killing bugs,” which has inevitably resulted in significant “collateral damage” (including adverse changes to our microbiomes in addition to widespread antibiotic resistance), we would do much better with a vision of peaceful coexistence with microbes. After all, microbes have always lived with us, they greatly outnumber us (9 out of every 10 cells in our bodies are microbes), and the genes that enable their immunity to antibiotics predate those drugs by billions of years. Our primary goal should be to mitigate harm rather than to annihilate.
There was universal agreement that stewardship efforts to decrease the inappropriate use of current antibiotics (in both humans and animals), and a restructuring of financial incentives to reward appropriate use, are essential. However, as speaker Dr. Brad Spellberg noted, in some ways these efforts represent “Band-Aids.” They do not adequately address the key driver of excessive use – fear – and so must be accompanied by concerted efforts to develop rapid and reliable diagnostics.
Moreover, a new therapeutic paradigm is needed, to include complementary and alternative therapies, often targeting host as well as bug. Options could include probiotics; phages; immune modulators; harnessing ”healthy” bacteria within the microbiome to deal with offending pathogens; pharmaceuticals that “disarm” pathogens without necessarily killing them; and narrow-spectrum drugs targeted to a specific pathogen when killing is required. This means robust R&D is necessary, as are new regulatory pathways for medical product development and improvements to existing pathways.
Fortunately, the National Institute of Allergy and Infectious Diseases (NIAID) and the Food and Drug Administration (FDA) have been proactive in these areas over the last few years. NIAID has provided numerous opportunities for public-private partnerships through its Antibacterial Resistance Research Program, while FDA’s “Advancing Regulatory Science” aims to help speed innovation to promote both safety and availability of medical products and food. Although the drying up of the antibiotic pipeline has been well-reported, recent reports suggest that this pipeline is starting to recover, perhaps in part due to these programs. Recognizing the need for a more comprehensive approach to deal with a multifaceted problem, NIAID recently updated its strategic plan for AMR research, greatly expanding its focus in pursuit of innovative and complementary approaches (see http://www.niaid.nih.gov/topics/antimicrobialResistance/ Documents/ARstrategicplan2014.pdf).
Early this year, CSIS convened a group of experts to assess the current status of AMR. Even as it acknowledged the gravity of the situation, it was clear to the group that over the past year a "sea change" had occurred, with accelerating global interest, increased recognition that AMR is a serious transnational threat, and a number of positive, if nuanced, indications that progress has begun to occur on a number of fronts. In addition to the evidence that the antibiotic pipeline is starting to pick up, these signals include improved strategic communications, including the eminently readable overview of AMR published late in 2013 by the CDC (http://www.cdc.gov/drugresistance/threat-report-2013/), a greater understanding of the nature of this threat by the American health care community and the public, along with more willingness to think disruptively; FDA's willingness to step forward publicly (against significant opposition) against inappropriate antibiotic use in animals; a willingness by the White House and Congress to tackle these issues; and improvements in both quality and availability of surveillance data.
Antimicrobial resistance is an extremely serious problem, for which there is no “magic bullet.” An “all of the above” strategy is necessary, and a great deal remains to be done. However, I am encouraged – even cautiously optimistic – that we may have reached a tipping point. With AMR’s appearance as a key item on both the Global Health Security Agenda and the agenda of this month’s World Health Assembly, 2014 may indeed be the year the world community finally begins to deal effectively with the natural consequences of interactions between microbes and antibiotics in a human host.