A "Report to the President on Combating Antibiotic Resistance," based on recommendations of the President's Council of Advisors on Science and Technology (PCAST), was submitted in September 2014. PCAST is an advisory group of scientists and engineers appointed by the President to provide advice relevant to policy in the domain of science, technology, and innovation.
The following is a summary of this eight-part proposal to deal with the crisis of antibiotic resistance in response to the President's request, along with my comments. This follows the generalized recognition of the rapid evolution of bacterial resistance attributed to the striking paucity of new antibiotics and massive overuse of existing agents.
The proposal is for federal spending of $450 million, a priority and budget presumably justified by the estimated cost of antibiotic resistance in human lives (23,000 deaths/year in the United States) and dollars ($55-$70 billion in healthcare costs).
I believe that the plan is very government-centric, with the appointment of a White House Director for National Antibiotic Resistance and major tasks assigned to the Centers for Disease Control and Prevention, the Department of Defense, the US Department of Agriculture (USDA), the Department of Veterans Affairs, the National Institutes of Health (NIH), and the Centers for Medicare & Medicaid Services (CMS).
The goal of the surveillance system is to systematically collect data from communities and healthcare settings throughout the United States, focusing on relevant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenemase-producing Enterobacteriaceae. This will be accompanied by complete genomic analysis to facilitate strain identity and identify transmission patterns.
The surveillance system will link with other relevant data sources (including surveillance systems in other countries) and with surveillance in agriculture, and results will be publicly available. The Health and Human Services allocation for this activity is $90 million, to pay for 60 grants to the states. The total cost of establishing and maintaining this system is $190 million annually.
From my perspective, this is an exciting part of the overall proposal in that it captures the long-awaited need for US data to define the magnitude, geography, and trajectory of microbial resistance throughout the country and internationally. The European Union has done this for 26 countries for 15 years with impressive results. An exciting addition in the US plan is genomic analyses to provide critical information about transmission patterns and sources.
The intent here is to "find new ways to stay ahead." Examples of new methods are drugs to inactivate beta-lactamases, new narrow-spectrum agents (combined with molecular diagnostics), drugs to attack virulence factors instead of the microbial source, methods to enhance the immune response, development of new vaccines and probiotics, provision of a library of relevant novel compounds for developing new antibiotics, developing alternatives to antibiotics for growth promotion in agriculture, and a better understanding of the basic science of resistance. The budget suggested for this component is $150 million/year.
My thought—it is hard to be critical of this effort but also easy to be skeptical.
This aim of this effort is to support a clinical trials network to test new antimicrobial agents and diagnostics in a fashion that is faster, cheaper, and more efficient compared with the current system. This will involve an infrastructure of relevant financial, logistical, and regulatory agencies, including the US Food and Drug Administration (FDA). The budget allocation for this component is $25 million annually.
I believe that the need for this network and a new model for antibiotic approval is clear. The trial network is already developed, reviewed, and established as the NIH Antibiotic Resistance Leadership Group (ARLG) and is presumably similar to the AIDS Clinical Trials Group that has proven so effective in guiding HIV care using scientific leaders and a trial network of qualified clinical sites. This new network has already undergone peer review.
Commercial Development of New Antibiotics
The problem addressed here is the paucity of new antibiotic development, based on economics. The unique features of these drugs are that they are taken for short periods, standard prices of antibiotics are low compared with other drug categories, clinicians are often intimidated about using them, and they are the only class of drugs that loses effectiveness with continued use. This is simply a bad financial investment for the pharmaceutical industry, and most large companies have left the field. In fact, there has not been a new class of antimicrobials for gram-negative bacilli in four decades.
This proposal provides economic incentives to industry, recognizing that they have the unique history and talent to take on this challenge. However, as one pharmaceutical company executive put it: "We are not in business to go out of business." The Biomedical Advanced Research and Development Authority has been very active in supporting this work now that bioterrorism is less worrisome. The goal will be to provide support for new antibiotic development that includes ensuring "substantially higher reimbursement" from CMS, patent extension, and special pathways to expedite FDA review.
My take—this is a needed facet in the antibiotic resistance challenge, but the major problem is the extremely high cost of new drug development (now estimated at $1.2-$1.8 billion per agent) combined with the continuing need to ensure safety and effectiveness.
Smart use of current antibiotics is facilitated by making an antibiotic stewardship program a requirement for CMS funding as a "condition of payment." The components are diverse, but current practice most often strives to reduce cost rather than encourage smart use. The stewardship program is to be applied in all relevant healthcare settings including hospitals, chronic care facilities, and outpatient facilities.
I believe that stewardship efforts are very important to the infectious diseases community because they are viewed as critical to reduce unnecessary use. However, "smart use" is not well defined, audited, or paid. The stewardship "bundle" presumably includes the use of the newer diagnostics, short-course antibiotics, procalcitonin guidance, intravenous-to-oral transition, review for antibiotic redundancy, implementing automatic stop orders, guideline-driven antibiotic use, infection prevention, and outpatient intravenous therapy services, among other things. However, none of these strategies are currently well-defined.
Animal Agriculture Stewardship
Use of antibiotics for growth promotion and infection prevention has been a highly controversial issue, and heavy responsibility for this area is assigned to the FDA and USDA.
While this issue has been fought rigorously by the agriculture lobby, it is clear that antibiotic use in agriculture accounts for 80% of the total consumption of antibiotics in the United States, and resistance genes in patients can be traced to "the farm." However, the magnitude of this problem and its consequences on the cost of meat are less clear.
The proposed collaboration includes the World Health Organization and the European Union to "strengthen surveillance of antibiotic resistance around the globe."
My perspective is that resistance is a global crisis, so this networking of systems makes much sense, especially given the extraordinary diversity of policies and, for example, the well-tracked international march of the New Delhi carbapenem-resistant strain of Klebsiella pneumoniae, the MRSA-USA300 strain, and the NAP-1 strain of Clostridium difficile.
Of special interest are the lessons from the European Union, including extensive reports with country-specific data for major pathogens (see Antimicrobial resistance interactive database [EARS-Net]), Europe-wide programs such as "e-Bug," and an annual antibiotic day, to encourage dialogue about the topic, research budget and priorities, and public reporting of all data on the Internet.
These methods have not been evaluated and their impact is unknown. Most important, however, is that scientists design the methods, the analysis, and the interventions, and they base it on great data.
The Overall Plan
The plan is late, considering that antibiotic resistance has been recognized as a looming health crisis for more than a decade. Nevertheless, the recognition of antibiotic resistance as a major health threat, the allocation of substantial resources to address it, and an aggressive eight-point plan of attack are great to see.
Possibly worrisome is the central role of government, with a pharmaceutical system needed for drug development and a healthcare system needed for implementation, both of which are largely private. This approach contrasts with the European Union model that is funded by the governments of participating countries, but the agenda is driven by leading scientists. Nevertheless, the US government is the largest payer for healthcare in the United States, and this control has strongly influenced other health issues in a favorable way.
The status of the plan is unclear. It has been presented to President Obama at his request, and the plan had input from diverse and reliable sources. What is the way forward in terms of need for Congressional review of the plan and/or the budget? No review processes, priority allocation for the eight facets, or timelines for any component are yet provided. Nevertheless, right now this is the brightest light at the end of the antibiotic resistance tunnel for the United States.
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Cite this: The President's Report on Antibiotic Resistance: What Does It Mean to Clinicians? - Medscape - Nov 14, 2014.