By Nick Guerin
The world is fast approaching a day when our fundamental medicines are rendered ineffective by antimicrobial resistance (AMR). AMR kills hundreds of thousands every year with a potential for millions more in the coming decades if nothing is done. One possible protection against AMR is the development of new medical countermeasures (MCMs). The strategies to find the best MCMs crisscross multiple organizations and functions, namely through either public or private initiatives. However, such divided efforts create limitations that might best be overcome through comprehensive public-private collaborative efforts.
What is AMR?
The Centers for Disease Control and Prevention (CDC) defines antimicrobial resistance as “the ability of microbes to resist the effects of drugs – that is, the germs are not killed, and their growth is not stopped.” Antibiotic use creates the inevitable spread of AMR; inadequate prescriptions, misuse, overuse, and other factors enable microbes that survive antibiotic use to spread their genetic traits (drug resistance) to later generations. In the United States, AMR causes 2 million infections and 23,000 deaths annually, while globally AMR death rates surpass 700,000 deaths each year. By 2050, the global rate could climb to 10 million annually if no MCMs (countermeasures) are successful in stemming the threat.
Past Approaches & Failures
The perils of AMR are well documented and understood, so what development and response capability should we expect to see? Governments and private organizations invest hundreds of millions of dollars and decades of man hours searching for the latest breakthrough against AMR. However, each has encountered limitations to their functional capabilities.
Private medical enterprises often find themselves at the forefront of medical innovation. The financial characteristics of antibiotic research motivate private sector AMR research and development. The current antibiotic market remains stocked with decades old drug developments or minute variations to existing antibiotics (see Figure 1).[i]
Despite the financial incentive, ambiguity over profit hinders antibiotic research in large pharmaceutical companies. For example, GlaxoSmithKline is closing in on producing one of the first new antibiotics in over thirty years. However, the company remains immensely uncertain over its ability to turn a profit due to repeated changes in AMR research demands, including greater requirements for broad-spectrum antibiotics. The economic uncertainty associated with developing new MCMs to combat AMR drove another major pharmaceutical company, AstraZeneca, out of the antibiotic market all together in 2016.
Further financial disincentives impact MCM efforts against Gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae (CRE), an AMR type public health officials label an issue of immediate concern. Only half of the roughly three dozen antibiotics in development by private initiatives are capable of fighting Gram-negative bacteria. Moreover, whereas the financial burden often hinders the largest of pharmaceutical companies, it outright prevents small biotech businesses from accumulating the necessary capabilities to confront these new biothreats.
The government prepares for the defense of the nation’s health from bioterrorism and natural outbreak events through the acquisition and stockpiling of MCMs. Unlike the private sector that acts based on profit seeking, the government can absorb the financial liabilities of broad funding approaches. The federal government coordinates MCM development and strategy through the interdepartmental Public Health Emergency Medical Countermeasures Enterprise (PHEMCE).
The PHEMCE primarily induces private MCM research through Project BioShield and the Biomedical Advanced Research and Development Authority (BARDA). Created in 2004, Project Bioshield sought to address the needs and concerns of the private sector for a stable and guaranteed market by creating artificial markets for MCM development. However, after BioShield failed to achieve success, the government organized the PHEMCE in 2006 with BARDA specifically founded to address BioShield’s limitations. A primary goal of BARDA is to bridge the “Valley of Death” (See Figure 2),[ii] the gap between pre-clinical development in NIH and the final procurement funding from BioShield. Specifically related to the realm of antibiotics, BARDA removed restrictions that prevented research and development into broad-spectrum antimicrobial solutions. Despite being a successful program overall, BARDA still has room for improvement. Small businesses are awarded most BARDA contracts yet they often lack the capabilities necessary for AMR development. As a result, BARDA is forced to implement repeated course corrections to sway large pharmaceutical companies into the high-risk world of AMR development.
Active collaboration portends the best solution to gaps in private and public forms of AMR MCM research. Possibly the most complete and far reaching public-private collaboration in the field of AMR research is the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator(CARB-X), a large-scale cooperative program between multiple government agencies and leading private national and international biotech, pharmaceutical, and advanced research enterprises. Specifically designed to counter the gaps of individualized private and government efforts to combat AMR, CARB-X focuses on preclinical discovery development of AMR MCMs by using government and private biopharmaceutical research partners to identify and accelerate key antimicrobial products through the risk-sodden safety and efficacy testing phases that traditional market incentives obstruct (See Figure 3 for CARB-X’s Process Snapshot).[iii]
BARDA’s partnership has already funded $30 million out of a possible 5-year, $250 million dollar contract, with accelerator partners like the AMR Centre funding $14 million out of a possible $100 million. In less than a year, CARB-X’s portfolio of nearly one dozen development partners created a pipeline of 11 products, four of which are already in the pre-clinical stage. One of those, Tetraphase Pharmaceuticals’ TP-6076 novel antibiotic, has already moved to Phase 1 studies (See Figure 4 for the CARB-X Pipeline).[iv] While much remains to be done, the success of a truly start to finish private-public collaborative effort demonstrates the progress such programs are cable of in the highly stagnant field of antibiotic development.
We only need to look to our European allies to see how comprehensive models of collaborative agreements create turnarounds in AMR pharmaceutical production. The European Union sponsors its own large-scale public-private AMR partnership, the New Drugs for Bad Bugs program. A €650 million investment has nearly tripled the number of large European pharmaceutical companies engaged in AMR research (from 4 to 11). Concrete results of the public-private collaborations include the first ever AMR phage therapy trials and the operation of AMR detection networks similar to those in the U.S.
AMR’s threat demands expedient solutions; the decade’s long wait for new antibiotics cannot continue. AMR poses one of the most difficult development requirements for these new MCMs, one that public and private sectors haven’t overcome on their own. Early progress in collaborative AMR solutions, both home and abroad, reveal that such efforts are the best way to fight the AMR threat.
 Centers for Disease Control and Prevention, “About Antimicrobial Resistance” https://www.cdc.gov/drugresistance/about.html
 CDC, “About Antimicrobial Resistance”
 Line Matthiessen, Richard Bergström, Shiva Dustdar, Pierre Meulien, and Ruxandra Draghia-Akli, “Increased Momentum in Antimicrobial Resistance Research,” The Lancet (British edition), (August 2016), pp. 865.
 Carolyn K. Shore and Allan Coukell, “Roadmap for Antibiotic Discovery,” Nature Microbiology, (May 2016), np. https://www-nature-com.mutex.gmu.edu/articles/nmicrobiol201683
 Stephanie Baker, “Why Superbugs Are Beating Big Pharma,” Bloomberg, (September 2016). https://www.bloomberg.com/news/articles/2016-09-21/inside-the-10-year-1-billion-battle-for-the-next-critical-antibiotic
 Natalie McGill, “As Antibiotic Resistance Rises, so do Research, Development.” The Nation’s Health, Vol. 46, Iss. 8 (October 2016), pp. 14.
 Robert Kadlec, “Renewing the Project BioShield Act What Has It Bought and Wrought?,” Center for New American Security, (January 2013), pp. 1-16. https://www.bio.org/articles/renewing-project-bioshield-act
 Jonathan Tucker, “Developing Medical Countermeasures: From BioShield to BARDA,” Drug Development Research, Vol. 70, Iss. 4 (June 2009), pp. 224–233.
 HHS Forges Unprecedented Partnership to Combat Antimicrobial Resistance,” Targeted News Service (July 2016)
 “HHS Forges Unprecedented Partnership”
 Matthiessen, Bergström, Dustdar, Meulien, & Draghia-Akli, “Increased Momentum,” pp. 865
[i] Figure 1: Timeline of Novel Antibiotic Discoveries
[ii] Figure 2: Valley of Death https://sigs.nih.gov/RACD/Lists/Calendar/Attachments/8/NIH_CC_19Nov2013.pptx
[iii] Figure 3: CARB-X Process http://www.carb-x.org/portfolio
[iv] Figure 4: CARB-X Product Pipeline http://www.carb-x.org/portfolio