The Antimicrobial Resistance Crisis – Reexamining the Incentives
Q&A with Dr. Emilio Emini
Emilio A. Emini, Ph.D. is the former CEO of the Bill & Melinda Gates Medical Research Institute. He joined the Institute in 2021 following a six-year tenure at the Bill & Melinda Gates Foundation as the Director of the Foundation’s Tuberculosis and HIV Programs. Dr. Emini joined that Foundation in 2015 following a greater than 30-year career in the biopharmaceutical industry during which he held multiple senior positions in anti-infectives and vaccine R&D. At the Merck Research Laboratories, from 1983 to 2004, Dr. Emini led the biological research that developed the first of the highly active antiretroviral therapies for HIV and led multiple research teams that participated in successful development of multiple vaccines, including for human papillomavirus and rotavirus. Following a two-year leave from the industry at the International AIDS Vaccine Initiative, Dr. Emini joined Wyeth/Pfizer as Senior Vice President of Vaccine R&D where he led the development of the Prevnar 13 vaccine for prevention of pneumococcal disease. Dr. Emini is a recipient of the Distinguished Alumnus Award from the Cornell University Graduate School of Medical Sciences. He is an elected Fellow of the American Academy of Microbiology, and the College of Physicians of Philadelphia. He is a former Trustee of the National Foundation for Infectious Diseases and served as a member of the National Preparedness & Response Science Board, an advisory committee to the US Secretary of Health and Human Services.
“Antimicrobial Resistance (AMR) occurs when bacteria, viruses, fungi and parasites no longer respond to antimicrobial medicines. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become difficult or impossible to treat, increasing the risk of disease spread, severe illness, disability and death.”
Tom Mahoney: Thank you, Dr. Emini, for joining me to discuss the challenges of antimicrobial resistance (AMR) to global public health and possible approaches we might take as a society to mitigate this growing threat. The Lancet estimated that in 2019 almost 5 million deaths were associated with resistant bacterial infections, and by 2050 per the UN, such syndromes could cause up to 10 million deaths globally, rivaling cancer in annual mortality burden. Help us frame the discussion by explaining what AMR is, why it’s an issue of high concern for public health professionals, and current and long-term consequences for US and global healthcare?
Dr. Emilio Emini: Antimicrobial resistance refers to the loss of activity of antimicrobial agents by evolutionary biological defense mechanisms in specific organisms. As you know, most antimicrobial agents used today were developed after World War II. Control of infectious diseases by such agents, as well as by vaccines and the provision of clean water, has probably had the greatest positive impact on global public health. Since World War II, unfortunately, we have seen a growing number of organisms, previously susceptible to treatment by antimicrobial agents developed to combat them, that have lost such susceptibility. For many of these resistant organisms, it is increasingly difficult to find replacement antimicrobial agents that are effective.
The global impact you just noted is not trivial. In the US alone, in recent US Centers for Disease Control and Prevention (CDC) data I've seen, each year there are over 2.8 million US cases and 35,000 deaths associated with AMR. And in the US alone, CDC estimates AMR has added over $4.6 billion to healthcare costs annually.
Mahoney: Given that development of anti-infective agents proved to be a key reason, as you indicated, for control of infectious diseases, particularly since World War II, why is the impetus for development of new agents no longer present? What has changed, as the need is clearly still present?
Dr. Emini: What has changed is not so much the impetus. The need is clearly there to develop novel antimicrobial agents. So where is the problem? Most of the successful antimicrobial agents that have been developed, certainly in latter years, came from large global pharmaceutical companies, simply because there is considerable expertise required both from a clinical development and discovery perspective. As you know, most antimicrobial agents are small molecules; the kind of medicinal chemistry and biology work these compounds require is substantial. This development expertise sits primarily in large biopharma companies.
Unfortunately, the economic circumstances for development of novel antimicrobial agents are difficult. I think one of the biggest challenges, other than the investment cost – which is high, as for any novel pharmaceutical – is the perception that the end market for these agents is limited from a commercial perspective. If you have an organism that has developed resistance to existing antimicrobial agents and you make the large investment to develop a novel effective agent, it is intuitive that one should not use the agent until it is absolutely required. This constraint limits the end market and negatively impacts the standard calculation of economic risk versus benefit. So, if the market is limited, the ability to recoup the investment in any reasonable time period will be a significant challenge. Of course, the potential market for novel antimicrobials to address AMR, at least in terms of numbers, is very large in global underprivileged populations. Unfortunately, from a financial commercial perspective, these are not attractive markets given (in many cases) the lack of appropriate healthcare delivery systems and the inability to command a high price for the novel agent.
Mahoney: Withholding the antibiotics from the market, so to speak, until they're most needed goes to the CDC's Core Elements of Antibiotic Stewardship. Please comment.
Dr. Emini: The CDC's Core Elements are clearly very important. One needs to use antimicrobial agents judiciously as opposed to broadly without a good assessment as to whether the agents are even active against the particular infection one is trying to deal with. Broad indiscriminate use drives antimicrobial resistance, so new therapeutics should be used sparingly and appropriately. In fact, in the absence of novel agents, the biggest impact in controlling AMR comes from using available countermeasures judiciously. It is ironic that appropriate stewardship disincentivizes the development of novel agents.
Mahoney: The National Institutes of Health (NIH) and other such agencies support basic research to understand and address AMR. Why has this not translated into a larger number of novel effective agents?
Dr. Emini: The funding NIH has placed into basic research is clearly important to help find novel targets for antimicrobial agents and conduct basic research on potentially usable agents against those targets. But this just addresses the front-end of the broader research and development effort required. Most of the associated investment expense occurs in the development phase, including the undertaking of clinical studies and in generating processes for making novel molecules at scale – those investments usually run into the hundreds of millions of dollars. These are the investments that developers of such agents, whether startups or large pharmaceutical organizations considering whether to develop them, must look at. The front-end research is important, but the middle development part is where the expense and investment become quite large.
Mahoney: So, whether in the foundational biological discovery research phase for these novel agents, or the time consuming and expensive clinical development phase, has there been a loss of scientific talent in the industry focused in this area, and what that does that mean going forward?
Dr. Emini: There's a mantra in the pharmaceutical industry that there's only one way to learn how to do pharmaceutical research and development and that is to do pharmaceutical research and development! Therefore, a considerable number of people who work in different aspects of development of novel pharmaceutical agents obtain their training in industry, and there is certainly an “anti-infectives field”. There’s an established knowledge base with respect to the full end-to-end requirements for research and development in this field. Given the pull back we’ve seen in industry’s interest, it follows that there will eventually be a loss of experience and essential knowledge. One of my biggest concerns is that when this “brain drain” becomes sufficiently acute, the base of experienced scientists involved in the development of novel anti-infective agents just simply won't be there. I do think the critical mass of human capital will come back when and if the investments return, but it will take time. And when that time comes there may be some ramp up required to build back that base of relevant experience.
Mahoney: Back to government intervention, the PASTEUR Act, directed to developing antimicrobial agents targeting drug resistant infections, appears to be stalled in Congress. Proponents say the bill can have a beneficial impact on bringing new antibiotics to market. How effective would this legislation be and the industry support model it represents?
Dr. Emini: The focus of this kind of legislation is to provide a commercial market on the back end, with the US government saying in effect, “if you make it, I'll buy it”, obviously under defined parameters. So, you've got NIH funding supporting the “front end” of the research and development continuum and, if the PASTEUR Act should pass, you've got the potential for supporting the “back end” by guaranteeing a predefined commercial market. However, the risk associated with the large development cost remains. This development and production scale-up phase is where the investment of hundreds of millions of dollars sits, which would still have to be covered by the developing biopharma organizations.
Mahoney: Focusing on the science, what are some of the most concerning strains of multi-drug resistant (MDR) bacteria? What are the more promising tools being evaluated to address such MDR infections?
Dr. Emini: The leading organisms currently losing susceptibility to existing or at least more commonly used antibiotics include, for example, Vancomycin-resistant Enterococci, drug-resistant Pseudomonas, Carbapenem-resistant Acinetobacter and one everyone is familiar with, methicillin-resistant Staphylococcus aureus (MRSA). The complete list is much longer. Then there are invasive fungi such as Candida and others. These major MDR (multi-drug resistant) organisms cause what are often called “end of life” infections, occurring in individuals who are highly debilitated or have poor immune responses, often older persons in hospital settings. These demographics are getting larger, not simply due to an aging population, but by increasing use of immunosuppressive agents as well as the prevalence of various other compromised immunity conditions. When infections with resistant organisms occur, we have a very limited repertoire, if any, of antimicrobial agents to deal with them. Community acquired or CA-MRSA is a very good example – a completely different organism from hospital acquired or HA-MRSA which can be deadly depending on circumstances of acquisition, even in very young people, and can very quickly progress absent a suitable intervention. Of particular concern are sexually transmitted infections such as Gonorrhea, for which even though there are novel effective agents right now, we don’t know how long these will be efficacious until even newer agents will be required globally. Finally, there's drug resistant Tuberculosis (TB), an enormous global problem, with huge patient numbers. There's a significant effort, supported by the Bill & Melinda Gates Foundation and other public health-focused organizations, to develop novel therapeutic agents to effectively treat multi-drug resistant TB, but the challenge is substantial, and the investment required is equivalently substantial.
Mahoney: What about some other approaches besides traditional small molecule anti-infectives, with vaccines being perhaps the foremost example?
Dr. Emini: Indeed, another mantra often used is that “it’s always better to prevent an infection than to treat it,” for obvious reasons. So, there has been increasing consideration towards expanding development and use of vaccines to prevent infections with drug-resistant organisms as it's getting so much more difficult to treat them. Besides biological challenges, development of a vaccine is, if anything, even more expensive and logistically difficult than for an anti-infective agent, in part because vaccines are typically used in healthy people, thus safety becomes another important consideration in the medical risk benefit calculation. Vaccines clearly need to be pursued but the investment needed will still be large.
The other ways to try to deal with the drug-resistant issue are good antibiotic stewardship and control of infectious agents’ transmission. Both have had a notable impact where these efforts have been appropriately implemented.
Mahoney: We’ve talked about therapeutics and vaccines. What about diagnostics?
Dr. Emini: Diagnostics are very important. Lack of appropriate and rapid diagnostics is one of the biggest challenges facing antibiotic stewardship. The intent is to avoid the use of antibiotics that are not fully effective for the infection being treated, thereby driving the development of additional resistance or even resistance among bystander organisms exposed to the antibiotic. Thus, ability to rapidly diagnose is critical: first, to identify the specific organism responsible for the infection at hand; and second, to determine in real time the microbe’s antibiotic susceptibility. Speed is critical, as recognized by the CDC who have pushed very hard in recent years to foster the development of rapid diagnostics.
Mahoney: Of course, development of any of these interventions, whether therapeutics, vaccines or diagnostics, invokes the same basic investment calculus that has been challenging for the pharmaceutical industry.
Dr. Emini: Correct. An important consideration in that investment calculus, which I didn't mention earlier, is that investing in development of a novel anti-infective agent to deal with a very specific or very important organism for which there is a fair amount of antimicrobial resistance can, in fact, be a reasonable economic decision. If you make the investment and successfully develop the agent, you will have a market, maybe not as large as you would like in the end, but given enough time, you can more than recover the product development cost. The challenge, however, is that biopharma companies do not make large investment decisions in a vacuum, looking only at a single product development program. Rather a program is assessed across the company’s overall product development portfolio. When viewed in a product portfolio or pipeline context, back-end commercial opportunities are generally substantially greater for noninfectious indications. A novel oncology treatment, for example, or correcting a genetic disease, are examples that offer relatively unconstrained commercial opportunities compared with a novel anti-infective product whose use will be judicious and limited. It stands to reason that from a commercial risk and benefit perspective, the former are preferred opportunities.
Mahoney: So, this is perhaps where a social impact component of the investment calculus somehow needs to be brought into the equation.
Dr. Emini: This is exactly where social impact opportunity needs to be brought to bear because risk-benefit calculations are obviously performed differently in a social impact context. The “commercial” opportunity is primarily considered from public burden of disease and epidemic preparedness standpoints. In this setting, the purely financial return comparisons to portfolio programs are not relevant. Even having a social impact investment component in the overall investment risk and financial return analysis is critical to support development of novel anti-infective agents. Without this component the investment calculus will remain challenging.
Mahoney: How would you rate the current state of US preparedness for major outbreaks of MDR infections, whether bacterial or fungal?
Dr. Emini: Or even a viral infection. We saw how unprepared we were for COVID. We are equivalently poorly prepared for these other pathogens. The COVID pandemic was a situation where the development of a vaccine in record time was reflective of the virus’ biology and previous knowledge. But when one is dealing with complex organisms, like pathogenic bacteria and fungi, the development of vaccines likely will be more difficult, and the development of novel anti-infective agents will be challenging. These interventions are not going to be available in a few months’ time. Within a few years we may have a new pandemic on our hands – then what do we do? We just aren’t ready. One can only get ready prospectively, not at the time an outbreak occurs. I'm afraid to say our ability to think about this proactively as a society has been disappointingly limited.
Mahoney: Looking globally, the inappropriate and excessive use of anti-infectives in low- and middle-income countries is a significant challenge that can only be addressed by improving healthcare delivery in these populations. This is likely a very much larger issue than any we've covered so far, but do you have any perspective on it?
Dr. Emini: You focus on a very important issue. In the end, treatment of any disease, whether infectious or not, is extremely difficult absent an effective primary healthcare delivery system. The uncontrolled and inappropriate use of anti-infective agents is much more likely to occur where primary healthcare delivery systems do not exist or do not function well, where there is lax regulation when it comes to availability of antimicrobial agents, and where effective rapid diagnostic methods are not readily available. The result is often an increase in antimicrobial resistance and the loss of effective treatment options.
Mahoney: On behalf of our Social Impact Review audience, thank you Dr. Emini for your distinguished leadership in thought and action addressing this vital problem, to bring the promise of a safer future for humanity by getting in front of the AMR menace now. Do you have any closing thoughts?
Dr. Emini: As we’ve discussed, countering AMR is an area that is particularly suited to the social investment concept and in which the impact will be significant. There are few other alternatives when it comes to the calculus around investment. Social impact investment is needed to cover the expense, time and effort required for early research through to full development of next generation anti-infective therapies. I just hope that the investment doesn’t come too late.
About the Author:
Tom Mahoney is a Senior Fellow at the Harvard Advanced Leadership Initiative focused on building a novel global venture philanthropy accelerator to catalyze investment in development of breakthrough vaccines, therapeutics and diagnostics for infectious diseases. A career investment banker, technology entrepreneur and asset management senior executive, Tom is a member of the Strategic Advisory Board of EdJen BioTech, LLC, a developer of novel viral vaccines, a Founding Sponsor of the Harvard Alumni Entrepreneurs Accelerator, and a member of the Venture Board of the Harvard HealthLab Accelerators, the Massachusetts Consortium on Pathogen Readiness, and the Council on Foreign Relations.
This Q&A has been edited for length and clarity.