Can we ESKAPE the problem which may kill thousands of human beings over the next decades?
First, what is ESKAPE?
Initially coined by Dr. Louis Rice, ESKAPE is a handy acronym for six of the most common antibiotic-resistant pathogens. These are:
Enterococcus faecium
Staphlococcus aureus
Klebsiella pneumoniae
Acinetobacter baumanni
Pseudomonas aeruginosa
Enterbacter sp.
As Rice puts it,
The ESKAPE bugs are extraordinarily important, not only because they cause the lion’s share of nosocomial infections but also because they represent paradigms of pathogenesis, transmission, and resistance….Unfortunately, the ESKAPE bugs are increasingly prevalent in our hospitals and increasingly resistant to many of our antimicrobial agents.
As Rice points out, federally-funded research has made tremendous, positive impact on other infectious diseases, such as HIV/AIDS.
By comparison, the hundreds of millions of dollars spent on by the NIAID is diluted amongst basic reasearch in antibacterials, antifungals, antiparasitics, and antivirals. While all of these areas deserve research attention, one can argue that the problems associated with ESKAPE pathogens deserve even more attention.
Rice also points out that the biggest problem with ESKAPE resistance is that these pathogens are nosocomial. Nosocomial transmission of other infectious diseases, such as HIV, is thankfully rare.
But, the fact that ESKAPE pathogens are transmitted nosocomially suggests that hospitals need to do a better job with pathogen control, since current antibiotics are increasingly unlikely to be effective. Indeed, more people die from nosocomial MRSA infections in the US than HIV/AIDS and tuberculosis combined.
If there is one glimmer of hope, it’s that better infection control procedures and processes may help us ESKAPE from this problem.
Regardless, the prevalence data speak for themselves.
For example, hospitalized incident cases of methicillin-resistant Staphylococcus aureaus is about 480,000 cases in the US alone, exceeding 500,000 cases in a few short years. While this may seem like a low growth rate (<1%), we should take into account that this is one of many resistant microbes.
Multiplying this small growth rate over many different resistant species globally, and the problem becomes unquestionably significant. In fact, resistant MRSA infections account for 12% or more of all hospitalizations in the US alone, and growing (Klein, 2013).
This is a problem which is not unique to the US. For example, a study in Romania found that ESKAPE pathogens were commonly found in hospitals, including ventilators. In that study, 89% of nosocomial pneumonia cases were associated with ventilators, with 67% of these coming from the surgical ICU.
How difficult would it be for one of these patients/carriers to hop on a plant to New York? Not very…
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Why is this happening?
Smart Bugs – These and other pathogens continue to develop novel and clever mechanisms to resist antibiotics. For example, there are over a dozen different known Beta-lactamases found in clinically relevant pathogens.
Some bacteria modify antimicrobial binding sites to reduce affinity. This is the mechanism by which Enterococcus becomes resistant to vancomycin, for example. Efflux pumps, biofilms, and other mechanisms make pathogens increasingly resistant to our efforts to eradicate them using conventional antibiotics.
Shifting Commercial Environment – Our industry has done a marvelous job developing new antibiotics over the past 20-30 years. Drugs like ciprofloxacin, azithromycin, and others have cured countless infections and saved many lives.
However, these antibiotics are now largely generic, making it extraordinarily difficult to develop a novel antibiotic with demonstrated superiority to existing (generic) antibiotics. Regrettably, repeated prescribing (largely driven by patient demand) of now cheap antibiotics (coupled with use in the food animal industry) continues to contribute to this problem.
Geography – The resistance trends will not affect large swaths of the US/EU population for decades, making it difficult to get many pharmaceutical companies excited about these markets. Where the real problems will arise, such as parts of Africa and Asia, are not large, established markets for the industry.
This points to a rather confounding issue in our collective efforts to fight antibiotic resistance, namely, that resistance patterns differ across geographies. For example, by 2050, it is projected that deaths due to antibiotic resistant infections will exceed 700,000 in the US and Europe combined.
This is dwarfed by the projected 4.7 million deaths in Asia, and an additional 4.1 million deaths in Africa. Couple those rates with the ease of international travel, and global epidemics can be easily envisioned (O’Neil, 2014).
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Government Intervention
Fortunately, regulatory agencies are developing policies and new rules to encourage investment and drug development in antibiotics. For example, in 2012 the US Congress approved the Generating Antibiotics Incentives Now (GAIN) act.
Under GAIN, novel antibiotics developed against pathogens which pose a serious health threat will receive 5 years of market exclusivity after patent expiration. This creates an additional profit stream incentive for the developers of such products.
However, whether an extra 5 years on the tail end of a product life cycle is sufficient is an open question. This is especially true since regulators will likely require additional, post-approval studies, extensive monitoring, and other activities which will reduce innovator profitability relative to other investment opportunities.
The US Congress is also evaluating the Limited Population Antibacterial Drug (LPAD) approval process. This process would enable innovators to develop novel antibacterials and antifungals via smaller, faster clinical development process for narrow, well-defined populations. Adaptive design approaches are a logical feature for these development plans. Other regulatory proposals to accelerate development and/or add exclusivity are being assessed both in the US and Europe.
Conclusion
We have a unique and serious problem on our collective hands. We have a therapeutic area with clear unmet (and global) medical needs…needs which may involve significant mortality in the decades to come.
And yet, there is a lack of investment and interest in developing novel therapeutics to address this unmet need. Regulators are slowly adjusting to this new reality, but adding a few years of Revenue towards the end of the products natural life cycle is of limited value, as stronger competitors are likely to be on the market by the time these extra years begin.
There is an additional complexity in that resistance patterns in the US and the five major European markets can be different from those in Asia and other markets. Further, it is in these other markets where the greatest mortality may take place.
Combine that with the increased speed and ease of travel, and this morbidity and mortality can easily spread.
Ultimately, there are no easy answers here. In the absence of strong financial and regulatory incentives, the development of novel antibiotics will likely remain limited. This, in turn, means that licensing activity in this therapeutic area will likely remain modest for decades to come.