How Merck is Staying Nimble in the Fight to Outsmart Superbugs

 

Merck’s commitment to antimicrobial stewardship (AMS) encompasses surveillance, R&D, and making the health policy case for a global approach to combating antimicrobial resistance.

 

By Barry Eisenstein, MD, Distinguished Physician, Antimicrobials, Merck

 

Infections in humans are nothing new. While the significance of the advancements in taking on infection control over the past century are hard to overstate, prevention and control of infectious disease will be one of the hottest areas of microbiology over the next decade. If Merck, and perhaps the entire healthcare community, has learned one thing from the bacteria that can infect us, it is that we need to continuously innovate to stay one step ahead of multidrug-resistant “superbugs” that the CDC has declared as serious – even urgent – public health threats.

There is a conundrum that every practicing physician has to face when treating a critically ill patient with an infection. Every passing hour prior to treatment increases the risk of sepsis and death, the urgency to treat in the hopes that it might be effective is balanced with the need to protect against antibiotic resistance, ensuring the antibiotic is not too broad, is used for the appropriate amount of time, and even that it is needed at all.

The more antibiotics are used, the more we lose power to use them in the future. And it’s for that reason the principles of antimicrobial stewardship (AMS) were developed. Making the right diagnosis, determining the cause of the infection, treating with the right product for the correct duration, and ultimately getting the patient to where they have recovered and can move on – in brief, the right antibiotic, at the right dose and duration, at the right time.

There are three important prongs to the AMS approach. First, stewardship involves surveillance and control on a local level, including diagnostics and algorithms that can help physicians make real-time decisions. Second, there must be a commitment to research and discovery to develop new antibiotics, as well as new ways to help antibiotics work better by disarming the resistant mechanisms that bacteria have masterfully developed. Finally, we know that it’s essential to work with government, regulators and public policy stakeholders to make a case for why infection control is so important before it becomes a crisis.

 

SMART Surveillance

We’ve long known that different microenvironments have different bacteria and different resistance patterns. This could be a hospital or nursing home, or even a broader community. Understanding the patterns of resistance is the first way that we can begin to learn, treat and even try to predict how microbes will behave.

The Merck-sponsored Study for Monitoring Antimicrobial Resistance Trends (SMART), has been tracking trends in antibiotic susceptibility of bacterial isolates collected from patients in different regions of the world since 2002. SMART looks at key microbes and antibiotics and compiles a picture, over time, of how organisms are adapting and responding to – or showing increasing signs of resistance to – treatment. It gives us a better understanding of the epidemiology of antibiotic resistance around the world.

The totality of this data can also help inform decisions for individuals, whereby learning about specific patient characteristics may inform treatment decisions including the right antibiotics for the right patient at the right time. Over time, we’ve found that such systems can lead directly into stewardship on a local level by helping practicing physicians make better informed decisions.

This is a major initiative for Merck, and the company has a very committed sense of leadership in this area.

 

R&D

Research and Development, naturally, is a critical component in the effort to prevent, control and contain the spread of infectious disease. Researchers contributed more than 30 scientific data presentations on Merck’s established and investigational infectious disease medicines and vaccines at the American Society for Microbiology’s ASM Microbe 2016 meeting in Boston last week.

For Merck, one of the most significant presentations at the meeting was the Phase II data surrounding relebactam, an investigational beta-lactamase inhibitor being studied in combination with imipenem, an antibiotic in the carbapenem class. Bacteria have evolved over time to create enzymes, including beta-lactamase, that essentially inactivate antibiotics. Relebactam can be seen as a potential anti-defense missile system, strapped onto the missile itself (the antibiotic), that inactivates the enzyme designed to disable the antibiotic.

The results of the Phase 2 non-inferiority trial showed that the combination was at least as effective as the carbapenem alone. So, why would we be excited about a new drug that works the same as an existing one? Because carbapenems are considered to be an important last-line agent against serious bacterial infections. The addition of the beta-lactamase inhibitor inactivates a potentially critical resistance mechanism, and can help preserve the efficacy of this important class of antibiotics.

Developing beta-lactamase is just one way that bacteria have evolved to defend themselves against antibiotics. Some bacteria have developed efflux pumps that provide the mechanism to expel noxious substances. Pseudomonas aeruginosa, the leading cause of nosocomial pneumonia, is one such bacteria that has developed this handy tool. It is therefore able to simply flush antibiotics out, rendering many traditional treatments ineffective.

Monoclonal antibodies represent another weapon in the arsenal against infectious disease. One investigational compound, bezlotoxumab, is not an antibiotic, but rather is designed to neutralize a key disease-causing toxin produced by Clostridium difficile (or C. diff), one of the three bacterial threats identified as urgent by the Centers for Disease Control and Prevention. C. diff is an intestinal infection paradoxically more common among people who have been exposed to antibiotics. While antibiotics are clearly crucial in fighting disease, bacterium like C. diff have opened our eyes in terms of their often deleterious effect on the microbiome – the intestinal flora that may play a greater role in our health and wellbeing than we may have appreciated previously.

One of the realizations that we’ve come to grips with is that there are 10 times the number of bacterial cells in our body than human cells. Over the past decade, we have learned that the gastrointestinal tract, where the vast bulk of our microbiome resides, is important in two major ways. First, colonization: as long as “good” bacteria are present, it’s harder for “bad” bacteria like C. diff to move in and flourish. Secondly, we are learning more – literally, every day – about how the microbiome is providing significant amounts of metabolic product back into the human body. Some of the product that we absorb may be important in ways that we can only now begin to understand.

The creation of new agents that don’t cause additional disruption to a healthy microbial flora, and do not select for increasing antimicrobial resistance, is what we think of as second generation “silver bullets.” The ideal is to kill the bacteria without collateral damage to the host. And that’s what a monoclonal antibody focused on a toxin is designed to do. Antibiotics for C. diff kill the bacteria, but may damage the gut microbiota, making a patient vulnerable to recurrent infection, which is a major issue with C. diff infection in particular.

 

Policy

Attacking infectious disease on a global level takes a multifaceted approach with stakeholders ranging from national governments to health systems, academia and manufacturers to physicians and individuals who comply with treatment. Beyond R&D, Merck’s commercial operations, medical affairs and policy personnel are working to align with the efforts of people working around the world to address the threat of antibiotic resistance.

The ultimate goal of antibiotic stewardship is to preserve antibiotics for as long as we can, helping to make the antibiotics as effective as possible and helping providers make the best decisions for the patient, for the environment and for the broader society. While cost is often a consideration, it’s not the only one, as inappropriate use of antibiotics can have far larger ramifications than the cost of treatment. This is also coupled with the realization that we won’t be able to perfectly preserve antibiotics forever, and we are constantly faced with the need to develop of new approaches to address infectious disease.