Category Archives: Health and Policy

Faculty, Health and Policy, Research

Guest post: We need a super agenda to tackle superbugs

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This article was written by Moaven Razavi, Senior Research Associate in the Schneider Institutes for Health Policy at the Heller School of Brandeis University.  It was originally published on Heller News. 

Drug resistant infections are turning into the biggest challenge that modern health systems will face in the near future. Statistics and estimates are breathtaking: by 2050, such infections are estimated to kill 10 million people per year. To put it in context, this is higher than the current global burden of cancer.

Today, there are 700,000 cases of drug resistant infections annually— and this is not just a problem for developing nations. In Europe and the U.S., these infections are already killing more than 50,000 people each year. If our response remains status quo, we would see the death toll rise more than 10 times by 2050, and the economic cost would spiral to $100 trillion.

The true gravity of the threat is being seriously examined in Europe. In July 2014, British Prime Minister David Cameron warned that we are in danger of being “cast back into the dark ages of medicine” if we fail to act, and announced an internationally focused review to address the problem. The taskforce was charged with developing a package of actionable recommendations in response to antimicrobial resistance (AMR) by the summer of 2016.

In the United States, however, the reaction to the problem has been sporadic and limited in scope. In January 2015, Senators Orrin Hatch (R-Utah) and Michael Bennet (D-Colo.) reintroduced legislation to accelerate the approval of new antibiotics to address drug-resistant “superbugs.” The bill, known as the PATH Act, would allow the FDA to expedite approval processes for novel medications.

While the U.S. Senate bill is tied to the threat that AMR poses to U.S. troops returning from Iraq and Afghanistan, the biggest risk is to senior citizens due to two major factors: the need for more invasive surgeries such as major joint replacements and heart surgeries, and the weakened immune system due to aging. The elevated risk level due to AMR poses a serious challenge to solvency of the Medicare program.

Even though the threat to the Medicare population is looming, the extent of the problem is not well assessed. Globally, the reliable estimates are scarce, and there is considerable variation in the patterns of AMR. However, drug resistant infections are a problem that should concern every country regardless of geography or income. According to the European Centre for Disease Prevention and Control’s Antimicrobial Resistance Interactive Database, in 2013, 15 European countries saw more than 10 percent of their bloodstream Staphylococcus aureus infections caused by methicillin-resistant strains (MRSA), with several of these countries seeing resistance rates closer to 50 percent.

Recognizing the severity of this issue, I joined several of my colleagues from the Institute on Healthcare Systems in investigating just how severely AMR is threatening the Medicare population. The study, which was funded by GlaxoSmithKline Pharmaceuticals (GSK), focused on Staphylococcus aureus (S. aureus), which is by far the most dangerous superbug. We examined the incidence of S. aureus infections following 219,958 major surgical procedures for a representative 5 percent sample of Medicare beneficiaries from 2004 to 2007.

We found that 0.3 percent of these patients had S. aureus infections immediately following their surgical procedures, while 1.7 percent were hospitalized with S. aureus infections within 60 days and 2.3 percent were hospitalized with S. aureus infections within 180 days. S. aureus infections within 180 days were most prevalent following gastric or esophageal surgery, with 5.9 percent of patients affected, followed by hip surgery (2.3 percent), and coronary artery bypass graft surgery (1.9 percent).

Of patients hospitalized with a major infection during the first 180 days after surgery, 15 percent of those infections were due to S. aureus, 18 percent were other documented organisms, and no specific organism was reported in 67 percent. We also found that infections prolonged the length of hospitalization by 130 percent, and S. aureus infection was associated with a 42 percent excess risk of mortality.

Due to incomplete documentation of organisms in Medicare claims, these statistics may underestimate the true magnitude of S. aureus infection; nevertheless, this study found a higher rate of S. aureus infections than previous investigations.

I believe that tackling the superbug crisis requires a super-agenda—one that involves both public and private stakeholders who are informed by solid research in a timely manner. Such an agenda should not only include promotion of research and investment in new drugs and treatment modalities, but also prevention measures in all domains. The role of Medicare and commercial payers is also critical and can be incorporated through payment reforms, value based purchasing efforts, and introduction of relevant re-admission and complication quality indicators.

Moaven Razavi is the lead author of the study, Postoperative Staphylococcus aureus Infections in Medicare Beneficiaries, which was published in the November 2014 edition of PLoS ONE. Other researchers include Donald S. Shepard and William B. Stason from Heller, and Jose A. Suaya form GlaxoSmithKline. 

Biochemistry, Faculty, Health and Policy

Evolution may hold the key to rational drug design

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This is the story of Abl and Src — two nearly identical protein kinases whose evolution may hold the key to unlocking new, highly specific cancer drugs.

Abl and Src are bad guys — oncogenes with a predilection to cause cancer in humans, mainly chronic myeloid leukemia (CML) and colon cancer. These two proteins are separated by 146 amino acids, and one big difference — Abl is susceptible to the cancer drug Gleevec, while Src is not.

 

From left, Src and Abl proteins
From left, Src and Abl proteins

Dorothee Kern, professor of biochemistry and Howard Hughes Medical Institute investigator, unraveled the journey of these two proteins over one billion years of evolution, pinpointing the exact evolutionary shifts that caused Gleevec to bind well with one and poorly with the other. This new approach to researching enzymes and their binding sites may have a major impact on the development of rational drugs to fight cancer.

Dorothee Kern
Dorothee Kern

The findings were published in the journal Science and coauthored by Doug Theobald, professor of biochemistry, with Christopher Wilson, Roman Agafonov, Marc Hoemberger, Steffen Kutter, Jackson Halpin, Vanessa Buosi, Adelajda Zorba, Renee Otten and David Waterman.

When Gleevec hit the market in 2001, it was hailed as the magic bullet against cancer.

That’s because most cancer drugs fight a scorched-earth campaign — killing as many healthy cells as cancerous ones. But Gleevec is specifically attracted only to Abl, the enzyme in cancerous cells responsible for growth and reproduction. Gleevec binds with Abl, deactivating it and stopping the spread of cancer in its tracks.

time-glivec

Developing more drugs to work like Gleevec — known as rational drug design —could create therapies that target specific enzymes in many types of cancer. Unfortunately, scientists haven’t known why Gleevec is so picky, binding with Abl but not with its close cousin Src.

To solve this puzzle, Kern and her team turned back the evolutionary clock one billion years to find Abl and Src’s common ancestor, a primitive protein in yeast they dubbed ANC-AS. They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids and we were looking for the handful that dictate Gleevec specificity,” says Kern. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles and catalysis processes — creating Abl and Src. By following this progression, while testing the proteins’ affinity to Gleevec along the way, Kern and her team were able to whittle down the different amino acids from 146 to 15 responsible for Gleevec specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium — a process in which the protein transitions between two structures. The main difference between Abl and Src, when it comes to binding with Gleevec, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why Gleveec works on Abl — and doesn’t work on Src — researchers have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity is opened the door wider to designing good drugs,” says Kern. “Our results pave the way for a different approach to rational drug design.”

This research was supported by HHMI, the Office of Basic Energy Science, the U.S. Department of Energy Catalysis Science Program and grants from the National Institutes of Health.