Connecting the Bug With the Drug

An Interview with Dr. Evgeni V. Sokurenko, M.D., Ph.D

Bacteria are not only becoming more resistant to antibiotics, but they are also becoming more virulent. Clonal diagnostics is a field of research that improves our understanding of the evolutionary past, present, and future of bacteria in order to guide antibiotic prescriptions. This is a topic I recently had the opportunity to discuss with an expert from this field: Dr. Evgeni V. Sokurenko, M.D., PhD.

Dr. Sokurenko has an M.D. and Ph.D. in medical microbiology, and is a professor of microbiology at the University of Washington. There he is the director of a lab which studies the mechanisms of molecular adaptive evolution of genes in bacterial pathogens. He is also the founder and CEO of ID Genomics. ID Genomics combines epidemiological surveillance, bioinformatics, and molecular diagnostics to improve the accuracy of antibiotic prescriptions. One of ID Genomics’ products, CLoNeT™, is a diagnostic test that fingerprints bacterial DNA in under 45 minutes. Urgent-care clinical trials have shown that CLoNeT™ reduces the rate of antibiotic prescription errors for urinary tract infections (UTIs) from 25% to less than 3% (1).

With 50–60% of women developing at least one, and often more, UTIs in their lifetime (2), this technology will improve the likelihood of appropriate antibiotic prescriptions. This is also exciting for resistance mitigation, since UTIs are a leading contributor to antibiotic resistance across a variety of organisms.

Finally, Dr. Sokurenko is also the founder of ARMADA (Antibiotic Resistance Monitoring, Analysis and Diagnostics Alliance)(3). ARMADA is a non-profit organization aimed at creating a global biobank of bacterial pathogens. This collection will contain the genetic fingerprints and resistance profiles of hundreds of thousands of bacterial strains. ARMADA collaborates with the medical community, academic institutions, veterinarians, environmental scientists, and citizen advocates to build this crucial network.

Clonal Diagnostics

“My interest was always in the evolution of pathogenic bacteria, especially how small changes in bacteria can make them more virulent, with a main focus on E.coli that causes urinary tract infections. The E. coli that is the primary pathogen isolated from the urine of people who are complaining about urinary symptoms, it together with Staphylococcus aureus, comprise 80% of all bugs that are isolated in clinical microbiology laboratories. These two provide the bulk of resistance as we now know. They might not be the most dangerous of the resistant bugs, but they are certainly the most numerous, and quite a few of the strains are becoming dangerous.”

“While I was studying the virulence, I encountered this phenomenon that most of the bugs, specifically E.coli, and most of the other human pathogens, exist in the form of multiple closely related genetic families. You can think about it like crime families. When we were studying these crime families from the perspective of virulence, we collaborated for years with big clinical institutions including Harborview, the University of Washington, Seattle Children’s Hospital, and Kaiser Permanente. We collected tens of thousands of strains from patients and we genotyped them, splitting them into different genetically related groups. We found that these clonal groups have a very distinct resistance profile. We realized that if we know from what clonal group the bug is coming, we can use this information to improve patient treatment.”

Sniper Shots vs. Carpet Bombing

"If you can accumulate data about clonal groups retrospectively, you know enormous amounts of information about it. It’s sort of like creating a crime database, where criminals and their families are traced by a common fingerprint. So now whenever a bug is causing any kind of infection, you determine its fingerprint and pull out information from the crime database. Right now we are fighting the crime [bacterial infections] without the crime database. We are shooting in the dark. And in order to get your target by shooting in the dark you do a broad shooting [i.e. broad-spectrum antibiotics]. You are using machine guns instead of using a sniper. We call it carpet bombing. Broad-spectrum antibiotics are very powerful, and we are creating bugs that are highly resistant to them. Even worse, somehow they are becoming tougher to treat even if you are using the correct antibiotic - they have increased virulence.”

Why is microbial history so important to current resistance profiles?

“It’s a continuity, because the bugs that are dominating right now, they evolved from the bugs that emerged a long time ago. So you need to understand exactly how the evolution happened. To understand it [resistance] better, you need to trace the roots in the past.”

With the discovery of antibiotics occurring over 90 years ago, why do you think resistance tracking has only recently begun?

“In the past, resistance was not a big issue because we always had new antibiotics coming. But then we started to run out of new antibiotics, because you can only target so many mechanisms of the bugs. To develop new antibiotics, it takes an average of 10 years and one billion dollars. Fewer and fewer companies are going into that due to how fast bugs can adapt to new antibiotics. If you spend one billion dollars coming up with a new antibiotic, you need to recoup this money. How do you do it? One of two ways: You can sell it a lot at an accessible price. But then you have resistance that will emerge from the broad use of the new antibiotic, eventually rendering the medication obsolete.”

“The second way for you to recoup your investment is to sell it less often, but for a much higher price. The issue here is that for medication like antibiotics, many argue that you should not pay too much. So that’s why you cannot easily recoup the investment. Worse still, the bugs that are already resistant are becoming tougher and can more easily adapt to new antibiotics.”

Climate change adds an unknown variable to the complex issue of antimicrobial resistance, creating an opportunity for collaboration between microbial and climate scientists. Dr. Sokurenko discussed the potential role that climate change will play in the epidemiology of virulent pathogens.

“I often put a parallel between the rise of the resistance to the rise of global warming because, purely psychologically, there is a lot of resemblance. In how late we are recognizing the problem, realizing how to deal with it, denying that it is happening, continuing with what we were doing...there are lots and lots of similarities between climate change and the rise of resistance, purely from a social perspective. But to be more specific, how climate change can impact the bacterial resistance and virulence, it's a great question that I don't know if many people have tackled. But if you think about it from a couple perspectives, that lots of bugs, including Staph aureus and E. coli...prefer warm temperatures. So you could say that overall, increasing the environmental temperature can only favor their ability to survive in the environment. We can make these parallels, that shifting the non-human ecology certainly can shift the balance in transmission in the bugs. This is the main danger - you are starting to deal with a new variable that you absolutely do not want to introduce.”

In the coming decade, which research endeavors (such as improved

diagnostics, vaccine design, etc.) do you predict will have the biggest impact on mitigating antibiotic resistance?

“Diagnostics. Better clinical diagnostics for better, faster identification of the bugs, and better public environmental surveillance.”

In that same vein, which initiatives (such as public awareness campaigns, governmental policies, etc.) do you predict will have the biggest impact on promoting antimicrobial stewardship?

Here, regarding policies such as the 2017 FDA policy curbing antibiotic use in agriculture (4), Dr. Sokurenko brings up the important distinction between larger corporations and small, independent farmers trying to make a living.

“We often blame farmers for what doctors should be blamed. Antibiotic use in agriculture does contribute, but it is not the only or, in my opinion, the major contributor. Farmers are low hanging fruit for the blame. They are using antibiotics because they are trying to preserve their competitiveness to survive. This use does have to be stopped, but to blame them as the major cause? No. It is doctors.”

For example, Dr. Sokurenko states, “MRSA [Methicillin-Resistant Staphylococcus aureus] emerged in humans, it did not jump from animals. There is one small clonal group of MRSA that could be traced to animals, but they are about 10% of all the MRSA. We have confirmed that it emerged from humans. The same goes for E. coli, that they [resistant strains] emerged from and are being sustained by doctors overusing broad-spectrum antibiotics.”

How important is optimism in a field that often seems so bleak? What keeps you motivated?

“We are starting to respect bugs. We are starting to understand that we need to learn more about them. We are starting to stop treating them as a dark matter that we need to bomb, and we are starting to better understand how they evolved, what makes them spread, and what their reservoirs are. We are starting to understand that we need antibiotic stewardship, and that is starting to show some resolve. We are starting to pay attention to what is happening. So instead of panicking about what is happening with the dark matter, we are starting to shed some light into it. There is more funding starting to be available, more awareness about the issue, and that is what makes us feel better, that you know, we are starting to understand our enemy better. We are starting to respect it, and by respecting it you are starting to overcome them.”

References:

Antibiotic Awareness

Connecting the Bug With the Drug

An Interview with Dr. Evgeni V. Sokurenko, M.D., Ph.D