Q & A—Antibiotic Resistance and the OVERCOME Trial

NIAID Now | May 06, 2019

Keith Kaye, M.D.

Credit: University of Michigan

Since the discovery of penicillin in 1928, antibiotics have been a cornerstone of modern medicine. However, bacteria are now developing resistance to many common antibiotics, which threatens their effectiveness and puts millions of lives at risk. This problem is so significant that the World Health Organization named antibiotic resistance as one of the top ten threats to global health in 2019. NIAID-supported researcher Dr. Keith Kaye is the Principal Investigator of the OVERCOME trial, which focuses on the best ways to use antibiotics in order to increase their lifespans as useful treatment options. NIAID Now spoke with Dr. Kaye about his research and how this trial is addressing the issue of antibiotic resistance. 

What do you see as the greatest priority in antibiotic resistance research?

Developing effective and safe treatments for drug-resistant Gram-negative pathogens is an important priority. Gram-negative pathogens, such as Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa, are a common cause of serious infection, particularly in hospitalized patients, and these infections are becoming progressively more resistant to the available antibiotics. In some instances, doctors rely on old antibiotics like colistin, which can have toxic side effects. Unfortunately, some Gram-negative infections are resistant to all available antibiotics. In these cases, physicians have to find new ways to use available drugs in combination in order to cure the infection.

What is the objective of the OVERCOME trial?

The OVERCOME trial is comparing the effectiveness of two treatment methods for Gram-negative infections: colistin alone (monotherapy) as opposed to colistin along with a carbapenem (combination therapy). In addition, we will investigate whether either treatment strategy is more likely to reduce the emergence of resistance to colistin.

There are two main issues with colistin. First, it can be toxic to the kidneys. Second, it is not easy to predict the dose of colistin needed to clear a particular infection. Even with these concerns, colistin is a last line of defense against many extensively drug-resistant Gram-negative infections. So, in this trial, we are hoping to learn more about this important antibiotic and how it may be synergistic with carbapenems.

There are many sites involved in this trial as well, including sites in Israel, Thailand and Taiwan. Why is it so critical to include international sites?

It is important to study pathogens where they occur the most, in order to get a large sample size and to gather as much data as possible for our trial. The drug-resistant Gram-negative infections that we’re studying are not as common in the United States as they are in other countries. We’ve been fortunate enough to work with a European clinical trials network called Combating Bacterial Resistance in Europe (COMBACTE). COMBACTE helped us survey hospitals in Europe to find those which use colistin, and those which have with the highest frequency of drug-resistant Gram-negative infections. With their assistance, we were able to add six more sites to our study in Greece, Italy and Bulgaria, and we plan to add a few more as well. With the sites we have established, it is likely that we’ll be able to enroll more patients, gather high-quality data, and complete our study in a timely manner.

What are your plans or goals for future studies?

I want to continue learning more about colistin. For instance, colistin is usually administered intravenously (through an IV). It is possible that an inhaled form could also be effective for treatment of pneumonia, while decreasing some of the side effects.  It would also be interesting to study different doses of colistin. It might be less toxic at a lower dose, and it could still be used in combination with a carbapenem to preserve its effectiveness.

Ultimately, my goal is to continue studying drug resistance. With NIAID support, we have established an international network of sites with many diverse investigators, which allows us to enroll the sickest patients with the most resistant infections. It wasn’t long ago that conducting a trial like this would have been viewed as impossible. However, there are still many other questions that need to be answered, and we need to continue to push the boundaries of biomedical research in order to successfully address the global issue of antibiotic resistance.

Learn more about the OVERCOME clinical trial.

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