Thomas Lodise, PharmD, PhD: Treatments and Strategies for Drug-Resistant Infections

After presenting new study data on treating drug-resistant infections such as Pseudomonas aeruginosa, Thomas Lodise, PharmD, PhD, sat down with MD Magazine^® to discuss strategies and methods to treat these challenging infections.

At the 2018 IDWeek Annual Meeting in San Francisco, CA, Lodise, a professor at the Albany College of Pharmacy and Health Sciences, discussed the importance of optimizing the risk stratification process for resistant infections as well as exploring combination therapy options for resistant infections. (Editor's Note: Transcript slightly modified for readability.)

MD Mag: With rising resistance, particularly in gram-negative infections, what do you see as the future in new treatments or strategies for drug-resistant infections?

Thomas Lodise PharmD, PhD: Clearly, we have all seen the reports from the US Centers for Disease Control and Prevention; infections are on the rise. WIth gram-negative infections, some are deemed urgent threats, some are serious threats, whether it be extended-spectrum beta-lactamases (ESBL), Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant Pseudomonas, or carbapenem-resistant Acinetobacter.

The threat is real, and we are seeing increasing rates of resistance among these common nosocomial or hospital-onset pathogens. The question is, what can we do as clinicians?

I think there are 2 things. First, I think we need to better risk stratify patients at risk for resistant infections. As part of that, we need to think about what pathogens they are at risk for because the risk factors for antibiotic-resistant pathogens are commonplace for all of them. In a given individual, and based on the loose local hospital epidemiology, we really should be risk stratifying our patient as: how likely is this an ESBL? How likely is this CRE? If [a patient is] mechanically ventilated, are we concerned about a carbapenem-resistant Acinetobacter or Pseudomonas?

Based on the probability of resistant infections, the goal is to pick a drug—or a combination of drugs—that has a higher likelihood of treating all [these pathogens].

When we think about treatment selection, particularly for gram-negative bugs, I think more and more that combination therapy is the rule and the reason why I say that is 2-fold. First, using 2 drugs increases the probability of getting it right the first time. I think we have ample data that show us that using 2 drugs, or even 3 drugs, has a higher probability of at least ensuring that the patient receives 1 active drug within the first 24 to 48 hours.

Second, many of these resistant gram-negative infections have high bacterial burdens, and so we are dealing with infections with resistant mutants at baseline and as we look at in vitro data, what we find is the best way to deliver antibiotics that have high bacterial killing and suppress emergence of resistance is through the use of combination therapy. Whether that is using 2 drugs in the same class or different class still remains to be defined, but I do believe there is an advantage.

[A caveat] is that people always ask, what is the clinical data to support the use of combination therapy? These data are derived from trials or meta-analyses and most do not really identify a major advantage of combination therapy.

We’re working on a paper right now, where we took a bit of a closer look at this and what we found is that, overall, there may not be an overall advantage of combination therapy; however, if you start looking at populations of patients—those who are critically ill, those in the intensive care units, those with pathogens that are less susceptible—you do see an advantage of using combination therapy, particularly with a beta-lactam and an aminoglycoside.

I think, to date, we have done trials that fail to demonstrate a demonstrable difference. I would argue many of those trials were not conducted in the patient population who would benefit most from combination therapy.

In in vitro studies particularly, and animal pharmacodynamic studies, there are compelling data that showed the true benefit of using combination therapy both for bacterial killing and resistant suppression.

When we start studying the treatments in sick patients who would benefit, we do see a clear benefit of combination therapy. What we’re seeing is less mortality, which is the hardest endpoint to show a difference on.