Multi-Drug Resistant Gram-Negative Bacteria and Novel Treatment Approaches - Episode 12
Thomas Lodise, PharmD, PhD: In future years, we have several things in development for the treatment of patients with multidrug-resistant bacteria, but there have been notable improvements in rapid diagnostics. And what we’ll be able to do is get better and better at identifying resistant pathogens earlier, and this will help us direct therapy. In addition, not only are we looking for pathogen identification, but there’s also technology being developed to get instantaneous antibiotic susceptibility data within the first day of therapy, if not sooner. So, again, I think this will be a breakthrough. When we think about our traditional methods, it usually takes us 3 to 4 days to identify a pathogen and what antibiotics we can use against it based on its susceptibility profile. There are things in development that would accelerate that within the first 12 hours.
Besides improvements in rapid diagnostics, I think we’re getting a bit better at looking at combination therapy for some of these multidrug-resistant bacteria. So, again, we think about multidrug-resistant bacteria, multiple mechanisms of resistance operating simultaneously. The thought that 1 drug is going to cover all bugs or even work against all resistance mechanisms within 1 organism is quite challenging. So, I think we’re getting better at assessing combinations and, hopefully, we will figure out ways to bring them forth for use in humans.
Currently, there’s not an FDA pathway for combination therapy, but we’re developing more sophisticated preclinical models to help us to identify optimal combinations for our patients with multidrug-resistant infections, and this would be a risk-versus-benefit type of situation. Beyond that, I think personalized medicine is always important, whether it be therapeutic drug monitoring in real time with agents beyond aminoglycosides and vancomycin or also thinking about how we do dosing across special populations. So, there has been an increased emphasis on that within the clinical development. I think in years past, we would pick a dose for patients with renal impairment or obesity, just based on empiricism, but now we’re becoming more sophisticated for dose selection in these specialized patient populations.
When thinking about patients who present with an infection, I think there should be a heightened awareness for the likelihood of having a multidrug-resistant infection. And really, when we stratify these patients, we should really think about those who present to the hospital with community-onset infections and where they were before—did they come from a long-term care facility, did they have a lot of prior antibiotic exposures? And in those individuals, there should be heightened awareness of a multidrug-resistant pathogen, and antibiotic selection should be appropriately broad to cover those likely resistant profiles.
Among those who develop infection within a hospital, again, we look for similar risk factors but really concentrate on how long they’ve been in the hospital, what is their time at risk, and how many prior antibiotics they received, particularly with gram-negative activity. And it’s in those individuals where we need to be aggressive up front. Again, we talk about antibiotic stewardship. The fundamental pillar of antibiotic stewardship is getting it right the first time. Time is of the essence, and what I do think about is, how long do you think a patient can survive and persist in the absence of effective antibiotics? If we fail to get it right the first time, there’s usually a 4- to 5-day lag before we get an active drug on board, so that initial decision making is of critical importance. We can always deescalate, we can always change, we can always discontinue therapy, but you can never go back in time and redo that initial therapy decision.
Transcript edited for clarity.