Initial Therapy for MDR Bacteria and Antibiotic Resistance

Jason Gallagher, PharmD, discusses the importance of appropriate initial therapy and the mechanism of resistance of multidrug-resistant bacteria.

Jason Gallagher, PharmD: In the treatment of infections, appropriate initial therapy is crucial. One of the problems that we have in infectious diseases is, at the time that we begin to treat a patient who is infected, we don’t know what it is that they’re infected with. So, choosing the correct option can be challenging in patients who are at risk for multidrug-resistant infections.

Many of the risk factors that put people at risk for multidrug-resistant infections are intrinsic and can’t be avoided; for example, age or comorbidities. But one of the actions we can take is to try to limit our prescribing of antibiotics to the shortest duration possible and the most narrow-spectrum drug possible.

Bacteria have many different ways in which they can become resistant to antibiotics. However, these all fall into 4 basic categories. First is decreased intake of the antibiotic, so decreased permeability of the bacterial membrane or cell wall preventing the antibiotic from getting in in the first place. Another is increased efflux. Bacteria can pump out antibiotics once they’ve reached the interior of the cell. They can produce enzymes that destroy the antibiotics, either by expressing those enzymes into their environment or by destroying the antibiotics once they reach the periplasmic space, and they can change their target site that the antibiotics bind to in the first place. Now, there are all these different mechanisms of antibiotic resistance, but they can be simplified into these 4 basic categories.

One of the challenging aspects of antibiotic resistance is bacteria are promiscuous, and they share extra chromosomal DNA with each other, primarily through plasmin exchange. So, once these genes exist on a plasma—the genes that encode for antibiotic resistance—not only does that individual bacteria have the ability to become resistant, but they can share that gene with other bacteria even between different species. So, once that bacterial resistance has evolved in 1 species, it can be exchanged between species to give that resistance to new bacteria.

Antibiotic resistance can be amplified through the administration of antibiotics. It sounds kind of counterintuitive in a way, but we give antibiotics, they kill off susceptible bacteria, and what does that leave to grow but resistant bacteria. An expression I like to think of is nature abhors a vacuum. So, if you have an area where previously susceptible bacteria exist after an antibiotic has been given to kill them, what’s left to grow are the resistant ones. And by this way, the use of antibiotics actually furthers resistance to those antibiotics.

The 21st Century Cures Act, passed by Congress and signed by President Obama several years ago, has several aspects to it that are important for antibiotic development. One of the most notable is the creation of a limited-population antibiotic pathway. Now, this sort of recognizes the issue with antibiotic development in that it is extremely difficult to develop antibiotics specifically for resistant infections. Because although they are becoming more common, they’re still relatively rare compared to susceptible infections. And, again, at the time that you begin therapy in someone with an infection, you do not know whether they have a resistant or susceptible infection. So, in clinical trials, the vast majority of patients will have susceptible ones, leading to a population that isn’t of interest to those of us who are treating people with highly resistant infections.

So, this pathway was created to try to create a way for smaller subsets of patients to make their way into studies in a way that gives us useful information about the treatment of resistant infections. Now, we’ll see how it goes. Some new drugs are testing this pathway out, and we’ll see whether it’s successful moving forward. They still will have to do large scale studies of the drug in a susceptible population. So, having a study, say, of 30 or 40 patients with a resistant infection like CRE (carbapenem-resistant Enterobacteriaceae) would probably not be enough for approval; it would require a study in a larger population that’s of less interest and, say, has susceptible infections in order to give enough safety data for a drug to be approved. But from my perspective, it is nice to see the FDA, and I’ll even give Congress credit, trying to come up with a pathway for these drugs to move through and get approved, creating data in their specific resistant population of interest, even if it is limited in number.