Gepotidacin’s Potential FDA Approval and Novel Mechanism Treating UTIs

Pharmacy Times^® interviewed Marilyn N. Bulloch, PharmD, BCPS, FCCM, SPP, associate clinical professor and director of strategic operations at the Harrison College of Pharmacy, Auburn University, on urinary tract infections (UTIs) and the current treatment landscape. Bulloch highlighted gepotidacin (GSK) and its potential approval, highlighting its novel mechanism of action that bypasses fluoroquinolone-resistant pathogens, making it a significant advancement in 20 years.

Pharmacy Times^®: Gepotidacin is currently being reviewed for FDA approval in the UTI space. What makes this treatment different than existing options?

Marilyn N. Bulloch, PharmD, BCPS, FCCM, SPP: First, I want to talk about what's similar, because I think that that's important. So, [gepotidacin (GSK)] is oral, which makes it very convenient for us, and it's twice a day, which is similar to 2 of the 3 first-line agents that we have, and it's only taken for 5 days which is very consistent with how long you take [nitrofurantoin] (Macrobid; Amneal Pharmaceuticals). So, I think that it really doesn't pose any additional administration burden for the patient. I think that that's going to be important to understand. And the dosing—like I said before—is not that different.

Where it is different...so, first, it is a completely different mechanism, which—for those of us who are in [the] infectious disease [space]—are very excited, we get very, very few novel mechanisms of actions in the 21st century. I think just having a new class and a new pharmacological way of working in itself, is exciting. So, if [gepotidacin is] approved, it would be the first new oral antibiotic for urinary tract infections (UTIs) approved in over 20 years. We've had IVs, but it's the first new oral agent. That's huge.

The biggest advantage is being able to cover pathogens that are current options...things that right now we would have to hospitalize [patients] for or get them aligned—if we were going to do treat them at home—to use IV. Mechanistically, it's similar to the fluoroquinolones...it circumvents fluoroquinolone-resistant mechanisms—which I think is big—and so, when we talk about being able to use it in those pathogens that other drugs don't cover, that includes pathogens that have developed resistance to fluoroquinolones. And I think that that's really a great advantage to it as well.

Pharmacy Times: Given concerns about antibiotic resistance, how might gepotidacin address this?

Bulloch: So, its biggest role—from everything I've seen—is really in patients with multi-drug persistent bacteria, particularly where, as I mentioned, other drugs can't [be] used. So, [gepotidacin] is not going to be a drug I'm going to recommend being reached for is, [for example,] empiric therapy or first-line [setting], at least, right now because I want to preserve it in its spectrum of activity. We are seeing a lot more of those multi-drug-resistant pathogens in our patients. So, for example...for the outpatient setting, E coli, Proteus, Klebsiella, those are very common pathogens that cause UTIs. We're seeing a lot more of those, around the country, we call extended-spectrum beta-lactamases (ESBLs), that have resistance to...penicillin [and] cephalosporins, and those ESBL infections are associated with recurrent infection, so getting [them again] and then worse outcomes as well. Right now, they're mostly treated empirically with carbapenems—which means we have to hospitalize you. And then sometimes, if it's uncomplicated, we can step you down to something like nitrofurantoin, but that's assuming your kidneys are good, and you can take nitrofurantoin. The coverage with this antibiotic [is that it] really seems to cover most of our uropathogens. As I mentioned before, including those that are resistant to fluoroquinolones, but also—and this is the exciting part—ones that might have resistance to nitrofurantoin, fosfomycin, and some ESBLs. Which, again, [is] very exciting because we have very few oral options for those multi-drug-resistant pathogens. We don't want to have to have somebody in the hospital or with an IV for the entire treatment.

Pharmacy Times: What should pharmacists be aware of regarding this treatment’s mechanism of action or possible adverse effects (AEs)?

Bulloch: So [gepotidacin]—and I got really excited—is a new class of type 2 topoisomerase inhibitors...but it's a mechanism that circumvents fluoroquinolone resistance, so, that's why it's not a fluoroquinolone. The topoisomerases are really important to causing DNA breaks in the novel binding it has. Basically, it's not the same as a fluoroquinoline, it works differently in terms of how it binds to bacteria. It selectively inhibits topoisomerase IV and the B-subunit of DNA gyrase to cause this high-level mediated single strand breaks.

In terms of side effects, the biggest AEs are gastrointestinal (GI) in nature, which is not surprising, we see that with a lot of oral antibiotics. From what I've been able to see from the studies, is administering it with food does seem to help lessen this, and I think that that's going to be important, because with so many medications—regardless of what type—if it makes you sick, people quit taking it, and we want you to finish your course. Giving [gepoptidacin] twice a day, not only is what they found to help with the UTI, but it also was found to reduce some of those GI AEs as well. And then the other thing is, one of the concerns we have with fluoroquinolones is that it can cause a prolongation of the QTC interval, which is a concern for arrhythmias. And it seems that the twice-a-day dosing with this drug—at least so far, we may be proven wrong later on—but so far, it looks by giving it twice a day, we minimize those maximum concentrations in the blood, and it lessens the potential for QTC prolongation. So that, again, would open it up to a group of patients that I can't use things like fluoroquinolones, whether because they already have a prolonged QTC or they're on other drugs that prolong the QTC, so it just gives us a lot more to work with.