Ryan Shields, PharmD, MS, provides insight on the current therapy and provides an overview of the newer agents.
Ryan Shields, PharmD, MS: One of the first new agents approved was ceftazidime/avibactam in 2015. Now, ceftazidime is in a cephalosporin that we’ve been using to treat gram-negative infections for a number of years. The new novel component here is avibactam. Avibactam is a novel agent because it is a beta-lactamase inhibitor that inhibits carbapenemases. Specifically it inhibits KPCs (Klebsiella pneumoniae carbapenemases), the predominant cause of carbapenem resistance among Enterobacteriaceae in the United States.
Because of this novel mechanism of inhibiting KPCs, many centers have positioned ceftazidime/avibactam as the frontline drug to treat CRE infections. In our clinical experience at the University of Pittsburgh, where we’ve positioned the agent as the frontline drug for CRE infections, we found that the drug is largely efficacious across many types of CRE infections. But even more importantly, compared to what we were doing previously with salvage agents, like aminoglycosides and polymyxins, treatment with ceftazidime/avibactam is associated with improved responses among our patients. Not only are patient responses better, but the drug is much better tolerated than older agents, like the polymyxins and aminoglycosides.
Now, since, our findings have been corroborated by multicenter studies in the literature that show ceftazidime/avibactam really is associated with better outcomes for your patient than these older salvage agents. As clinical experience continues to grow with this agent, it’s important to address a few outstanding questions, one of which is, how do we best position this agent as either monotherapy for CRE infections or perhaps in combination? One of the challenges with using ceftazidime/avibactam is that among a minority of patients, resistance has emerged to this agent following treatment. So, it’s incumbent upon us as a medical community then to identify strategies that not only use the agent most judiciously and effectively, but also to identify strategies where we can limit the emergence of resistance, which prolongs the lifespan of some of these new agents like ceftazidime/avibactam.
Meropenem/vaborbactam was approved in late 2017 and gives us another option to treat CRE infections. Here, you have a carbapenem backbone plus another carbapenem ACE inhibitor, like vaborbactam, that inhibits KPCs. Now, this agent has just come to the market and there’s limited clinical experience with using this drug. But we can rely on some of the clinical trial data, particularly the phase III trial known as TANGO II, which compared meropenem/vaborbactam to the best available therapy for patients with CRE infections.
In the study, what we see is that patients who received meropenem/vaborbactam had much better clinical responses than did those patients who received best available therapy. The limitations of this study, however, is that there’s a small number of patients who were included, and the best available therapy included a number of different treatment regimens, which included monotherapy with some of the older salvage agents. But the data overall are very compelling and add to the cumulative experience that these newly approved agents are probably going to be better than what we were doing previously with salvage agents. So, it’ll be important to see, as people and clinicians start to use meropenem/vaborbactam in the real world, what’s their experience and is this agent going to be at least as good as ceftazidime/avibactam as it moves forward.
Another new agent I’d like to talk about is cefiderocol, which is not yet FDA approved but has a very exciting new mechanism of action. This is a siderophore/cephalosporin that forms a chelating complex with ferric iron in the environment, allowing active transport into the bacterial cell. Once inside the cell, it disassociates with iron and binds to its target at penicillin-binding protein.
Now, the drug itself is very stable against many mechanisms of action, and because of this, we see in vitro activity to all of the major carbapenem-resistant pathogens. This includes CRE, which produce metallo—beta lactamases. It includes carbapenem-resistant Acinetobacter, and it includes carbapenem-resistant pseudomonas. So, of all the new agents, this one has the broadest spectrum of activity. Now, clinical data are not yet available in phase III studies for targeted resistant pathogens. But once this drug is approved, it has a chance to change the landscape on how we treat some of these resistant pathogens, specifically Acinetobacter and pseudomonas, for which we have very few options currently.
Two other non—beta lactam agents that are in late stages of development, or have recently been approved, are eravacycline and plazomicin. Let’s start first with the eravacycline. This is a synthetic fluorocycline antibiotic that has in vitro activity against resistant Acinetobacter and resistant CRE, or carbapenem-resistant Enterobacteriaceae. Now, compared to a relatively close molecule like tigecycline, the in vitro potency appears to be better with eravacycline and you get higher serum levels of the drug, which means we have improved pharmacokinetics. The drug’s still in late stages of development. We don’t know exactly how it’s going to be used for patients, but 1 potential indication might be for complicated intraabdominal infections where you’re worried about multidrug-resistant pathogens.
The other drug I want to talk about is plazomicin. Plazomicin is a new aminoglycoside antibiotic that has shown great efficacy in late stages of development, specifically a phase III clinical trial known as the CARE study. Here plazomicin was compared to colistin in combination with either meropenem or tigecycline. Now, in combination, patients who received plazomicin plus either meropenem or tigecycline had improved survival rates at 28 days compared to patients who received colistin in combination. So, these are really exciting data that show us we have another new antibiotic that is associated with better response rates than what we’ve been doing historically.
Plazomicin is still an aminoglycoside, so it’s an agent that we’re going to have to monitor closely, specifically for nephrotoxicity among our patients. But we know that the aminoglycosides are effective antibiotics, and when used in combination for resistant pathogens, this could be a very useful addition to our antibiotic armamentarium.