Multidrug-Resistant Gram-Negative Bacteria and Novel Treatment Approaches - Episode 4
New or Upcoming Treatment Options for MDR Bacteria
Jason Gallagher, PharmD, discusses the recently approved agents and agents in late stage development for multidrug-resistant bacteria and their potential role in treatment.
Jason Gallagher, PharmD: Meropenem/vaborbactam is a recently approved drug, combining meropenem and antipseudomonal carbapenem, that has been around for many years with vaborbactam, a new type of beta-lactamase inhibitor that gives the drug activity against carbapenem-resistant Enterobacteriaceae, so particularly those expressing KPC enzymes. Meropenem, like I said, has been a drug we’ve had for a long time, and vaborbactam basically restores its activity against those CRE-producing organisms. They have 2 studies. One that got their approval was in the treatment of complicated urinary tract infections and patients with acute pyelonephritis. The drug was approved for that. They also did another study specifically in patients with CRE infections, which it does not have a specific indication for. This is a shame, because that study did show superiority of meropenem/vaborbactam over the competitor, which were best available therapy or Colistin-based regimens. So, as it stands right now, meropenem/vaborbactam looks to be a good option in the treatment of infections caused by CRE. I do think it’s important to note, though, that vaborbactam does not improve the activity of meropenem against Pseudomonas, so it is no better against Pseudomonas than meropenem alone is.
Cefiderocol is the first siderophore cephalosporin, or siderophore drug, that’s making its way forward into phase III trials. And this combines a cephalosporin, a beta-lactam with a known mechanism of action, with a siderophore, which is a structure similar to what bacteria produced to bring iron in. Iron is an essential nutrient for bacteria. They require it to grow, and one of the body’s responses to infection is actually to sequester free iron and prevent bacteria from utilizing it. So, bacteria have sort of a counter defense, or offense I suppose, in that they release these substances to grab iron and pull it in. And what siderophore antibiotics do, the first one being cefiderocol, is they have this siderophore structure attached to the antibiotic, so it kind of looks like something the bacteria needs to get in through iron transport channels inside the bacteria to do its job. So, what’s interesting about this is where other beta-lactams have to go through porin channels to be active against gram-negative rods, which is a passive process, here the antibiotic is actively uptaken by bacteria. And the bacteria not knowing what isn’t good for them, I suppose, brings in the antibiotic that then acts to kill them once it gets to its site of activity.
Now, it’s an interesting compound. I’m interested to see it going forward and see where it’s going to end up in our armamentarium. Because it is a very broad-spectrum antibiotic against highly resistant gram-negative rods, including Pseudomonas, carbapenem-resistant Enterobacteriaceae with Klebsiella and so forth, and Acinetobacter. So, it has activity not just against Pseudomonas and Klebsiella and different types of CRE as well, not just KPC producers, but also it seems to have some activity against NDM-producing bacteria where we have very limited options. Basically, aztreonam is one of the few drugs that we have that can work against that, except aztreonam is destroyed by beta-lactamases that NDM producers also can make.
So, we really haven’t had any good options, and this may be a good option for that type of bacteria. And then its activity against Acinetobacter is a nice characteristic as well, because with all of these new antibiotics that have been approved, it’s nice to see new antibiotics approved. And we didn’t have that for a long time. In the past 5 years, we’ve had a nice little burst of that. None of them have particularly good activity against Acinetobacter. So, Acinetobacter may not be the most common drug-resistant organism. It is probably the most difficult to treat, and this agent does have good activity against that.
There are new compounds in the tetracycline class being developed as well, including eravacycline, which is a fluorocycline that is an agent that has broad spectrum of activity against gram-negative organisms, not including Pseudomonas, though. So, that’s an important hole to mention, similar to the other tetracyclines and tigecycline, which also have the same hole in their spectrum of activity. However, eravacycline has fairly potent activity against CRE and other Enterobacteriaceae that are resistant to beta-lactams. It has gone through 4 clinical trials, 2 in complicated intra-abdominal infections, which were successful, and 2 in urinary tract infections, which were not successful. So, we clearly are not going to be seeing it used for urinary tract infections but for complicated intra-abdominal infections. I think that they will file for that and the FDA will review it this year.
Plazomicin is a new-generation aminoglycoside that has strong activity against CRE as well. It doesn’t have potent antipseudomonal activity, but it does have strengthened activity against Enterobacteriaceae, including KPC-producing CRE. Plazomicin is at the point where it has gone to the FDA advisory committee, which recommended its approval for the treatment of complicated urinary tract infection but did not recommend its approval for the treatment of CRE infection along that limited population antimicrobial pathway. So, we’ll see what that means when it goes to the full FDA review in the next few weeks or so.