Multi-Drug Resistant Gram-Negative Bacteria and Novel Treatment Approaches - Episode 11
Thomas Lodise, PharmD, PhD: In recent years, we’ve been very fortunate to have several agents approved for the treatment of patients with serious gram-negative infections. One of those is ceftazidime/avibactam. Ceftazidime/avibactam is currently FDA approved for the treatment of adults with complicated urinary tract infections when combined with metronidazole and treatment of adults with complicated intra-abdominal infections, and, most recently, it’s indicated for the treatment of adults with hospital-acquired pneumonia and ventilator-associated pneumonia. This is an important agent in our armamentarium. A lot of our use right now at our institution is off-label, and really, we target it for patients who have serious infections with KPC-producing Klebsiella pneumoniae. So, really, it has become a go-to agent for CRE at our institution.
In addition, it’s also an option for patients with multidrug-resistant Pseudomonas infections where many of our commonly available or commercially available β-lactams like meropenem, imipenem, piperacillin/tazobactam, and cefepime isolate resistance. Again, it’s that kind of risk-versus-benefit situation, much like CRE, where we consider using ceftazidime/avibactam for a patient with a multidrug-resistant Pseudomonas infection.
Another drug that was recently approved is meropenem/vaborbactam, or Vabomere, which is currently FDA approved for the treatment of adults with complicated urinary tract infections. Again, when we think about this drug, a lot of its use is off-label. In a recently conducted trial, TANGO II, it was looked at relative to best available therapy, which was largely patients who received colistin-based therapy for patients with CRE infections. Overall, looking across several infection types in the urine and bloodstream, as well as the lung, what we saw with Vabomere was hard clinical response rates and numerically higher survival rates. So, again, we have a situation where we have a drug that has a better response than colistin-based therapy. And much like ceftazidime/avibactam, we consider its use largely in patients with CRE infections.
In addition to several recently approved agents, we have a number of promising agents in development. One of those antibiotics is cefiderocol. Cefiderocol is a siderophore antibiotic and really has a unique mechanism of action. And trials are currently under way for patients with carbapenem-resistant infections. So, we find that the way cefiderocol works is that in addition to functioning like any other β-lactam…it has a high-binding affinity to iron. So, when patients have infection, one of our innate immune responses is to create an iron-deficient environment surrounding bacteria.
So, in these circumstances, what bacteria do is, they open up pumps to increase uptake of iron, which is necessary for survival. And what cefiderocol does is bind to iron and is actively transported into bacteria during these acute phases—very promising drug, and the thing I like most about cefiderocol is that as we think about antibiotics currently available, they all have their place in therapy, but they all have gaps in coverage. In contrast, with cefiderocol, it’s very active against carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter, and Stenotrophomonas, as well as our CREs, both KPC-producing Klebsiella, and many of our MBL-producing gram-negative bacteria. So, again, it’s really a broad-spectrum agent that covers a lot of the major resistant pathogens we worry about most in the clinical arena.
To date, it has been studied in patients with complicated urinary tract infections. It was actually found to be superior to imipenem-based therapy, and it’s currently under way. And there’s a study looking at patients with carbapenem-resistant infections where it’s being compared with best available therapy, which is at the discretion of the investigator, and I believe that it is an open-label study.
In addition to the agents that were recently approved, another agent under development is plazomicin. Plazomicin is a next-generation aminoglycoside. It’s derived from sisomicin, and the thing that distinguishes it from other commercially available aminoglycosides is its ability or its lack of degradation by aminoglycoside-modifying enzymes. So, one of the major mechanisms of resistance against aminoglycosides is degradation by aminoglycoside-modifying enzymes, or AMEs. And what we found with plazomicin on the way it was structured and developed is that it really is immune to the activity of most AMEs. So, it’s really impervious to breakdown by them. To date, it has been studied in patients with complicated urinary tract infections and looked very favorable against meropenem-based therapy.
And more recently, they conducted the CARE trial. Again, this was a trial looking at plazomicin versus best available therapy, which, again, was colistin-based therapy. And what we found in this trial looking at patients with bloodstream infections…was a mortality benefit with plazomicin-based therapy. It carries all the risk associated with aminoglycosides. Worry about nephrotoxicity with prolonged use. So, what we have here is a drug with very good efficacy, same adverse event risk but very compelling data, particularly in patients with CRE bloodstream infections.
Transcript edited for clarity.