Multi-Drug Resistant Gram-Negative Bacteria and Novel Treatment Approaches - Episode 3

Current Treatments for MDR Bacteria and Their Drawbacks

Jason Gallagher, PharmD: Once a patient has been identified with a multidrug-resistant gram-negative organism, our options become more limited once we see a susceptible organism—but we do have options. There are beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin/tazobactam, that may be active against some of them. That would be active against some of the ESBLs (extended-spectrum beta-lactamases), though there’s a debate whether that is a good option for those infections and some resistant Pseudomonas infections—although it’s common for Pseudomonas to be resistant to that as well. We have carbapenems that can be utilized. Carbapenems are active. They’re kind of our most broad-spectrum category of antibiotics, and they’re active against some of these resistant species. For example, they’re active against ESBL-producing organisms. However, obviously carbapenem-resistant organisms would be resistant to carbapenems basically by definition.

There are polymyxin antibiotics, colistin and polymyxin B. These, in my opinion, are truly terrible options. They’re really last-line drugs that we don’t use until we absolutely have to, for a couple of reasons. One is that they have significant toxicities, and they also have limited pharmacokinetics. Colistin, in particular, is administered as a prodrug, and that prodrug is eliminated renally, and patients that have, ironically, very good kidney function may eliminate so much of the prodrug that it’s hard to get them to a therapeutic concentration. This is not an issue with polymyxin B. However, polymyxin B has pharmacokinetics. While it’s not eliminated renally, it’s so old that its package insert actually recommends dosing it by renal function even though it’s not eliminated that way. So, kind of a significant knowledge gap that we’ve been working to fix ever since.

The aminoglycosides are options. However, aminoglycosides have their own toxicities to them, probably a little bit overexaggerated in people’s minds compared to how they really are. However, they also have pharmacokinetic limitations. They’re not ideal choices of monotherapy, particularly for infections like pneumonia. We have some new agents, 2 cephalosporin and inhibitor combinations: ceftolozane/tazobactam and ceftazidime/avibactam. Both of them are active against resistant Pseudomonas. Ceftazidime/avibactam is active against CRE as well and has become a useful agent in those infections. And recently, the drug meropenem/vaborbactam has been approved, which is highly active against CRE infections as well.

Recently, there has been a lot of attention to colistin resistance, which was detected originally in China through the mcr-1 gene that has been found in, basically, agricultural samples of E. coli and since then has been found in other places, which is not surprising. Whenever someone finds something bad, it seems that everyone else just needs to look and then they find out that they have some of the same issues. Now, colistin resistance is certainly a significant concern because it’s a last-line agent, and if you’re resistant to that, what are you going to use? However, I think it’s an issue that has been around for a long time and we just didn’t know because we didn’t look. It is not typical to test isolates in the hospital for colistin unless you already have an isolate that’s resistant to so many other things. So, if we start looking back to see how many of those isolates over the past 5 or 10 years are colistin resistant, I think we’d be surprised at just how often we would see that.

Many of our agents that we have available for multidrug-resistant infections have limitations. Colistin and polymyxin B have pharmacokinetic limitations, including potentially limited penetration into the lungs. There is some controversy as to whether they achieve sufficient therapeutic concentrations when given intravenously. But there’s no argument about how nephrotoxic the agents are. They are significantly nephrotoxic, and, unfortunately, we’re often giving them to patients who are most vulnerable already, who have been in the hospital for a long period of time, and who have significant comorbidities. And these drugs can insult their kidneys, which have already been insulted from other things. The aminoglycosides have limitations as well. While not as toxic as the polymyxins, they also do have nephrotoxicity and limited pharmacokinetic penetration into areas such as the lungs. They actually get in there fairly well but not at high enough concentrations relative to the MIC (minimal inhibitory concentration) of the organisms that are often causing infection, most notably KPC-producing organisms and Pseudomonas aeruginosa. Tigecycline is another agent that is available and active against some of these infections, such as ESBL producers and CRE. Tigecycline, unfortunately, has a warning for increased mortality relative to its competitors. That increased mortality was not high but it was statistically significant and that has led to a significant decrease in its overall use. It also has a high incidence of causing nausea and vomiting.

Transcript edited for clarity.