Battling Against Resistant Pseudomonas Infections in the ICU - Episode 7

<i>Pseudomonas</i> Infections Continue to Acquire Resistance, Complicating Treatment

Peter L. Salgo, MD; Jason Pogue, PharmD, BCPS-AQID; and Yoav Golan, MD, discuss Pseudomonas infections’ ability to evolve and acquire resistance to fluoroquinolones, polymyxins, aminoglycosides, and other such agents, complicating treatment approaches.

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Peter L. Salgo, MD: We’ve outlined a whole set of classes of antibiotics. We’ve got the β-lactams; the aminoglycosides; the fluoroquinolones, for better or worse; and then detergent, or polymyxins. How often do we see Pseudomonas resistant to all of these?

Jason Pogue, PharmD, BCPS-AQID: Resistant to all of them, as in extensively resistant?

Peter L. Salgo, MD: By the way, we ought to at least get the definition down. Nothing is 100% resistant necessarily, but the MICs are really high. So, let’s just call it resistance.

Jason Pogue, PharmD, BCPS-AQID: Luckily, we don’t commonly see pandrug resistance to all of those agents, and we actually have some new agents that might play a role in that situation.

Peter L. Salgo, MD: We’re going to get to those.

Jason Pogue, PharmD, BCPS-AQID: I know. Foreshadowing is what I like to call that. But we do see those patients, I would say infrequently. One of the things that’s important to know with β-lactam, and I think it’s an important lesson to understand, is that we’re used to dealing in the world of carbopenamases and β-lactamases, but for β-lactamase resistance in Pseudomonas, it’s much more complicated. Sure, there are some β-lactamases, but the different mechanisms of resistance will hit different β-lactams to different degrees. So you could have something that’s carbapenem resistant but also susceptible and so on and so forth. And so it is rare that you completely lose all those options, but it does occur. But multidrug resistance is the norm.

Yoav Golan, MD: But there’s a caveat to that. If you see oscillations in ICUs, if there is a bacterium that’s resistant to everything available, which one would it be in your ICU? In many cases, you hear it will be Pseudomonas. Even though it’s not very common, it exists. But the problem is that if the Pseudomonas is susceptible to only aminoglycoside, it’s not treatable by aminoglycoside monotherapy. It’s practically resistant to everything. We now know from several studies that were done recently that when you test as susceptible to the polymyxins—colistin, for example—at least in 1 study that was published recently, half of the cases were actually resistant and susceptibility was misread. And so you don’t really know. Another factor that’s really important is that we talked about resistance in Pseudomonas. What’s important is that Pseudomonas is one of the most capable bacteria of developing resistance to therapy.

When you start with a high inoculum infection, you hit it with 1 antibiotic or maybe 2, but it’s not susceptible to all antibiotics you have. With high inoculum, bacteria divide and mutate after 3 or 4 days. If you look at different classes of antibiotics that are most vulnerable to this development of resistance on therapy, the product carbapenems are actually the most vulnerable to that. And so you have to take all those and tailor the treatment. If you start the patient on what looks rational—maybe you have the culture result that guides you—and the patient does not respond the way you would expect the patient to respond, you should think about reculturing. You should think about changing your antibiotic.

Peter L. Salgo, MD: Somebody once said to me, and this is almost a direct quote, “If you don’t believe in evolution, take a look at Pseudomonas.” It’s evolving; it’s changing to accommodate to its environment, in a bad way for us. You mentioned some of the mechanisms of resistance. One of them is this brick wall that develops. What else does it do to become resistant to antibiotics?

Yoav Golan, MD: It does many different things, but 1 of the 3 different mechanisms that are perhaps the most substantial, quantitatively, is its ability to produce enzymes that break the antibiotics, mostly β-lactamases but also aminoglycosides. Hydrolyzing or breaking enzymes. At some institutions, this is the main mechanism of resistance. If you are going to discuss the new antibiotics coming to the market with those bodyguards against those enzymes, you’ll see that those antibiotics are very, very good in some institutions and not the best in other institutions depending on that. So, producing an enzyme that will break an antibiotic is 1 approach. And of course, to protect the antibiotic, you can give a drug with a bodyguard that will prevent the enzyme from breaking the antibiotic.

Another mechanism is efflux. It allows the antibiotic to come in, but it pumps it out, and carbapenems are particularly susceptible to that. One of the main mechanisms of resistance is the fact that the Pseudomonas has this fluffy additional external membrane that gram-negatives have, and it doesn’t allow antibiotics to go in by downregulating the genes that encode for those channel proteins. The carbapenems are very susceptible to those.