Determining Resistance Patterns in Difficult-to-Treat Resistant Pseudomonas Infections

EP: 1.Looking at Mortality Rates Comparing Treatments for Gram-Negative Resistant Pseudomonas aeruginosa Infections

Now Viewing

EP: 2.Determining Resistance Patterns in Difficult-to-Treat Resistant Pseudomonas Infections

In this short series with Pranita Tamma, MD, MHS, associate professor of pediatrics in the Division of Pediatric Infectious Diseases at The Johns Hopkins University School of Medicine, she has a discussion around ceftolozane-tazobactam vs ceftazidime-avibactam for gram-negative resistant Pseudomonas aeruginosa infections and the latest data supporting these decisions.

In one retrospective observational study, which compared ceftolozane-tazobactam and ceftazidime-avibactam, and was funded by the National Institutes of Health (NIH), the findings showed similar 30-day mortality rates but higher resistance emergence in the ceftolozane-tazobactam group (38% vs 25%). Tamma was the senior investigator on this trial.

Enclosed below are responses from a conversation with her around this trial as well as other data on this topic.

Contagion: Resistance emergence was higher in the ceftolozane-tazobactam group, though not statistically significant. How should clinicians interpret this trend when selecting therapy?

Tamma: Yeah, so the resistance outcome was interesting. As you know, we didn’t see a statistically significant difference in the emergence of resistance. There was a numerical difference that stood out, though. I don’t want to misquote the numbers, but I believe resistance emerged in 38% of the ceftolozane/tazobactam group and 25% in the ceftazidime/avibactam group. Again, not statistically significant—but still notable.

In my opinion, our study doesn’t provide enough data to draw firm conclusions. But what I appreciated—and I want to highlight that Derek Hareza is the first author—is that we had access to both the index Pseudomonas isolates and subsequent isolates, which allowed us to perform broth microdilution testing for MICs. That’s the reference standard, and this kind of detailed susceptibility testing wasn’t done in the other two studies. In those, isolates were either unavailable or not tested with broth microdilution.

That’s not a criticism of those studies—they’re still good—but I do think it’s important. If we’re comparing two drugs for resistance or clinical outcomes, it’s essential to know whether the isolates were actually susceptible to the drugs being studied. Otherwise, the foundation of the study is shaky—we don’t even know if the treatments were active up front.

Using broth microdilution, we were able to look for emergence of resistance. Still, our sample size was small, so I don’t think we can draw meaningful conclusions from it. Personally, I tend to prefer using ceftolozane/tazobactam over ceftazidime/avibactam for DTR Pseudomonas, just because ceftolozane/tazobactam is more focused on Pseudomonas. I typically reserve ceftazidime/avibactam for carbapenem-resistant Enterobacterales, like KPC producers and OXA-48-like producers. So, despite the findings from our study and the two other observational studies, I don’t think there's enough evidence to favor one drug over the other based on mortality or resistance alone.

From an antibiotic stewardship perspective, I still lean toward starting with ceftolozane/tazobactam, assuming both drugs are active against the Pseudomonas, simply because I want to preserve ceftazidime/avibactam for other resistant infections that these patients might develop.

Sorry for the long response—but speaking more generally about resistance, it’s important to note that ceftolozane, as a beta-lactam, is engineered to be more active against Pseudomonas than ceftazidime. It’s less prone to efflux and porin channel issues, both of which limit beta-lactam entry into the bacterial cell. It also has higher affinity for PBP3, its target, and is more stable against hydrolysis by the Pseudomonas AmpC enzyme.

So, as a molecule, ceftolozane is clearly superior to ceftazidime. What ceftazidime gains, though, is avibactam, which inhibits AmpC and allows ceftazidime to reach its target. Mechanistically, I would have expected ceftolozane/tazobactam to be less likely to lead to resistance than ceftazidime/avibactam.

But we were surprised in our study: numerically, resistance seemed more frequent with ceftolozane/tazobactam. One hypothesis for this is that both drugs share a common resistance mechanism—amino acid changes in the Pseudomonas AmpC enzyme. These mutations make the enzyme’s active site more flexible and better able to hydrolyze beta-lactams like ceftolozane or ceftazidime. It’s possible that avibactam—as a more potent beta-lactamase inhibitor—can still bind to some of these non-mutated enzymes and protect ceftazidime, whereas tazobactam may not effectively inhibit these mutated AmpC enzymes.

So going into the study, I would’ve guessed ceftolozane/tazobactam would have a lower resistance rate. We were surprised. But again, the numbers are small, and the other two studies didn’t assess resistance emergence in a robust way because they lacked MIC data from reference methods.

So, in my view, this remains an open question and one that deserves further investigation.

The conversation was edited for grammar and clarity.