A newly published study, the CACTUS Study, compared the effectiveness of ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) in treating multidrug-resistant (MDR) Pseudomonas aeruginosa infections. The study found that both treatments had similar clinical outcomes. Of the 234 patients treated with CT, 62% had clinical success, compared to 55% for those treated with CZA. The 30-day mortality rates were also similar: 20% for CT and 19% for CZA.
In the final part of our interview with Jason M Pogue, PharmD, BCPS, BCIDP, clinical professor at the University of Michigan and investigator of the study, we discussed the high rates of emergent resistance observed in Pseudomonas treatments. Resistance developed in 1 in 5 patients, regardless of the treatment arm. Pogue noted that Pseudomonas resistance is driven by upregulated chromosomal mechanisms, rather than by transferable beta-lactamases. This type of resistance is more common in clinical settings where traditional agents like cefepime, meropenem, and piperacillin-tazobactam (piptazo) are not used, as these drugs often contribute to elevated resistance levels.
The Nature of Pseudomonas Resistance
When asked about the high rates of resistance observed, Pogue emphasized the nature of Pseudomonas as a particularly challenging pathogen. He explained that the resistance seen with newer agents like CT and CZA is not unexpected, given the bacteria’s ability to upregulate chromosomal resistance mechanisms.
“When we sat and looked at these results, when we first got them, we started thinking through them. This is what jumped out to us first: Regardless of what treatment arm you were in, you’re giving this novel, or I guess at least novel-ish, since they’re like, 10 years old now, novel agents for resistant Pseudomonas, and one out of every five times in both arms, you’re seeing resistance development.”
“And simply put, Pseudomonas is a jerk. I don’t know how else to say this—it’s kind of the nature of Pseudomonas.”
He further explained the biological mechanisms behind this resistance, “What’s unique about Pseudomonas is a lot of the beta-lactam resistance that we see is driven by upregulation of chromosomal mechanisms of resistance. So, rather than passing beta-lactamases from one to another, the resistance is in the chromosome of the organism. And in the presence of certain things, notably antibiotics, you can see upregulation of these resistance mechanisms.”
Building on this, he clarified why resistance development should be viewed in the context of treatment settings, “It’s not shocking that this happens because, when you’re using these drugs, you’re already in a situation where resistance is present in the background. You’re just kind of taking it to the next level with these agents. And I think it’s important for us to think about the fact that this happens 1 out of 5 times. That’s kind of the nature of Pseudomonas.”
Pogue’s insight reveals why resistance remains a challenge even with newer agents like CT and CZA: Pseudomonas’s ability to adapt and upregulate its resistance mechanisms makes it difficult to achieve long-term success with many treatments.
Historical Context of Pseudomonas Resistance
Pogue also highlighted that Pseudomonas resistance is not new, nor is it specific to the newer beta-lactam agents. Historically, carbapenems have been associated with resistance development in about 20% of patients, and there is limited data on the resistance patterns seen with piptazo and cefepime.
“If you look historically at the carbapenems, they cause resistance in 20% of patients. Not a lot of good data out there on piptazo and cefepime, but just as a clinician, those of you watching know that it’s not shocking when you treat a patient for Pseudomonas and they develop resistance. That’s kind of the nature of the beast,” This emphasizes that Pseudomonas resistance is a longstanding issue in clinical practice, and resistance development remains common even with first-line antibiotics.
Despite the high rates of resistance observed in the study, Pogue emphasized that strategies exist to help mitigate its emergence. He discussed potential avenues for improving treatment outcomes, including dose optimization, combination therapy, and exploring adjunctive therapies.
“One of the things we’ll want to do moving forward, and as a community, we need to do, is ask: “Are there strategies that can limit the emergence of resistance?” Whether that’s dose optimization, whether that’s robustly comparing combination therapy to monotherapy, or some sort of adjunctive therapy, I think those are next steps. And it just shows you the need for continued drug development in this space as well.”
Pogue’s focus on exploring these strategies highlights the importance of finding new ways to manage and reduce resistance. He also stressed that continued innovation in antibiotic development is essential for staying ahead of evolving bacterial threats like Pseudomonas.
The findings of the CACTUS Study offer valuable insights into the challenges of treating MDR Pseudomonas aeruginosa infections, highlighting the ongoing issue of resistance. While the clinical success rates for CT and CZA were similar, the development of resistance in 1 in 5 patients remains a key concern. Pogue’s recommendations to optimize dosing, explore combination therapies, and continue drug development will be crucial for addressing these issues moving forward.
Part 1 of our interview introducing The CACTUS study: CACTUS Study Compares Ceftolozane-Tazobactam vs. Ceftazidime-Avibactam for MDR Pseudomonas
Part 2 of our interview discussing ceftolozane tazobactam’s effectiveness over ceftazidime avibactam: Ceftolozane Tazobactam Linked to Increased Clinical Success in Pneumonia
