The CACTUS study found a 10% improvement in clinical success with ceftolozane tazobactam (CT), which was linked to a 1.5-fold increased chance of clinical success. After adjusting for residual differences between the treatment arms, the likelihood of success was nearly twice as high with CT. Despite these findings, mortality rates were similar between the two arms, and both therapies, CT and ceftazidime avibactam (CZA) showed high rates of resistance development.
Clinical Success and Mortality Rates
The study’s primary outcome was clinical success at day 30, defined as the patient being alive, free from the initial infection (with no escalation of therapy), and without infection recurrence within 30 days.
with Jason M Pogue, PharmD, BCPS, BCIDP explained, “What we found in the study was that CT was associated with about a 10% absolute improvement in that variable of clinical success. They weren’t great rates of clinical success in either arm. It was about 61% in the CT arm and 52% in the CZA arm. And so, if you got CT you had about a one-and-a-half-fold increased chance of having clinical success. Once we adjusted for residual differences between the two groups, it was about a two-fold increased chance.”
Although this difference might seem modest, the results suggest that CT offered a 1.5-fold increased chance of success. After adjusting for residual differences between the two groups, the chance of clinical success was approximately twice as high for patients treated with CT. Pogue further emphasized, “I like the idea of a therapy being twice as likely to have a positive outcome, but I think it’s very fair to note that success rates still weren’t optimal. We still need to think about ways to further improve outcomes for these patients.”
Mortality rates were similar across both arms of the study. The 30-day mortality rates ranged between 20-25%, and 90-day mortality rates were around 35%. These rates align with findings from other studies on drug-resistant Pseudomonas infections.
Regarding mortality, Pogue commented that there was no difference observed between the two treatment arms. “When we looked at mortality, we saw no difference between the two arms,” he said. “When we looked at resistance development, we saw high rates in both treatment arms. So neither therapy was perfect, but CT was associated with increased clinical success.”
Impact on Pneumonia Patients
The study’s findings were particularly notable in pneumonia patients, where CT showed a clear benefit in reducing recurrent infections. Pogue shared, “When we looked at the nitty-gritty of the data, it was really driven by pneumonia patients. That’s where you really saw the effect, and the biggest driver was actually being less likely to have recurrent pneumonia after therapy. And again, that’s very consistent with our hypothesis, because if there was a place we thought this PK/PD (pharmacokinetics/pharmacodynamics) was most likely to manifest itself as clinically meaningful, we would have thought it would have been in pneumonia patients.”
This observation confirms the importance of pharmacokinetics and pharmacodynamics in shaping treatment outcomes, particularly for infections that involve the lungs.
Subgroup Analysis and Future Studies
While the clinical success rates were not optimal, Pogue acknowledged limitations due to the severely ill patient population. Over three-quarters of the cohort were in the ICU, mechanically ventilated, and on vasopressors. The average age was over 60 years, and many patients had significant comorbidities, including solid organ transplants and immunosuppressive conditions.
Pogue explained, “This cohort was incredibly ill, complicated patients… you do, to some degree, just have a really complicated patient population. And you would expect for a hard outcome like mortality, infection is certainly a piece of the story, but there’s a lot of other things that are going on in this patient population as well.”
He noted that the severity of illness in these patients makes it difficult to show the impact of the drug on mortality, as a superior therapy can only significantly impact mortality rates in a “sweet spot” patient population. “The amount of mortality rates that can be impacted by a superior therapy is really going to be limited to a sweet spot patient population,” he explained. “They have to be sick enough where they are going to die if you don’t effectively treat them, but not too sick, where they probably won’t get better either way.”
Pogue suggested that more patients are needed to truly test the mortality hypothesis and emphasized the importance of subgroup analysis for gaining insights into mortality differences. “If you take a look at the supplemental table 2, we actually look at mortality rates compared between the two arms for different subgroups of populations. There are some interesting little nuggets that I think are in there.”
Looking ahead, Pogue discussed the potential for more research in the area of resistant infections. While the current study provided valuable observational data, a randomized controlled trial would be ideal to further validate these results. “The key thing you want to do now is design a randomized control trial where you actually put patients in these two arms. Unfortunately, I think that’s probably pretty unlikely, just because you’d need someone to support such a trial. It’s a complex study to do, and the chances of that occurring are quite low, in my opinion.”
Pogue emphasized that the current evidence should still influence clinical practice. “I believe pretty strongly that this is probably the best evidence we’re going to get… and I do think it should influence how we treat these patients.”
Part 1 of our interview introducing The CACTUS study: CACTUS Study Compares Ceftolozane-Tazobactam vs. Ceftazidime-Avibactam for MDR Pseudomonas
