By Gina Shaw
A multicenter, observational study that compared the effectiveness of ceftazidime-avibactam (CZA) with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Pseudomonas aeruginosa infections shows no difference in overall clinical success, mortality, recurrent infections or resistance development between the two combinations, in data presented at IDWeek in Boston, on Oct. 13, 2023 (poster 1109).
The CACTUS study “was designed to answer what we think is an outstanding clinical question in the field, comparing the effectiveness of some of these newer beta-lactamase inhibitors, particularly in some of these extremely sick patients,” said the study’s co-lead investigator Ryan Shields, PharmD, MS, an assistant professor of medicine in the Division of Infectious Diseases and the co-director of the antibiotic management program at the University of Pittsburgh.
Although both C/T (Zerbaxa, Merck) and CZA (Avycaz, AbbVie) are recommended as preferred treatment options for difficult-to-treat, resistant (DTR) P. aeruginosa infections, these recommendations are primarily based on in vitro activity observational reports and limited clinical trials, according to Dr. Shields. “In these trials, most patients didn’t have Pseudomonas infections, and very few had MDR Pseudomonas,” he said.
“We have now started to see real-world evidence emerge that both agents are superior to aminoglycoside- or polymyxin-based combinations, but even these data have important limitations. Many times, we see that the vast majority of patients don’t have the more invasive infections where we would try to detect a difference between these agents.”
The interim data reported at IDWeek are from the CACTUS trial, which is an initiative of the Precedent Network, a consortium of leading U.S. medical centers focused on the real-world effectiveness of antimicrobial agents, which aims to define optimal treatment pathways for patients infected by MDR pathogens. CACTUS ultimately aims to enroll 420 patients (210 pairs matched on study site, severity of illness, infection site and time to initiation of treatment).
In the interim analysis, 234 patients were included from 20 sites. Patient demographics, severity of illness, infection types and treatment durations were similar in both groups. At study drug initiation, 77% of patients were in the ICU, with 67% receiving mechanical ventilation. “This was an incredibly sick population,” Dr. Shields said. “These are the patients we often resonate with when using these new antibiotics that are incredibly complex, but they are patients that are often not included in clinical trials.”
Clinical success, defined as the composite end point of survival, completion of the intended treatment course without needing to extend therapy due to clinical response or toxicity, and absence of recurrent infections, occurred in 62% and 55% of patients receiving C/T and CZA, respectively (P=0.35). Corresponding rates of success for pneumonia were 63% and 52%, respectively (P=0.13). All-cause, 30-day mortality rate was 20% and 19%, respectively. Microbiological failures, recurrent infections and development of resistance within 90 days were similar in the groups. Time to a composite end point of recurrent infection or death within 90 days was similar in both groups in the overall analysis and the subgroup of patients with pneumonia.
“We had hypothesized that if there were to be a difference in clinical efficacy, we might see it in pneumonia, where penetration of the agents may vary, but when we analyzed that subgroup, there was an absolute difference of 7.9% in clinical success favoring C/T, but that was not statistically significant,” he said (P=0.26). “On the metric of resistance within 90 days, we did see what might be a trend, with resistance in 27.3% of the CZA group compared with 19.5% of the C/T group, but that also did not reach statistical significance” (P=0.18).
The investigators also conducted a Desirability of Outcome Ranking (DOOR) analysis in the pneumonia cohort; this is a scoring system that assigns each patient a single-digit score based on one of five outcomes:
- alive, cure with the study regimen and no recurrence or resistance development;
- alive, cure with the study regimen, but documented resistance development;
- alive, cure with the study regimen, but documented recurrent infection within 30 days;
- alive, failure of study regimen (i.e., remain on study drug, escalate due to failure or switch due to toxicity); and
- death from any cause within 30 days.
Here, too, there was no statistically significant difference, with an overall probability of a better DOOR outcome with C/T of 52.7% (P=0.41).
“We also did not see any differences in secondary outcomes, including days on ventilator, hospital and ICU length of stay, and disposition at discharge,” Dr. Shields said. “I would caution that this is a preliminary analysis, with only about 75% enrollment, and the study is still actively enrolling. However, to date our findings show no difference in overall clinical success, mortality, recurrent infections or development of resistance between C/T and CZA. The subgroup analyses of patients with pneumonia do suggest a potential benefit for treatment with C/T resulting in fewer recurrent infections and lower rates of resistance, but future subgroup analysis will be important in teasing out if these are real differences.”
Results from the completed CACTUS trial are expected in the first quarter of 2024.
Dr. Shields reported that the study was funded by an investigator-initiated grant from Merck, and that he is an advisor/consultant to AbbVie, Cidara, Entasis, GlaxoSmithKline, Melinta, Menarini, Merck, Pfizer, Roche, Shionogi and Venatorx. He also receives unrelated research funding from Melinta, Merck, Roche, Shionogi and Venatorx.
