A newly published study, the CACTUS Study, compares the effectiveness of ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) in treating multidrug-resistant (MDR) Pseudomonas aeruginosa infections. The findings show that CT and CZA have similar clinical outcomes: 62% of CT-treated patients achieved clinical success, compared to 55% of CZA-treated patients. The overall 30-day mortality rates were also similar: 20% for CT and 19% for CZA.
In this first part of our interview with Jason M.Pogue, PharmD, BCPS, BCIDP, clinical professor at the University of Michigan and investigator of the CACTUS Study we discuss the background and purpose of the study. The study involved 420 patients, with 210 matched pairs, ensuring robust statistical power to compare the two drugs’ efficacy.
Pogue discussed how CT and CZA are cephalosporins that have shown superior efficacy over older, more toxic treatments such as polymyxins and aminoglycosides, which have been previously used to treat resistant Pseudomonas infections. “Both of these agents are recommended in guidelines for the treatment of drug-resistant Pseudomonas. The reason they’re included in these guidelines is that they have been shown to be superior to older treatments that were used before the availability of these novel cephalosporins.”
Before the CACTUS Study, some smaller studies compared CT and CZA, but these studies had significant limitations. Many had small sample sizes, inconsistent susceptibility testing, and heterogeneous patient populations. “Some of the studies haven’t routinely tested susceptibility to these two drugs, so you don’t even know whether or not they’re active all the time in patients who got it,” Pogue said.
Also, disease state could play a role in how patients respond to therapy. “Some disease states are more or less likely to respond to nuanced differences in therapies,” Pogue explained. For instance, if patients with urinary tract infections were included, any differences between the two drugs might not be observed, as both drugs concentrate well in the urine.
The CACTUS Study was designed to address these issues by focusing specifically on pneumonia and bloodstream infections, conditions where treatment could have a significant impact on patient outcomes. In addition, pharmacokinetics (PK) and pharmacodynamics (PD) differences between CZA and ceftolozane-tazobactam could influence treatment success, making these infection types ideal for comparison.
“We wanted to limit it to disease states where we thought therapy might have a big impact on outcomes,” said Pogue, adding that pneumonia was chosen due to these potential PK/PD differences. To ensure high-quality data, the study included 28 US sites with leading researchers in resistant gram-negative infections. “The reason we did that is because we were going to get good data, and that allows you to get significantly more numbers,” Pogue said.
One challenge with observational studies like CACTUS is dealing with biases such as indication bias or residual confounding, which can affect the interpretation of results. To minimize bias, the study used a matched-pair design. “For every CZA patient, they had a matched ceftolozane-tazobactam patient, and they were matched on severity of illness, infection type, and time to treatment initiation,” Pogue explained.
Patients treated with CT were more likely to receive longer infusions of the drug (≥3 hours), with 36% of patients receiving the prolonged infusion compared to just 19% of those on CZA (P=0.005). However, no significant differences were found between the two drugs regarding microbiologic failures, recurrent infections, or resistance development.
“We hypothesized that ceftolozane-tazobactam would be superior because of some of these PK/PD advantages,” said Pogue. “We adequately powered the study to show if there was a difference.” Despite the similar outcomes, the study’s robust design helps provide a clearer understanding of these two treatments and their comparative effectiveness.
Stay tuned for the next parts of our interview with Pogue, where we dive deeper into clinical success, mortality rates, treatment-emergent resistance, and more.
