Difficult-to-treat resistant Pseudomonas aeruginosa is defined as “isolates demonstrating resistance to all first-line antibiotics” and carries a mortality rate of 40%. The top treatment options are ceftolozane-tazobactam and ceftazidime-avibactam. While observational studies have shown similar outcomes for these two antibiotics, there have been some factors, such as small sample sizes and mixed infection types, that have limited those findings.
However, there are important differences between these two agents, which would seem to favor ceftolozane-tazobactam in efficacy, such as lower MICs in vitro, enhanced stability against AmpC β-lactamases and better penetration of the respiratory epithelial lining. In short, the pharmacokinetic-pharmacodynamic profile of ceftolozane-tazobactam favors it as a better option.
The CACTUS study was a matched, retrospective, observational study at 28 U.S. hospitals looking at adult patients with microbiologically confirmed pneumonia or bacteremia between Jan. 1, 2016, and Dec. 31, 2023. Isolates had to be non-susceptible to at least one agent in three or more antibiotic classes. Patients with deep seeded infections, such as intra-abdominal abscess or osteomyelitis, were excluded due to concern for source control and need for long-term antibiotics, respectively. In the study, 420 patients were matched 1:1 for infection type, presence or absence or severe sepsis or septic shock and time to initiation of study drug (≤ 72 hours or >72 hours). Primary outcomes included clinical success at day 30 (survival, resolution of signs and symptoms, completion of intended treatment course and the absence of recurrence). Secondary outcomes were all-cause mortality at 30 and 90 days.
Of the patients treated with ceftolozane-tazobactam, 61% had clinical success versus 52% treated with ceftazidime-avibactam. While this did not quite reach statistical significance, once adjustments were made for severity of illness and other factors, treatment with ceftolozane-tazobactam was associated with improved odds of clinical success. In looking at patients with pneumonia versus bacteremia, outcomes in patients with bacteremia were similar for both antibiotics. However, clinical success rates were 63% for patients with pneumonia treated with ceftolozane-tazobactam and 51% for those treated with ceftazidime-avibactam. Interestingly, treatment-emergent resistance during or after treatment was similar (22% vs. 23% for ceftolozane-tazobactam vs. ceftazidime-avibactam, respectively).
While CACTUS hasn’t answered all of our questions in this high-mortality pathogen, it has given us some guidance. For patients with DTR Pseudomonas pneumonia, ceftolozane-tazobactam has an advantage over ceftazidime-avibactam. Bacteremic patients seem to do equally well with either antibiotic. Hopefully, more research will be done to quench our thirst on this topic.