CACTUS

A multicenter, observational study to compare the effectiveness of Ceftazidime-Avibactam versus Ceftolozane-Tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the United States

Treatment of Pseudomonas aeruginosa infections remains one of the foremost challenges in infectious diseases and an urgent public health priority. Conservative estimates indicate that multidrug resistant (MDR) P. aeruginosa infections account for more than 32,000 cases and 2,700 deaths annually in the U.S. leading to more than $700 million in healthcare costs. Hospital-acquired (HAP) and ventilator-associated pneumonia (VAP) due to P. aeruginosa are associated with high rates of treatment failure, recurrent infections, and rapid development of antimicrobial resistance.1,2 Antimicrobial selection and dosing are among the most important decisions clinicians can make in management of HAP/VAP where effective treatment and optimized drug exposures lead to decreased mortality and shorter lengths of stay.3 In the setting of difficult to treat (DTR) P. aeruginosa infections, consensus guidelines recommend treatment with one of three novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations, ceftolozane-tazobactam (C/T), ceftazidime-avibactam (CZA), or imipenem-relebactam (I/R).4

C/T and CZA have been shown to be safer and more effective than aminoglycoside- or polymyxin-based regimens in real-world studies.5-7 While in vitroactivity against MDR P. aeruginosa varies by geographic region and underlying mechanisms of resistance,8-10 susceptibility rates generally exceed 80% for both agents throughout the United States. As such, C/T and CZA are used interchangeably for the treatment of MDR P. aeruginosa in clinical practice.

Background

CACTUS is a retrospective, multicenter, observational cohort study of patients with MDR P. aeruginosa infection designed to compare the clinical efficacy of C/T and CZA among patients with MDR P. aeruginosa pneumonia or bacteremia. The primary outcome of the study is clinical success at 30 days. Only patients with microbiologically-confirmed pneumonia or bacteremia will be enrolled based on their first treatment course with C/T or CZA.

Patients will be matched 1:1 within each study site by:

  • type of infection

  • severity of illness

  • time to treatment initiation

In addition to clinical efficacy, we will compare rates of microbiologic response to treatment, including recurrent infections and the emergence of resistance to C/T and CZA.  Available isolates are collected from participating sites for molecular characterization, identification of resistance mechanisms, and testing for collateral sensitivity to other β-lactams, including imipenem-relebactam.

Details

Progress

Data collection is complete!

420 cases were provided by
28 member sites

Results

A pre-print is available here while we await peer-review process completion.

The abstract for the preliminary data presented at IDWeek 2023 can be found here.

References:
1. Fink, M.P., et al., Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group. Antimicrob Agents Chemother, 1994. 38(3): p. 547-57.
2. Rea-Neto, A., et al., Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study. Curr Med Res Opin, 2008. 24(7): p. 2113-26.
3. Kalil, A.C., et al., Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis, 2016. 63(5): p. e61-e111.
4. Tamma, P.D., et al., Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum beta-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance. Clin Infect Dis, 2020.
5. Pogue, J.M., et al., Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-based Regimens for the Treatment of Drug-resistant Pseudomonas aeruginosa. Clin Infect Dis, 2020. 71(2): p. 304-310.
6. Shields, R.K., et al., Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother, 2017. 61(8).
7. van Duin, D., et al., Colistin vs. Ceftazidime-avibactam in the Treatment of Infections due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis, 2017.
8. Fraile-Ribot, P.A., et al., Activity of Imipenem-Relebactam against a Large Collection of Pseudomonas aeruginosa Clinical Isolates and Isogenic beta-Lactam-Resistant Mutants. Antimicrob Agents Chemother, 2020. 64(2).
9. Grupper, M., C. Sutherland, and D.P. Nicolau, Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds. Antimicrob Agents Chemother, 2017. 61(10).
10. Sader, H.S., et al., Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam and Comparators Tested Against Pseudomonas aeruginosa and Klebsiella pneumoniae Isolates from United States Medical Centers in 2016-2018. Microb Drug Resist, 2021. 27(3): p. 342-349.