A Multicenter, Observational Study to Compare the Effectiveness of Ceftazidime-Avibactam Versus Ceftolozane-Tazobactam for Multidrug-Resistant Pseudomonas Aeruginosa Infections in the United States (Cactus)

Abstract

Background. Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) are preferred treatment options for multidrug-resistant (MDR) Pseudomonas aeruginosa infections; however, real-world comparative-effectiveness studies are lacking.

Methods. To compare the efficacy of C/T and CZA, adult patients with MDR P. aeruginosa pneumonia or bacteremia treated with C/T or CZA for >48 hours were enrolled. Patients were matched 1:1 by study site, severity of illness, time to treatment initiation, and infection type. The primary outcome was clinical success at day 30.

Findings. 420 patients were enrolled from 28 study sites; 83% and 17% had pneumonia and bacteremia, respectively. Baseline demographics, comorbidities, and severity of illness indicators were all similar between groups. Upon treatment initiation 80% (336/420) of patients were in the intensive care unit, 70% (296/420) received mechanical ventilation, and 40% (168/420) required vasopressor support. Clinical success was achieved in 61% (128/210) and 52% (109/210) of patients treated with C/T and CZA, respectively (P=0.05). By conditional logistic regression analysis, the adjusted odds ratio (aOR) of success following treatment with C/T compared to CZA was 1·97 [95% CI:1·10–3·53]. Corresponding rates of success for patients with pneumonia were 63% (110/175) and 51% (89/175), respectively (aOR=2·23 [95% CI:1·17–4·26]). There were no differences in 30- or 90-day mortality rates. Resistance developed in 22% (38/173) and 23% (40/177) of patients treated with C/T and CZA, respectively.

Interpretation. Treatment with C/T resulted in higher rates of clinical success compared to CZA for MDR P. aeruginosa pneumonia. Resistance development was common with both agents.

Funding: Investigator-initiated grant from Merck Sharp & Dohme, LLC.

Declaration of Interest: RKS has served as a consultant for AbbVie, Biomerieux, Cidara, Shionogi, Menarini, Melinta, Merck, Entasis, Utility, GlaxoSmithKline, and Venatorx, and has received investigator-initiated funding from Merck, Melinta, Shionogi, and Venatorx. LMA has served on advisory boards for Biomerieux, Roche, Pfizer, Shionogi, La Jolla/Innoviva, Ferrig, and AbbVie, and has received speaker honorarium from Gilead. SLA has served on advisory boards for Shionogi, GlaxoSmithKline, Melinta, and Basilea. AB has served on an advisory board for Beckman Coulter. RB has received travel funds from Biomerieux. KCC has served as a consultant for Biomerieux. KED has served on advisory boards for Shionogi, Spero, Melinta, Entasis, AbbVie, Melinta, Basilea, and GlaxoSmithKline, has received a speaker honorarium from MAD- ID, and has received travel funds from Society of Infectious Diseases Pharmacists where she serves as Treasurer. JCG has received honoraria from MJH, Inc where he serves as Associate Editor for Clinical Infectious Diseases, has received payment for expert testimony from German, Gallagher, & Murtagh, has served on advisory boards for Allergan, GlaxoSmithKline, Merck, Novavax, Qpex, Shionogi, and Spero. He serves as Editor in Chief for Contagion and received authorship royalties from JB Learning. ELH has served as a consultant for Wolters-Kluwer. KMH has served on a speaker’s bureau for Cepheid Diagnostics and has received travel funds from Biomerieux. KSK has served as a consultant for Merck, GlaxoSmithKline, Allecra, Shionogi, MicuRx, VenatoRx, and AbbVie. WDK has received funding from Merck and Shionogi. AM has received funding from F2G Biotech GmbH. EKM has served as a consultant for Abbvie, Merck, Basilea, Shionogi, Melinta, Ferring, Cidara, Entasis, LabSimply, Pfizer, and GlaxoSmithKline, received speaker honorarium from GlaxoSmithKline, Shionogi, and Pfizer, and has served as a safety monitor for the SNAP Trial and DMID. She is President Elect for the Society of Infectious Diseases Pharmacists. WRM has received funding from the NIH and royalties from UpToDate. JMP has served as a consultant for Merck, Shionogi, Melinta, Entasis, GlaxoSmithKline, and VenatoRx. He has received investigator-initiated funding from Merck, and has research grants from Merck, Shionogi, and Melinta. MJS has received funding from Merck, Biomerieux, and Selux Diagnostics, has served as a consultant from Shionogi, and has served on an advisory board for AbbVie. DV has received funding from Merck, has served as a consultant for Utility, Shionogi, Merck, Union, Roche, and Qpex, has received honoraria from Pfizer, Entasis, and Clinical Care Options, has received fees from the British Society of Antimicrobial Chemotherapy and Universidade Federal do Rio Grande do Sul. MV has served on an advisory board for Shionogi. VV has received funding from the Florida Department of Health, has received honoraria from the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, ID Week, the American Society of Microbiologists, and Merck, has received payment for expert testimony from Silver, Golub, & Teitell, LLP. All other authors have nothing to declare.

Ethical Approval: The CACTUS study was approved by local Institutional Review Boards at each participating site. The University of Pittsburgh was also approved as a coordinating center by local IRB, STUDY22020151.

Keywords: Pseudomonas aeruginosa, pneumonia, ceftolozane-tazobactam, ceftazidime-avibactam, Gram negatives, multidrug resistance