Clinical outcomes and emergence of resistance of Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam

Abstract

  • Few studies compare outcomes of patients with difficult-to-treat resistant (DTR) Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam.

  • A multicenter prospective study was conducted from 2018 to 2023.

  • Patients received >72 hours of ceftolozane-tazobactam or ceftazidime-avibactam, confirmed susceptible by broth microdilution.

  • Inverse probability weighting (IPW) was used for balanced baseline characteristics.

  • The study assessed 30-day mortality and emergence of resistance (≥4-fold increase in MIC).

  • Among 186 patients, 102 (55%) received ceftolozane-tazobactam, and 84 (45%) received ceftazidime-avibactam.

  • Thirty-day mortality was similar between groups (21% vs. 17%).

  • Emergence of resistance was higher with ceftolozane-tazobactam (38% vs. 25%) but did not reach statistical significance.

  • Durations of longer treatment and use of CRRT were linked to increased emergence of resistance.

  • Both agents appear equally effective for survival, but ceftolozane-tazobactam may have a greater concern for resistance emergence.

Introduction to Pseudomonas aeruginosa

  • Pseudomonas aeruginosa poses significant morbidity and mortality risks, especially for complex medical conditions (e.g., cystic fibrosis, burns, prosthetics).

  • It accumulates resistance through mechanisms like decreased outer membrane porin expression, increased efflux pump expression, and penicillin-binding protein modifications.

  • Defined as DTR, isolates exhibit non-susceptibility to traditional β-lactams and fluoroquinolones.

  • New β-lactam agents (e.g., ceftolozane-tazobactam, ceftazidime-avibactam) for DTR P. aeruginosa were approved, yet comparative outcome studies are limited.

Study Design and Methods

Study Design

  • Conducted a prospective observational study within the Johns Hopkins Health System from January 2018 to December 2023.

Eligibility Criteria

  • Inclusion: Clinical P. aeruginosa isolate meeting DTR definition, infection confirmation, susceptibility to administered β-lactam, treatment for ≥72 hours.

  • Exclusion: Patients dying within 72 hours post treatment initiation.

Antibiotic Stewardship

  • Both antibiotics require prior approval by the Antibiotic Stewardship Program before administration.

  • Treatment guidelines favor ceftolozane-tazobactam and ceftazidime-avibactam for DTR P. aeruginosa.

  • Dose adjustments based on renal function are outlined, but specific guidelines for CRRT are lacking.

Outcomes and Data Collection

Outcomes

  • Primary outcomes: 30-day all-cause mortality and emergence of resistance defined as a ≥4-fold rise in MIC.

  • Data collected included demographics, medical histories, renal function, and outcomes via chart review.

Statistical Analysis

  • Baseline characteristics were analyzed using t-tests and Fisher’s exact test.

  • Inverse probability weighting (IPW) was applied; balance was checked before and after weighting.

Results

Cohort Overview

  • 186 patients analyzed: 102 (55%) on ceftolozane-tazobactam, 84 (45%) on ceftazidime-avibactam.

  • 30-day mortality was close (21% vs 17%).

  • Resistance emergence was higher for ceftolozane-tazobactam (38% vs 25%), nearing significance (P = 0.09).

Baseline Characteristics Comparison

  • Both groups compared pre-and post-IPW showed similar baseline characteristics.

  • Annotations of severe immunocompromise were higher in the ceftolozane-tazobactam group prior to adjustments.

  • Common infection sources included pneumonia, bloodstream, skin & soft tissue.

Risk Factors for Emergence of Resistance

  • Continuous renal replacement therapy (CRRT) linked with increased resistance emergence (P = 0.04).

  • Longer treatment duration also associated with increased subsequent resistance likelihood.

Discussion and Conclusion

  • Although survival rates are similar between treatments, ceftolozane-tazobactam has a concerning higher rate of resistance emergence.

  • This implies careful selection in empiric antibiotic therapy could benefit patient outcomes, especially in cases needing renal replacement therapy.

  • Limitations include the observational nature of the study and potential bias in sample selection and outcomes.

Acknowledgments

  • Support received from various NIH grants focused on antibacterial resistance leadership.

  • The content represents the authors' views not necessarily reflective of the NIH.

Funding and Contributions

  • Detailed grants and author contributions provided, highlighting collaborative efforts across multiple departments.