CONVINCE
CefiderOcol treatmeNt Versus ceftolozane/tazobactam for the treatment of pneumonia and/or bloodstream INfeCtions due to multidrug-resistant PsEudomonas aeruginosa
Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in the United States.1,2 In recent years, several novel beta-lactam antibiotics have been developed with enhanced activity against multidrug-resistant (MDR) P. aeruginosa, including ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and cefiderocol. Ceftolozane-tazobactam is recommended as the preferred agent for MDR P. aeruginosa infections due to ceftolozane’s stability against key β-lactam resistance mechanisms in P. aeruginosa,3-5 favorable PK/PD characteristics,6-9 efficacy in a phase III trial of patients with ventilated pneumonia,10 and superiority to alternative treatment options (polymyxins or aminoglycosides) for MDR P. aeruginosa infections.11,12 Ceftazidime-avibactam and imipenem-relebactam are also recommended as preferred treatment options by the Infectious Diseases Society of America (IDSA) for the treatment of difficult-to-treat P. aeruginosa.13
In contrast, cefiderocol is not recommended as a preferred treatment option, and the agent’s efficacy against MDR P. aeruginosa infections remains undefined. Unlike ceftazidime-avibactam and imipenem-relebactam, cefiderocol is not reliant upon a β-lactamase inhibition to restore in vitro activity of a partner β-lactam. Cefiderocol has been designed to overcome most β-lactam resistance mechanisms in P. aeruginosa and is not readily hydrolyzed by chromosomal AmpC or other clinically relevant carbapenemase enzymes in P. aeruginosa.14 Iron transport pathways allow cefiderocol to enter the periplasm and inhibit PBP3 with high affinity.15 These unique mechanisms translate into high rate of in vitro activity against P. aeruginosa, including against isolates non-susceptible to other novel beta-lactams16. Whether this enhanced in vitro activity is associated with improved clinical efficacy is unknown.
Background
Details
CONVINCE is a retrospective, multicenter, observational study comparing the clinical efficacy of cefiderocol and ceftolozane/tazobactam among patients with multidrug-resistant P. aeruginosa infections in the United States. We aim to define short- and long-term outcomes of patients over 90 days from study treatment initiation. Acknowledging that cefiderocol and ceftolozane-tazobactam are rarely used interchangeably, we have designed CONVINCE to account for inherent indication biases. We will use inverse probability of treatment weighting to adjust for baseline confounders across patient cohorts.
Whenever available, isolates will be collected from participating sites for molecular characterization, identification of resistance mechanisms, and broth microdilution susceptibility testing.
Progress
Sites are currently completing onboarding tasks.
References
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3. Takeda S, Ishii Y, Hatano K, Tateda K, Yamaguchi K. Stability of FR264205 against AmpC beta-lactamase of Pseudomonas aeruginosa. Int J Antimicrob Agents 2007; 30(5): 443-5.
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14. Ito A, Nishikawa T, Ota M, et al. Stability and low induction propensity of cefiderocol against chromosomal AmpC beta-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae. J Antimicrob Chemother 2018; 73(11): 3049-52.
15. Ito A, Sato T, Ota M, et al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother 2018; 62(1).
16. Shields RK, Kline EG, Squires KM, Van Tyne D, Doi Y. In vitro activity of cefiderocol against Pseudomonas aeruginosa demonstrating evolved resistance to novel beta-lactam/beta-lactamase inhibitors. JAC Antimicrob Resist 2023; 5(5): dlad107.