STEWARDS

Optimizing escalation: Ceftolozane/tazobactam versus treatment with traditional anti-pseudomonal β-lactams for pneumonia or bloodstream infections due to MDR P. aeruginosa

For patients infected with MDR P. aeruginosa, the Infectious Disease Society of America and European Society of Clinical Microbiology and Infectious Diseases recommend preferential treatment with dose-optimized traditional β-lactam agents that retain in vitro susceptibility (aztreonam, cefepime, ceftazidime, meropenem, imipenem or piperacillin/tazobactam).^1,2 The clinical efficacy of these anti-pseudomonal β-lactam agents, however, relies upon individual minimum inhibitory concentrations (MICs), dosing regimens employed, and drug concentrations achieved at the site of infection. Even with ideal conditions, pharmacokinetic-pharmacodynamic targets may not be met.³ Co-resistance amongst traditional anti-pseudomonal β-lactams is common,⁴ and agents that retain in vitro activity tend to demonstrate MIC values at or near the susceptibility breakpoint in multidrug-resistant isolates. Ceftolozane-tazobactam on the other hand shows potent in vitro activity, demonstrates lower MIC₉₀ values than traditional anti-pseudomonal β-lactam agents in this setting, and achieves reliable exposures at the site of activity in the setting of pneumonia.⁵ Nonetheless, the agent is typically reserved for difficult-to-treat P. aeruginosa isolates by consensus guidelines, implying that other antibiotic options should be exhausted first.^1,2 It is unclear if earlier utilization of ceftolozane-tazobactam would result in improved outcomes for patients.

Background

Details

STEWARDS seeks to compare the clinical outcomes and rates of resistance development between ceftolozane-tazobactam and traditional anti-pseudomonal β-lactam agents used to treat multidrug-resistant P. aeruginosa pneumonia or bacteremia. Site investigators will record details on treatment choices prospectively, without intervening. Patients will be followed 90 days from the time of first in vitro active treatment for P. aeruginosa. To ensure equipoise between treatment options, eligible patients must be infected by an isolate susceptible to ceftolozane-tazobactam and at least one traditional beta-lactam.
The enrolling culture isolate, and all subsequent isolates for 90 days, will be shipped to the University of Pittsburgh. Serial isolates will be collected and matched to clinically-relevant events for the patient. Extended broth microdilution testing will be linked to whole genome sequences, allowing us to explore potential causes of resistance development.

Progress

Data collection has begun! Subcontracting and regulatory approvals are underway at additional sites. Check back for updates!

References
1. Paul M, Carrara E, Retamar P, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect 2022; 28(4): 521-47.
2. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. 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 (DTR-P. aeruginosa). Clin Infect Dis 2021; 72(7): e169-e83.
3. Abdul-Aziz MH, Portunato F, Roberts JA. Prolonged infusion of beta-lactam antibiotics for Gram-negative infections: rationale and evidence base. Curr Opin Infect Dis 2020; 33(6): 501-10.
4. Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev 2009; 22(4): 582-610.
5. Lizza BD, Betthauser KD, Ritchie DJ, Micek ST, Kollef MH. New Perspectives on Antimicrobial Agents: Ceftolozane-Tazobactam. Antimicrob Agents Chemother 2021; 65(7): e0231820.