Comparison of Ceftolozane–Tazobactam Versus Meropenem Regimens in Treating Bloodstream Infections Caused by Extended-Spectrum β-Lactamase-Producing Enterobacterales: Real-World Data from a Greek Tertiary Center

Background/Objectives: The rise of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales has led to an increased carbapenem use, raising concerns regarding selection pressure for carbapenem-resistant organisms. Ceftolozane–tazobactam (C/T) is a potential effective carbapenem-sparing alternative. This single-centre retrospective study evaluated the clinical effectiveness and mortality predictors of ceftolozane–tazobactam versus meropenem as definitive targeted therapy for ESBL-producing Enterobacterales bloodstream infections (BSIs). Methods: We conducted a single-center retrospective analysis of adult hospitalized patients between January 2022 and February 2024 who presented with BSIs caused by ESBL-producing Enterobacterales. Patients (N = 185) were included if they received either C/T (n = 73) or optimized high-dose meropenem (n = 112) for at least 48 h. The primary clinical endpoint was all-cause 30-day mortality. Secondary endpoints included clinical success (cure), in-hospital mortality, treatment duration, microbiological eradication, and infection recurrence rates. A multivariable logistic regression model was executed to determine independent predictors of 30-day mortality. Results: Escherichia coli (54.1%) and Klebsiella pneumoniae (35.1%) were the primary pathogens. The raw clinical success rate was higher with C/T than meropenem (83.6% vs. 71.6%, p = 0.078). Unadjusted 30-day mortality was 12.3% for C/T and 19.6% for meropenem (p = 0.342). Zero recurrences occurred with C/T compared to an 8.0% recurrence rate with meropenem (0/73 [0.0%] in C/T vs. 9/112 [8.0%] in meropenem, p = 0.015). In the multivariable logistic regression analysis, definitive targeted treatment with C/T was independently associated with lower odds of all-cause 30-day mortality (Adjusted Odds Ratio [aOR] 0.60; 95% Confidence Interval [CI] 0.33–0.92; p = 0.022). Conversely, independent clinical mortality risks included male gender (p = 0.027), baseline SOFA score (p = 0.001), septic shock (p = 0.001), and an unknown primary infection source (p = 0.001). Conclusions: In this single-center retrospective observational cohort, definitive targeted therapy with ceftolozane–tazobactam was associated with favorable clinical success and lower adjusted 30-day mortality compared to meropenem in patients with ESBL Enterobacterales BSIs. These observational data support further prospective evaluation of C/T as a potential carbapenem-sparing option. Prospective randomized controlled trials are required to confirm these findings before clinical practice algorithms are modified.