Keeping the horse with the cart: are we underdosing tazobactam even when using continuous-infusion ceftolozane/tazobactam for effectively preventing resistance development by ESBL-producing Enterobacterales?

Ceftolozane/tazobactam is widely used against extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, yet FDA-approved dosing relies on intermittent infusion and a fixed 2:1 ratio that assumes adequate β-lactamase inhibition. Tazobactam's faster and variable clearance raises concerns for subtherapeutic exposure. This study evaluated whether continuous infusion (CI) improves pharmacokinetic target attainment and whether current dosing adequately covers both components. We conducted an analysis of 139 hospitalized adults receiving CI ceftolozane/tazobactam with therapeutic drug monitoring (TDM). Free steady-state concentrations (<i>f</i>Css) and observed clearance were calculated and assessed across kidney function strata. Population pharmacokinetic modeling and Monte Carlo simulations evaluated the probability of target attainment (PTA) for each drug. Despite kidney function-adjusted CI, 38.1% of patients had tazobactam <i>f</i>Css <4 mg/L, a threshold linked to reduced efficacy and resistance emergence, while only 2.5% had ceftolozane <i>f</i>Css <8 mg/L (namely 4× MIC the Enterobacterales clinical breakpoint for susceptibility). Tazobactam clearance (mean 7.41 L/h) was 2.5-fold higher than ceftolozane and highly variable (CV 115%). Kidney function explained only 23% of clearance variability. The cohort's older age (median 66 years; 26.6% ≥75 years) likely led to lower tazobactam clearance, suggesting even greater underexposure in younger patients. Simulations showed standard dosing achieved only 29%-54% cumulative response against ESBL-producing Enterobacterales, versus 73%-82% with optimized regimens using 2-3× higher ceftolozane/tazobactam doses of magnitude similar to those licensed for pneumonia. Current ceftolozane/tazobactam dosing, even with CI, is often subtherapeutic for tazobactam. These findings challenge fixed-ratio formulations and support individualized, component-guided dosing to preserve efficacy and suppress resistance.