High-dose ceftriaxone: Pharmacokinetic and pharmacodynamic insights in hospitalized patients with suspected sepsis in Thailand.

AIM: Appropriate drug exposure is as crucial as proper selection and timely antibiotic administration in sepsis treatment. However, evidence is lacking regarding the current dosing regimen to achieve pharmacodynamic targets. This study aimed to describe ceftriaxone pharmacokinetic (PK) parameters and establish optimal dosing regimens for sepsis patients.

METHODS: This study investigated the pharmacokinetics of ceftriaxone in sepsis patients receiving ceftriaxone 2 g every 12 or 24 h. Blood samples (11-14 samples per patient) were collected within the first 24 h post-administration. PK parameters were estimated from unbound plasma concentrations using a nonlinear mixed-effects modelling approach (NONMEM® software). Monte Carlo simulations were conducted to evaluate the probability of target attainment of standard and high-dose ceftriaxone at various minimum inhibitory concentrations (MICs).

RESULTS: Population PK analysis of 238 concentration-time data points from 20 patients revealed that a two-compartment model best described ceftriaxone PK. Glomerular filtration rate (GFR), serum albumin, and body weight significantly affected clearance, volume of distribution, and intercompartmental clearance, respectively. Simulation demonstrated that standard dose of 2 g every 24 h was adequate for pathogens with MIC ≤1 mg L-1. At higher MIC values, target attainment decreased, particularly in with GFR > 130 mL·min-1, with twice-daily dosing yielding higher exposures.

CONCLUSION: Standard ceftriaxone (2 g intravenous q 24 h, 30-min infusion) provided adequate target attainment at low MICs in this exploratory study of suspected sepsis. PTA decreased with higher MICs and higher renal function, with higher dose regimens showing numerically greater exposures. These findings may help guide future studies on dosing optimization.