Linezolid use in postoperative central nervous system infections: a pharmacokinetic simulation-based approach for critically ill patients.

BACKGROUND

Postoperative central nervous system (CNS) infections pose a significant challenge in neurosurgery. While linezolid may offer advantages over vancomycin, its optimal dosing for critically ill patients remains unclear. This study aims to optimize linezolid treatment in ICU patients with postoperative CNS infections using pharmacokinetic/pharmacodynamic modeling and simulation.

METHODS

ICU population PK models were analyzed using Monte Carlo simulations (n = 1,000) to evaluate six LZD regimens: 600 mg q12 h, 600 mg q8h, 600 mg q6h, and equivalent total daily doses by continuous infusion. Probability of target attainment (PTA) was calculated for time above MIC (%T>MIC) ≥85% and AUC/MIC > 100 in plasma and cerebrospinal fluid. MIC distributions of common pathogens were incorporated to estimate the cumulative fraction of response (CFR) for each regimen.

RESULTS

Standard 600 mg q12 h dosing failed to achieve >90% PTA at MIC = 1 mg/L in all models. Intensified regimens (600 mg q8h, q6h, or continuous infusion) improved target attainment. A 2400 mg/day continuous infusion was required to consistently cover pathogens with MIC = 2 mg/L, albeit with a non-negligible toxicity risk. As approximately 90% of clinical isolates show linezolid MICs of 1-2 mg/L, CFR analysis suggested that ∼50% of ICU patients may be underdosed with the standard regimen.

CONCLUSIONS

Standard linezolid dosing appears inadequate for postoperative CNS infections in ICU patients. Optimized regimens are necessary to reliably target pathogens with MIC ≥ 1 mg/L. Due to linezolid's narrow therapeutic window and toxicity risk at higher doses, individualized dosing and therapeutic drug monitoring may be recommended in neurocritical care settings.