Cerebrospinal fluid penetration of new antibiotics in the treatment of central nervous system infections

Background: Multidrug-resistant (MDR) bacterial infections present significant challenges to the management of central nervous system (CNS) infections, particularly in neurosurgical patients and those with cerebrospinal fluid (CSF) diversion devices. Achieving adequate CNS exposure is complicated by variable blood–brain barrier permeability and physiological changes, and CSF concentrations are not reliably predicted by plasma concentrations. Several new antibiotics have been introduced in response to rising MDR rates. To date, none are licensed for CNS infections, and data on CSF penetration and clinical utility are limited. Summary: Evidence describing CSF penetration of new antibiotics is limited and largely derived from small pharmacokinetic studies and case reports, predominantly in post-neurosurgical meningitis and ventriculitis. ?-Lactams (BL) such as cefiderocol, and the ?-lactam/?-lactamase inhibitor (BL/BLI) combinations ceftazidime–avibactam, ceftolozane–tazobactam and sulbactam–durlobactam, have achieved target CSF concentrations in individual cases, particularly with meningeal inflammation and intensive dosing. Predictors of adequate penetration are poorly defined, limiting identification of patients most likely to benefit, and the role of therapeutic drug monitoring (TDM) remains uncertain. Lipoglycopeptides and newer tetracyclines generally demonstrate low CSF penetration after systemic administration, with sparse clinical data supporting their use. Key messages: CSF exposure to new antibiotics is highly variable, inconsistently achieves pharmacodynamic targets, and cannot be reliably inferred from plasma concentrations. Limited evidence suggests that BLs and BL/BLI combinations may have utility, whereas newer lipoglycopeptides and tetracyclines do not. Prospective studies and multicentre registries are required to better define CNS exposure, clarify the role of TDM, and inform practice.