Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges

Abstract

Serum and cerebrospinal fluid (CSF) concentrations of fosfomycin were evaluated in 45 patients. Mean serum concentration was 260.1 mg/l at 15 min postinfusion in 35 patients receiving a 5 g bolus dose, and 440 mg/l in five patients receiving a 10 g bolus dose. Mean distribution volume was 18.5 l (5 g dose), the total clearance was 118.8 ml/min, half-life was nearly 2 h, and the determined AUC were 420.95 mg/l.h (5 g dose) and 423.57 mg/l.h (10 g dose). The average peaks at 360 min in CSF reached 11.6 mg/l (5 g dose) and 17.7 mg/l (10 g dose). The CSF/serum ratio was 9.24% (5 g dose), and 13.81% (10 g dose). The CSF levels were not below 30 mg/l from the second day on in patients receiving 3 X 5 g fosfomycin per day. Meningeal inflammation increased the CSF concentrations from 30 mg/l at 6 h up to 150 mg/l at 120 h in the saturation phase, e. g., up to 300% more in comparison to non-inflamed meninges.

Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

“…In patients with cerebrospinal fluid (CSF) drainage, the CSF concentration of fosfomycin was 9.2% and 13.8% of the corresponding concentration in serum after a 5 g and 10 g i.v. dose, respectively [24]. Furthermore, in patients who received 5 g of fosfomycin three times daily, drug levels of >30 mg/L were reached in the CSF by the second day of treatment.…”

Fosfomycin

“…In patients with CSF drainage, a single 5-g or 10-g dose resulted in CSF levels 9.2% and 13.8%, respectively, of those in plasma. When given at a dose of 5 g every 8 h, its CSF levels were 30 mg/liter or more after the second day of treatment and tripled in cases of inflammation (196). In a small study enrolling 6 ICU patients with ventriculostomy-associated ventriculitis, fosfomycin's AUC at steady state in CSF was 27% of that in plasma (197).…”

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

“…Fosfomycin is a very small hydrophilic compound with a molecular mass of only 138 Da, which is neither metabolized nor protein bound (115). Because of its low molecular mass and despite its hydrophilicity, it enters the CNS in the presence and absence of meningeal inflammation more readily than ␤-lactam antibiotics (115,193).…”