Prolonged infusion of linezolid is associated with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles in patients with external ventricular drains.

OBJECTIVE: We previously investigated the pharmacokinetic and pharmacodynamic (PK/PD) parameters of routine linezolid infusions (1 h) in patients with external ventricular drains (EVD). The aim of the study was to determine whether extended linezolid infusions (200 mg/h for 3 h) were more efficacious than short linezolid infusions (600 mg/h for 1 h). METHODS: We collected cerebrospinal fluid (CSF) and plasma samples from 10 patients who received linezolid infusions after cerebral hemorrhage surgery with EVDs. Linezolid concentrations were measured by high-performance liquid chromatography (HPLC). A Monte Carlo simulation was used to measure the probability of target attainments (PTA) and the PK/PD indexes at four minimum inhibitory concentrations (MIC). RESULTS: When the same dose (600 mg) was given as an extended infusion (3 h), linezolid reached its maximum concentrations in the plasma and CSF at 3.00 h and 4.40 h, respectively. The mean penetration of linezolid in CSF was 41.31%. Using the parameter of AUC0-24 h/MIC ≥ 100, the plasma PTA provided good coverage at > 90% when MIC was ≤ 1 µg/mL, while the values were 0 in CSF. Using the parameter %T (time) > MIC ≥ 85%, the PTA in both the plasma and CSF provided good coverage when MIC ≤ 2 µg/mL. Compared with routine infusions, prolonged infusion times (3 h) showed increased PTA of linezolid. CONCLUSIONS: Prolonged infusion times increased the concentration of linezolid in the plasma, leading to improved therapeutic outcomes. However, this improvement did not exist in CSF. Lastly, the PK/PD indicator AUC/MIC ≥ 100 may be used to achieve improved outcomes in patients with critical infections.

Staphylococcal meningitis therapy with linezolid in a young infant: efficacy, CSF levels and side effects.

BACKGROUND: Linezolid is a synthetic antibiotic which is active against most Gram-positive bacteria, especially on Staphylococcus aureus. Its administration can be required when the infection is due to staphylococcus strains, which are resistant to vancomycin. Although mostly well tolerated, some mild to moderate side effects have been reported. CASE PRESENTATION: This case report describes an infant with multiloculated hydrocephalus, staphylococcal meningitis and prolonged linezolid therapy, in which we observed the association between linezolid administration and a lengthened QTc interval at the electrocardiogram (ECG). To rule out toxic levels during the therapy, plasma and cerebro-spinal fluid concentrations of linezolid were measured and reported. CONCLUSIONS: Although generally well tolerated in neonates and infants, linezolid prolonged administration seems be able to cause QTc interval prolongation. Therefore, its administration in such patients should be limited to cases of bacterial resistance to other antibiotics. In addition to well-known close monitoring of the platelet level, we suggest serial ECG controls before and during linezolid administration. In the case we report, linezolid plasma concentrations resulted within the therapeutic range during therapy, while cerebrospinal fluid (CSF) concentrations appeared lower than those considered effective.

Pharmacokinetics and pharmacodynamics of linezolid in plasma/cerebrospinal fluid in patients with cerebral hemorrhage after lateral ventricular drainage by Monte Carlo simulation.

OBJECTIVE: We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of linezolid in patients who had suffered cerebral hemorrhage after lateral ventricular drainage. MATERIALS AND METHODS: Ten patients with cerebral hemorrhage after lateral ventricular drainage with stroke-associated pneumonia who were given linezolid were enrolled. Plasma and cerebrospinal fluid (CSF) samples were taken at appropriate intervals after the first administration of linezolid and assayed by high-performance liquid chromatography (HPLC). Then, PK parameters were estimated, and a Monte Carlo simulation was used to calculate the probability of target attainments (PTAs) for linezolid achieving the PK/PD index at different minimal inhibitory concentrations (MICs). RESULTS: The maximum concentration of linezolid in plasma and CSF was reached at 1.00 h and 3.10 h, respectively. The average penetration of linezolid in CSF was 56.81%. If the area under the plasma concentration vs time curve from zero to the final sampling time (AUC0-24 h)/MIC ≥ 59.1 was applied as a parameter, the PTA of linezolid in plasma could provide good coverage (PTA ≥ 90%) only for pathogens with a MIC of ≤2 µg/mL, whereas it could be achieved in CSF with a MIC of ≤1 µg/mL. If %T > MIC ≥ 40% was applied as a parameter, the PTA of linezolid in plasma/CSF could provide good coverage if the MIC was ≤4 µg/mL. CONCLUSIONS: For patients with infection of the central nervous system and who are sensitive to the drug, the usual dosing regimens of linezolid can achieve a good therapeutic effect. However, for critically ill or drug-resistant patients, an increase in dose, the frequency of administration, or longer infusion may be needed to improve the curative effect.