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.

Diagnostic and prognostic value of procalcitonin for early intracranial infection after craniotomy.

Intracranial infection is a common clinical complication after craniotomy. We aimed to explore the diagnostic and prognostic value of dynamic changing procalcitonin (PCT) in early intracranial infection after craniotomy. A prospective study was performed on 93 patients suspected of intracranial infection after craniotomy. Routine peripheral venous blood was collected on the day of admission, and C reactive protein (CRP) and PCT levels were measured. Cerebrospinal fluid (CSF) was collected for routine biochemical, PCT and culture assessment. Serum and CSF analysis continued on days 1, 2, 3, 5, 7, 9, and 11. The patients were divided into intracranial infection group and non-intracranial infection group; intracranial infection group was further divided into infection controlled group and infection uncontrolled group. Thirty-five patients were confirmed with intracranial infection after craniotomy according to the diagnostic criteria. The serum and cerebrospinal fluid PCT levels in the infected group were significantly higher than the non-infected group on day 1 (P<0.05, P<0.01). The area under curve of receiver operating characteristics was 0.803 for CSF PCT in diagnosing intracranial infection. The diagnostic sensitivity and specificity of CSF PCT was superior to other indicators. The serum and CSF PCT levels have potential value in the early diagnosis of intracranial infection after craniotomy. Since CSF PCT levels have higher sensitivity and specificity, dynamic changes in this parameter could be used for early detection of intracranial infection after craniotomy, combined with other biochemical indicators.

Diagnostic and prognostic value of procalcitonin for early intracranial infection after craniotomy

Intracranial infection is a common clinical complication after craniotomy. We aimed to explore the diagnostic and prognostic value of dynamic changing procalcitonin (PCT) in early intracranial infection after craniotomy. A prospective study was performed on 93 patients suspected of intracranial infection after craniotomy. Routine peripheral venous blood was collected on the day of admission, and C reactive protein (CRP) and PCT levels were measured. Cerebrospinal fluid (CSF) was collected for routine biochemical, PCT and culture assessment. Serum and CSF analysis continued on days 1, 2, 3, 5, 7, 9, and 11. The patients were divided into intracranial infection group and non-intracranial infection group; intracranial infection group was further divided into infection controlled group and infection uncontrolled group. Thirty-five patients were confirmed with intracranial infection after craniotomy according to the diagnostic criteria. The serum and cerebrospinal fluid PCT levels in the infected group were significantly higher than the non-infected group on day 1 (P<0.05, P<0.01). The area under curve of receiver operating characteristics was 0.803 for CSF PCT in diagnosing intracranial infection. The diagnostic sensitivity and specificity of CSF PCT was superior to other indicators. The serum and CSF PCT levels have potential value in the early diagnosis of intracranial infection after craniotomy. Since CSF PCT levels have higher sensitivity and specificity, dynamic changes in this parameter could be used for early detection of intracranial infection after craniotomy, combined with other biochemical indicators.

Early monitoring of ventriculostomy-related infections with procalcitonin in patients with ventricular drains.

Several factors are implicated in the increased vulnerability of multiple trauma victims to infection, especially in intensive care units. The incidence of EVD related infections ranges from 5 to 20%. To assess the accuracy of serum procalcitonin (PCT) in predicting central nervous system (CNS) infection in patients with EVDs. Thirty-six adult patients with severe head trauma were enrolled in this prospective study, after exclusion of other causes of fever; patients were subjected to sampling of C-reactive protein (CRP), PCT, and cerebrospinal fluid (CSF) cultures every other day. Five patients developed ventriculostomy-related infections, and all had an elevated serum PCT concentration. Patients with negative CSF cultures had mean serum PCT <2.0 ng/ml, while patients with positive culture had early elevation of serum PCT with mean of 4.18 ng/ml, CRP did not show similar early changes. Patients who acquire CNS infection had prolonged length of stay in hospital and length of ventilation. In absence of other nosocomial infections, early high serum PCT concentrations appear to be a reliable indicator of bacterial CNS infection in patients with EVD.

The methodology and pharmacokinetics study of intraventricular administration of vancomycin in patients with intracranial infections after craniotomy.

OBJECTIVE: The purpose of the study was to investigate the pharmacokinetics of combined intravenous (i.v.) and intracerebroventricular (i.c.v.) vancomycin for patients with intracranial infections after craniotomy and to provide the basis for establishing the intracranial local administration criterion. METHODS: Fourteen postoperative intracranial infection cases with surgical cavity/ventricular drainages were given vancomycin (1.0 g, i.v. drip for 2 hours, quaque 12 h, and a simultaneous i.c.v. injection of 10 mg). Their blood and cerebral spinal fluid (CSF) specimens were collected at each time point before and after administrations. The concentrations and biochemical properties were measured. RESULTS: The 1-hour serum vancomycin concentration reached a peak of 46.38 ± 33.39 mg/L; the trough concentration of 48 hours was 8.10 ± 7.11 mg/L; the CSF vancomycin concentration reached a peak of 382.17 ± 421.00 mg/L at 0.25 hours, and the 48-hour trough concentration was 30.82 ± 29.53 mg/L. The inhibitory quotient was calculated at 15.4 by the minimum inhibitory concentration 2 mg/L of target bacteria and had reached the range of 10 to 20 recommended by Infectious Diseases Society of America guidelines. The pH value and osmotic pressure of CSF were found to have no significant changes before and after administration. There was no increasement of seizures and ototoxicity in our study. Before the drug administration and 1 week later, the changes of creatine had no statistically significant, with P > .05. CONCLUSIONS: The combined i.v. and i.c.v. administration may improve CSF vancomycin concentrations without side effects at the same dosage. Our finding suggests that it can be an option for the treatment of severe intracranial infections after craniotomy; however, its safety and effectiveness need to be confirmed by further large-scale studies.

Low flucloxacillin concentrations in a patient with central nervous system infection: the need for plasma and cerebrospinal fluid drug monitoring in the ICU.

OBJECTIVE: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. CASE SUMMARY: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration; MIC, 1 µg/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 µg/mL), and the corresponding CSF concentrations were undetectable (<0.1 µg/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 µg/mL) and CSF (0.1 µg/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 µg/mL; CSF, 4 µg/mL). DISCUSSION: The presence of physiological changes associated with critical illness-namely, hypoalbuminemia and augmented renal clearance-may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery. CONCLUSIONS: Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness.

Pharmacokinetics of single-dose daptomycin in patients with suspected or confirmed neurological infections.

There are currently few or no published data on the amount of cerebrospinal fluid (CSF) penetration of daptomycin in patients with suspected or documented neurosurgical infections. We conducted a prospective study, assessing the pharmacokinetics and CSF penetration of a single intravenous daptomycin dose administered at 10 mg/kg, based on total body weight (TBW), in six neurosurgical patients with indwelling external CSF shunts with suspected or documented meningitis or ventriculitis. Each patient had four blood and CSF samples drawn simultaneously at specific times after the end of infusion: 30 min, 6 h, 12 h, and 24 h. Pharmacokinetic parameters of daptomycin in serum were calculated using standard noncompartmental methods, and daptomycin was assayed using high-performance liquid chromatography (for serum) or liquid chromatography with mass spectrometry (for CSF). The mean (± standard deviation [SD]) maximum measured daptomycin concentrations were 93.7 ± 17.3 mg/liter in serum at 0.5 h postinfusion and 0.461 ± 0.51 mg/liter in CSF at 6 h postinfusion. The mean (± SD) daptomycin minimum concentrations were 13.8 ± 4.8 mg/liter in serum at 24 h postinfusion and 0.126 ± 0.12 mg/liter in CSF at 0.5 h postinfusion. The mean daptomycin penetration, determined by the area under the concentration-time curve in CSF (AUC(CSF))/(AUC(serum) ratio), was 0.8%. Corrected for protein binding, the overall CSF penetration was 11.5%. Additional pharmacokinetic studies evaluating multiple and/or higher dosages of daptomycin are necessary in human subjects to better characterize the CSF penetration of daptomycin in neurosurgical patients.

Correction of ventricular cerebrospinal fluid (CSF) samples for blood content does not increase sensitivity and specificity for the detection of CSF infection.

BACKGROUND: Blood contamination is commonly observed in ventricular cerebrospinal fluid (CSF) samples from patients with extraventricular drainage systems. Because the introduction of blood may interfere with the white blood cell count as a useful marker for the diagnosis of an infection, correction for blood content would be desirable. METHODS: In a retrospective study, we analysed the use of correction formulas in 724 blood-contaminated ventricular CSF samples. RESULTS: Using a standard correction method the white blood cell count was not normalised in most CSF samples, with pleocytosis indicating an inflammatory stimulus set by the blood itself or by the foreign body. When correcting white blood cell counts in the CSF of culture-positive patients, some samples were normalised or overcorrected. In addition, correction of the CSF white blood cell count did not increase sensitivity and specificity for the detection of culture-positive CSF samples. CONCLUSIONS: Correction is not necessary when using the white blood cell count as a parameter to predict CSF infection in ventricular CSF samples.

Residual brain infection in relapsing-fever borreliosis.

BACKGROUND: Neurological involvement is common in the spirochetal infection relapsing fever (RF) in both humans and experimental animals. RF is best known for antigenic variation caused by the sequential expression of variable outer membrane lipoproteins of 2 sizes, variable small (Vsp) and variable large (Vlp) proteins. Less understood is the persistence of RF borreliae in the brain after they are cleared from the blood, referred to as residual brain infection (RBI). Our goal was to investigate the phenomenon of RBI in RF. METHODS: We studied RBI in immunocompetent mice by culturing blood and perfused brain samples 1 month after intraperitoneal inoculation with Borrelia turicatae serotype 1 (Bt1). Mice deficient in Toll-like receptor 2 (TLR2-/-) or in B and T cells (scid) were included for comparison. RESULTS: All scid mice had persistent infection in blood and brain. RBI was found in 3 (19%) of 16 immunocompetent and TLR2-/- mice. RBI was caused by either persistence of the original serotype (Bt1) or newly emerged Vsp (n=1, renamed Bt3) or Vlp serotypes. The Vsp of Bt1 (Vsp1) and Bt3 (Vsp3) were 75% identical. CONCLUSIONS: RBI in RF is relatively frequent and can occur by persistence of the original or newly emerged serotypes.