Rapid Colloidal Gold Immunoassay for Pharmacokinetic Evaluation of Vancomycin in the Cerebrospinal Fluid and Plasma of Beagle Dogs.

Vancomycin (VAN), a glycopeptide antibiotic, is the preferred therapeutic agent for treating Gram-positive bacteria. Rapid and precise quantification of VAN levels in cerebrospinal fluid (CSF) and plasma is crucial for optimized drug administration, particularly among elderly patients. Herein, we introduce a novel clinical test strip utilizing colloidal gold competitive immunoassay technology for the expedient detection of VAN. This test strip enables the detection of VAN concentrations in clinical samples such as plasma within 10 min and has a limit of detection of 10.3 ng/mL, with an inhibitory concentration 50% (IC50) value of 44.5 ng/mL. Furthermore, we used the test strip for pharmacokinetic analysis of VAN in the CSF and plasma of beagle dogs. Our results provide valuable insights into the fluctuations of the drug concentration in the CSF and plasma over a 24 h period after a single intravenous dose of 12 mg/kg. The test strip results were compared with the results obtained via liquid chromatography-mass spectrometry methods, and the measured VAN concentrations in the CSF and plasma via both of the methods showed excellent agreement.

[Therapeutic monitoring of cerebrospinal fluid vancomycin concentrations and analysis of their influencing factors in neurosurgical intensive care unit patients].

OBJECTIVE: To evaluate cerebrospinal fluid (CSF) vancomycin concentrations and identify factors influencing CSF vancomycin concentrations in critically ill neurosurgical patients. METHODS: A retrospective study was conducted. Adult patients who received vancomycin treatment and CSF vancomycin concentrations monitoring admitted to neurosurgical intensive care unit (ICU) of the First Affiliated Hospital of Sun Yat-sen University from January 2016 to June 2019 were enrolled. General information, vancomycin dosing regimens, CSF vancomycin concentrations, CSF drainage methods and volume of the previous day, and concurrent medications, etc. were collected for analysis. CSF vancomycin concentrations of patients with definite or indefinite central nervous system (CNS) infection, different vancomycin dosing regimens and their influencing factors were analyzed. RESULTS: A total of 22 patients were included. 168 CSF specimens were collected for culture, 20 specimens of which were culture positive, with a positive rate of 11.9%. Sixty cases of CSF vancomycin concentration were obtained. Among the 22 patients, 7 patients (31.8%) were diagnosed with proven CNS infection, 11 patients (50.0%) clinically diagnosed, 2 patients (9.1%) diagnosed with uncertain CNS infection, and 2 patients (9.1%) diagnosed without CNS infection. Intravenous (IV) administration of vancomycin alone was used in 15 cases (25.0%), intrathecal injection in 17 cases (28.3%), IV+intrathecal injection in 23 cases (38.3%), and IV+intraventricular administration in 5 cases (8.3%). The CSF vancomycin concentrations ranged from < 0.24 to > 100 mg/L, with an average level of 14.40 (4.79, 42.34) mg/L. (1) Administration methods of vancomycin affected CSF vancomycin concentrations. The CSF vancomycin concentration with intrathecal injection or intraventricular administration was higher than that of IV administration alone [mg/L: 25.91 (11.28, 58.17) vs. 2.71 (0.54, 5.33), U = 42.000, P < 0.01]. (2) When vancomycin was administered by IV treatment alone, CSF vancomycin concentrations were low in both groups with definite CNS infection (proven+probable) and indefinite CNS infection (possible+non-infection), the CSF vancomycin concentrations of which were 4.14 (1.40, 6.36) mg/L and 1.27 (0.24, 3.33) mg/L respectively, with no significant difference (U = 11.000, P = 0.086). (3) CSF vancomycin concentrations rose with the increased dose of vancomycin delivered by intrathecal injection or intraventricular administration. According to the dose of vancomycin administered locally on the day before therapeutic drug monitoring (TDM), cases were divided into the following groups: 0-15 mg group (n = 22), 20-35 mg group (n = 33), and 40-50 mg group (n = 5), the CSF vancomycin concentrations of which were 4.14 (1.09, 8.45), 30.52 (14.31, 59.61) and 59.43 (25.51, 92.45) mg/L respectively, with significant difference (H = 33.399, P < 0.01). Moreover, the cases of CSF vancomycin concentration of ≥ 10 mg/L accounted for 18.2%, 84.8% and 100% of these three groups, respectively. CSF vancomycin concentrations mostly reached target level when dose of vancomycin administered locally were 20 mg/L or more. CONCLUSIONS: It is difficult to reach target CSF vancomycin concentration for critically ill neurosurgical patients with or without CNS infection by IV treatment. Local administration is an effective treatment regimen to increase CSF vancomycin concentration.

Validation of a immunoassay for the determination of vancomycin in cerebospinal fluid. / [Validación de un método inmunológico para la determinación de vancomicina en líquido cefalorraquídeo.]

Introduction: Vancomycin (VAN) is an antibiotic used to treat serious infections. Its use is related to adverse effects such as acute facial hyperemia, nephrotoxicity and ototoxicity. By having a very narrow therapeutic range, its monitoring is necessary to maximize efficiency and minimize toxic effects. It is estimated that its concentration in CSF is approximately 10% of the plasma level in patients who receive intravenous treatment and who have meninges inflammation. Plasma concentrations of VAN are not a reliable indicator of those present in CSF. The aim of this study was to validate an immunological method based on the kinetic interaction of microparticles in solution (KIMS) for the determination of VAN in CSF. Materials and Methods: KIMS was validated for the evaluation of VAN in CSF. For this, the parameters of linearity, precision, accuracy, limit of detection, limit of quantification, interference, selectivity and specificity were determined. Results: The method was linear in a range between 0 and 15 µg/mL, the CV% obtained oscillated between 0.7 and 2.5% on the linear range. The LOD and LOQ were 0.4 µg/mL and 1.4 µg/mL respectively. The equation of the line obtained based on the correlation of methods between KIMS and HPLC-UV was y = 0.9151x + 1.1695, R² = 0.9453. Conclusion: The KIMS method demonstrated to have an adequate sensitivity and specificity to determine VAN in CSF and being a useful tool for monitoring patients who present complicated infections at CNS level. Materials and Methods: KIMS was validated for the evaluation of VAN in CSF. For this, the parameters of linearity, precision, accuracy, limit of detection, limit of quantification, interference, selectivity and specificity were determined. Results: The method was linear in a range between 0 and 15 µg/mL, the CV% obtained oscillated between 0.7 and 2.5% on the linear range. The LOD and LOQ were 0.4 µg/mL and 1.4 µg/mL respectively. The equation of the line obtained based on the correlation of methods between KIMS and HPLC-UV was y = 0.9151x + 1.1695, R² = 0.9453. Conclusion: The KIMS method demonstrated to have an adequate sensitivity and specificity to determine VAN in CSF and being a useful tool for monitoring patients who present complicated infections at CNS level.

Introducción: La vancomicina (VAN) es un antibiótico utilizado para el tratamiento de infecciones graves. Su uso está relacionado con efectos adversos como hiperemia facial aguda, nefrotoxicidad y ototoxicidad. Al tener un rango terapéutico muy estrecho, el monitoreo terapéutico resulta necesario para maximizar la eficiencia y minimizar los efectos tóxicos. Se estima que su concentración en LCR es, aproximadamente, un 10% de la plasmática en pacientes que reciben tratamiento endovenoso del mismo y que presentan inflamación de las meninges. Las concentraciones plasmáticas de VAN no son un indicador confiable de las presentes en LCR. El objetivo de este trabajo fue validar un método inmunológico basado en la interacción cinética de micropartículas en solución (KIMS) para la determinación de VAN en LCR. Materiales y Métodos: Se validó el método KIMS para la valoración de VAN en LCR. Para ello, se determinaron los parámetros de linealidad, precisión, exactitud, límite de detección, límite de cuantificación, interferencia, selectividad y especificidad. Resultados: el método fue lineal en un intervalo entre 0 y 15 µg/mL, los CV% obtenidos oscilaron entre 0,7 y 2,5% en el rango lineal. Los LOD y LOQ fueron 0,4 µg/mL y 1,4 µg/mL respectivamente. La ecuación de la recta obtenida en base a la correlación de métodos entre KIMS y HPLC-UV fue y= 0,9151x + 1,1695, R²=0,9453. Conclusión: El método KIMS demostró tener una sensibilidad y especificidad apropiadas para la determinación de VAN en LCR y, ser una herramienta útil para el monitoreo de pacientes que presenten infecciones complicadas a nivel del SNC.

Comparation of vancomycin penetration into cerebrospinal fluid in postoperative intracranial infection and community-acquired meningitis patients.

WHAT IS KNOWN AND OBJECTIVE: To compare the penetration of vancomycin into cerebrospinal fluid (CSF) in patients with postoperative intracranial infection and community-acquired meningitis, and to identify related factors influencing the penetration in these two diseases. METHODS: The concentrations of vancomycin in serum and CSF were determined by enzyme amplified immunoassay, and the CSF-to-serum ratios were calculated. The correlation between CSF-to-serum ratios of vancomycin and CSF elements was analyzed. RESULTS AND DISCUSSION: In postoperative intracranial infection patients and community-acquired meningitis patients, the vancomycin concentration in CSF was 1.90 ± 1.29 mg/L and 2.47 ± 1.15 mg/L, while the CSF-to-serum ratio was 0.19 ± 0.12 and 0.26 ± 0.12, respectively. There was a significant correlation between vancomycin serum concentration and bodyweight (P < 0.05). The CSF-to-serum ratio in postoperative intracranial infection patients was correlated to white blood cell count in CSF. However, in community-acquired meningitis patients, no relationship was seen with regards to CSF white blood cell count, protein or glucose. WHAT IS NEW AND CONCLUSION: Cerebrospinal fluid vancomycin penetration was similar in postoperative intracranial infection and community-acquired meningitis patients. The CSF-to-serum ratio was only correlated to CSF white blood cell count in postoperative intracranial infection patients.

Correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid/serum albumin ratio.

Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 ± 7.2 µg/mL and 3.31 ± 3.14 µg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis.

Brain Microdialysis Study of Vancomycin in the Cerebrospinal Fluid After Intracerebroventricular Administration in Mice.

Vancomycin (VCM) is an important antibiotic for treating methicillin-resistant Staphylococcus aureus (MRSA) infections. To treat bacterial meningitis caused by MRSA, it is necessary to deliver VCM into the meninges, but the rate of VCM translocation through the blood-brain barrier is poor. Additionally, high doses of intravascularly (i.v.) administered VCM may cause renal impairments. Thus, VCM is sometimes administered intracerebroventricularly (i.c.v.) for clinical treatment. However, information on the VCM pharmacokinetics in cerebrospinal fluid (CSF) after i.c.v. administration is lacking. In the present study, we evaluated the VCM pharmacokinetics in the CSF and systemic circulation after i.c.v. compared to that after i.v. administration, using the brain microdialysis method in mice. VCM administered via i.c.v. showed a highly selective distribution in the CSF, without migration to systemic circulation. Moreover, to assess renal impairments after i.c.v. administration of VCM, we histologically evaluated damage to the mouse kidney by hematoxylin and eosin staining. No significant morphological change in the kidney was observed in the i.c.v. administration group compared to that in the i.v. administration group. Our results demonstrate that i.c.v. administration of VCM can be partially prevented from entering the systemic circulation to prevent renal impairments caused by VCM.

Intrathecal penetration of meropenem and vancomycin administered by continuous infusion in patients suffering from ventriculitis-a retrospective analysis.

BACKGROUND: Vancomycin and meropenem are frequently used as empiric treatment for ventriculitis. Penetration into the cerebrospinal fluid (CSF) depends on various factors with a high inter-individual variability. Because attaining and maintaining adequate concentrations of meropenem and vancomycin in the CSF is crucial for their bactericidal effect, we introduced a routine therapeutic drug monitoring (TDM) from CSF and serum for both antibiotics. We studied the antibiotic penetration into the CSF. METHODS: Patient data including serum and CSF concentrations for meropenem and vancomycin were collected in a retrospective fashion. Antibiotic CSF penetration ratio was calculated for each patient. Antibiotics were administered by continuous infusion aiming for serum target concentrations of 20-30 mg/L for vancomycin and 16-32 mg/L for meropenem. RESULTS: Twenty-two patients with 36 CSF/serum pairs for meropenem and 43 pairs for vancomycin were studied. No patient suffered from renal or liver insufficiency. Mean vancomycin serum concentration was 22 ± 8 mg/L and the mean CSF concentration 4.5 ± 2.6 mg/L. CSF penetration was 20 ± 11% (coefficient of determination (R2) 0.02). For meropenem, the mean serum concentration was 30.7 ± 14.9 mg/L, mean CSF concentration 5.5 ± 5.2 mg/L, and a penetration of 18 ± 12%, R2 = 0.42. CONCLUSION: Penetration of meropenem and vancomycin into the CSF is low while showing a high interindividual variability. Various patients in our study cohort were at risk for insufficient target attainment in CSF. Continuous administration of antibiotics under routine TDM appears to be a feasible and reasonable approach for optimization of intrathecal drug levels in patients suffering from ventriculitis. TDM might guide individual dosing adaptation and efforts to predict the CSF penetration of meropenem and vancomycin in cases of ventriculitis.

Factors Influencing Norvancomycin Concentration in Plasma and Cerebrospinal Fluid in Patients After Craniotomy and Dosing Guideline: A Population Approach.

PURPOSE: Antibacterial spectrum and activity of norvancomycin are comparable with vancomycin, and it has been widely used in China. Norvancomycin can penetrate into the cerebrospinal fluid (CSF) through the damaged blood-brain barrier in patients after craniotomy. Because higher inter-individual variability was observed, we aimed to identify factors related to drug concentration to guide clinicians with norvancomycin dosing. METHODS: After craniotomy, patients with an indwelling catheter in the operational area/ventricle were intravenously administered norvancomycin. Venous blood and CSF specimens were collected at a scheduled time for measuring drug concentrations. Blood and CSF data were fitted simultaneously with the use of the nonlinear fixed-effects modeling method to develop the population pharmacokinetic model. Covariate analysis was applied to select candidate factors associated with pharmacokinetic parameters. A model-based simulation was performed to find optimized regimens for different subgroups of patients. FINDINGS: A 3-compartmental model (central, peripheral, and CSF compartments) with 2 elimination pathways (drug elimination from the kidney and CSF outflow) was developed to characterize the in vivo process of norvancomycin. The covariate analysis identified that weight and drainage amount were strongly associated with the central volume and the drug clearance from CSF, respectively. Goodness-of-fit and model validation suggested that the proposed model was acceptable. A dosage regimen table was created for specific patient populations with different weights and drainage amounts to facilitate clinical application. IMPLICATIONS: We identified 2 clinical markers associated with plasma and CSF concentrations. The proposed simulation may be useful to clinicians for norvancomycin dosing in this specific population with normal kidney function.

Plasma and cerebrospinal fluid population pharmacokinetics of vancomycin in postoperative neurosurgical patients after combined intravenous and intraventricular administration.

PURPOSE: Combined intravenous and intraventricular administration of vancomycin into the cerebrospinal fluid (CSF) has been increasingly utilized for neurosurgical patients, but little is known about the population pharmacokinetics of vancomycin in the plasma and CSF. The aim of our study was to identify significant factors associated with plasma and CSF vancomycin concentrations to guide clinicians with vancomycin dosing. METHODS: Patients with an indwelling ventricular drainage catheter who received intravenous and intraventricular vancomycin were enrolled in this study. Blood and CSF samples were collected at scheduled times and vancomycin concentrations determined. A three-compartmental model (central, peripheral and CSF compartments) was proposed to describe the in vivo behavior of vancomycin. CSF outflow resulted in vancomycin loss, and the clearance of CSF compartment (CLCSF) was used to describe this loss. The nonlinear mixed-effects modeling method was applied to structure the population model, and the stepwise incorporation of seven covariates into the final model was attempted. Simulation was performed with the goal of CSF concentrations reaching or exceeding the minimum inhibitory concentration during therapy. RESULTS: Serum creatinine clearance had a significant influence on clearance of the central compartment. CLCSF had a positive correlation with drainage amount and a negative correlation with elapsed time. Model validation (bootstrap and visual predictive check) demonstrated the stability and performance of the proposed population model. A simple-to-use dosage regimen table was created based on the simulation results. CONCLUSIONS: The proposed final model may be used to guide clinicians with vancomycin dosing in this specific patient population.

Penetration of Vancomycin into the Cerebrospinal Fluid: A Systematic Review.

INTRODUCTION: Infectious disease and pharmacokinetic textbooks indicate that vancomycin has poor penetration into the central nervous system due to its hydrophilic nature and high molecular weight. Recent literature suggests that penetration of vancomycin into cerebrospinal fluid (CSF) is higher than previously reported; therefore, we conducted a systematic review to assess the penetration of vancomycin into CSF. METHODS: We searched the MEDLINE, EMBASE, and CENTRAL electronic databases for English-language human studies evaluating serum and CSF concentrations of intravenous vancomycin. RESULTS: In 13 identified studies, the CSF-to-serum ratio of vancomycin varied from 0.00 to 0.81. CSF penetration ranged 0.06-0.81 in patients with meningitis, 0.05-0.17 in ventriculitis, 0.00-0.36 in other infections, and 0-0.13 in patients without infection. Despite variable CSF penetration, 83% of patients with meningitis and 100% of patients with ventriculitis achieved clinical cure. No factor predicted vancomycin CSF penetration. CONCLUSION: Contrary to prior belief, studies included in our review did not show universally low penetration of vancomycin into CSF. CSF vancomycin levels were variable and did not predict clinical cure.

Pharmacokinetics and cerebrospinal fluid penetration of norvancomycin in Chinese adult patients.

Norvancomycin is an antibiotic that has been approved for the treatment of infections caused by antibiotic-resistant Gram-positive bacteria and has been used in China for more than a decade. However, the cerebrospinal fluid (CSF) penetration of norvancomycin has not been evaluated. The aims of the study were (i) to investigate the pharmacokinetics and CSF penetration of norvancomycin in meningitis and non-meningitis patients and (ii) to recommend favourable dosing regimens in meningitis patients. Twenty adult patients (ten with meningitis and ten without meningitis) requiring norvancomycin treatment were enrolled. All patients received a norvancomycin regimen of 800 mg every 12 h. Blood and CSF samples were consecutively collected up to 12 h after the end of the fourth 60-min infusion. Norvancomycin concentrations both in serum and CSF were measured using a high-performance liquid chromatography (HPLC) assay. CSF penetration of norvancomycin was evaluated by calculating the CSF/serum ratio. Mean norvancomycin serum trough levels were 9.9 ± 1.44 µg/mL in patients with meningitis and 10.08 ± 1.12 µg/mL in patients without meningitis (P > 0.05). In addition, norvancomycin penetrated into the inflamed meninges, with mean CSF concentrations of 3.93-10.52 µg/mL and mean CSF/serum ratios of 0.18-0.43, both of which were significantly higher than in patients without meningitis (P <0.05). These results suggest that norvancomycin has higher CSF penetration in patients with meningitis compared with other groups and that norvancomycin is effective in treating patients with purulent meningitis at a comparably low dose.

A UPLC-MS/MS method for analysis of vancomycin in human cerebrospinal fluid and comparison with the chemiluminescence immunoassay.

Vancomycin (VCM) is clinically used in treating patients with postoperative intracranial infections. The cerebrospinal fluid (CSF) concentration of VCM varies greatly among patients. To guide the dosage regimens, monitoring of VCM in CSF is needed. However a method for analysis of VCM in human CSF is lacking. An ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for analysis of VCM in human CSF, and the agreement of UPLC-MS/MS and chemiluminescence immunoassay (CLIA) in the analysis of CSF VCM was evaluated. The ion transitions were m/z 725.5 > 144.1 for VCM and m/z 455.2 > 308.2 for methotrexate (internal standard). The agreement between UPLC-MS/MS and CLIA was evaluated by Bland-Altman plot in 179 samples. The calibration range of the UPLC-MS/MS method was 1-400 mg/L. The inaccuracy and imprecision were -0.69-10.80% and <4.95%. The internal standard normalized recovery and matrix factor were 86.14-99.31 and 85.84-92.07%, respectively. The measurements of CLIA and UPLC-MS/MS were strongly correlated (r > 0.98). The 95% limit of agreement of the ratio of CLIA to UPLC-MS/MS was 61.66-107.40%. Further studies are warranted to confirm the results.

Flucloxacillin does not achieve therapeutic cerebrospinal fluid levels against meticillin-sensitive Staphylococcus aureus in adults: A case report and review of the literature.

It is uncertain whether flucloxacillin achieves therapeutic concentrations against meticillin-sensitive Staphylococcus aureus (MSSA) in cerebrospinal fluid (CSF). In this study, plasma and CSF concentrations of flucloxacillin and vancomycin in an adult patient were compared. Unlike vancomycin, the flucloxacillin CSF level was not therapeutic. Flucloxacillin monotherapy should be used with caution for MSSA central nervous system infection in adults.

Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients.

Neurosurgical procedures may damage the blood-brain barrier to allow more vancomycin distribution into the cerebrospinal fluid (CSF) from blood after intravenous administration. However, a large intersubject variability in CSF vancomycin concentration was observed. We aimed to develop a population pharmacokinetic model to guide vancomycin dosing in patients after neurosurgical operation. Blood and CSF samples were collected and determined from postoperative neurosurgical patients after vancomycin administration. A three-compartment (central, peripheral, and CSF) model was proposed to characterize the pharmacokinetics of vancomycin. A nonlinear mixed-effects modeling approach was applied to fit the blood and CSF data simultaneously. The covariate analysis found that the CSF albumin level was strongly associated with the clearance between central and CSF compartment. Visual predictive check indicated that the proposed population pharmacokinetic model agrees well with the observed vancomycin concentrations. Individualized vancomycin dosage regimens could be developed for postoperative neurosurgical patients with different CSF albumin levels through model simulations. The CSF albumin level is a determinant of CSF vancomycin concentration.

An investigation into the vancomycin concentration in the cerebrospinal fluid due to vancomycin intraventricular administration in newborns: a study of 13 cases.

Treatment against shunt infection by transvenous antimicrobial treatment is difficult, with a high risk of relapse. Consequently, to maintain a sufficient cerebrospinal fluid (CSF) concentration, intraventricular administration is utilized in combination with the transvenous administration of vancomycin (VCM). Few studies have so far investigated the optimum administration dose for newborns and the concentration in the CSF. Therefore, we chronologically measured the VCM concentration in the CSF after VCM intraventricular administration in newborns and attempted to elucidate the optimum administration method.The participants consisted of newborns admitted to Juntendo University Neonatal intensive care unit from March 2007 to June 2011 who underwent interventricular shunting placement. VCM was intraventricularly administered to 10 patients for a total of 13 cases. The CSF concentration of VCM was chronologically measured at 12 to 120  hours following the intraventricular administration of VCM.The intraventricular administration groups with VCM of 20 (n = 6) and 10  mg (n = 2) had a high concentration in the CSF at 24  hours following administration (95-168  mg/L), with the concentration remaining high at 72  hours (13.2-72  mg/L). At the same time, in the 5  mg group (n = 5), the concentration in the CSF 24  hours following VCM administration was sufficiently maintained (33.2-62.9  mg/L), with a sufficient trough concentration still maintained at 72  hours (11.7-16.5  mg/L).The concentration in the CSF is prolonged in newborns, thus allowing a sufficient therapeutic range to be maintained even at an intraventricular administration of 5  mg. It is therefore believed that the monitoring of the CSF is very important regarding the administration interval because the VCM concentration in the CSF differs depending on the case.

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.

Vancomycin therapeutic drug monitoring in cerebrospinal fluid.

Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year-old man with post traumatic meningitis with vancomycin concentration measured in CSF.

Determination of vancomycin trough level in serum and cerebrospinal fluid of patients with acute community-acquired meningitis: a prospective study.

BACKGROUND: Penetration and concentration of vancomycin is still an elusive and complex issue particularly in Cerebrospinal Fluid (CSF). The aim of this study was to clarify the penetration of this antimicrobial agent in CSF during meningeal inflammation. METHODS: In a prospective study, adult patients, with clinical and CSF analysis compatible with acute meningitis, who received vancomycin (15 mg/kg loading and 30 mg/kg daily maintenance dose) with ceftriaxone (4 gr/daily) were enrolled. CSF analysis including vancomycin trough levels before the fourth maintenance dose and during the 8-10th days of treatment, and simultaneous serum levels were performed by High-Pressure Liquid Chromatography (HPLC). RESULTS: Twenty-seven patients (18 men, 9 women; mean age of 39.4 ± 14.7) were enrolled. The first serum trough level of vancomycin was 13.82 ± 1.28 mg/l. The mean of corresponding trough level in CSF was 11.2 ± 1.41 mg/l. The serum and CSF trough levels revealed positive linear correlation (r: 0.60) and was significant at the 0.01 level (P: 0.004). The penetration CSF/serum ratio was 0.811 ± 0.082 (coefficient of variation: 10.1%). The second trough levels of serum and CSF in (14 patients) vancomycin were 13.32 ± 1.02 and 10.64 ± 1.21, respectively. The serum and CSF trough levels revealed positive linear correlation (r: 0.71). The serum and CSF concentrations revealed no variation compared to the first trough levels. CONCLUSION: Vancomycin has appropriate concentration in CSF during the treatment of meningitis and do not decrease along with the alleviation of meningeal inflammation in spite of concerns in this regard.

Antibacterial therapeutic drug monitoring in cerebrospinal fluid: difficulty in achieving adequate drug concentrations.

This report illustrates the difficulty in managing CNS infection in neurosurgical patients, the altered drug pharmacokinetics associated with critical illness, and the role that therapeutic drug monitoring (TDM) of CSF can play in assisting clinical decision making. The authors present a case of external ventricular drain-related ventriculitis in a critically ill patient who initially presented with a subarachnoid hemorrhage. They discuss the physiological changes found in such patients, in particular augmented renal clearance (demonstrated in this patient by a measured creatinine clearance of 375 ml/min/1.73 m(2)), noting the effect this had on drug pharmacokinetics and leading to dosing requirements 2-3 times those recommended in standard regimens. The authors consider the bacterial "kill" characteristics of 2 different antibacterial agents (meropenem and vancomycin) and describe the unique approach of using plasma and CSF TDM to achieve optimal drug exposure at the site of infection while limiting toxic side effects. The authors demonstrate that simply using plasma TDM as a surrogate marker for drug concentration in the CNS may lead to underdosing, exemplified in this patient by CSF vancomycin concentrations as little as 13% of that in plasma. Finally, by measuring CSF and plasma ratios, the authors illustrate the disparity in pharmacokinetic properties between drugs, reminding the clinician of the importance of CNS penetration when selecting antibacterial agents in such cases. This work raises an important hypothesis in the accurate prescription of antibacterial agents in neurosurgical critical care, namely underdosing in the context of augmented elimination and impaired target site penetration. However, prior to any recommendations regarding empirical dose modification, more data are clearly needed, particularly with respect to the safety and efficacy of such an approach. In this respect, the authors would advocate further research using TDM in the management of CNS infection in this setting, in addition to work defining plasma and CSF concentrations associated with antibacterial efficacy and toxicity.

Simultaneous determination of vancomycin and ceftazidime in cerebrospinal fluid in craniotomy patients by high-performance liquid chromatography.

A simple, accurate and rapid method for simultaneous analysis of vancomycin and ceftazidime in cerebrospinal fluid (CSF), utilizing high-performance liquid chromatography (HPLC), has been developed and thoroughly validated to satisfy strict FDA guidelines for bioanalytical methods. Protein precipitation was used as the sample pretreatment method. In order to increase the accuracy, tinidazole was chosen as the internal standard. Separation was achieved on a Diamonsil C18 column (200 mm x 4.6mm I.D., 5 microm) using a mobile phase composed of acetonitrile and acetate buffer (pH 3.5) (8:92, v/v) at room temperature (25 degrees C), and the detection wavelength was 240 nm. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. The method was applied to determine vancomycin and ceftazidime concentrations in CSF in five craniotomy patients.