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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% (IC 50 ) 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.

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.

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., (Universidad Nacional de Córdoba)

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., (© 2018 John Wiley & Sons Ltd.)

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., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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.

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 (R 2 ) 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%, R 2  = 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.

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., (Copyright © 2018. Published by Elsevier Inc.)

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 (CL CSF ) 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. CL CSF 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.

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.

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., (Copyright © 2017 John Wiley & Sons, Ltd.)

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., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

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., (Copyright © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

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., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

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.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

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.

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.

Background: The purpose of this study was to investigate whether vancomycin CSF concentration can reach therapeutic level when administered intravenously after neurosurgical operation., Methods: After patients were admitted to the ICU, vancomycin (1.0 g) was injected intravenously, and CSF was collected from either ventricular drainage (VD group, n = 9) or LPD (LPD group, n = 10). The CSF concentration of vancomycin was measured using HPLC., Results: Peak concentration occurred at 15 to 30 minutes after venoclysis (6.24 +/- 3.46 mg/L in the VD group and 4.49 +/- 3.14 mg/L in the LPD group, respectively) and reached or even exceeded the MIC(90) for MRSA (2 mg/L) and MRCoNS (2 mg/L). Twelve hours later, CSF vancomycin concentration in the VD and LPD groups was 2.55 +/- 1.13 and 2.43 +/- 0.41 mg/L, respectively., Conclusions: Neurosurgical operation may disrupt the integrality of BBB so that vancomycin can penetrate through the BBB easily and reach therapeutic concentration of CSF when administered intravenously after operation. This finding suggests that vancomycin can be administered intravenously when used to treat intracranial infection after neurosugical operation.

A simple MEKC with UV detection at 214 nm for simultaneous analysis of cefepime and vancomycin in plasma and in cerebrospinal fluid (CSF) by direct injection without any sample pretreatment is described. The separation of cefepime and vancomycin from biological matrices was performed at 25 degrees C using a BGE consisting of a Tris buffer with SDS and methanol as the electrolyte solution. Under optimal MEKC conditions for biological samples, good separations with high efficiency and short analysis time are achieved. Several parameters affecting the separation of the drugs from biological matrices were studied, including methanol, pH, and concentrations of the Tris buffer and SDS. The linear ranges of the method for the determination of cefepime and vancomycin in plasma and in CSF using imidazole or cefazolin as an internal standard, respectively, were all over the range of 1-30 microg/mL; the detection limits of cefepime and vancomycin in biological matrices (injection 10 kV, 15 s) were 0.3 and 0.5 microg/mL, respectively. The applicability of the proposed method for the determination of cefepime and vancomycin in plasma and CSF collected after intravenous administration of the drugs in patients with meningitis was demonstrated.

Background: Evidence from a recent randomized controlled trial suggests that dexamethasone as adjunct therapy in adult pneumococcal meningitis reduces mortality and neurological sequelae. However, adding dexamethasone has the potential to reduce penetration of vancomycin into the cerebrospinal fluid (CSF). We sought to determine concentrations of vancomycin in serum and CSF of patients with suspected or proven pneumococcal meningitis receiving dexamethasone to assess the penetration of vancomycin into the CSF during steroid therapy., Methods: In an observational open multicenter study, adult patients admitted to the intensive care unit because of suspected pneumococcal meningitis received recommended treatment for pneumococcal meningitis, comprising intravenous cefotaxime (200 mg per kg of body weight per day), vancomycin (administered as continuous infusion of 60 mg per kg of body weight per day after a loading dose of 15 mg per kg of body weight), and adjunctive therapy with dexamethasone (10 mg every 6 h). Vancomycin levels in CSF were measured on day 2 or day 3 of therapy and were correlated with protein levels in CSF and vancomycin levels in serum (determined at the same time as levels in CSF)., Results: Fourteen patients were included. Thirteen had proven pneumococcal meningitis; 1 patient, initially suspected of having pneumococcal meningitis, was finally determined to have meningitis due to Neisseria meningitidis. Mean levels of vancomycin in serum and CSF were 25.2 and 7.2 mg/L, respectively, and were positively correlated (r=0.6; P=.025). A positive correlation was also found between the ratio of vancomycin in CSF to vancomycin in serum and the level of protein in CSF (r=0.66; P=.01)., Conclusions: Appropriate concentrations of vancomycin in CSF may be obtained even when concomitant steroids are used. Dexamethasone can, therefore, be used without fear of impeding vancomycin penetration into the CSF of patients with pneumococcal meningitis, provided that vancomycin dosage is adequate. This study is registered at http://www.ClinicalTrials.gov/ (registration number NCT00162578).

The object of the study was to assess the efficacy of rifampicin and the combination of rifampicin plus vancomycin in a rabbit model of experimental penicillin-resistant pneumococcal meningitis. We also studied the effect of concomitant dexamethasone on the CSF antibiotic levels and inflammatory parameters. The rabbit model of pneumococcal meningitis was used. Groups of eight rabbits were inoculated with 106 cfu/mL of a cephalosporin-resistant pneumococcal strain (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours later they were treated with rifampicin 15 mg/kg/day, vancomycin 30 mg/kg/day or both plus minus dexamethasone (0.25 mg/kg/day) for 48 h. Serial CSF samples were withdrawn to carry out bacterial counts, antibiotic concentration and inflammatory parameters. Rifampicin and vancomycin promoted a reduction of >3 log cfu/mL at 6 and 24 h, and cfu were below the level of detection at 48 h. Combination therapy with vancomycin plus rifampicin was not synergic but it had similar efficacy to either antibiotic alone and it was able to reduce bacterial concentration below the level of detection at 48 h. Concomitant use of dexamethasone decreased vancomycin levels when it was used alone (P< 0.05), but not when it was used in combination with rifampicin. Rifampicin alone at 15 mg/kg/day produced a rapid bactericidal effect in this model of penicillin-resistant pneumococcal meningitis. The combination of vancomycin and rifampicin, although not synergic, proved to be equally effective. Using this combination in the clinical setting may allow rifampicin administration without emergence of resistance, and possibly concomitant dexamethasone administration without significant interference with CSF vancomycin levels.

In biological systems, it is difficult to determine free radicals because of their reactivity and their very short time of existence. On the basis of markers, which come into being as a result of radical processes, one might believe that there exist reactive oxygen species. One of the determinants of free radical activity of oxygen is the presence of malondialdehyde (MDA), a final product of lipid peroxidation. This study aimed at finding the answer to the question whether the concentration of netylmicin and vancomycin influences the amount of substances reacting with thiobarbituric acid (TBA) in cerebrospinal fluid (CSF) in children with hydrocephalus. Applying the TBA test for examinations with antibiotics added both in vivo and in vitro, we could demonstrate that increased concentration of the examined antibiotics in cerebrospinal fluid reduces the amount of MDA. The results obtained demonstrate that products of lipid peroxidation are present in the CSF samples analyzed. In this study, we found that the concentration of vancomycin and netilmicin influenced the lipid peroxidation process in cerebrospinal fluid in children with hydrocephalus, thus confirming anti-inflammatory properties of the antibiotics applied.

The case of 40 years old man with subarachnoid hemorrhage with intraventricular bleeding and with consecutive cerebro-meningitis is presented. The bacterial pathogen was Enterococcus faecalis sensitive only to glycopeptide antibiotics. The standard therapy with intravenously administered Vancomycin and Teicoplanin was not effective. Because of the worsening of patient's clinical status and clinical symptoms of sepsis the intraventricular Vancomycin (20 mg/day) was introduced. At the second day of the therapy the gradual patient's recovery was observed. The symptoms typical for meningitis diminished as well as cerebro-spinal fluid (CSF) parameters normalized. There was no bacterial growth in the blood serum and in CSF. As we can observe the intraventricular administration of Vancomycin is efficient method of cerebro-meningitis treatment. In our opinion the blood-brain barrier, even pathologically changed by infection, do not allow antibiotics to penetrate CSF, even in the maximal intravenous doses. In the cases of cerebro-meningitis caused by bacteria sensitive only to glycopeptide antibiotics, the intraventricular administration of the drug might be an alternative way of therapy especially when the doses of intravenous antibiotics need to be reduced.

Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher (P < 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Intraventricular application of vancomycin is an effective therapeutic regimen for the treatment of shunt-associated staphylococcal ventriculitis. We examined the in vitro activity of vancomycin at high concentrations against Staphylococcus aureus ATCC 25923 and Staphylococcus epidermidis ATCC 12228 in human cerebrospinal fluid samples. Time-kill curves revealed equal efficacies for concentrations of 10, 100, and 300 microg/ml, and incubation times of 24 to 48 h were needed to achieve a 3 log(10) reduction of viable bacteria. A concentration of 5 microg/ml showed a slightly lower activity, but this difference was not significant. In an infant who was successfully treated for shunt-associated ventriculitis due to S. epidermidis by once-daily local administration of vancomycin (3 mg for 2 days and 5 mg for 4 days [0. 5 to 0.8 mg/kg of body weight]) the in vivo kill kinetics were similar to those for the in vitro results. These results support time-dose regimens that provide trough vancomycin levels of 5 to 10 microg/ml.

Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (-0.33 +/- 0.13 delta log10 CFU/ml.h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (-0.39 +/- 0.18 delta log10 CFU/ml.h; i.v. admininistered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 micrograms/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (-0.60 +/- 0.23 delta log10 CFU/ml.h) compared to that produced by either monotherapy. These results were also confirmed in vitro.

With the emergence of beta-lactam antibiotic resistance among strains of Streptococcus pneumoniae, vancomycin has assumed an important role in the treatment of bacterial meningitis. Using the rabbit meningitis model, we evaluated the pharmacokinetics and pharmacodynamics of vancomycin in this setting. Animals were given 80 mg/kg of body weight daily in two or four divided doses to determine the penetration and activity of vancomycin in cerebrospinal fluid (CSF); each regimen was administered with and without dexamethasone. Mean peak (2 h) concentrations in CSF that were four- to eightfold higher than the minimum bactericidal concentration (MBC; 0.5 microgram/ml) for the pathogen were adequate for bacterial clearance. In both groups concentrations in CSF remained higher than the MBC for greater than 80% of the respective dosing intervals, and the penetration of vancomycin into CSF was 20%. Mean concentrations in CSF at 24 to 36 h of therapy were lower than those achieved during the first 12 h, consistent with a decline in the level of antibiotic entry into CSF as inflammation wanes. Rates of bacterial clearance were similar for the two regimens, and for all animals cultures of CSF were sterile by 36 h. The coadministration of dexamethasone significantly reduced the penetration of vancomycin into CSF by 29% and significantly lowered the rate of bacterial clearance during the first 6 h in animals receiving 20-mg/kg doses of vancomycin. For animals receiving 40-mg/kg doses, therapeutic peak concentrations in CSF were obtained even with steroid use, suggesting that the effect of steroids may be circumvented by the use of larger daily doses of vancomycin.

The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively. Against penicillin-resistant strains, the best killing activity at cerebrospinal fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin. However, while the killing activity of imipenem was significantly greater than that of meropenem, no significant difference was observed between the activities of meropenem and ceftriaxone-vancomycin.

Cerebrospinal fluid (CSF) was taken from 19 children with bacterial meningitis treated with cefotaxime (300 mg/kg of body weight/day) and vancomycin (60 mg/kg/day). Median levels of drugs in CSF were smaller than expected, as follows: 4.4 microg/ml for cefotaxime, 3.2 microg/ml for desacetylcefotaxime, and 1.7 microg/ml for vancomycin. The median CSF bactericidal titer against an intermediately cefotaxime-resistant pneumococcus was 1:4. Our data suggest at least an additive interaction between the drugs used in this study.

We studied the efficacy and pharmacokinetics of intraventricularly administered vancomycin in three patients with shunt-associated staphylococcal ventriculitis. We instilled 10 mg of the drug intraventricularly every 24 hours. Cerebrospinal fluid (CSF) levels were measured 1 hour after instillation and then every 2 hours. Peak vancomycin levels reached a mean of 292.9 microg/mL. The mean trough levels, measured immediately before readministration of vancomycin, were 7.6 microg/mL; this level has proved to be sufficient for maintaining the necessary steady-state serum concentration of vancomycin. All three patients were cured clinically and bacteriologically, and CSF parameters returned to normal within 5-13 days. No side effects were observed. Our results suggest that intraventricularly administered vancomycin is a valuable therapeutic strategy for treating shunt-associated staphylococcal ventriculitis. In addition, we provide evidence that 10 mg of vancomycin, administered intraventricularly every 24 hours, allows maintenance of therapeutic drug levels in the CSF for at least 24 hours.

Glycopeptides which have excellent in vitro activity against the Gram-positive causal agents of meningitis unfortunately have a poor CSF penetration. Vancomycin distribution into CSF is improved when administered by a continuous intravenous route and staphylococcal shunt related infection have been reported to be cured. Teicoplanin has good in vitro activity against a lot of staphylococci, and activity superior to vancomycin, against streptococci and is less toxic. In three children with shunt ventriculitis (S epidermidis 2, S. faecalis 1) despite a continuous infusion, vancomycin 15 mg/kg over 60 minutes onset, then 50 mg/kg/day was clinically and bacteriologically ineffective with very poor CSF levels even if high blood levels. After failure of vancomycin we used teicoplanin as a continuous i.v. infusion 6 mg/kg over 60 mn onset, then 12 mg/kg/day. This treatment was quickly effective and well tolerated.

There are reports of failure of extended-spectrum cephalosporin treatment in pneumococcal meningitis. On the basis of in vitro and animal experimental studies, the addition of vancomycin or rifampin to an extended-spectrum cephalosporin has been recommended for empiric treatment of these patients. Cerebrospinal fluid (CSF) was taken from 31 children with bacterial meningitis randomized to receive ceftriaxone alone (n = 11), ceftriaxone plus rifampin (n = 10), or ceftriaxone plus vancomycin (n = 10). The CSF from children receiving ceftriaxone alone was unable to kill intermediately ceftriaxone-resistant or fully resistant strains when the concentration of ceftriaxone in the CSF was less than 5 micrograms/ml. At higher concentrations bactericidal activity was present. We have shown that vancomycin penetrates reliably into the CSF of children with acute meningitis, which is in contrast to previous studies with adults. The addition of vancomycin or rifampin to ceftriaxone resulted in significantly enhanced CSF bactericidal activity compared with that of ceftriaxone alone against these resistant strains. Our data suggest that the addition of rifampin or vancomycin to ceftriaxone may be useful for the treatment of cephalosporin-resistant pneumococcal meningitis.

Eight adult patients with post-surgery meningitis caused by methicillin-resistant staphylococci were treated with continuous intravenous infusion of vancomycin in mean doses of 50 mg/kg/day. This treatment, which lasted 3 to 6 weeks, was well tolerated by the kidneys and resulted in cure in all cases; its effect on the ear was not evaluated. Stable concentrations of 4 to 7 mg/l in cerebrospinal fluid were obtained after the 48th hour of treatment.

Objective: To discuss administering vancomycin directly into the cerebrospinal fluid (CSF) to treat serious central nervous system (CNS) infections., Data Sources: References were obtained through an online search of MEDLINE, limited to material published in English. In addition, information was extracted from clinical trials, review articles, abstracts, and textbooks., Study Selection: Systematic evaluation of this topic in humans has not been done in a prospective manner. Related research articles describing the pathophysiology of CNS infections, intrathecal drug administration, and case reports of CSF vancomycin administration were reviewed., Data Extraction: Case reports regarding CSF vancomycin dosing were evaluated and included: drug dosing, infecting organism, infectious disease state, infectious outcome, CSF dynamics/flow abnormalities, methods of drug administration, drug monitoring, and toxicities., Data Synthesis: The results of this review are based on qualitative evaluations of anecdotal case reports and a basic understanding of intrathecal and intraventricular drug dosing principles. CSF administration of vancomycin is an effective means of bypassing the blood-brain barrier to achieve greater drug concentrations within the CSF. Current limitations to the CSF administration of vancomycin include a lack of data describing its safety, efficacy, and pharmacokinetics., Conclusions: CNS infections may require the CSF administration of vancomycin for successful eradication. Recommendations for dosing in the literature vary. Because of the potential toxicities associated with elevated CSF concentrations of vancomycin, dosing should be conservative.

The transferability of vancomycin (VCM) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus. VCM was administered intravenously for 30 minutes at a dose level of 30 mg/kg. Serum concentration reached a maximum of 75 +/- 3.80 micrograms/ml (mean +/- S.E.) at the completion of administration (i.e., 30 minutes) and CSF concentration reached a maximum of 2.4 +/- 0.39 micrograms/ml at 60 minutes. Pharmacokinetic parameters calculated from this concentration-time curve were as follows: Cmax (CSF/Serum) 3.21%, AUC (CSF/Serum) 2.39% between 15 and 60 minutes, 3.99% between 15 and 120 minutes, and 4.40% between 15 and 150 minutes. T 1/2 for VCM in CSF: 143 minutes, T1/2 (CSF/Serum):2.09. Based on this investigation, VCM appears to be effective in the treatment of meningitis caused by MRSA (Methicillin-resistant S. aureus).

Occasionally, requests are made by our physicians for the measurement of gentamicin, tobramycin, or vancomycin in cerebrospinal fluid (CSF) specimens during the course of treating patients for bacterial meningitis. We evaluated CSF as a specimen type for the measurement of amikacin, gentamicin, tobramycin, and vancomycin on the Abbott TDx analyzer. Coefficients of variation for CSF spiked with these antimicrobial agents ranged from 0.8% to 6.5% for intra-assay values and from 2.1% to 2.3% for inter-assay values. Serum and CSF specimens were spiked at various levels with equal amounts of the antibiotics. Correlation coefficients for serum vs. CSF for these agents were 0.999. Recoveries ranged from 86% to 134%. Sensitivity for these assays is about fourfold better for CSF than for serum. CSF appears to be an acceptable specimen type for the measurement of these antibiotics using the Abbott TDx analyzer.

The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy.

Vancomycin instilled in an Ommaya reservoir was used to treat a reservoir-associated infection. Vancomycin concentrations in cerebrospinal fluid (CSF) were measured, and derivation of pharmacokinetic parameters allowed tailoring of dosing. First-order kinetics were observed. The calculated half-life of 3.52 h was less than reported by others, and the apparent volume of distribution (60 ml) was less than anticipated. The elimination constant was 0.197 h-1. Empiric dosing based on schedules suggested in the literature would have led to high peak and low mean concentrations of intrareservoir vancomycin. Patients with reservoir-associated infections have a variety of pathophysiologic conditions that can result in alteration of normal CSF dynamics. Pharmacokinetic analysis is useful to individualize dosing and to optimize therapy with intrareservoir vancomycin.

Vancomycin pharmacokinetics were determined in 25 patients receiving ventriculoperitoneal shunts for hydrocephalus. Computed tomography scan-derived ventricular-brain ratio as an expression of hydrocephalus varied between 9.3% and 15.4% (12.9% +/- 1.7%). One hour prior to surgery each patient received 1 g of vancomycin infused intravenously over 60 minutes. Samples of cerebrospinal fluid and venous blood were obtained 1 hour later and vancomycin levels assayed by fluorescence polarization immunoassay. There were 11 females and 14 males, with a mean age of 44.5 +/- 10.3 years and a mean weight of 72.0 +/- 11.4 kg. All had normal renal function. Levels of vancomycin in the cerebrospinal fluid at 1 hour ranged from 0.1 to 1.5 micrograms/mL (0.9 +/- 0.3). Weight did not affect these values (p greater than 0.1). Simultaneous blood vancomycin levels varied between 9.1 and 38.7 micrograms/mL (22.3 +/- 8.3). Ventricular volume, expressed as the ventricular-brain ratio, did not correlate with cerebrospinal fluid vancomycin levels (p greater than 0.5). There was no significant increase in concentrations of vancomycin in CSF as cerebrospinal fluid protein concentration increased, nor when blood vancomycin concentration was greater than 20 mg/dL (therapeutic range) (p greater than 0.1). No patient had evidence of infection at 6 months follow up. These results indicate minimal cerebrospinal fluid penetrance of vancomycin when administered systemically 1 hour prior to shunt surgery. In addition concentrations of vancomycin in cerebrospinal fluid bear no relationship to weight, ventricular volume, meningeal inflammation, or blood levels in the therapeutic range. The minimum inhibitory concentration of vancomycin for staphylococci is 1.5 to 3.1, and as bactericidal levels of 5 to 8 minimum inhibitory concentration are needed to kill organisms, a combination of both systemic and intraventricular vancomycin may be needed to ensure adequate cerebrospinal fluid and tissue concentration of antibiotic during shunt prophylaxis.

Staphylococcus epidermidis has been established as the common pathogen causing cerebrospinal fluid shunt infections. In addition, clinical isolates of S. epidermidis from infected shunts are typically resistant to methicillin. Vancomycin is often used for neurosurgical prophylaxis due to its excellent in vitro activity against methicillin-resistant staphylococci. Limited data are available about the pharmacokinetics and cerebrospinal fluid concentrations of vancomycin in pediatric patients intraoperatively. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations of vancomycin. Eight patients (mean age 8.3 +/- 7.0 years) received three doses of intravenous vancomycin, 15 mg/kg every 6 h. The first dose was administered 1 h prior to surgery. Blood samples were collected at 0, 0.5, 1, 2, 4, and 5 h after the end of the infusion. A cerebrospinal fluid sample was collected at the time of shunt insertion. Urine samples were collected over a 24-hour period. Vancomycin was measured with a fluorescence polarization immunoassay. The peak serum concentrations ranged from 15.6 to 33.7 micrograms/ml; cerebrospinal fluid concentrations ranged from less than 0.6 to 0.8 microgram/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.11 +/- 0.05 l/h/kg, 0.07 +/- 0.02 l/h/kg, 0.54 +/- 0.15 l/kg, and 4.8 +/- 4.0 h, respectively. Approximately 70% of total vancomycin dose was excreted in the urine. A 2- to 5-fold variation in total clearance and a 2.5-fold variability in renal clearance were observed. Low cerebrospinal fluid concentrations of vancomycin were present at the time of shunt insertion in these pediatric patients.(ABSTRACT TRUNCATED AT 250 WORDS)