CSF Vancomycin Research Articles

Validación de un método inmunológico para la determinación de vancomicina en líquido cefalorraquídeo

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. 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. 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. 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.

CSF penetration of vancomycin in critical care patients with proven or suspected ventriculitis: a prospective observational study.

Vancomycin is recommended for ventriculitis. However, penetration into the CNS is relatively poor. To investigate the population pharmacokinetics of vancomycin in serum and CSF in critical care patients with proven or suspected CNS infections from neurosurgical procedures. This was an observational pharmacokinetic study in critical care patients with proven or suspected CNS infections receiving intravenous vancomycin. Multiple blood and intraventricular CSF samples were collected. Population pharmacokinetic analysis and simulation were undertaken with ADAPT5 and Pmetrics. A total of 187 blood and CSF samples were collected from 21 patients. The median (range) Cmax and Cmin concentrations in serum were 25.67 (10.60-50.78) and 9.60 (4.46-23.56) mg/L, respectively, with a median daily dose of 2500 (500-4000) mg. The corresponding median concentrations in CSF were 0.65 (<0.24-3.83) mg/L and 0.58 (<0.24-3.95) mg/L, respectively. The median AUC0-24 in serum and CSF was 455.09 and 14.10 mg·h/L, respectively. A three-compartment linear population pharmacokinetic model best fitted the observed data. Vancomycin demonstrated poor penetration into CSF, with a median CSF/serum ratio of 3% and high intersubject pharmacokinetic variability of its penetration. Therapeutic drug monitoring in both serum and CSF and higher daily doses may be an option to ensure adequate trough levels and to optimize patient therapy. Novel dosing strategies designed to reduce renal toxicity, such as administration by continuous infusion, should be investigated in further clinical studies to avoid antibiotic underexposure in CSF.

Monitoring intraventricular vancomycin for ventriculostomy access device infection in preterm infants.

Ventriculitis is a known complication during external CSF drainage in preterm infants with posthaemorrhagic ventricular dilatation. Staphylococci are most frequently isolated in device-associated ventriculitis, and hence, intraventricular vancomycin is a commonly used therapy. Our aim was to study the CSF vancomycin level pattern and drug safety in ventriculostomy access device infection in preterm infants less than 28weeks gestation. This single-centre, retrospective case series included seven infants with a median gestational age of 25+4weeks (range 23+6 to 27+5weeks). Ventriculitis was defined as elevated CSF white cell count of >20/mm3 or positive CSF culture. The CSF vancomycin concentrations following intraventricular vancomycin administration were studied. Forty treatment episodes of intraventricular vancomycin administration were studied in seven preterm infants. Maximum CSF vancomycin concentrations were 24.9mg/L (3mg, n=8, observed concentration-time (OCT), hours (h) =19), 96.3mg/L (5mg, n=17, OCT(h) =14), 94mg/L (10mg, n=14, OCT(h) =24), and 230.7mg/L (15mg, n=1, OCT(h) =24). The threshold for re-dosage is set at CSF vancomycin level of <10mg/L. In all patients, ventriculitis resolution (defined as sterile CSF and CSF WCC of <20/mm3) was achieved in a median of 5.5days (range 2-31days). Individual microbiology data is provided in the online resource. Intraventricular vancomycin is an effective treatment for ventriculostomy access device infection in preterm infants. In doses ranging from 3 to 15mg, sufficient CSF vancomycin level is generated to achieve microbiological cure without any reported adverse effects. Daily CSF drug monitoring is recommended to define dosage interval to maintain drug concentration above breakpoint of minimum inhibitory concentration.

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.

Systematic Review of Efficacy, Pharmacokinetics, and Administration of Intraventricular Vancomycin in Adults

Central nervous system infections requiring treatment with intraventricular (IVT) vancomycin are becoming increasingly common with advent of intracranial devices and increasing prevalence of multi-drug resistant and nosocomial organisms. Administering vancomycin via IVT route bypasses the blood-brain barrier to allow localized and controlled delivery directly to the desired site of action, achieving high concentrations for more reliable bactericidal action. This article systematically reviews current literature on IVT vancomycin in adults, compiles current knowledge, and integrates available evidence to serve as a practical reference.Medline (1946-July 2012), Embase (1974-July 2012), and International Pharmaceutical Abstracts (1970-July 2012) were searched using terms vancomycin, intraventricular, shunt infection, cerebrospinal fluid, and intraventriculitis. Seventeen articles were included in this review. Indications for IVT vancomycin included meningitis unresponsive to intravenous antibiotics, ventriculitis, and intracranial device infections. No serious adverse effects following IVT vancomycin have been reported. Dosages reported in literature ranged from 0.075-50 mg/day, with the most evidence for dosages of 5 to 20 mg/day. Duration of therapy most commonly ranged from 7 to 21 days. Therapeutic drug monitoring was reported in 11 studies, with CSF vancomycin levels varying widely from 1.1 to 812.6 mg/L, without clear relationships between CSF levels and efficacy or toxicity. Using IVT vancomycin to treat meningitis, ventriculitis, and CNS device-associated infections appears safe and effective based on current evidence. Optimal regimens are still unclear, and dosing of IVT vancomycin requires intricate consideration of patient specific factors and their impact on CNS pathophysiology. Higher-quality clinical trials are necessary to characterize the disposition of vancomycin within CNS, and to determine models for various pathophysiological conditions to facilitate better understanding of effects on pharmacokinetic and pharmacodynamic parameters.

Postoperatively administered vancomycin reaches therapeutic concentration in the cerebral spinal fluid of neurosurgical 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.

CSF Vancomycin Levels in Steroid-Treated Meningitis Patients

A recent, randomized, controlled study evaluating the effect of adding dexamethasone (10 mg every 6 hours for 4 days) to amoxicillin therapy in adults with pneumococcal meningitis demonstrated significant reductions in mortality and morbidity (see Journal Watch Emergency Medicine Dec 30 2002). With the increasing resistance of …

Vancomycin for Treating Cerebrospinal Fluid Shunt Infections in Pediatric Patients

Infection is a major cause of CSF shunt failure that places the patient at risk of intellectual impairment, development of loculated CSF compartments, and death. The purpose of this article is to review the published literature related to vancomycin for treatment of pediatric CSF shunt infections. Fifty percent of shunt infections appear within 2 months of shunt placement or revision; 90% occur within 6 months. Ninety percent of organisms infecting CSF shunting devices are Staphylococcus and Streptococcus species. The emergence of methicillin-resistant strains of staphylococci has made vancomycin the antibiotic of choice for these infections. The usual intravenous regimen is 60 mg/kg/day divided every 6 hours. Intraventricular vancomycin should be considered for most patients, starting with 10 mg daily. CSF vancomycin concentrations should be monitored and dosing adjustments made as needed to maintain CSF trough vancomycin concentrations between 5 and 20 mg/L.

Experimental study of the efficacy of vancomycin, rifampicin and dexamethasone in the therapy of pneumococcal meningitis.

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.

Antibiotic pharmacodynamics in cerebrospinal fluid.

The CSF half-lives of lipophilic agents, such as quinolones, are similar to those in serum and peak concentrations in CSF are achieved relatively quickly. In contrast, the pharmacokinetics of hydrophilic agents (beta-lactams and vancomycin) in CSF often differ from those in serum. In particular, the half-lives of these agents in CSF tend to be extended, and the time to achieve peak concentrations in CSF is delayed. Hydrophilic antibiotics, such as beta-lactams, penetrate poorly through the BBB, but CSF penetration is significantly increased in the presence of inflammation. In contrast, lipophilic antibiotics, such as quinolones, enter the CSF more efficiently and their penetration is not inflammation dependent. The pharmacodynamic properties of antibiotics in CSF are generally similar to those in other body sites; beta-lactam agents and vancomycin are time-dependent, whereas the quinolones and aminoglycosides are concentration-dependent. However, a notable difference from infections in other sites is that quinolones have a short PAE in CSF and need to continually exceed the MBC for maximal effectiveness. Thus, in CSF, quinolones demonstrate features of both concentration-dependency and time-dependency, evidence that the AUC/MBC is an important predictor of effectiveness. With the exception of quinolones, many antibiotics appear to have prolonged sub-MIC effects and longer half-lives in CSF than in serum, suggesting that dosing intervals longer than those used traditionally would be effective in meningitis. However, this requires clinical verification.

Vancomycin pharmacokinetics in hydrocephalic shunt prophylaxis and relationship to ventricular volume

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 μg/mL (0.9 ± 0.3). Weight did not affect these values ( p > 0.1). Simultaneous blood vancomycin levels varied between 9.1 and 38.7 μg/mL (22.3 ± 8.3). Ventricular volume, expressed as the ventricular-brain ratio, did not correlate with cerebrospinal fluid vancomycin levels ( p > 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 > 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.