Cerebrospinal fluid-compensated medication reservoir for an implantable infusion device: concept and preliminary evaluation.

Conventional gas-compensated medication reservoirs used for implantable infusion devices require perfect sealing of the gas chamber, because the gases used are generally toxic. In addition, the physical properties of selected gas critically affect the performance of infusion devices and hydraulic performance of the infusion device can be affected by the amount of medication discharged.
In this study, we suggest a new medication reservoir that adopts a cerebrospinal fluid (CSF)-compensating mechanism, such that when a medication is released from the reservoir by a mechanical actuator, native CSF enters into the reservoir to minimize the build-up of pressure drop. We evaluated in vitro performance and conducted in vivo feasibility tests by using an intrathecal infusion device developed at the Korean National Cancer Center. Experimental results showed that the proposed CSF-compensated infusion pump was essentially less affected by ambient temperature or pressure conditions compared to the gas-compensated infusion pump. Moreover, it showed moderate implant feasibility and operating stability during an animal experiment performed for 12 days. We believe that the proposed volume-compensating mechanism could be applied in various medical fields that use implantable devices.

The influence of lidocaine on the permeability of the blood-cerebrospinal fluid barrier in experimental acute hypercapnia in the rabbit.

In a previous study we have provided evidence, that acute experimental hypercapnia due to hypoventilation in the rabbit alters blood-cerebrospinal fluid barrier function in the brain (Pakulski et al. 1998). The purpose of this study therefore was to determine if lidocaine would prevent the observed alterations in the blood-cerebrospinal fluid barrier function. The experiments were conducted in 16 adult Chinchilla rabbits submitted to acute hypercapnia due to mechanical hypoventilation (PaCO2 between 8-9.5 kPa over 180 minutes) under pentobarbital anaesthesia. The studied group (n = 8) was treated by lidocaine infusion 10 mg kg-1 h-1. After 180 minutes of hypercapnia the value of cerebrospinal fluid-blood index of gentamycin concentration, indicating the permeability of the blood-cerebrospinal fluid barrier, was significantly lower in animals treated with lidocaine (4.03 +/- 2.32 vs. 19.05 +/- 5.49; P < 0.01). We conclude that lidocaine may attenuate the increase of blood-cerebrospinal fluid barrier permeability under conditions of experimental acute hypercapnia lasting 180 minutes in the mechanically ventilated rabbit.

[Acute hypercapnia increases the permeability of blood/cerebrospinal fluid barrier for gentamicin in rabbits under general anesthesia]. / Ostra hiperkapnia zwieksza przepuszczalnosc bariery krew-plyn mózgowo-rdzeniowy dla gentamycyny w warunkach znieczulenia ogólnego u królików.

The aim of the work was to demonstrate whether acute hypercapnia (paCO2 > 65 mmHg) influenced the permeability of BBCSF. 12 Chinchilla rabbits which underwent general anaesthesia were randomly divided into 2 groups. To maintain normal paCO2 values, the investigation was performed under normal ventilation in control group (No I). Controlled hypoventilation was applied to achieve acute hypercapnia in the shortest possible time in the investigated group (No II). BBCSF function was evaluated using gentamicin permeability indexes QG (defined as gentamicin concentration in the cerebrospinal fluid-to-serum gentamicin concentration in given moment of investigation). Mean haemodynamic and haematologic parameter values showed no significant within-group and between-group deviation. Statistically insignificant increase of QG values after the first hour of hypercapnia was found when comparing mean QG values in the investigated group. Mean QG value was statistically significantly higher in the animals hypoventilated for 3 hours when compared with animals which underwent normal ventilation during the whole procedure. Severe, acute hypercapnia disturbs the integrality of the blood/cerebrospinal fluid barrier.

Prophylactic antibiotics for spine surgery: description of a regimen and its rationale.

Cefazolin, an antibiotic commonly used for surgical prophylaxis, may not adequately penetrate the intervertebral disk or cerebrospinal fluid. The combination of gentamicin and cefuroxime has been found to penetrate both structures in adequate levels and was used in 40 consecutive elective spine cases without a postoperative infection or antibiotic-related complications.

Once-daily gentamicin therapy for experimental Escherichia coli meningitis.

In vitro and in vivo studies have demonstrated that the bacteriologic efficacy of once-daily aminoglycoside therapy is equivalent to that achieved with conventional multiple daily dosing. The impact of once-daily dosing for meningitis has not been studied. Using the well-characterized rabbit meningitis model, we compared two regimens of the same daily dosage of gentamicin given either once or in three divided doses for 24 or 72 h. The initial 1 h mean cerebrospinal fluid (CSF) gentamicin concentration for animals receiving a single dose (2.9 +/- 1.7 micrograms/ml) was threefold higher than that for the animals receiving multiple doses. The rate of bacterial killing in the first 8 h of treatment was significantly greater for the animals with higher concentrations in their CSF (-0.21 +/- 0.19 versus -0.03 +/- 0.22 log10 CFU/ml/h), suggesting concentration-dependent killing. By 24h, the mean reduction in bacterial titers was similar for the two regimens. In animals treated for 72 h, no differences in bactericidal activity was noted for 24, 48, or 72 h. Gentamicin at two different dosages was administered intracisternally to a separate set of animals to achieve considerably higher CSF gentamicin concentrations. In these animals, the rate of bacterial clearance in the first 8 h (0.52 +/- 0.15 and 0.58 +/- 0.15 log10 CFU/ml/h for the lower and higher dosages, respectively) was significantly greater than that in animals treated intravenously. In conclusion, there is evidence of concentration-dependent killing with gentamicin early in treatment for experimental E. coli meningitis, and once-daily dosing therapy appears to be at least as effective as multiple-dose therapy in reducing bacterial counts in CSF.

In vitro postantibiotic effects following multiple exposures of cefotaxime, ciprofloxacin, and gentamicin against Escherichia coli in pooled human cerebrospinal fluid and Mueller-Hinton broth.

Multiple exposures with cefotaxime in either Mueller-Hinton broth or cerebrospinal fluid had no effect on killing or the duration of postantibiotic effect (PAE) in Escherichia coli strains tested. However, upon multiple exposures in Mueller-Hinton broth, ciprofloxacin and gentamicin PAEs significantly decreased with a concomitant reduction in bacterial killing. A reduction in bacterial killing following multiple ciprofloxacin and gentamicin exposures was also seen with cerebrospinal fluid; however, the PAE was maintained.

Measurement of antimicrobial agents in cerebrospinal fluid using the Abbott TDx analyzer.

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.

Gentamicin penetration into cerebrospinal fluid in experimental Haemophilus influenzae meningitis.

We studied the effect of meningitis and the method of parenteral gentamicin administration (intramuscular injection, a 30-min intravenous infusion, or intravenous bolus administration) on achievable concentrations of drug in cerebrospinal fluid (CSF). In normal animals, only intravenous bolus administration of 2 to 8 mg/kg produced a gentamicin concentration of greater than 0.1 microgram/ml in CSF in some animals. All CSF samples contained less than the limit of detection (0.1 microgram/ml) after the intramuscular administration of 6 mg/kg. In animals with meningitis, gentamicin penetration into cisternal CSF was increased significantly after a bolus administration of 6 mg/kg (mean, 0.197 +/- 0.063 microgram/ml in normal animals versus 1.68 +/- 0.38 micrograms/ml in animals with meningitis; P less than 0.01). In meningitic animals that received 6 mg/kg as an intravenous bolus, lumbar CSF had the highest maximum concentration (4.25 +/- 1.08 micrograms/ml), in comparison with ventricular CSF (3.10 +/- 0.66 micrograms/ml). The gentamicin concentration in cisternal CSF decreased more slowly than it did in serum (elimination half-life, 238.70 +/- 64.56 min in cisternal CSF versus 82.73 +/- 2.91 min in serum), yielding a relative increase in the percentage of penetration. We conclude that maximum penetration by gentamicin into CSF occurs after intravenous bolus administration and that the maximum concentration occurs in lumbar CSF.

Continuous sampling for determination of pharmacokinetics in rat cerebrospinal fluid.

A method for determining drug concentration relationships between plasma and cerebrospinal fluid (CSF) in rats is described. Continuous CSF samples were collected directly from the third anterior ventricle with an indwelling cannula inserted through the bregma point, and drug concentrations were determined by high-pressure liquid chromatography and radioimmunoassay micromethods. Three antibiotics with different abilities to cross the blood-CSF barrier (chloramphenicol, piperacillin, and gentamicin) were tested. This method was found to be reproducible for each drug even if the antibiotic levels were low and the sample volumes very small. Peak CSF concentrations occurred between 0.75 and 1.25 h after injection for all three antibiotics. Percent penetration values at 1 h were 50, 1.2, and 5.4% for chloramphenicol, piperacillin, and gentamicin, respectively.

Netilmicin in human CSF after parenteral administration in patients with slightly and severely impaired blood CSF barrier.

After administration of 150 mg netilmicin samples of CSF and blood were obtained. In one group of nine patients with no or only slight impairment of the blood-CSF-barrier 29 samples of CSF were assayed for netilmicin concentrations. All samples, obtained after the first dose, failed to reveal detectable drug levels. Drug levels up to 0.18 mg/l were detected in samples of CSF of three patients after 3 to 22 doses. Only the lumbar CSF of one patient contained netilmicin concentrations higher than 1.0 mg/l. In comparison 19 samples of CSF, obtained from patients with meningitis after more than one dose of netilmicin, had levels of 0.27-5.0 mg/l. Three CSF samples from patients out of this group, collected after the first dose of netilmicin failed to show any drug activity.

Effect of methylprednisolone on entry of ampicillin and gentamicin into cerebrospinal fluid in experimental pneumococcal and Escherichia coli meningitis.

The influence of methylprednisolone on the passage of ampicillin and gentamicin into and activity within cerebrospinal fluid was examined in two models of experimental meningitis. Steroid pretreatment reduced the concentrations of these drugs in purulent cerebrospinal fluid of rabbits with experimental pneumococcal and Escherichia coli meningitis (P less than 0.05). However, the resultant mean concentrations of these antibiotics in cerebrospinal fluid still exceeded the minimal bactericidal concentrations of the infecting organisms. The rate of bactericidal effect in vivo was unaffected by steroid therapy in each model. Methylprednisolone did not have deleterious effects on the course of treated experimental meningitis under these short-term (24-h) experiments.

Ototoxicity of intracisternal gentamicin in cats.

The intrathecal administration of gentamicin has been used to treat bacterial meningitis. However, the influence of this route of administration on the well-known ototoxic activity of gentamicin is unknown. This route of administration should facilitate access to the inner ear and should increase the ototoxic liability. The possible ototoxic and neurotoxic effects of intrathecally administered gentamicin (0.5, 1, 2, 4, 6, 10 mg/day) in cats were evaluated. Hearing thresholds were obtained by a noninvasive technique prior to and on the 7th and 21st days after the initiation of a seven-day dosage regimen. Histological examination of the organ of Corti was routinely done. Additionally, the vestibular organs of one animal on the 4 mg/day regimen were examined. The concentrations of gentamicin in the cerebrospinal fluid were also determined. The data indicate that the 2 mg/day dose may be very close to the threshold dose for ototoxicity when gentamicin is given by intracisternal administration.

Determination of cerebrospinal fluid gentamicin in the beagle using an indwelling cerebral ventricular cannula.

This study compared the concentrations of gentamicin in the blood and cerebrospinal fluid (CSF) of young beagles. Indwelling cannulas were surgically implanted into the external jugular vein and the left lateral cerebral ventricle of two 5-month-old beagles. Gentamicin was given intravenously (10 mg/kg) and CSF and blood samples were taken. This was repeated in 1 dog three times over 42 days. CSF collected 2 weeks after cannula implantation was cytologically normal. Significant levels of gentamicin were detected in the CSF shortly after injection in the absence of inflammation. Levels persisted when inflammation was present. The use of an indwelling ventricular cannula was effective for the long-term monitoring of CSF drug levels.

Infection in a functioning ventriculoperitoneal shunt treated with intraventricular gentamicin.

A case of successful treatment of a functioning ventriculoperitoneal (VP) shunt infection with high doses of intraventricular gentamicin sulfate is reported. The VP shunt reservoir of a four-month-old girl with hydrocephalus became infected. The scalp wound was debrided and intravenous methicillin sodium, 200 mg every six hours, was administered. When culture and sensitivity tests later showed Enterobacter cloacae, methicillin was discontinued. Intraventricular gentamicin, 2 mg/day, and intravenous carbenicillin, 400 mg/kg/day, were administered. Gentamicin dosage was increased twice over the next eight days to 6 mg/day. The trough cerebrospinal fluid (CSF) gentamicin level at 2 mg/day was 1.7 micrograms/ml, at 4 mg/day was 0.7 microgram/ml and at 6 mg/day was 19.6 micrograms/ml. Gentamicin was discontinued after 14 days; carbenicillin was continued for 7 more days. For a second shunt infection with Klebsiella pneumoniae, intraventricular gentamicin and intravenous chloramphenicol were given for 21 days. Previous reports of ventricular shunt infections are reviewed. The report indicates that it is possible to achieve therapeutic CSF levels of gentamicin in patients with patent VP shunts by administering 2--5 times (depending on ventricle size) the usual intraventricular dose.

[Gentamicin concentrations in cerebrospinal fluid of patients with inflamed and uninflamed meninges (author's transl)]. / Gentamicin-Konzentrationen im Liquorraum bei Patienten mit entzündeten und nicht entzündeten Meningen.

Determinations of gentamicin levels in serum and cerebrospinal fluid were performed in 11 tests of eight patients suffering from memingitis and in 18 tests of eight patients after neurosurgical operations. Neurosurgical operations had been performed in this group at least four days prior to testing. Only in four tests in neurosurgical patients were the gentamicin levels in CSF higher than the lowest measurable concentration of 0.4 mcg/ml, serum levels in this group ranged from below 0.4 mcg/ml up to 5.0 mcg/ml. No gentamicin level in CSF exceeded 1.5 mcg/ml. Gentamicin levels in CSF of patients with meningitis ranged from below 0.4 mcg/ml to 5.66 mcg/ml. This equals a CSF/serum ratio of 7.4-57.6%, mean 25.8%.

Cerebrospinal fluid antibiotic levels during treatment of shunt infections.

Twenty patients with documented cerebrospinal fluid shunt infections were treated with daily intraventricular injections of methicillin, cephalothin, or gentamicin without removal of the shunt or external ventricular drainage. Periodic determinations of intraventricular antibiotic concentration revealed significant levels in relation to the established minimum inhibitory concentration in all cases.

Response to therapy in an experimental rabbit model of meningitis due to Listeria monocytogenes.

A uniformly fatal, reproducible model of experimental meningitis due to Listeria monocytogenes was developed in rabbits for study of the natural progression of the disease and was used to evaluate treatment regimens. Bacterial titers in cerebrospinal fluid and pleocytosis approximated those found in humans. Therapeutic studies in vivo revealed that rifampin was less rapidly bactericidal than ampicillin or penicillin, the agents usually recommended for treatment of meningitis; that penicillin plus rifampin was no more efficacious than penicillin alone; that ampicillin demonstrated greater bactericidal activity in vivo than did penicillin; and that addition of an aminoglycoside (gentamicin) to either penicillin or ampicillin significantly enhanced their bactericidal activity in vivo. Ampicillin plus gentamicin was the most effective combination in vivo and may represent the preferred mode of therapy for listeria meningitis.