Intraventricular cerebrospinal fluid antibiotic concentrations in patients with intraventricular infections.

The antibiotic concentration of the fluid from either lateral ventricle was determined 104 times in 37 patients through direct ventricular puncture, external ventricular drainage (EVD), or cerebrospinal fluid shunt sampling. The patients were 1 month to 12 years old. When the patients were receiving maximal intravenous antibiotic therapy alone, the concentrations for the most part were below 5 microgram/ml, whereas patients receiving an antibiotic through direct ventricular puncture, EVD, or a shunt reservoir usually had concentrations over 5 microgram/ml. However, wide variations from patient to patient were found with all forms of treatment despite similar dosages. Clustering of the concentration tended to occur in each individual patient. The authors conclude that, to obtain a high concentration of an antibiotic in the ventricular fluid, one should administer it directly into the ventricle.

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.

[Experimental studies on the passage of antibiotics into cerebrospinal fluid in staphylococcal meningitis in rabbits. II. Cephaloridine, cephalothin and cefazolin (author's transl)].

Passage of cephaloridine, cephalothin and cefazolin into cerebrospinal fluid (CSF) was evaluated in Staphylococcus aureus meningitis in rabbits and the following results were obtained. 1. Concentration in CSF (microgram/ml) [CSF/serum ratio (%)] was determined 1/2, 1 and 2 hours after a single intravenous injection of 100 mg/kg of each antibiotic, respectively; cephaloridine-7.5 [8.9], 9.7 [13.8], 9.1 [22.6]; cephalothin-0.42 [3.6], 0.23 [6.4], not detectable [0]; cefazolin-7.5 [11.8], 5.2 [19.3], 2.0 [17.5]. 2. When results with cefazolin after an intravenous injection 100 mg/kg and 200 mg/kg were compared, a definite dose response was noted in blood concentration but not in CSF concentration. 3. A standard error of CSF concentrations of each antibiotic was larger than that of penicillins, and "Unpredictability" of their passage into CSF was considered to be one of the characteristics common to these three drugs in respect of their passage into CSF. 4. There was no significant difference noted in antibiotic passage into CSF between cephaloridine of low protein binding rate and cefazolin of very high binding rate. Cephalothin, of which binding rate was intermediate, showed a remarkably lower passage into CSF. These results indicate that a correlation does not always exist between protein binding rate of the antibiotics and their passage into CSF. 5. Based on the above results, a review of the literature was made on clinical applicability of these three antibiotics in the treatment of bacterial meningitis. Low transport rate of cephalothin into CSF and nephrotoxicity of cephaloridine make them to be unsuitable for bacterial meningitis. Cefazolin is considered to be suitable in the treatment of ampicillin-resistant Escherichia coli meningitis and Gram-positive coccal meningitis in which penicillins are not applicable.

[Penetration of cephaloridine and cephalothin into the cerebrospinal fluid-clinical study (author's transl)].

There were 35 cases, treated with Cephaloridine or Cephalothin after neurosurgical operation. Neurological surgeon always troubled with passage of blood-brain barrier when drug was given. Antibiotics was not exceptionally, therefore we, neurological surgeon, must select the effective drug to bacterium, that which penetrated enough to the intracranial organ through the blood-brain barrier. In this paper, we measured the concentration of Cephaloridine and Cephalothin into cerebrospinal fluid in the cases with non inflammatory meninges. We collected the cerebrospinal fluid from continued ventricle tap and serum, then measured the concentration of the drug with bioassay. Cephaloridie treated cases. 22 cases. 1) 1 g intramuscular injection. 4 cases. Serum level got to highest value, 64 mug/ml (mean value) 1 hour after injection. CSF level got to maximum concentration 46.8 mug/ml. (mean value) serum mean level 21.5 mug/ml. CSF mean level 0.73 mug/ml. 2) 1 g 3 minutes-intravenous injection 5 cases. Serum level got to highest value 67.5 mug/ml. CSF maximum level was 5.25 mug/ml. Serum mean level 19.74 mug/ml. CSF mean level 0.61 mug/ml. 3) 1 g 1 hour-intravenous drip. 9 cases. Serum maximum level 121.0 mug/ml. CSF maximum level 2.30 mug/ml. Serum mean level 20.08 mug/ml. CSF mean level 0.67 mug/ml. 4) 1 g 8 hours-intravenous drip. 3 cases. Serum maximum level 61.0 mug/ml. CSF maximum level 1.36 mug/ml. Serum mean level 14.78 mug/ml. CSF mean level 0.47 mug/ml. Cephalothin treated cases, 12 cases. 1) 1 g 8 hours-intravenous drip, 4 cases. In fact we could detect the drug only in one case, in CSF, and we could not in other three cases. In KF - 4 case, serum maximum concentration was 26.0 mug/ml, CSF maximum concentration was 0.07 mug/ml. Serum mean level 16.97 mug/ml. CSF mean level 0.01 mug/ml 2) 2 g 1 hour-intravenous drip, 9 cases. Serum maximum level 690.0 mug/ml. CSF maximum level 2.03 mug/ml. Serum mean level 29.59 mug/ml. CSF mean level 0.06 mug/ml. In cephaloridine cases, the tendency was observed, that which, as concentration of the drug in CSF increased, cell count and protein decreased, and, as concentration of the drug decreased, cell count and protein increased. CSF/serum concentration ratio of Cephaloridine increased, when time passed, in intramuscular, 3 minutes intravenous, and 1 hour-intravenous drip group. Then only in 8-hours-intravenous prip group. Then only in 8-hours-intravenous drip group, concentration ratio decreased. In Cephaloridine group, mean value of CSF/serum ratio showed. 1 g i.m. 0.084 1 g 3 minutes-i.v. 0.098 1 g 1 hour-i.v. 0.194 1 g 8 hours-i.v. 0.044.

[Clinical study on penetration of antibiotics into cerebrospinal fluid (second report),-Study on intravenous administration of sodium cephalothin with mannitol solution (author's transl)].

Penetration of Sodium Cephalothin (CET) into CSF follwing intravenous administration was studied in 23 patients with intracranial diseases excluding inflammation and severe subarachnoid hemorrhage. 1) After intravenous injection of 2 g of CET, ventricular CSF was obtained in 4 cases. All these 4 cases showed CET concentration in CSF to be below 0.1 mcg/ml. 2) After intravenous injection of 2 g of CET, lumbar CSF was obtained in 6 cases. In two cases out of these 6 cases, CET concentration in CSF was higher than 0.7 mcg/ml. 3) In 13 cases 2 g of CET with 200ml of 20% Mannitol was injected intravenously and lumbar CSF was examined. CET concentrations in CSF between 0.7 mcg/ml and 6.0 mcg/ml were observed in 9 cases of this group. 4) According to the results it is strongly suggested that the administration of Monnitol and CET is very effective for penetration of CET into CSF.

Paper chromatographic techniques for the determination of cephalothin and desacetylcephalothin in body fluids.

Paper chromatographic procedures may be used to detect cephalothin and its metabolite desacetylcephalothin in urine, plasma, synovial fluid, and cerebrospinal fluid. Protein-bound antibiotics are released from plasma, cerebrospinal fluid, and synovial fluid by dilution with an equal volume of dimethylformamide. Data are presented on the sample preparation, paper chromatographic system, and other specific techniques.

Meningitis developing during cephalothin therapy of septicaemia.

A 63-year-old woman developed pneumococcal meningitis during cephalothin treatment for pneumococcal septicaemia. The poor penetration of this antibiotic over the blood-brain barrier makes it unsuitable for the therapy of meningitis. If cephalothin is used in other serious infections, the patient should be closely observed for the development of meningitis.

Comparison of cefamandole, cephalothin, ampicillin, and chloramphenicol in experimental Escherichia coli meningitis.

The activities of cefamandole, cephalothin, ampicillin, and chloramphenicol were compared in fulminant and temperate Escherichia coli meningitis in rabbits. Intensive dosing schedules were employed to achieve maximal therapeutic benefits with short-term treatment. In an 8-h schedule chloramphenicol was significantly more effective in sterilizing the cerebrospinal fluid and curing both fulminant and temperate infections than cefamandole or ampicillin. Cephalothin was without effect in fulminant meningitis. Cefamandole and ampicillin were equivalent in activity in this and longer (12- and 24-hr) treatment schedules. The therapeutic benefits of chloramphenicol were purchased via use of doses above those generally regarded as safe for human use. The mean serum, cerebrospinal fluid, and brain concentrations of chloramphenicol, cefamandole, and ampicillin were significantly greater in rabbits with fulminant meningitis than in those with temperate meningitis. The difference was of such magnitude as to support the need to monitor drug concentrations.

Cerebrospinal fluid antibiotic concentrations in ventricular shunt infections.

The concentration of antibiotic in cerebrospinal fluid was measured during treatment of seven children with infected ventricular shunts. Antibiotics were administered via the ventricular shunt or through an external ventricular drain. 53 CSF samples were obtained 7-19 h after antibiotic administration. Wide variation in cerebrospinal fluid antibiotic concentration occurred from patient to patient following either route of administration. For optimal management of shunt infections, we recommend periodic assessment of antibiotic concentration or activity in ventricular fluid and determination of the minimum inhibitory concentration of antibiotic required for each pathogen.

Penetration of cefotaxime and moxalactam into cerebrospinal fluid of rabbits with experimentally induced Escherichia coli meningitis.

Penetration of the new beta-lactam antibiotics cefotaxime and moxalactam into cerebrospinal fluid (CSF) was studied in rabbits with experimentally produced Escherichia coli meningitis. Cefotaxime reached peak concentrations (mean +/- SEM) of 31.9 +/- 5.4 micrograms/ml in serum and 2.8 +/- 0.3 micrograms/ml in CSF after an infusion of 50 mg/kg per hr for 8 hr. Moxalactam, after an infusion of 12.5 mg/kg per hr iv, produced peaks of 31.0 +/- 13.1 micrograms/ml in serum and 9.7 +/- 1.2 micrograms/ml in CSF. Both drugs reduced the initial concentration of E. coli in the CSF by greater than 1,000-fold. An infusion of 100 mg/kg per hr of cephalothin produced a peak concentration of 76.5 +/- 15.2 micrograms/ml in serum but resulted in a concentration of only 0.17 +/- 0.05 micrograms/ml in CSF and had no bactericidal activity in CSF. Paper chromatography of CSF from cefotaxime-treated rabbits showed that 85.3% (+/- 3.1%) of the antibiotic activity was ascribed to desacetylcefotaxime, a metabolite that is less potent than the parent drug. Neither cefotaxime nor moxalactam was taken up in vitro by rabbit choroid plexus tissue, but cephalothin was taken up at a rate of 9.6 +/- 1.1 microgram/g per hr. Perhaps cefotaxime and moxalactam reached higher concentrations in CSF than did cephalothin because they are not removed from the CSF by the exit pump of the choroid plexus. The fact that levels of cefotaxime in CSF are lower than those of moxalactam could be attributed to the presence of desacetylcefotaxime, a metabolite that is less active than cefotaxime.

A study of cephalothin and desacetylcephalothin in cerebrospinal fluid in therapy for experimental pneumococcal meningitis.

One explanation for the failure of cephalothin to cure patients with bacterial meningitis is that desacetylcephalothin, as in vivo metabolite that has less antibacterial activity than the parent drug, penetrates more efficiently into cerebrospinal fluid (CSF); In experimental pneumococcal meningitis in rabbits, the peak levels of cephalothin and desacetylcephalothin in CSF after an intramuscular injection of 250 mg of cephalothin/kg were, respectively, 1.43 +/- 4.9 microgram/ml (2.8% of peak serum level) and 1.69 +/- 0.57 microgram/ml (2.2% of peak serum level). The observed half-life of desacetylcephalothin in CSF (3.32/hr) was longer (P less than 0.01) than that of cephalothin (0.72/hr). Choroid plexuses isolated from the lateral cerebral ventricles of rabbits with meningitis took up cephalothin in vitro more avidly than desacetylcephalothin (P less than 0.05), and metabolism of cephalothin to desacetylcephalothin by isolated choroid plexuses was demonstrated directly. Thus, intrathecal metabolism of cephalothin by the choroid plexus may contribute to the unsatisfactory performance of cephalothin in bacterial meningitis.