Pharmacokinetics and cerebrospinal fluid concentration of nafcillin in pediatric patients undergoing cerebrospinal fluid shunt placement.

Postoperative infection is among the most common complications in patients with cerebrospinal fluid shunt placement. Nafcillin is often used for prophylaxis but not pharmacokinetic data are available perioperatively in pediatric patients. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal concentrations of nafcillin. Ten patients (mean age 8.0 +/- 5.6 years) received three doses of intravenous nafcillin, 50 mg/kg every 6 h; the first dose was administered 1 h prior to surgery. Multiple blood samples were collected during and after surgery and the cerebrospinal fluid sample was obtained at the time of shunt insertion. Urine samples were collected for 24 h after initiation of nafcillin. Nafcillin was analyzed with an HLPC method. The peak serum concentrations ranged from 22 to 107 micrograms/ml; cerebrospinal fluid concentrations ranged from 0.02 to 0.30 (mean 0.16 +/- 0.11) micrograms/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.90 +/- 0.55 l/kg/h, 0.12 +/- 0.04 l/kg/h, 0.70 +/- 0.52 l/kg, and 0.5 +/- 0.1 h, respectively. 16% of total nafcillin dose was excreted in the urine. A 4-fold variability in total clearance and a 10-fold variation in cerebrospinal fluid concentrations of nafcillin was observed in these patients. Further, the concentrations of nafcillin attained in the cerebrospinal do not appear to be adequate, based on its minimum inhibitory concentration of 0.5 micrograms/ml against very susceptible staphylococci. These data, in addition to the fact that an increasing number of staphylococci are becoming resistant to nafcillin, question the usefulness of prophylactic nafcillin in pediatric patients undergoing shunt procedures.

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus.

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Penetrance of nafcillin into human ventricular fluid: correlation with ventricular pleocytosis and glucose levels.

Fourteen hydrocephalic pediatric patients with suspected shunt infections were studied for penetrance of nafcillin into the ventricular fluid after intravenous administration. In seven patients with bacterial ventriculitis, the concentration of nafcillin in ventricular fluid was 0.8 to 20.4% of the peak concentration in serum. In the remaining seven patients without bacterial ventriculitis, ventricular fluid levels ranged between less than or equal to 0.02 to 4% of peak serum concentrations. Although the degree of pleocytosis correlated poorly with penetrance, ventricular fluid glucose levels correlated inversely with penetrance of nafcillin (r = -0.7275, P less than 0.001).

Synergistic action of nafcillin and ampicillin against ampicillin-resistant Haemophilus influenzae type b bacteremia and meningitis in infant rats.

Infant rats with bacteremia and meningitis induced by ampicillin-resistant Haemophilus influenzae type b were treated with ampicillin and nafcillin, alone or in combination. Neither ampicillin alone (in 19 animals) nor nafcillin alone (in 20 animals) sterilized the blood or cerebrospinal fluid of any treated infant rat. When the combination of ampicillin and nafcillin was used, blood cultures were negative in 18 of 19 infant rats, and cerebrospinal fluid cultures were sterile in 15 of 19 when cultured 30 h after initiation of treatment. In vitro results demonstrated definite synergism between ampicillin and nafcillin against ampicillin-resistant H. influenzae type b. The study suggests that such synergism also exists in vivo.

Antibiotic prophylaxis in ventricular shunt surgery. II. Antibiotic concentrations in cerebrospinal fluid.

Investigation of cerebrospinal fluid (CSF) antibiotic levels from patients operated upon under short-term prophylactic protocols for shunt insertions or revisions revealed low-level CSF penetration by nafcillin and virtually no methicillin activity. Nafcillin levels were not influenced by route of injection or CSF sampling time, but were inversely proportional to ventricular size. The authors recommend nafcillin over methicillin as the preferred prophylactic agent in shunt surgery. Although the 25 mg/kg preoperative dose may be adequate for reducing infection risk, higher dosages should be considered when the ventricles are markedly dilated.

Nafcillin concentration in cerebrospinal fluid during treatment of staphylococcal infections.

The nafcillin concentration of simultaneous cerebrospinal fluid (CSF) and serum specimens from nine patients being treated with parenteral nafcillin for staphylococcal infection were measured. Marked variations in the ratio of CSF/serum nafcillin concentration were observed. However, the concentration of nafcillin in the CSF was greater than the minimum lethal concentration (MLC) for Staphylococcus aureus in eight of the nine patients. In five patients with CSF pleocytosis, the nafcillin concentration was three to 100 times the MLC. These results support the recommendation to use nafcillin in doses of at least 100 to 200 mg/kg body weight-day for treatment of meningitis caused by S. aureus.

Nafcillin entry into human cerebrospinal fluid.

The entry of nafcillin into the cerebrospinal fluid (CSF) of humans was studied in the absence of meningeal inflammation. Twenty studies were performed in 18 patients receiving 40 mg of sodium nafcillin per kg intravenously over 30 min. The CSF specimens were obtained at 1, 2, 3, and 4 h postinfusion, and sera were obtained at 5 min and 1, 2, 3, and 4 h. Nafcillin was uniformly detected in the lumbar CSF at 1 h, peaked at 2 h postinfusion, and was still detectable in the CSF of three of four patients studied at 4 h.

Nafcillin treatment of Staphylococcus aureus meningitis.

Serial serum and cerebrospinal fluid nafcillin concentrations were determined in a patient successfully treated with nafcillin (200 mg/kg per day) for Staphylococcus aureus bacteremia and meningitis. Nafcillin and methicillin cerebrospinal fluid concentrations were compared.