Pharmacokinetics of Ceftriaxone in Pediatric Patients With Meningitis

Abstract

Pharmacokinetics of ceftriaxone after a single dose of 50 or 75 mg/kg were determined in 30 pediatric patients with bacterial meningitis. Data for doses of 50 and 75 mg/kg, respectively, were as follows (mean ± standard deviation): maximum plasma concentrations, 230 ± 64 and 295 ± 76 ,ug/ml; elimination rate constant, 0.14 ± 0.06 and 0.14 ± 0.04 h-1; harmonic elimination half-life, 5 infants, aged 6 weeks to 2 years, who were receiving conventional therapy for documented bacterial meningitis at Arkansas Children's Hospital, Little Rock. Written informed consent was obtained from the parents of all participants. Between days 2 and 5 of therapy, when infection was judged to be under adequate control, and without alteration of the antimicrobial regimen, a single dose of ceftriaxone was administered intravenously over a 10-min period. The study was randomized so that half of the patients received 50 mg/kg and half received 75 mg/kg for this one infusion.Plasma samples were obtained just before infusion and at 15, 30, and 60 min and 2, 4, 6, and 10 h after infusion. A lumbar puncture was performed 1 to 6 h after drug administration, and a sample of CSF was obtained for analysis of ceftriaxone concentration.Susceptibility studies. Mean inhibitory concentrations (MICs) of ceftriaxone for each pathogen were determined by standard microtiter broth dilution (6). An inoculum of 105 organisms per ml in logarithmic growth phase was introduced into wells containing appropriate nutrients for that organism and serial dilutions of ceftriaxone. Cftriaxone concentrations. Plasma and CSF concentrations of ceftriaxone were analyzed by highpressure liquid chromatographic techniques (9). To monitor ceftriaxone levels on a daily basis for patients receiving this investigational antibiotic, microbiological methodology was employed; briefly, this was a standard agar well diffusion assay in which susceptible Escherichia coli is used after dilution of the specimen with pooled plasma (1).Pharmacokinetic determinations. The elimination rate constant, 1, was determined from the regression Clinical and laboratory studies. Patients were carefully monitored for adverse reactions during infusion by one of the investigators and followed during the duration of hospitalization. In addition, laboratory parameters for bone marrow, renal, or hepatic toxicity were obtained preinfusion and at 2 and 4 days. These included CBC, blood urea nitrogen, creatinine, urinal-

Comparison of ceftriaxone and traditional therapy of bacterial meningitis

“…It is highly active against those organisms that usually cause bacterial meningitis (1,16). Its halflife is 6 to 8 h and perhaps as long as 10 h (1,11,15,18). In early animal studies, ceftriaxone was found to achieve good cerebrospinal fluid (CSF) levels; in general, bactericidal activity was superior to that of traditional drugs or the other third-generation cephalosporins previously mentioned (6).…”

Increased Resistance to Multiple Antimicrobials and Altered Resistance Gene Expression in CMY-2-Positive Salmonella enterica following a Simulated Patient Treatment with Ceftriaxone

“…Additionally, the isolates were exposed to ceftriaxone in a manner which simulated patient infection and treatment. The simulated patient treatment with ceftriaxone closely mimics the mean plasma concentrations seen in both adult and pediatric patients (14,18). Thus, this study contributes to the growing body of knowledge of Salmonella enterica drug resistance and response to antimicrobial treatment.…”

Ceftriaxone Kinetics and Cerebrospinal Fluid Penetration in Infants and Children with Meningitis

“…An im portant pharm acokinetic character istic o f cefriaxone is its long elim ination half-life, allowing twice daily adm inistra tion in infants and children [1,2,5,[7][8][9]. These studies, however, have reported the pharm acokinetics [1,4,[6][7][8] and cerebro spinal fluid concentrations (CSF) [1,2,7] only after single doses of ceftriaxone.…”

“…After the loading dose o f 75 m g/kg, peak serum concentrations of ceftriaxone ranged from 150 to 484,ug/ml; and serum concentrations at 12 h ranged from 16.7 to 28.2ug/m l. Steady-state peak and trough serum concentrations ranged from 295 to 440 and 32.6-44.8 jug/ml, respectively. Even the lowest CSF concentration of 1.1 t/g/m l exceeded the reported minimum inhibitory concentra tions of 0.002 jUg/ml for H. influenzae by 500-and 0.0001 ,ug/ml for N. meningitidis by 10,000-fold [7], The CSF concentration o f ceftriaxone ranged from 3 to 25% (mean 12%) of the serum concentration which is higher than the previously re ported range of 1 -12% [ 1,4,7,9]. This was probably due to the fact that our studies were done at 11.4-12.8 h after the dose com pared to the previous studies at 1-6 h after the dose.…”