Pharmacokinetics and penetration into tissue fluid of cefotaxime in bovines.

Concentrations of cefotaxime in serum and tissue fluid were studied in the bovine after intravenous and intramuscular administration at a dosage of 10 mg.kg-1 body weight. Steers implanted subcutaneously with tissue cages were used. After intravenous bolus administration, profiles of mean concentrations in serum over time were described by a two-compartment open model. The rate constant of elimination was 1.4 +/- 0.3 h-1 and the half-life 0.6 +/- 0.1 h. The rate constant of distribution was 11.5 +/- 1.9 h-1, and the half-life was 0.06 +/- 0.01 h. The volume of distribution at steady state was 250.6 +/- 37.3 ml.kg-1. The area under the curve was 31.8 +/- 7.4 micrograms.ml-1.h. The penetration ratio into tissue fluid was 36.5 +/- 15.4%. After intramuscular injection, the half-life was 1.1 +/- 0.3 h, the area under the curve was 27.5 +/- 6.8 micrograms.ml-1.h, and the penetration ratio into tissue fluid was 47.1 +/- 15.8%. The concentrations in tissue fluid after intravenous and intramuscular administration of cefotaxime were elevated during a 6-hour period after administration.

Cefotaxime and desacetylcefotaxime pharmacokinetics in very low birth weight neonates.

The single-dose pharmacokinetics of cefotaxime (CTX) and desacetylcefotaxime (dCTX) after a 50.0 mg/kg intravenous dose were evaluated in 18 very low birth weight neonates (13 male; 1015.6 +/- 349.8 gm; 28.4 +/- 2.4 weeks gestational age) during the first week of life. Microanalytic high-performance liquid chromatography was used to quantitate both CTX and dCTX from serum. A two-compartment open model best characterized the disposition of CTX during a 24-hour post-dose period. The disposition of dCTX was adequately characterized by a one-compartment model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of CTX (mean +/- SEM) were 4.44 hours, 0.461 +/- 0.027 L/kg, and 0.074 +/- 0.003 L/hr/kg, respectively. Peak concentrations (mean +/- SD) of dCTX (17.96 +/- 5.54 mg/L) occurred at 0.6 to 8.3 hours (5.9 +/- 1.9 hours) after CTX administration, and the apparent elimination half-life of dCTX was 9.36 hours. Comparison of CTX and dCTX pharmacokinetic parameters between very low birth weight neonates who weighed less than 1000 gm (n = 9; 703.3 +/- 46.6 gm; 27.0 +/- 0.8 weeks gestational age) and greater than or equal to 1000 gm (n = 9; 1328.8 +/- 48.6 gm; 29.8 +/- 0.5 weeks gestational age) revealed no significant differences, but significant linear correlations were found between gestational age and weight versus CTX half-life and total body clearance. Because of the prolonged clearance of both CTX and dCTX in the very low birth weight neonate, a CTX dose of 50 mg/kg every 24 hours may provide effective serum concentrations for susceptible infections outside the central nervous system.

Pharmacokinetics of ceftriaxone in neonates and infants with meningitis.

The pharmacokinetics of ceftriaxone was studied in the plasma, urine, and cerebrospinal fluid of seven neonates and seven infants with meningitis. In addition, plasma and urine data were obtained in five neonates and one infant receiving ceftriaxone for other serious infections. All neonates younger than 14 days received daily doses of 50 mg/kg ceftriaxone; all other patients but two received 100 mg/kg. The average weight-corrected values for total body clearance (ClT), volume of distribution (Vdss), and biologic half-life (t 1/2) were 0.37 ml/min/kg, 0.45 L/kg, and 16.2 hours in neonates younger than 1 week; 0.77 ml/min/kg, 0.48 L/kg, and 9.2 hours in neonates older than 1 week; and 1.03 ml/min/kg, 0.39 L/kg, and 7.1 hours in older infants, respectively. There was a significant difference in ClT and t 1/2 between the neonates younger and both neonates older than 1 week, and infants. The Vdss was not significantly different among the three age groups. The average renal clearance in neonates younger than 1 week (0.28 ml/min/kg was 70%, in neonates older than 1 week (0.54 ml/min/kg) was 77%, and in older infants (0.49 ml/min/kg) was 47% of ClT, indicating that nonrenal elimination was less developed in neonates. The quantitation of CSF diffusion of ceftriaxone was assessed by comparison of the areas under the CSF and plasma concentration-time curve. The mean ceftriaxone penetration into the CSF in neonates and infants with bacterial meningitis was 17%. On the other hand, penetration in patients with aseptic meningitis amounted to only 4%. Mean ceftriaxone concentrations in the CSF in patients with bacterial meningitis were 2.8 mg/L after 24 hours, exceeding by many times the minimum inhibitory concentration of the common meningitis pathogens at this time.

Treatment of severe neonatal infections with cefotaxime. Efficacy and pharmacokinetics.

We studied the pharmacokinetics and efficacy of cefotaxime in 32 neonates with severe gram-negative infections. Many of these patients had been treated unsuccessfully with combinations of antibiotics. Eighty-one percent of these patients were cured, 6% improved, and 13% had treatment failures; there were three deaths. Eighteen patients received cefotaxime alone; 16 were cured and two improved. These data indicate an efficacy of cefotaxime sufficient to warrant more rigorous future trials. The elimination half-life of cefotaxime ranged from 2.0 +/- 0.4 hours in term neonates more than one week of age to 5.7 +/- 0.8 hours in preterm neonates less than one week of age. A volume of distribution of approximately 0.63 L was similar for all infants irrespective of age and maturity. These kinetic data can be used in design of future therapeutic regimens in more rigidly controlled trials assessing indications for cefotaxime therapy in neonates. We recommend dosing as follows, using a dose of 25 mg/kg: every 12 hours for preterm infants less than one week of age, every 8 hours for preterm infants one to four and term infants less than one week of age, and every 6 hours for term infants more than one week of age.