cefotaxime and Body-Weight

The time above the minimum inhibitory concentration (MIC) is an important surrogate parameter for the efficacy of cephalosporines. In clinical practice cefotaxime (CTX) is usually administered every 8 h or 12 h. Unfortunately the limit of quantification (LOQ) of the available assay is not low enough to detect CTX concentrations in serum later than 6 h after a 2 g i.v. dose. Consequently the time above MIC has to be estimated by extrapolation of the available serum data. Due to the concentrating properties of the kidney, concentrations in urine following a 2 g dose however remain above the LOQ for up to 16 h. It is therefore possible to follow the pharmacokinetics of CTX in urine within a 12 h dosing interval. Due to the linear pharmacokinetics of CTX, serum concentrations, and accordingly the time above MIC, can be estimated by using the measured urinary excretion and the calculated renal clearance. The pharmacokinetics of cefotaxime were studied in 12 healthy subjects who received a single 2 g i.v. dose administered as a short infusion. Blood and fractional urine were collected up to 24 h after dosing. For the characterization of the true terminal half-life only sparse and unbalanced serum and urinary data was available. In such situations, the population approach is the method of choice for estimating the kinetic parameters. The combined analysis of serum and urinary data using NONMEM shows the superiority of a tri-exponential compared to a bi-exponential pharmacokinetics model. As a result, the predicted serum trough levels of cefotaxime following twice daily dosing are about 30-fold higher than those extrapolated from the bi-exponential model. Consequently, the concentrations of CTX- and its metabolite desacetyl-CTX--are above the MIC of many therapeutically relevant pathogens for a longer period of time than previously assumed. In conclusion, a twice daily dosing regimen for cefotaxime is adequate for a number of clinically relevant pathogens. This is supported by the positive outcome in previous clinical trials following this dosing regimen.

Topics: Body Weight; Cefotaxime; Cephalosporins; Chromatography, High Pressure Liquid; Half-Life; Humans; Infusions, Intravenous; Models, Theoretical; Predictive Value of Tests

To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.. This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.. A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.. A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Body Weight; Cefotaxime; Creatinine; Female; Humans; Intensive Care Units; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological

Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.

Topics: Anti-Bacterial Agents; Body Weight; Cefotaxime; Chromatography, High Pressure Liquid; Computer Simulation; Drug Administration Schedule; Drug Dosage Calculations; Female; Gestational Age; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Intensive Care Units; Male; Models, Statistical; Monte Carlo Method; Sepsis; Tandem Mass Spectrometry

To determine the probability of meropenem (Merrem, AstraZeneca Pharmaceuticals L.P., Wilmington, DE, USA) and cefotaxime (Claforan, Aventis Pharmaceuticals Inc., Bridgewater, NJ, USA) achieving bactericidal exposures in the cerebrospinal fluid against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.. A 5,000-patient Monte Carlo simulation in a population of 10-year-old children with meningitis was conducted. Pediatric pharmacokinetic data were derived from the literature. Pathogen minimum inhibitory concentrations (MICs) were obtained from common bacteria that had caused meningitis collected during pediatric clinical trials. Time above the MIC exposures in the cerebrospinal fluid was calculated. Bactericidal exposure or probability of target attainment was defined as 40% and 50% time above the MIC for meropenem and cefotaxime, respectively. High cumulative fractions of responses were defined as >90% probability of target attainment against the populations of bacteria.. Meropenem was calculated to achieve 94.7%, 94.3%, and 96.1% cumulative fractions of response against S. pneumoniae, H. influenzae, and N. meningitidis, respectively. Cefotaxime only achieved a high likelihood of bactericidal attainment against N. meningitidis (91.6%). Against S. pneumoniae and H. influenzae, cefotaxime was only calculated to achieve 84.3% and 84.8% cumulative fractions of response, respectively.. In a simulated population of 10-year-old children, meropenem had a high likelihood of attaining bactericidal exposures in the cerebrospinal fluid. Cefotaxime had a >90% cumulative fraction of response against only N. meningitidis. Therefore, at the doses simulated, meropenem may be a more appropriate empiric choice for the treatment of bacterial meningitis in pediatric patients presumed to be caused by these pathogens until culture and susceptibility data are available.

Topics: Anti-Bacterial Agents; Body Weight; Cefotaxime; Child; Computer Simulation; Dose-Response Relationship, Drug; Humans; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Meropenem; Monte Carlo Method; Thienamycins

To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients.. Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66-93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach.. Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data.. Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

Topics: Aged; Aged, 80 and over; Aging; Blood Proteins; Body Weight; Cefotaxime; Drug Administration Schedule; Female; France; Geriatric Assessment; Half-Life; Humans; Infusions, Intravenous; Inpatients; Kidney; Male; Models, Biological; Time Factors

The selection of dosage regimens for different animal species requires the establishment of pharmacokinetic equivalency between species. Pharmacokinetic equivalency can be defined in terms of the magnitude of exposure (i.e., an identical peak serum concentration in each species) and the duration of exposure (i.e., an identical area under the serum concentration-time curve in a finite dosing interval). Using ceftizoxime [(6R,7R)-7-[2-(2-imino-4-thiazolin-4-yl)glyoxylamido]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 7(2)-(Z)-(O-methyl-oxime)] as a model compound, pharmacokinetic equivalency in mice, rats, monkeys, dogs, and humans was established by selecting a dose for each species that produced similar peak serum concentrations, and by selecting a dosage schedule for each species that produced an equivalent area under the serum concentration-time curve in a 24-h dosing interval. The relationships of animal weight to dose and animal weight to dosing schedule were well described by the power equation Y = aWb, where Y is the dosage variable, W is animal weight, log a is the y-intercept, and b is the slope obtained from the plot of log Y versus log W. Toxicology data for 14 antineoplastic agents were obtained from the literature. The power equation adequately described the relationship between toxic dose and animal weight for most of the compounds, demonstrating the utility of the power equation in the assessment of dosing regimens for toxicity studies as well.

Topics: Animals; Antineoplastic Agents; Body Weight; Cefotaxime; Ceftizoxime; Dogs; Humans; Kinetics; Macaca mulatta; Mice; Pharmaceutical Preparations; Rats; Species Specificity

Cefotaxime sodium (1 g) was injected intravenously in 12 normal (90-110% ideal body weight) and 11 obese (190-210% ideal body weight) male and female subjects. Plasma and urine levels were measured for cefotaxime and its active metabolite desacetylcefotaxime. Kinetic parameters were calculated. Results indicate that a dose adjustment for body weight in obese subjects is not needed, whereas a dose adjustment on the basis of body surface area is reasonable. Metabolite plasma levels in female subjects were significantly higher than in male subjects in both the normal and the obese populations.

Topics: Body Surface Area; Body Weight; Cefotaxime; Female; Humans; Injections, Intravenous; Kinetics; Male; Mathematics; Obesity; Sex Factors