Cefotaxime In Plasma Research Articles

Pharmacokinetics and Withdrawal Times of Cefotaxime in White Leg Shrimp (Litopenaeus vannamei) after Oral Administration

A high-performance liquid chromatography method coupled to tandem mass spectrometry was validated in order to study the pharmacokinetics of cefotaxime in shrimp hepatopancreases and plasma, as well as its withdrawal time related to a maximum residue limit (MRL) in shrimp muscle. Pharmacokinetics parameters were investigated through oral medication at a single dose of 25 mg/kg shrimp body weight and subsequent hepatopancreas and plasma cefotaxime concentration measurements at 0.5, 1, 2, 4, 8, 12 and 24 h after shrimp were fed with medication. The maximum concentration of cefotaxime was observed after one hour in the hepatopancreas (Cmax, 19.45 ± 2.10 mg/kg) and 4 h in plasma (0.184 ± 0.061 mg/L). Based on a minimum inhibitory concentration (MIC) of cefotaxime of 4.13 mg/L against Vibrio parahaemolyticus (known to cause acute hepatopancreatic necrosis disease (AHPND) in white leg shrimp), it was observed that the time during which the hepatopancreas cefotaxime concentration was above the MIC was 23 h. An every 24 h cefotaxime treatment could thus be effective in fighting against this bacterium in shrimp. The withdrawal time of cefotaxime was determined after shrimp were fed with medicated feed once a day and twice a day for three consecutive days. Shrimp muscle was collected on day 1 and day 3 during medication and 1, 3, 7, 14 and 21 days after medication was stopped. Considering an MRL of 50 μg/kg, the withdrawal times were 8.5 degree-days (corresponding to 6.9 h at 29.5 °C) after shrimp were fed with medicated feed once a day for 3 days and 95.5 degree-days (77.7 h at 29.5 °C) after shrimp were fed with medicated feed twice a day for 3 days. Moreover, histological analysis revealed that feeding shrimp with cefotaxime at the given dose in once- or twice-a-day treatments did not negatively impact the shrimp hepatopancreas.

Variability in plasma concentration of cefotaxime in critically ill patients in an Intensive Care Unit of India and its pharmacodynamic outcome: A nonrandomized, prospective, open-label, analytical study.

Background:Cefotaxime is a widely utilized cephalosporin in most intensive care units of India. However, no data are available about its pharmacokinetic/pharmacodynamic variability in critically ill patients of the Indian population.Aim:To investigate the variability in the plasma concentration and pharmacodynamic profile of intermittent dosing of cefotaxime in critically ill patients, according to their locus of infection and causative organism.Materials and Methods:Cefotaxime levels were determined using high-performance liquid chromatography by grouping patients according to their locus of infection as hepatobiliary, renal, pulmonary, and others. Patients with cefotaxime concentration below the minimum inhibitory concentration (MIC) and 5 times below the MIC for the isolated organism were determined.Results:The difference in the plasma cefotaxime concentration between the hepatobiliary and the nonhepatobiliary groups was significant at 1 h (P = 0.02) following drug dosing, while the difference was significant between the renal and nonrenal group at 1 h (P = 0.001), 4 h (P = 0.009), and 8 h (P = 0.02) after drug dosing. The pulmonary group showed significantly (P < 0.05) lower plasma cefotaxime levels than the nonpulmonary group at all-time points. The cefotaxime levels were below the MIC and below 5 times the MIC for the isolated organism in 16.67% and 43.33% of the patients, respectively.Conclusion:The concentration of cefotaxime differs according to the locus of an infection in critically ill patients. Use of another class of antibiotic or shifting to continuous dosing of cefotaxime, for organisms having MIC values above 1 mg/L, is advisable due to the fear of resistance.

Delivery of cefotaxime to the brain via intranasal administration

The purpose of this study was to investigate the plausibility of delivery of cefotaxime to the brain via intranasal administration. In vitro permeation studies were carried out using Franz diffusion cells, and the effect of different concentrations of chitosan (0.1% w/v and 0.25% w/v) on drug permeation across the bovine olfactory mucosa was determined. Samples were collected from the receiver compartment at different time points and analyzed using HPLC. The amount of cefotaxime that permeated across the olfactory mucosa when 0.25% w/v of chitosan was used as a permeation enhancer was ~1.5- and ~2-fold higher at the end of the first hour and second hour, respectively, over control (29.56 ± 6.18 µg/cm2). There was no significant enhancement in drug permeation when 0.1% w/v chitosan was used as the permeation enhancer. Pharmacokinetic studies were carried out using Sprague-Dawley rats. Cefotaxime solution with 0.25% w/v chitosan (40 mg/kg) was administered intravenously (i.v.) to rats in groups 1 and 3 and intranasally to those in group 2 and 4. The time course of drug in the brain was investigated by performing microdialysis in rats of groups 1 and 2. Blood samples were withdrawn from rats in groups 3 and 4, and cefotaxime in plasma was analyzed using HPLC after extraction with a hydrochloric acid–chloroform:1-pentanol (3:1) and phosphate buffer solvent system. Pharmacokinetic parameters were calculated using the trapezoidal rule. The results imply that the drug levels attained in the brain following i.v. and intranasal administrations were comparable. These results suggest that intranasal administration of cefotaxime could be a potential method of delivering antibacterial agents because of it being noninvasive and patient compliant.

Oral bioavailability enhancement of a hydrophilic drug delivered via folic acid-coupled liposomes in rats

Abstract Objectives A liposome preparation that is amenable to receptor-mediated endocytosis has been developed to enhance the oral bioavailability of poorly absorbable peptidomi-metic drugs by use of folic acid as the mediator of liposomal uptake. Methods Folic acid was physically coupled to the surface of the liposomes and cefotaxime was used as the model drug. In-vivo evaluation was carried out on eight Sprague-Dawley rats in a two-way crossover study to compare the oral bioavailability of cefotaxime loaded in folic acid-free liposomes and folic acid-coupled liposomes. Blood samples were collected from the tail vein and plasma cefotaxime levels were determined using an HPLC method. Key findings Enhanced oral bioavailability (AUC0-∞) of cefotaxime was observed when administered via folic acid-coupled liposomes. The peak plasma concentration (Cmax) of cefotaxime was increased when administered via folic acid-coupled liposomes as compared with folic acid-free liposomes. At 90% confidence interval, the value for AUC0-∞ was 1.4–2-times higher and the value for Cmax was 1.2–1.8-times higher for the folic acid-coupled liposomes compared with folic acid-free liposomes. Conclusions Folic acid could enhance the uptake of liposomally entrapped drug. It could be a useful candidate to supplement liposome delivery systems.

Oral bioavailability enhancement of a hydrophilic drug delivered via folic acid-coupled liposomes in rats

A liposome preparation that is amenable to receptor-mediated endocytosis has been developed to enhance the oral bioavailability of poorly absorbable peptidomimetic drugs by use of folic acid as the mediator of liposomal uptake. Folic acid was physically coupled to the surface of the liposomes and cefotaxime was used as the model drug. In-vivo evaluation was carried out on eight Sprague-Dawley rats in a two-way crossover study to compare the oral bioavailability of cefotaxime loaded in folic acid-free liposomes and folic acid-coupled liposomes. Blood samples were collected from the tail vein and plasma cefotaxime levels were determined using an HPLC method. Enhanced oral bioavailability (AUC(0-infinity)) of cefotaxime was observed when administered via folic acid-coupled liposomes. The peak plasma concentration (C(max)) of cefotaxime was increased when administered via folic acid-coupled liposomes as compared with folic acid-free liposomes. At 90% confidence interval, the value for AUC(0-infinity) was 1.4-2-times higher and the value for C(max) was 1.2-1.8-times higher for the folic acid-coupled liposomes compared with folic acid-free liposomes. Folic acid could enhance the uptake of liposomally entrapped drug. It could be a useful candidate to supplement liposome delivery systems.

Plasma and peritoneal concentration following continuous infusion of cefotaxime in patients with secondary peritonitis

The aim of this study was to determine the steady-state plasma and peritoneal concentrations of cefotaxime and its metabolite desacetyl-cefotaxime administered by continuous infusion to critically ill patients with secondary peritonitis. In 11 patients, a continuous infusion of 4 g/24 h of cefotaxime following a bolus of 2 g was evaluated. Plasma and peritoneal levels of cefotaxime and desacetyl-cefotaxime were measured at steady state on days 2 and 3 (plasma) and on day 3 (peritoneal) by HPLC. Results are expressed as means +/- SD. Total and unbound plasma levels of cefotaxime were 24.0 +/- 21.5 and 20.3 +/- 19.8 mg/L on day 2 and 22.1 +/- 20.7 and 18.9 +/- 19.2 mg/L on day 3, respectively. Total and unbound levels of cefotaxime in the peritoneal fluids were 16.2 +/- 11.5 and 14.3 +/- 10.4 mg/L, respectively. The unbound fraction of plasma cefotaxime was 81.8 +/- 5.9% on day 2 and 82.6 +/- 7.7% on day 3, and the unbound fraction at the peritoneal site was 87.0 +/- 5.5% on day 3. Total and unbound plasma levels of desacetyl-cefotaxime were 9.0 +/- 8.1 and 8.4 +/- 8.1 mg/L on day 2 and 7.6 +/- 7.6 and 7.2 +/- 7.6 mg/L on day 3, respectively. Total and unbound levels of desacetyl-cefotaxime in the peritoneal fluids were 11.9 +/- 11.5 and 10.9 +/- 10.8 mg/L, respectively. The MICs for the enterobacteria recovered ranged from 0.016 to 0.25 mg/L. Continuous infusion of 4 g/24 h of cefotaxime provided a peritoneal concentration >5x MIC for the recovered Enterobacteriaceae and the susceptibility breakpoint of cefotaxime for facultative Gram-negative bacilli.

Subcutaneous pharmacokinetics and dosage regimen of cefotaxime in buffalo calves (Bubalus bubalis)

The pharmacokinetics and dosage regimen of cefotaxime following its single subcutaneous administration (10 mg/kg) were investigated in buffalo calves. Plasma and urine samples were collected over 10 and 24 h post administration, respectively. Cefotaxime in plasma and urine was estimated by microbiological assay technique using E. coli as test organism. The pharmacokinetic profiles fitted one-compartment open model. The peak plasma levels of cefotaxime were 6.48 ± 0.52 µg/ml at 30 min and the drug was detected upto 10 h. The absorption half-life and elimination half-life were 0.173 ± 0.033 h and 1.77 ± 0.02 h, respectively. The apparent volume of distribution and total body clearance were 1.17 ± 0.10 l/kg and 0.45 ± 0.03 l/kg/h, respectively. The urinary excretion of cefotaxime in 24 h, was 5.36 ± 1.19 percent of total administrated dose. A satisfactory subcutaneous dosage regimen for cefotaxime in buffalo calves would be 13 mg/kg repeated at 12 h intervals.

Validation of a high-performance chromatographic method for determination of cefotaxime in biological samples

An analytical method for detecting and quantifying cefotaxime in plasma and several tissues is described. The method was developed and validated using plasma and tissues of rats. The samples were analyzed by reversed phase liquid chromatography (HPLC) with UV detection (254 nm). Calibration graphs showed a linear correlation (r > 0.999) over the concentration ranges of 0.5–200 μg/mL and 1.25–25 μg/g for plasma and tissues, respectively. The recovery of cefotaxime from plasma standards prepared at the concentrations of 25 μg/mL and 100 μg/mL was 98.5 ± 3.5% and 101.8 ± 2.2%, respectively. The recovery of cefotaxime from tissue standards of liver, fat and muscle, prepared at the concentration of 10 μg/g was: 89.8 ± 1.2% (liver), 103.9 ± 6.5% (fat) and 97.8 ± 2.1% (muscle). The detection (LOD) and quantitation (LOQ) limits for plasma samples were established at 0.11 μg/mL and 0.49 μg/mL, respectively. The values of these limits for tissues samples were approximately 2.5 times higher: 0.3 μg/g (LOD) and 1.25 μg/g (LOQ). For plasma samples, the deviation of the observed concentration from the nominal concentration was less than 5% and the coefficient of variation for within-day and between-day assays was less than 6% and 12%, respectively. The method was used in a pharmacokinetic study of cefotaxime in the rat and the mean values of the pharmacokinetic parameters are given.

Pharmacokinetic profile of cefotaxime in goats

Cefotaxime was administered to goats intravenously, intramuscularly and subcutaneously to determine blood and urine concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time curve indicated a two compartment open model, with an elimination half-life value (t1/2 beta) of 22.38 +/- 0.41 minutes. Both intramuscular and subcutaneous routes showed slower values, that is, 38.64 and 69.58 minutes. The apparent volume of distribution of cefotaxime in goats was less than 1 litre kg-1 and suggested a lower distribution in tissues than in blood. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 77.8 +/- 1.7 and 44.0 +/- 0.8 micrograms ml-1 at 29.6 and 40.4 minutes, respectively. The average bioavailability of cefotaxime given by intramuscular and subcutaneous injection was 1.08 and 1.25 times the intravenous availability, respectively. The cefotaxime concentration remained in urine 24 hours longer after subcutaneous injection than after intramuscular administration.

Disposition of cefotaxime and its metabolite, desacetylcefotaxime, in rat: application of a pharmacokinetic-protein binding model.

1. The pharmacokinetics and protein binding of cefotaxime and desacetylcefotaxime were studied in rat. 2. After i.v. dosing of cefotaxime (100 mg/kg) the concentration-time profiles of cefotaxime and its metabolite desacetylcefotaxime followed biphasic decays, giving the kinetic parameters for cefotaxime: VTss and AUC of 127 ml/kg and 8.2 mg/min per ml, respectively. The beta-elimination half-life was 17 min with Cls of 13.1 ml/min per kg. The average association constant (K x 10(3) M-1) and total protein binding site concentration (Pt x 10(-3) M) for cefotaxime were 3.87 and 0.68, respectively, with saturation of plasma protein binding occurring at about 30 micrograms/ml. The average free fraction of cefotaxime in plasma (Fp) was 0.48. 3. The metabolite desacetylcefotaxime had a plasma Cmax of 74.4 micrograms/ml (35 min). The respective elimination half-life and AUC were 53 min and 7.2 mg/min per ml. The binding profile, unlike that of cefotaxime, was non-saturable with a K value of 13.90M-1. The Fp of desacetylcefotaxime was 0.89. 4. The concentration-time behaviour of total and free desacetylcefotaxime (i.v. bolus, 50 mg/kg) declined biexponentially with respective VTss and AUC of 125 ml/kg and 19.4 mg/min per ml (total drug), and 192 ml/kg and 13.9 mg/min per ml (free drug). The beta-phase half-life of total and free drug was about 36 min, whereas CLs (ml/min per kg) were 2.7 (total) and 3.7 (free). The binding characteristics were in good agreement with those of the metabolite produced in vivo, with a K value of 8.58 M-1. The Fp value of desacetylcefotaxime in plasma was 0.73.

Pharmacokinetics of cefotaxime in the dog.

Each of five dogs was given cefotaxime at a dose rate of 50 mg/kg by intravenous, intramuscular and subcutaneous routes, in three separate treatments. Plasma concentration time profiles were characterised by a linear two-compartment model after the intravenous administration. After intravenous, intramuscular and subcutaneous injections the mean biological half-lives were 0.74, 0.83 and 1.71 hours, respectively. The apparent steady state volume of distribution was 0.48 litre/kg and body clearance after intravenous injection was approximately 0.63 litre/hour/kg. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 47 +/- 15 and 29.6 +/- 16 micrograms/ml at 0.5 and 0.8 hours, respectively. The average bioavailability of cefotaxime given by intramuscular injection was 86.5 per cent and for cefotaxime given subcutaneously it was approximately 100 per cent. After two hours, the cefotaxime plasma concentration remained higher after subcutaneous than after intramuscular administration.

Effect of probenecid on the pharmacokinetics of cefotaxime in sheep.

The effect of probenecid given by intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection on the pharmacokinetics of cefotaxime was studied in six Merino ewes. When given intravenously, probenecid increased significantly (P less than 0.05) the plasma half-life of cefotaxime three-fold (to 0.94 +/- 0.32 h) and the area under the curve (AUC) approximately two-fold (to 41.1 +/- 16.8 micrograms.h/ml), and decreased plasma cefotaxime clearance (ClB) 45% (to 0.648 +/- 0.191 l/h/kg). When given with probenecid intravenously, renal clearance (ClR), volume of the central compartment (VC), volume of distribution steady state (Vd(ss], and the amount excreted in urine unchanged did not alter significantly. When given by i.m. injection, probenecid and cefotaxime were well tolerated and cefotaxime was well absorbed (101 +/- 45%). When given by s.c. injection, only 40 +/- 25% cefotaxime was absorbed. When given intramuscularly or subcutaneously, probenecid appeared to reduce the ClB and ClR of cefotaxime, probably because plasma probenecid concentrations are prolonged. Probenecid did not appear to affect the distribution of cefotaxime.