Effect of food on the pharmacokinetics of oral cefuroxime axetil in dogs.

Cefuroxime axetil pharmacokinetic profile was investigated in 12 Beagle dogs after single intravenous and oral administration of tablets or suspension at a dose of 20 mg/kg, under both fasting and fed conditions. A three-period, three-treatment crossover study (IV, PO under fasting and fed condition) was applied. Blood samples were withdrawn at predetermined times over a 12-hr period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. No statistically significant differences were observed between formulations and feeding conditions on PK parameters. Independently of the feeding condition, absorption of cefuroxime axetil after tablet administration was low and erratic. The drug has been quantified in plasma in 3 out of 6 and 5 out of 6 dogs in the fasted and fed groups. For this formulation, the bioavailability (F), peak plasma concentration (Cmax ), and area under the concentration-time curve (AUC) of cefuroxime axetil were significantly enhanced (p < .05) by the concomitant ingestion of food (32.97 ± 13.47-14.08 ± 7.79%, 6.30 ± 2.62-2.74 ± 0.66 µg/ml, and 15.75 ± 3.98-7.82 ± 2.76 µg.hr/ml for F, Cmax, and AUC in fed and fasted dogs, respectively), while for cefuroxime axetil suspension, feeding conditions affected only the rate of absorption, as reflected by the significantly shorter absorption half-life (T½(a) ) and time to peak concentration (Tmax ) (0.55 ± 0.27-1.15 ± 0.19 hr and 1.21 ± 0.22-1.70 ± 0.30 for T½(a) and Tmax in fed and fasted dogs, respectively). For cefuroxime axetil tablets, T > MIC (≤1 µg/ml) was <2 hr in fasted and ≈4 hr in fed animals, and for cefuroxime axetil suspension, T > MIC (≤1 µg/ml) was ≈5 hr and for T >MIC (≤4 µg/ml) was ≈2.5 hr for fasted and fed dogs, respectively. Cefuroxime axetil as a suspension formulation seems to be a better option than tablets. However, its short permanence in plasma could reduce its clinical usefulness in dogs.

Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs.

Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12-h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (Cmax ), time-to-peak plasma concentration (Tmax ), and bioavailability for the intramuscular and subcutaneous administration were (mean ± SD) 22.99 ± 7.87 µg/mL, 0.43 ± 0.20 h, and 79.70 ± 14.43% and 15.37 ± 3.07 µg/mL, 0.99 ± 0.10 h, and 77.22 ± 21.41%, respectively. Elimination half-lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 ± 0.19 h and 1.49 ± 0.21 h; 1.13 ± 0.13 and 1.79 ± 0.24 h; and 1.04 ± 0.23 h and 2.21 ± 0.23 h, respectively. Significant differences were found between routes for Ka , MAT, Cmax , Tmax , t½(a) , and MRT. T > MIC = 50%, considering a MIC of 1 µg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 µg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h.

Influence of cardiopulmonary bypass on cefuroxime plasma concentration and pharmacokinetics in patients undergoing coronary surgery.

OBJECTIVES: The aims of this study were to evaluate the influence of cardiopulmonary bypass (CPB) on the plasma concentrations and pharmacokinetics of cefuroxime and to assess whether the cefuroxime dose regimen (a 1.5 g dose, followed by 750 mg every 6 h for 24 h) is adequate for cardiac surgery antibiotic prophylaxis. METHODS: A prospective, controlled, observational study compared patients undergoing coronary surgery with CPB (CPB group, n = 10) or off-pump surgery (off-pump group, n = 9). After each cefuroxime dose, blood samples were sequentially collected and analysed using high-efficiency chromatography. For demographic data and pharmacokinetic parameters, the authors used Fisher's exact test for nominal variables and Student's t-test and the Mann-Whitney U-test for parametric and non-parametric variables, respectively. Plasma concentrations were compared using ANOVA, and the percentage of patients with a remaining plasma concentration of >16 mg/l within 6 h after each bolus was quantified in tabular form. RESULTS: After each cefuroxime bolus was administered, both groups presented a significant decrease in plasma concentration over time (P < 0.001), without differences between the groups. The mean CPB time of 59.7 ± 21.1 min did not change cefuroxime plasma concentrations or pharmacokinetics. The mean clearance ± SD (ml/kg/min) and median elimination half-life (h) of the CPB group versus the off-pump group were 1.7 ± 0.7 versus 1.6 ± 0.6 (P = 0.67), respectively, and 2.2 versus 2.3 (P = 0.49), respectively. Up to 3 h following the first bolus of 1.5 g, but not after 6 h, all patients had plasma concentrations >16 mg/l (CPB group = 20% and off-pump group = 44%). However, after all 750 mg boluses were administered, concentrations <16 mg/dl were reached within 3 h. CONCLUSIONS: CPB does not influence cefuroxime plasma concentrations. The dosing regimen is adequate for the intraoperative period, but in the immediate postoperative period, it requires further review.

Comparative bioavailability of cefuroxime axetil suspension formulations administered with food in healthy subjects.

OBJECTIVE: To assess the comparative bioavailability of two formulations (250 mg/5 mL suspension) of cefuroxime axetil (CAS 64544-07-6), administered with food, in healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval. Plasma samples were obtained for up to 12 h post dose. Plasma cefuroxime axetil concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) with negative ion electrospray ionization using multiple reactions monitoring (MRM). From the cefuroxime axetil plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained: AUClast and Cmax. RESULTS: The limit of quantification was 0.1 microg/mL for plasma cefuroxime axetil analysis. The geometric mean and 90% confidence interval CI of test/reference product percent ratios were: 106.1% (100.8%-111.8%) for Cmax, 109.4% (104.8%-114.2%) for AUClast. CONCLUSION: Since the 90% CI for AUClast and Cmax ratios were within the 80-125% interval proposed by the US FDA, it was concluded that cefuroxime axetil (test formulation, 250 mg/5 mL suspension) was bioequivalent to a reference formulation under fed conditions, for both the rate and extent of absorption.

Effect of severity disease on the pharmacokinetics of cefuroxime in children with multiple organ system failure.

The aim of the present study was to investigate if the severity of illness affected the pharmacokinetics of cefuroxime in 11 children diagnosed with multiple organ system failure. The patients were assigned to a severely ill group (group 1), a very severely ill group (group 2), or a control group (group 0). Blood samples were taken and cefuroxime concentrations were measured in plasma by HPLC after the first intravenous infusion of 100 mg of cefuroxime per kg of body weight. The pharmacokinetic profile of cefuroxime exhibited both one and two compartmental distribution. Statistically significant differences between the pharmacokinetic parameters of the severe (group 1) and the very severe patients (group 2) were found, and significant differences (p<0.05) in the pharmacokinetic parameters between groups 1 and 2 vs. the control group were observed for most of the parameters analyzed. However, there was no statistical difference in clearance between group 1 and the control group. The data indicate that the pharmacokinetic differences determined by severity of disease are useful for establishing an individualized regimen dosage in children with multiple organ system failure.

Perioperative cefuroxime pharmacokinetics in cardiac surgery.

OBJECTIVE: The objective was to investigate the plasma levels and to compare the pharmacokinetics of cefuroxime during and after surgery in adult patients with elective indication for coronary artery bypass grafting. METHODS: Seventeen patients received three 1.5-g bolus IV doses of cefuroxime, one every 12 hrs. Serial blood samples (3 mL) were collected 1, 3, 6, 9, and 12 hrs after the first dose (given during the intervention) and after the second and third doses (postsurgery). Blood samples were centrifuged and stored frozen until being assayed. For assessment of the cefuroxime plasma levels by liquid chromatography, only 200 microL of plasma were required. Determination of cefuroxime plasma levels was followed by a pharmacokinetic (PK)-modeling using PK Solutions 2.0 software. RESULTS: The kinetic parameters obtained remained unchanged after the first, second, and the third dose as follows: elimination half-life: 1.8 h, 1.9 h, and 1.8 h; clearance: 1.4, 1.5, and 1.5 mL/min/kg, respectively. Additionally, the apparent volume of distribution did not change during and after the intervention: 0.19, 0.25, and 0.22 L/kg, after the first, second, and the third dose, respectively. Since the drug has a low volume of distribution, plasma levels obtained after a 1.5-g IV bolus injection of cefuroxime decreased rapidly due to the high plasma clearance, with a consequent short half-life. CONCLUSIONS: The kinetic disposition of cefuroxime remains unaltered in patients undergoing coronary artery bypass grafting; to reduce the fluctuation in plasma concentrations so that the antibiotic prophylaxis in the peri-operative period is guaranteed, the dose regimen should be reviewed.

Perioperative cefuroxime pharmacokinetics in cardiac surgery

OBJECTIVE: The objective was to investigate the plasma levels and to compare the pharmacokinetics of cefuroxime during and after surgery in adult patients with elective indication for coronary artery bypass grafting. METHODS: Seventeen patients received three 1.5-g bolus IV doses of cefuroxime, one every 12 hrs. Serial blood samples (3 mL) were collected 1, 3, 6, 9, and 12 hrs after the first dose (given during the intervention) and after the second and third doses (postsurgery). Blood samples were centrifuged and stored frozen until being assayed. For assessment of the cefuroxime plasma levels by liquid chromatography, only 200 æL of plasma were required. Determination of cefuroxime plasma levels was followed by a pharmacokinetic (PK)-modeling using PK Solutions 2.0 software. RESULTS: The kinetic parameters obtained remained unchanged after the first, second, and the third dose as follows: elimination half-life: 1.8 h, 1.9 h, and 1.8 h; clearance: 1.4, 1.5, and 1.5 mL/min/kg, respectively. Additionally, the apparent volume of distribution did not change during and after the intervention: 0.19, 0.25, and 0.22 L/kg, after the first, second, and the third dose, respectively. Since the drug has a low volume of distribution, plasma levels obtained after a 1.5-g IV bolus injection of cefuroxime decreased rapidly due to the high plasma clearance, with a consequent short half-life. CONCLUSIONS: The kinetic disposition of cefuroxime remains unaltered in patients undergoing coronary artery bypass grafting; to reduce the fluctuation in plasma concentrations so that the antibiotic prophylaxis in the peri-operative period is guaranteed, the dose regimen should be reviewed.

OBJETIVO: Investigar os níveis plasmáticos e comparar a farmacocinética da cefuroxima durante e após cirurgia de revascularização do miocárdio. MÉTODOS: Dezessete pacientes receberam três doses intravenosas de 1,5 g de cefuroxima, a cada 12 horas. Foram coletadas amostras de sangue nos tempos de 1, 3, 6, 9 e 12 horas após a primeira dose (durante a cirurgia) e após a segunda e terceira dose (administradas após a cirurgia). As amostras de sangue foram centrifugadas e armazenadas congeladas até o momento da análise. Os níveis plasmáticos da cefuroxima foram determinados através de cromatografia líquida, utilizando-se apenas 200 mL de plasma. A determinação da farmacocinética da cefuroxima foi realizada utilizando o software PK-solutions 2.0. RESULTADOS: Todos os parâmetros cinéticos obtidos permaneceram inalterados após a adminstração da 1ª, 2ª e 3ª doses: meia vida de eliminação 1,8h, 1,9h and 1,8h, depuração 1,4, 1,5 and 1,5 mL/min/kg respectivamente. Adicionalmente, o volume aparente de distribuição, não se alterou durante ou após a intervenção: 0,19, 0,25 and 0,22 L/kg, após 1ª, 2ª e 3ª dose, respectivamente. Os níveis plasmáticos obtidos após administração da cefuroxima reduziram rapidamente devido à alta depuração plasmática com conseqüente curta meia-vida plasmática, atingindo valores abaixo da concentração inibitória mínima a partir da 9ª hora da administração. CONCLUSÕES: A disposição cinética da cefuroxima permanece inalterada em pacientes submetidos à cirurgia de revascularização do miocárdio, e com vistas à redução da flutuação no período perioperatório, o regime de dose para a antibioticoprofilaxia poderia ser revisto.

Systemic availability of prophylactic cefuroxime in patients submitted to coronary artery bypass grafting with cardiopulmonary bypass.

Cardiopulmonary bypass and hypothermia (HCPB) is a procedure commonly used during heart surgery, representing a risk factor for the patient by promoting extensive haemodilution and profound physiological changes. Cefuroxime is used for the prevention of infection following heart surgery, and several dose schemes have been suggested for prophylaxis with cefuroxime. The objective of the present study was to assess, in a comparative manner, the systemic availability of cefuroxime administered intravascularly as a bolus dose of 1.5 g to 17 patients having heart surgery with or without HCPB. Plasma cefuroxime concentrations were determined by high-pressure liquid chromatography-UV, and the following values, expressed as medians, were obtained for the study group compared with controls: 69.1 vs. 62.7 mg/L (1st h), 35.8 vs. 26.0mg/L (3rd h), 14.6 vs. 8.7 mg/L (6th h, P<0.05), 6.1 vs. 3.0mg/L (9th h, P<0.05) and 2.6 vs. 1.0mg/L (12th h, P<0.05). Despite the differences recorded during the study period as a consequence of HCPB, low antibiotic concentrations were found as early as 6h post dose for both groups investigated. Thus, the low systemic availability of cefuroxime after the administration of a 1.5-g dose may not protect against postoperative infections. The data obtained permit us to recommend a change in the dose scheme in order to maintain adequate plasma levels of cefuroxime.

Estudo da disposição cinética da cefuroxima em pacientes submetidos à cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia / Study of kinetic disposition of cefuroxime on patients submitted to cardiac surgery with extracorporea and hypothermia circulation

A circulação extracorpórea com hipotermia (CEC-H) é um procedimento comumente utilizado em cirurgias cardíacas, que representa um fator de risco para o paciente por promover extensa hemodiluição e profundas alterações fisiológicas. Nestas cirurgias, utiliza-se a cefuroxima com antimicrobiano para profilaxia de infecções, estando sua concentração inibitória mínima (CIM IND. 90) na faixa de 4 a 16g/mL dependendo da espécie e cepa bacteriana. Vários esquemas posológicos tem sido propostos para a profilaxia com este antimicrobiano. Assim, o objetivo do presente estudo foi investigar a farmacocinética e a disponibilidade sistêmica da cefuroxima, administrada I.V., bolus, na dose de 1,5g a 17 pacientes submetidos à cirurgia cardíaca com ou sem CEC-H...(AU)

[Cefuroxime Bayesian pharmacokinetics in severely ill septic children]. / Farmacocinética bayesiana de cefuroxima en niños infectados gravemente enfermos.

OBJECTIVE: To estimate the cefuroxime pharmacokinetic parameters in critically ill pediatric septic patients using a Bayesian pharmacokinetic method and three serum drug assays per patient. DESIGN: Cross-sectional study of critically ill pediatric patients undergoing therapeutic monitoring of cefuroxime serum concentrations. SETTING: Tertiary care center. PATIENTS: Nine critically ill pediatric patients with sepsis and septic shock treated with cefuroxime. METHODS: Timed serum concentrations of cefuroxime were obtained in each patient. The Vd (volume of distribution) and the Kel (constant of elimination) were estimated by means of a Bayesian iterative two-stage algorithm, using the information of three serum drug concentrations per patient at optimal times. The parameters were also estimated by the traditional method of non linear least square regression in eight samples. RESULTS: The Bayesian Vd was very similar to the traditional Vd with a correlation coefficient of 0.99 and a small bias of -0.04 L/kg whereas the Kel had a correlation of 0.90 and bias of -0.29 h-1. The mean Bayesian Vd was 0.68 L/kg, a larger value than that reported in non critically ill patients. CONCLUSIONS: We offer a tentative cefuroxime pharmacokinetic model for critically ill pediatric septic patients which may be useful for the control of cefuroxime serum concentrations. Also, our study underscored the potential usefulness of a Bayesian pharmacokinetic approach as a tool for therapeutic drug monitoring in critically ill patients.

Farmacocinética bayesiana de cefuroxima en niños infectados gravemente enfermos / Bayesian pharmacokinetics of cefuroxime in critically ill septic children

Objetivo. Estimar los párametros farmacocinéticos de cefuroxima en el paciente pediátrico críticamente enfermo utilizando un método farmacocinético bayesiano y un número limitado de muestras por paciente. Diseño. Estudio transversal de pacientes pediátricos gravemente enfermos que recibieron tratamiento y monitoreo de concentraciones séricas de cefuroxima. Lugar. Centro de atención de tercer nivel. Pacientes. Nueve pacientes pediátricos sépticos gravemente enfermos. Métodos. Se midió la cefuroxima a diferentes tiempos y se estimaron los parámetros Vd(volumen de distribución) y Kel(constante de eliminación) utilizando un algoritmo iterativo en dos etapas hayesiano y la información de tres muestras de cada paciente. El Vd y la Kel fueron también estimados por el método tradicional de regresión no lineal en 8 muestras. Resultados. La comparación de algunos métodos mostró que la Vd bayesiano fue muy similar al tradicional (r=0.99 y sesgo de -0.04 l/kg) mientras que para la Kel la correlación fue de 0.90 y el sesgo de -0.29 h. el Vd bayesiano promedio fue de 0.68 l/kg, un valor mayor que el reportado para pacientes no críticamente enfermos. Conclusiones. Ofrecemos un modelo farmacocinético de cefuroxima para niños sépticos gravemente enfermos que puede ser integrado a un predictor bayesiano para establecer dosis individualizadas. Asimismo, ilustran la utilidad de un abordaje farmacocinético bayesiano para establecer dosis individualizadas. Asimismo, ilustran la utilidad de un abordaje farmacocinético bayesiano como herramienta de investigación clínica

Actividad comparativa in vitro de la combinación amoxicilina-sulbactam y otros 4 antimicrobianos frente a bacterias aisladas de pacientes con infecciones respiratorias adquiridas en la comunidad / In vitro activity of amoxicillin-sulbactam and other 4 antimicrobial agents against community acquired respiratory pathogens

En los últimos años, a nivel mundial se han producido cambios en la etiología de la infección respiratoria y los microorganismos causases muestran resistencia progresiva a los antimicrobianos de uso habitual. Esto ha llevado a la búsqueda de nuevas alternativas terapéuticas. El propósito de este estudio fue comparar la susceptibilidad antimicrobiana in vítro, de 150 cepas bacterianas aisladas durante el primer semestre 1997, de adultos y niños con infeccion respiratoria superior o inferior, frente a la nueva asociación amoxicilina/ sulbactam (amox/sul) y otros 4 antimicrobianos de uso frecuente en Chile en estas patologías. Se determinó la CIM mediante técnica de dilución en agar de amoxicilina (amox), amox/ sul, cefuroxima (cefu), azitromicina (azit) y claritromicina (ciarl) frente a 55 cepas de S. pneumoniae, 44 cepas de H. ínfluenzae, 19 cepas de S. pyogenes y 32 S. aureus. Resultados. De las 55 cepas de S. pneumoniae, 9.1 por ciento fueron resistentes 1 amox, 7,3 por ciento a amox/Sul y cefu y ninguna presentó resistencia a azit o ciarl. Las 19 cepas de S. pyogenes estudiadas fueron sensibles a los 5 antimicrobianos, aunque cepas presentaron CIM límite a azit y ciarl (igual al valor de corte). De las 44 cepas de H. influenzae, 12,3 por ciento presentaron resistencia a amox y 9,1 por ciento a clarí. No se observó resistencia a amox/sul, cefu ni azit. En las cepas de S. aureus se observó resistencia importante a todos los antimicrobianos estudiados: 96 por ciento para amox, 56,3 por ciento para cefu, 59,4 por ciento para ciarl y azit y 46,9 por ciento para amox/sul. Conclusión: De acuerdo a nuestros resultados in vitro, la combinación amoxicilina/sulbactam, frente a bacterias causantes de infecciones respiratorias, tiene una cobertura comparable a otros antimicrobianos en uso e incluidos en este estudio (entre 100 y 54 por ciento) con la excepción de S. aureus que debería ser tratado con antimicrobianos con actividad antiestafilocóccica específica