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1.
J Pharm Biomed Anal ; 248: 116259, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38870837

RESUMO

BACKGROUND: The investigation of drug disposition in tissues is critical to improving dosing strategy and maximizing treatment effectiveness, yet developing a multi-tissue bioanalytical method could be challenging due to the differences among various matrices. Herein, we developed an LC-MS/MS method tailored for the quantitation of piperacillin (PIP), cefazolin (CFZ), and cefoxitin (CFX) in rat plasma and 12 tissues, accompanied by validation data for each matrix according to the FDA and EMA guidelines. RESULTS: The method required only a small sample volume (5 µL plasma or 50-100 µL tissue homogenates) and a relatively simple protocol for simultaneous quantitation of PIP, CFZ, and CFX within different biological matrices. Mobile phase A was composed of 5 mM ammonium formate and 0.1 % formic acid in water, while mobile phase B contained 0.1 % formic acid in acetonitrile. The mobile phase was pumped through a Synergi Fusion-RP column equipped with a guard column with a gradient elution program at a 0.3 mL/min flow rate. The mass spectrometer was operated in positive ionization mode (ESI+) using multiple reaction monitoring. SIGNIFICANCE: The validated method has been successfully applied to quantify PIP, CFZ, and CFX from the plasma and tissue samples collected in a pilot rat study and will further be used in a large pharmacokinetic study. To our knowledge, this is also the first report presenting long-term, freeze-thaw, and autosampler stability data for PIP, CFZ, and CFX in rat plasma and multiple tissues.


Assuntos
Cefazolina , Cefoxitina , Piperacilina , Espectrometria de Massas em Tandem , Animais , Espectrometria de Massas em Tandem/métodos , Ratos , Cefazolina/sangue , Cefazolina/farmacocinética , Cefazolina/análise , Piperacilina/sangue , Piperacilina/farmacocinética , Piperacilina/análise , Cefoxitina/farmacocinética , Cefoxitina/sangue , Cefoxitina/química , Cefoxitina/análise , Cromatografia Líquida/métodos , Reprodutibilidade dos Testes , Distribuição Tecidual , Ratos Sprague-Dawley , Antibacterianos/sangue , Antibacterianos/farmacocinética , Antibacterianos/análise , Masculino , Espectrometria de Massa com Cromatografia Líquida
2.
Anaesth Crit Care Pain Med ; 43(3): 101376, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38494157

RESUMO

BACKGROUND: This study describes the population pharmacokinetics of cefoxitin in obese patients undergoing elective bariatric surgery and evaluates different dosing regimens for achievement of pre-defined target exposures. METHODS: Serial blood samples were collected during surgery with relevant clinical data. Total serum cefoxitin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. The cefoxitin unbound fraction (fu) was estimated. Dosing simulations were performed to ascertain the probability of target attainment (PTA) to achieve cefoxitin fu above minimum inhibitory concentrations (MIC) from surgical incision to wound closure. Fractional target attainment (FTA) was calculated against MIC distributions of common pathogens. RESULTS: A total of 123 obese patients (median BMI 44.3 kg/m2) were included with 381 cefoxitin concentration values. Cefoxitin was best described by a one-compartment model, with a mean clearance and volume of distribution of 10.9 ± 6.1 L/h and 23.4 ± 10.5 L, respectively. In surgery <2 h, a 2 and a 4 g doses were sufficient for an MIC up to 4 and 8 mg/L (fu 50%), respectively. In prolonged surgery (2-4 h), only continuous infusion enabled optimal PTA for an MIC up to 16 mg/L. Optimal FTAs were obtained against Staphylococcus aureus and Escherichia Coli only when simulating with 50% cefoxitin protein binding (intermittent regimen) and regardless of the protein binding for the continuous infusion. CONCLUSION: Intermittent dosing regimens resulted in optimal FTAs against susceptible MIC distributions of S. aureus and E. coli when simulating with 50% cefoxitin protein binding. Continuous infusion of cefoxitin may improve FTA regardless of protein binding. STUDY REGISTRATION: Registration on ClinicalTrials.gov, NCT03306290.


Assuntos
Antibacterianos , Antibioticoprofilaxia , Cirurgia Bariátrica , Cefoxitina , Procedimentos Cirúrgicos Eletivos , Testes de Sensibilidade Microbiana , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Cefoxitina/farmacocinética , Cefoxitina/administração & dosagem , Obesidade/cirurgia , Estudos Prospectivos , Infecção da Ferida Cirúrgica/prevenção & controle
3.
Clin Exp Pharmacol Physiol ; 49(10): 1126-1135, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35748860

RESUMO

We aimed to evaluate the predictive performance of previously constructed free (Cfree ) and total (Ctotal ) cefoxitin pharmacokinetic models and the possibility of administering cefoxitin via the target-controlled infusion (TCI) method in clinical practice. Two external validation studies (N = 31 for Cfree model, N = 30 for Ctotal model) were conducted sequentially. Cefoxitin (2 g) was dissolved in 50 mL of normal saline to give a concentration of 40 mg mL-1 . Before skin incision, cefoxitin was infused with a TCI syringe pump. Target concentrations of free concentration and total concentration were set to 25 and 80 µg mL-1 , respectively, which were administered throughout the surgery. Three arterial blood samples were collected to measure the total and free plasma concentrations of cefoxitin at 30, 60 and 120 min, after the start of cefoxitin administration. The predictive performance was evaluated using four parameters: inaccuracy, divergence, bias and wobble. The pooled median (95% confidence interval) biases and inaccuracies were - 45.9 (-47.3 to -44.5) and 45.9 (44.5 to 47.3) for Cfree model (Choi_F model), and - 16.6 (-18.4 to -14.8) and 18.5 (16.7 to 20.2) for Ctotal model (Choi_Told model), respectively. The predictive performance of the newly constructed model (Choi_Tnew model), developed by adding the total concentration data measured in the external validation, was better than that of the Choi_Told model. Models constructed with total concentration data were suitable for clinical use. Administering cefoxitin using the TCI method in patients maintained the free concentration above the minimal inhibitory concentration (MIC) breakpoints of the major pathogens causing surgical site infection throughout the operation period.


Assuntos
Cefoxitina , Cirurgia Colorretal , Antibacterianos , Cefoxitina/farmacocinética , Humanos , Testes de Sensibilidade Microbiana , Infecção da Ferida Cirúrgica/prevenção & controle
4.
Eur J Drug Metab Pharmacokinet ; 46(4): 479-485, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33959888

RESUMO

BACKGROUND AND OBJECTIVES: A high inter-individual variability in pharmacokinetic parameters in obese patients is observed. The objective of this study was to evaluate the effect of obesity parameters on the pharmacokinetics of cefoxitin administered for antibiotic prophylaxis during bariatric surgery. METHODS: This a secondary analysis of a pharmacokinetic study involving 174 obese patients scheduled for bariatric surgery and receiving a 4-g dose of cefoxitin. Blood samples were collected at incision and wound closure. The total plasma concentrations were assessed utilising a validated high-performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic and pharmacodynamic target was defined as an estimated free concentration of cefoxitin at the time of wound closure >8 mg/L. Specific evaluated obesity parameters were fat body mass, fat body mass/height2, lean body mass, lean body mass/height2, visceral adipose tissue and presence of a metabolic syndrome. RESULTS: A total of 174 patients (median age 47 years) with a majority of women (75.3%) and a median BMI of 44 kg/m2 were analysed. The percentage of patients who met the pharmacokinetic and pharmacodynamic target was 85.1%. In the whole population, a tendency to fail to reach the target was observed with a higher lean mass over height2 [OR = 0.79; 95% CI (0.62-1.01); P = 0.060]. In the female subgroup, higher lean mass over height2 [OR = 0.63; 95% CI (0.41-0.97); P = 0.037] and the presence of a metabolic syndrome [OR = 0.17; 95% CI (0.03-0.83); P = 0.030] were associated with failure to reach the pharmacokinetic and pharmacodynamic target. CONCLUSION: Obese patients with a higher lean mass and a metabolic syndrome could constitute a subgroup at risk for cefoxitin under-dosage.


Assuntos
Antibacterianos/farmacocinética , Cirurgia Bariátrica , Cefoxitina/farmacocinética , Obesidade/metabolismo , Adulto , Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Índice de Massa Corporal , Cefoxitina/administração & dosagem , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Obesidade/cirurgia , Fenótipo , Estudos Prospectivos , Fatores Sexuais , Espectrometria de Massas em Tandem
5.
Br J Clin Pharmacol ; 87(12): 4648-4657, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33929765

RESUMO

AIMS: There are several limitations to the existing method of administering cefoxitin as a prophylactic antibiotic, and the limitations may be overcome by applying the target-concentration controlled infusion (TCI) method. Population pharmacokinetic parameters are required to administer cefoxitin by the TCI method. The aim of this study was to construct a new pharmacokinetic model of cefoxitin for the TCI method in colorectal surgical patients. METHODS: In patients undergoing colorectal surgery, 2 g of cefoxitin was dissolved in 50 mL of saline and administered for 10 minutes prior to skin incision. Arterial blood samples were obtained at preset intervals to measure the total and free plasma concentrations of cefoxitin. Population pharmacokinetic analysis was performed using NONMEM software (ICON Development Solutions, Dublin, Ireland). Additionally, stochastic simulation was used to indirectly evaluate the effectiveness of the two administration methods (standard method vs TCI). RESULTS: In total, 297 plasma concentration measurements from 31 patients were used to characterize the pharmacokinetics of cefoxitin. A three-compartment mammillary model described the pharmacokinetics of cefoxitin. Body weight and creatinine clearance were significant covariates for clearance. The stochastic simulation showed that when compared with the standard method, the TCI method has a significantly higher fraction of time that the free concentration of cefoxitin is maintained above the minimum inhibitory concentration (P < .001). CONCLUSIONS: TCI has the potential to become a new infusion method for patient-tailored dosing in surgical patients. To administer cefoxitin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.


Assuntos
Cefoxitina , Neoplasias Colorretais , Antibacterianos , Peso Corporal , Cefoxitina/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana
6.
Pediatr Infect Dis J ; 39(7): 609-614, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32221166

RESUMO

BACKGROUND: Available data about pharmacokinetics (PK) of antimicrobials administered as surgical prophylaxis to children undergoing cardiac surgery with cardiopulmonary bypass (CPB) showed that drug concentrations during CPB may be supra or subtherapeutic. The aim of this study was to determine the population PK and pharmacodynamic target attainment (PTA) of cefoxitin during pediatric CPB surgery. METHODS: A prospective interventional study was conducted. Cefoxitin (40 mg/kg, up to max 1000 mg) was administered before skin incision. Blood samples were obtained in the operatory room throughout surgery. Population PK, PTA, and safety of cefoxitin were evaluated in neonates, infants, children <10 and >10 years old. RESULTS: Forty patients were enrolled. Cefoxitin levels correlated with time from bolus administration (r = -0.6, P = 0.0001) and, after 240 minutes from bolus, drug values below the target (8 mg/L) were shown. Cefoxitin concentrations were best described by a one-compartment model with first order elimination. A significant relationship was identified between body weight, age, body mass index, and serum creatinine on drug clearance and age, body weight, and body mass index on cefoxitin volume of distribution. The PTA for free drug concentration being above the minimum inhibitory concentration of 8 mg/L for at least 240 minutes was >90% in all age groups except in patients >10 years of age (PTA = 62%). CONCLUSIONS: Cefoxitin PK appears to be significantly influenced by CPB with generally reduced drug clearance. The PTA was adequately achieved in the majority of patients except in patients >10 years old or longer surgeries.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Procedimentos Cirúrgicos Cardíacos , Cefoxitina/farmacocinética , Cefoxitina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Testes de Sensibilidade Microbiana , Modelos Estatísticos , Método de Monte Carlo , Estudos Prospectivos
7.
J Antimicrob Chemother ; 74(7): 1975-1983, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220258

RESUMO

OBJECTIVES: Cefoxitin is frequently used for surgical antibiotic prophylaxis (SAP). Using microdialysis, we evaluated whether the currently recommended dosing regimen is appropriate to maintain cefoxitin subcutaneous tissue concentrations above the MIC for pathogens involved in abdominal surgical site infection. METHODS: Data from eight patients undergoing major abdominal surgery were analysed using population pharmacokinetic modelling, and Monte Carlo simulations were conducted to determine the PTA for aerobic and anaerobic pathogens. ClinicalTrials.gov: NCT02703857. RESULTS: Only 2.3% and 47.4% of the simulated patients maintained cefoxitin subcutaneous concentrations above the MIC breakpoint for anaerobic (MIC = 16 mg/L) and aerobic (MIC = 8 mg/L) pathogens, respectively. New simulations with administration of a loading dose followed by a constant infusion of cefoxitin were conducted and demonstrate that, notwithstanding using the same total dose per unit of time, continuous infusion of cefoxitin can cover aerobes in 96.6% of the simulated patients, but remains insufficient for anaerobic bacteria. CONCLUSIONS: The recommended dosing regimen of cefoxitin is insufficient for covering the usual bacteria during abdominal surgery. Administration of a loading dose followed by a constant infusion should be considered for aerobic bacteria and cefoxitin should be avoided as SAP for anaerobic bacteria.


Assuntos
Abdome/cirurgia , Antibacterianos/administração & dosagem , Antibioticoprofilaxia , Cefoxitina/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacocinética , Cefoxitina/farmacocinética , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-31061149

RESUMO

Mycobacterium abscessus is responsible for difficult-to-treat chronic pulmonary infections in humans. Current regimens, including parenteral administrations of cefoxitin (FOX) in combination with amikacin and clarithromycin, raise compliance problems and are frequently associated with high failure and development of resistance. Aerosol delivery of FOX could be an interesting alternative. FOX was administered to healthy rats by intravenous bolus or intratracheal nebulization, and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. After intrapulmonary administration, the FOX area under the curve within ELF was 1,147 times higher than that in plasma, indicating that this route of administration offers a biopharmaceutical advantage over intravenous administration. FOX antimicrobial activity was investigated using time-kill curves combined with a pharmacokinetic/pharmacodynamic (PK/PD) type modeling approach in order to account for its in vitro instability that precludes precise determination of MIC. Time-kill data were adequately described by a model including in vitro degradation, a sensitive (S) and a resistant (R) bacteria subpopulation, logistic growth, and a maximal inhibition-type growth inhibition effect of FOX. Median inhibitory concentrations were estimated at 16.2 and 252 mg/liter for the S and R subpopulations, respectively. These findings suggest that parenteral FOX dosing regimens used in patients for the treatment of M. abscessus are not sufficient to reduce the bacterial burden and that FOX nebulization offers a potential advantage that needs to be further investigated.


Assuntos
Antibacterianos/farmacologia , Cefoxitina/farmacocinética , Cefoxitina/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/efeitos dos fármacos , Administração Intravenosa/métodos , Animais , Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Claritromicina/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana/métodos , Infecções por Mycobacterium não Tuberculosas/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia
9.
Pediatr Infect Dis J ; 38(5): 484-489, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30169486

RESUMO

BACKGROUND: This study aimed to explore inter-individual variability of cefoxitin trough levels, predictors of serum cefoxitin concentration and the probability of target attainment of drug levels above 4 mg/L after pediatric cardiac surgery. METHODS: Retrospective study on children scheduled for elective cardiac surgery and having cefoxitin trough levels available up to 24 hours postsurgery. RESULTS: Overall, 68 children (9 neonates, 34 infants, 15 children below or equal to 10 years old and 10 patients above this age) were included. Of these, 16 surgeries were performed off cardiopulmonary bypass and 52 were performed on cardiopulmonary bypass. The free cefoxitin concentrations showed a median (interquartile range) concentration of 1.7 (0.6-4.2) mg/L. The range of cefoxitin concentrations showed a 150-fold and 340-fold variability at cardiac intensive care unit admission and after 24 hours, respectively. The pharmacodynamics (PD) targets of free cefoxitin at 100% of the dosing interval, considering Eucast breakpoints for Methicillin Sensitive Staphylococcus Aureus (4 mg/L) and E.Coli (8 mg/L), were obtained in 28% and 16% of patients, respectively. Patient weight (odds ratio, 0.7; 95% confidence interval, 0.62-0.92; P = 0.006) and serum creatinine concentrations (odds ratio, 25; 95% confidence interval, 18-36; P = 0.004) showed a significant relationship with the PD targets. CONCLUSIONS: Cefoxitin trough concentrations vary significantly in the first 24 hours after pediatric cardiac surgery. Both serum creatinine and body weight showed independent associations with cefoxitin concentration. The PD target was not obtained in the vast majority of the explored population, regardless of the target bacteria.


Assuntos
Antibacterianos/farmacocinética , Antibioticoprofilaxia/métodos , Cefoxitina/farmacocinética , Cuidados Pré-Operatórios/métodos , Soro/química , Cirurgia Torácica , Adolescente , Antibacterianos/administração & dosagem , Cefoxitina/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Tempo
10.
Antimicrob Agents Chemother ; 60(10): 5885-93, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27458209

RESUMO

The objective of this study was to determine the pharmacokinetics and pharmacodynamics (PK/PD) of a weight-based cefoxitin dosing regimen for surgical prophylaxis in obese patients. Patients received a single dose of cefoxitin at 40 mg/kg based on total body weight. Cefoxitin samples were obtained over 3 h from serum and adipose tissue, and concentrations were determined by validated high-performance liquid chromatography. Noncompartmental pharmacokinetic analysis was performed, followed by Monte Carlo simulations to estimate probability of target attainment (PTA) for Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis over 4-h periods postdose. Thirty patients undergoing bariatric procedures were enrolled. The body mass index (mean ± standard deviation [SD])was 45.9 ± 8.0 kg/m(2) (range, 35.0 to 76.7 kg/m(2)); the median cefoxitin dose was 5 g (range, 4.0 to 7.5 g). The mean maximum concentrations were 216.15 ± 41.80 µg/ml in serum and 12.62 ± 5.89 in tissue; the mean tissue/serum ratio was 8% ± 3%. In serum, weight-based regimens achieved ≥90% PTA (goal time during which free [unbound] drug concentrations exceed pathogen MICs [fT>MIC] of 100%) for E. coli and S. aureus over 2 h and for B. fragilis over 1 h; in tissue this regimen failed to achieve goal PTA at any time point. The 40-mg/kg regimens achieved higher PTAs over longer periods in both serum and tissue than did the standard 2-g doses. However, although weight-based cefoxitin regimens were better than fixed doses, achievement of desired pharmacodynamic targets was suboptimal in both serum and tissue. Alternative dosing regimens and agents should be explored in order to achieve more favorable antibiotic performance during surgical prophylaxis in obese patients.


Assuntos
Cefoxitina/administração & dosagem , Cefoxitina/farmacocinética , Obesidade Mórbida/cirurgia , Obesidade/cirurgia , Infecção da Ferida Cirúrgica/prevenção & controle , Adulto , Antibioticoprofilaxia , Peso Corporal , Cefoxitina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Infecção da Ferida Cirúrgica/microbiologia , Distribuição Tecidual
11.
Clin Ther ; 38(1): 204-10, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26686826

RESUMO

PURPOSE: Antibiotic dosing in obese surgical patients has not been adequately evaluated. The objective of this study was to identify whether currently prescribed doses of cefoxitin achieve adequate and sustained plasma and tissue concentrations in obese patients undergoing sleeve gastrectomy. METHODS: A prospective evaluation of plasma and tissue cefoxitin concentrations in patients undergoing sleeve gastrectomy was performed. On the day of the surgical procedure, venous blood samples (5 mL) were collected just before cefoxitin administration and then at 5, 30, 60, 120, and 240 minutes after dose administration. In addition, subcutaneous adipose tissue was collected from the surgical site at the time of surgical incision and at closure. Cefoxitin concentrations in the collected samples were quantified by using an HPLC-ultraviolet method. A standard noncompartmental analysis was performed for each individual cefoxitin plasma concentration-time profile. In addition, the ratio of tissue to plasma concentration was calculated for all patients. FINDINGS: Plasma and tissue pharmacokinetics of cefoxitin were evaluated in 6 patients undergoing sleeve gastrectomy. The mean age and BMI were 48.7 (6.2) years and 42.8 (7.1) kg/m(2), respectively. At the time of surgical closure, subcutaneous adipose tissue concentrations of cefoxitin were subtherapeutic (<8 µg/mL) in all evaluated patients. IMPLICATIONS: Current dosing strategies for cefoxitin in obese surgical patients may be inadequate, and there is an urgent need to define the appropriate dosage.


Assuntos
Antibacterianos/farmacocinética , Antibioticoprofilaxia , Cefoxitina/farmacocinética , Dermatopatias Bacterianas/prevenção & controle , Infecções dos Tecidos Moles/prevenção & controle , Gordura Subcutânea/metabolismo , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Índice de Massa Corporal , Cefoxitina/administração & dosagem , Cefoxitina/sangue , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/cirurgia , Estudos Prospectivos
13.
Antimicrob Agents Chemother ; 58(8): 4899-901, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24777104

RESUMO

Cefoxitin could be an alternative to carbapenems in extended-spectrum-beta-lactamase-producing Escherichia coli (ESBL-EC) infections. However, pharmacological and clinical data regarding cefoxitin are limited. Using a recent pharmacological model and the MICs of ESBL-EC collected from pyelonephritis, we determined the probabilities to reach four pharmacological targets: free cefoxitin concentrations above the MIC during 50% and 100% of the administration interval (T>MIC = 50% and T>MIC = 100%, respectively) and free cefoxitin concentrations above 4× MIC during 50% and 100% of the administration interval (T>4MIC = 50% and T>4MIC = 100%, respectively). Cefoxitin could be used to treat ESBL-EC pyelonephritis, but administration modalities should be optimized according to MICs in order to reach pharmacological targets.


Assuntos
Antibacterianos/farmacologia , Cefoxitina/farmacologia , Escherichia coli/efeitos dos fármacos , Modelos Estatísticos , Resistência beta-Lactâmica , Antibacterianos/farmacocinética , Carbapenêmicos/farmacocinética , Carbapenêmicos/farmacologia , Cefoxitina/farmacocinética , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Escherichia coli/enzimologia , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Expressão Gênica , Humanos , Testes de Sensibilidade Microbiana , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , beta-Lactamases/biossíntese , beta-Lactamases/genética
14.
Eur J Clin Pharmacol ; 68(5): 735-45, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22246211

RESUMO

PURPOSE: To elucidate whether a dose of 2 g cefoxitin as a prophylactic agent in patients undergoing elective colorectal surgery is able to maintain free drug concentrations above the minimum inhibitory concentration of the microorganisms involved in surgical site infection. METHODS: This was a prospective study involving 56 patients electively undergoing rectal or colon surgery. All plasma concentration-time data were analyzed simultaneously using the population approach to estimate population pharmacokinetic parameters and study the influence of the subjects' demographic characteristics, disease status, surgical procedure, and clinical laboratory values on the pharmacokinetic properties of cefoxitin. RESULTS: A one-compartment open model was chosen to describe plasma concentrations of cefoxitin. Since cefoxitin is eliminated almost entirely via the kidney, creatinine clearance was identified as a covariate of cefoxitin clearance. The relationship between total cefoxitin clearance (CL) and creatinine clearance (CL(CR)) was best described using a nonlinear model [CL = 11.5 × (CL(CR)/77)(0.52)]. The population apparent volume of distribution was 12 L. Computer simulations carried out to determine the probability to maintain free plasma concentrations above 8 mg/L (the concentration threshold for susceptible bacteria) 2 h after drug administration revealed that this probability decreased from 84% in patients with a CL(CR) of 40 mL/min to 28% in patients with a CL(CR) of 100 mL/min. CONCLUSIONS: To ensure cefoxitin target concentrations during surgery, we recommend that cefoxitin be administered every 1.5 h in patients with a CL(CR) ≥ 60 mL/min and every hour if the CL(CR) is ≥ 100 mL/min. Administration by continuous infusion preceded by a bolus injection should also be considered.


Assuntos
Antibacterianos/farmacocinética , Antibioticoprofilaxia , Cefoxitina/farmacocinética , Colo/cirurgia , Reto/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Cefoxitina/sangue , Cefoxitina/uso terapêutico , Creatinina/sangue , Creatinina/metabolismo , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Taxa de Filtração Glomerular , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Estudos Prospectivos , Infecção da Ferida Cirúrgica/prevenção & controle
15.
Anesth Analg ; 113(4): 730-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21642605

RESUMO

BACKGROUND: Obesity is a significant risk factor for surgical site infections (SSIs), for poorly understood reasons. SSIs are a major cause of morbidity, prolonged hospitalization, and increased health care cost. Drug disposition in general is frequently altered in the obese. Preoperative antibiotic administration, achieving adequate tissue concentrations at the time of incision, is an essential strategy to prevent SSIs. Nonetheless, there is little information regarding antibiotic concentrations in obese surgical patients. This investigation tested the hypothesis that the prophylactic antibiotic cefoxitin may have delayed and/or diminished tissue penetration in the obese. METHODS: Plasma and tissue concentrations of cefoxitin were determined in obese patients undergoing abdominal and pelvic surgery (body mass index 43 ± 10 kg/m(2), n = 14, 2 g cefoxitin) and in normal-weight patients and healthy volunteers (body mass index 20 ± 2 kg/m(2), n = 13, 1 g cefoxitin). Tissue concentrations were measured using a microdialysis probe in the subcutaneous layer of the abdomen, and in adipose tissue excised at the time of incision and wound closure. RESULTS: Plasma concentrations and area under the concentration-time curve (AUC) were approximately 2-fold higher in the obese patients because of the 2-fold-higher dose. Dose-normalized concentrations were higher, although AUCs were not significantly different. Measured and dose-normalized subcutaneous cefoxitin concentrations and AUCs in the obese patients were significantly lower than in the normal-weight subjects. There was an inverse relationship between cefoxitin tissue penetration (AUC(tissue)/AUC(plasma) ratio) and body mass index. Tissue penetration was substantially lower in the obese patients (0.08 ± 0.07 vs 0.37 ± 0.26, P < 0.05). Adipose tissue cefoxitin concentrations in obese patients were only 7.8 ± 7.3 and 2.7 ± 1.4 µg/g, respectively, at incision and closure, below the minimum inhibitory concentration of 8 and 16 µg/mL, respectively, for aerobic and anaerobic microorganisms. CONCLUSION: Obese surgical patients have impaired tissue penetration of the prophylactic antibiotic cefoxitin, and inadequate tissue concentrations despite increased clinical dose (2 g). Inadequate tissue antibiotic concentrations may be a factor in the increased risk of SSIs in obese surgical patients. Additional studies are needed to define doses achieving adequate tissue concentrations.


Assuntos
Antibacterianos/farmacocinética , Antibioticoprofilaxia , Cefoxitina/farmacocinética , Obesidade/complicações , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Abdome/cirurgia , Tecido Adiposo/metabolismo , Tecido Adiposo/cirurgia , Adolescente , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Índice de Massa Corporal , Estudos de Casos e Controles , Cefoxitina/administração & dosagem , Cefoxitina/sangue , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Microdiálise , Pessoa de Meia-Idade , Missouri , Obesidade/diagnóstico , Obesidade/metabolismo , Pelve/cirurgia , Medição de Risco , Fatores de Risco , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/metabolismo , Distribuição Tecidual , Resultado do Tratamento , Adulto Jovem
16.
Rev. ciênc. farm. básica apl ; 31(3)set.-dez. 2010.
Artigo em Inglês | LILACS | ID: lil-570166

RESUMO

As nanopartículas de D, L-PLA (PLA) contendo cefoxitina (CEF) foram preparadas pelo método de emulsão múltipla / evaporação do solvente. As partículas foram avaliadas em relação à morfologia, à eficiência de encapsulação, às interações polímero-fármaco, bem como à cinética de liberação do fármaco in vitro . As nanopartículas são esféricas e isoladas, com um diâmetro médio de cerca de 600 nm. O comportamento térmico (DSC) das nanopartículas contendo CEF sugeriu que o fármaco está disperso em um nível molecular dentro do sistema. A eficiência de encapsulação do fármaco no sistema quando a concentração de CEF é 30 mg / mL foi de 5,5%, determinada após a extração de fármaco, através de um método de HPLC validado. Esta baixa eficiência de encapsulação é compreensível, uma vez que a CEF é altamente hidrofílica. Os ensaios in vitro mostraram um perfil de liberação do fármaco a partir das nanopartículas fortemente sustentado e com uma cinética de difusão Fickiana pura.


Nanoparticles containing cefoxitin (CEF) made of D,L-PLA (PLA) were designed by a multiple emulsion/solvent evaporation method. The particles were extensively evaluated in relation to morphology, encapsulation efficiency, drug-polymer interactions as well as in vitro drug release kinetics. Nanoparticles were spherical in shape and isolated, with a mean diameter of about 600 nm. The thermal behaviour (DSC) of CEF-containing nanoparticles suggested that the drug was dispersed at a molecular level within the system. The drug encapsulation efficiency in the system for a CEF concentration of 30 mg/mL was 5.5%, as assessed after the drug extraction, by a validated HPLC method. This low encapsulation efficiency is understandable, since CEF is highly hydrophilic. The in vitro assays showed a strong sustained drug release profile from the nanoparticles with kinetics following pure Fickian diffusion.


Assuntos
Cefoxitina/farmacocinética , Cefoxitina/síntese química , Nanopartículas
19.
Int J Pharm ; 271(1-2): 31-9, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15129971

RESUMO

To conquer the clinical restriction of relative short half-life and poor tissue retaining activities, liposomes containing cefoxitin were prepared using three methods in this study. The physicochemical properties including cefoxitin encapsulation percentage, vesicle size, stability, as well as the in vivo biodistribution were studied. The highest entrapment percentage was observed by using reverse phase evaporation method, and the molar ratio of cefoxitin to phospholipids was 1:3, DMPC to cholesterol was 2:1, respectively. From the result of stability, the freeze-drying powder and then stored in the frozen condition of cefoxitin-loaded liposome was an ideal storage state. Accordingly, the formulation by reverse-phase evaporation method was selected to investigate the biodistribution of cefoxitin-loaded liposome and compared to free cefoxitin in rats. It was observed that the cefoxitin levels and the duration retained in the liver, spleen, and pancreas of liposome-injected animals were higher and longer than that of free cefoxitin-injected animals. The drug concentrations of bile after post-injection of liposomal cefoxitin at 0.5, 1 and 2 h were all approximately 2.7 times higher than that of free cefoxitin injection group.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Cefoxitina/administração & dosagem , Cefoxitina/farmacocinética , Animais , Antibacterianos/química , Bile/metabolismo , Cefoxitina/química , Colesterol/química , Cromatografia Líquida de Alta Pressão , Dimiristoilfosfatidilcolina/química , Estabilidade de Medicamentos , Liofilização , Lipossomos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar , Tecnologia Farmacêutica , Distribuição Tecidual
20.
Artif Organs ; 27(7): 623-30, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12823417

RESUMO

Liposomal cefoxitin was prepared and applied to the pretreatment of human saphenous vein (HSV) for implantation. The possible use of liposomal cefoxitin to improve cellular viability and function and to maintain its potential sterilization effect was investigated. Entrapment efficiency and size distribution of liposomal cefoxitin were 75.7% and 652 +/- 75.7 nm, respectively. The weight ratio between cefoxitin and liposome was calculated at 1 : 40.6. When cefoxitin was entrapped with liposome, the released amount of cefoxitin was not affected by temperature conditions (37 degrees C, 25 degrees C, and 4 degrees C). The amount of free cefoxitin present in HSV reached 59% at 0.5 h and gradually decreased with time, while liposomal cefoxitin showed a maximum amount (63%) at 1.5 h, indicating that liposomal cefoxitin seemed to control the initial amount of cefoxitin present in HSV. Liposomal cefoxitin showed better viabilities of whole cells and endothelial cells dissociated from HSV than free cefoxitin and remarkably superior function of endothelial cells, as determined by Griffonia simplicifolia agglutinins-fluorescein isothiocyanate/propidium iodide double-staining methods combined with flow cytometry and endothelial nitric oxide synthase assay, respectively. In terms of sterilization effect, there was no significant difference between liposomal cefoxitin and free cefoxitin. These results suggest that liposomal entrapment of cefoxitin could improve cellular viability and functions and maintain the original sterilization effect.


Assuntos
Antibacterianos/administração & dosagem , Cefoxitina/administração & dosagem , Veia Safena/citologia , Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Cefoxitina/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Ponte de Artéria Coronária , Portadores de Fármacos , Endotélio Vascular/citologia , Feminino , Humanos , Técnicas In Vitro , Lipossomos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase Tipo III , Veia Safena/metabolismo , Veia Safena/microbiologia , Veia Safena/transplante , Esterilização
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