RESUMO
PURPOSE: To determine the efficacious cefazolin prophylactic dose for bariatric surgery using free subcutaneous concentrations accessed by microdialysis after 2 g or 3 g i.v. bolus dosing to morbidly obese women and POPPK modeling. METHODS: A POPPK model with variable plasma and subcutaneous tissue protein binding was developed to simultaneously describe plasma and tissue data sets. The outcomes was predicted for common surgical site infection (SSI) bacteria over 3, 4, 5 and 6 h periods postdose, as probability of target attainment (PTA) using Monte Carlo simulation. RESULTS: CFZ 2 g warrant up to 5 h SSI prophylaxis for bacteria with MICs ≤1 mg/L such as Escherichia coli and Staphylococcus aureus. For species such as Klebsiella pneumoniae, which present MIC distribution frequency of 2 mg/L, the maintenance of PTA ≥ 90% occurs with a 3 g dose for surgeries lasting up to 5 h, and 2 g dose provide an adequate response up to 4 h (PTA of 89%). CONCLUSIONS: Effectiveness of CFZ 2 g is similar to 3 g against bacteria with a MIC up to 2 mg/L, especially if the surgery does not last for more than 4 h.
Assuntos
Antibioticoprofilaxia/métodos , Cirurgia Bariátrica/efeitos adversos , Cefazolina/administração & dosagem , Modelos Biológicos , Infecção da Ferida Cirúrgica/prevenção & controle , Adulto , Cirurgia Bariátrica/métodos , Cefazolina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Testes de Sensibilidade Microbiana , Microdiálise , Pessoa de Meia-Idade , Obesidade Mórbida/cirurgia , Tela Subcutânea/metabolismo , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/microbiologia , Adulto JovemRESUMO
Antimicrobial prophylactic dosing of morbidly obese patients may differ from normal weighted individuals owing to alterations in drug tissue distribution. Drug subcutaneous tissue distribution can be investigated by microdialysis patients and animals. The need for cefazolin prophylactic dose adjustment in obese patients remains under discussion. The paper describes the validation of an HPLC-UV method for cefazolin quantification in plasma and microdialysate samples from clinical and pre-clinical studies. A C18 column with an isocratic mobile phase was used for drug separation, with detection at 272 nm. Total and unbound cefazolin lower limit of quantitation was 5 µg/mL in human plasma, 2 µg/mL in rat plasma, and 0.5 and 0.025 µg/mL in human and rat microdialysate samples, respectively. The maximum intra- and inter-day imprecisions were 10.7 and 8.1%, respectively. The inaccuracy was <9.7%. The limit of quantitation imprecision and inaccuracy were < 15%. Cefazolin stability in the experimental conditions was confirmed. Cefazolin plasma concentrations and subcutaneous tissue penetration were determined by microdialysis in morbidly obese patients (2 g i.v. bolus) and diet-induced obese rats (30 mg/kg i.v. bolus) using the method. This method has the main advantages of easy plasma clean-up and practicability and has proven to be useful in cefazolin clinical and pre-clinical pharmacokinetic investigations.
Assuntos
Cefazolina/sangue , Cefazolina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Obesidade/metabolismo , Espectrofotometria Ultravioleta/métodos , Adolescente , Adulto , Animais , Cefazolina/química , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Microdiálise , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tela Subcutânea/química , Adulto JovemRESUMO
Objectives The aim of this study was to determine the plasma pharmacokinetic profile, tissue concentrations and urine elimination of cefazolin in cats under surgical conditions after a single intravenous dose of 20 mg/kg. Methods Intravenous cefazolin (20 mg/kg) was administered to nine young mixed-breed cats 30 mins before they underwent surgical procedures (ovariectomy or orchiectomy). After antibiotic administration, samples from blood, some tissues and urine were taken. Cefazolin concentrations were determined in all biological matrices and pharmacokinetic parameters were estimated. Results Initial plasma concentrations were high (Cp(0), 134.80 ± 40.54 µg/ml), with fast and moderately wide distribution (distribution half-life [t½(d)] 0.16 ± 0.15 h; volume of distribution at steady state [V(d[ss])] 0.29 ± 0.10 l/kg) and rapid elimination (body clearance [ClB], 0.21 ± 0.06 l/h/kg; elimination half-life [t½], 1.18 ± 0.27 h; mean residence time 1.42 ± 0.36 h). Thirty to 60 mins after intravenous administration, cefazolin tissue concentrations ranged from 9.24 µg/ml (subcutaneous tissue) to 26.44 µg/ml (ovary). The tissue/plasma concentration ratio ranged from 0.18 (muscle) to 0.58 (ovary). Cefazolin urine concentrations were high with 84.2% of the administered dose being eliminated in the first 6 h postadministration. Conclusions and relevance Cefazolin plasma concentrations remained above a minimum inhibitory concentration of ⩽2 µg/ml up to 4 h in all the studied cats. This suggests that a single intravenous dose of 20 mg/kg cefazolin would be adequate for perioperative prophylactic use in cats.