RESUMO
Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32 L h-1 (22.6%), apparent central volume of distribution 35.8 L (45.2%), apparent peripheral volume of distribution 39.7 L, intercompartmental clearance 40.6 L h-1 (43.8%), absorption rate constant 7.45 h-1 (150%), mean absorption transit time 0.355 h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000 mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5 mg L-1 , while a dose of 1500 mg was required for strains with an MIC of 1 mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.
Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Levofloxacino/administração & dosagem , Levofloxacino/farmacocinética , Modelos Biológicos , Administração Oral , Adolescente , Adulto , Simulação por Computador , Voluntários Saudáveis , Humanos , Levofloxacino/sangue , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) Acinetobacter baumannii remains one of the leading causes of the high mortality rate in critically ill patients. Sulbactam has been considered as an alternative concomitant medication with other effective antimicrobial agents for the treatment of these MDR microorganisms. The aims of this study were (i) to characterize the population pharmacokinetics (PK) and (ii) to assess the efficacy of various dosage regimens of sulbactam in terms of probability of target attainment (PTA). METHODS: The PK studies were carried out following administration of 2â¯g of sulbactam every 12â¯h on the 7th dose of drug administration in 16 patients with VAP, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% and 60% the exposure time during which the total plasma drug concentration remained above the MIC (T>MIC). RESULTS: The volume of distribution and total clearance of sulbactam were 22.17⯱â¯1.60â¯L and 6.76⯱â¯2.37â¯L/h, respectively. For pathogens with a MIC of 8⯵g/mL, the high PTAs of achieving (≥90%) 60% T>MIC in patients with serum albumin 1.7-2.4â¯g/dL and CLCR 90-120â¯mL/min following administration of sulbactam as a 4-h infusion of 1â¯g every 6â¯h, 2â¯g every 12â¯h, and 2â¯g every 8â¯h were 98.65%, 78.07% and 98.23%, respectively. For pathogens with a MIC of 16⯵g/mL, the high PTAs of achieving (≥90%) 60% T>MIC in patients with serum albumin 1.7-2.4â¯g/dL and CLCR 90-120â¯mL/min following administration of sulbactam as a 4-h infusion of 2â¯g every 6â¯h, and 3â¯g every 8â¯h were 98.83% and 95.59%, respectively. CONCLUSION: These findings indicate that high dosage combination regimens are required for the treatment of life-threatening infections in critically ill patients with VAP.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Sulbactam/farmacocinética , Sulbactam/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Método de Monte Carlo , Pneumonia Associada à Ventilação Mecânica/microbiologia , Adulto JovemRESUMO
This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0-0.5, 0.5-2, 2-4 and 4-6 or 8 h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment model best described the data. Piperacillin clearance (CL) was 5.37 L/h, central volume of distribution (V1) was 9.35 L, and peripheral volume of distribution was 7.77 L. Creatinine clearance (CLCr) and mean arterial pressure had a significant effect on CL while adjusted body weight had a significant impact on V1. Subtherapeutic concentrations can occur during the early phase of sepsis in critically ill patients with normal renal function. The usual dosage regimen, 4 g of piperacillin infused over 0.5 h every 6 h, could not achieve the target for susceptible organisms with MIC 16 mg/L in patients with CLCr ≥ 60 mL/min. Our proposed regimen for the patients with CLCr 60-120 mL/min was an extended 2 h infusion of 4 g of piperacillin every 6 h. Most regimens provided CFR ≥ 90% for the E. coli infection while there was no dosage regimen achieved a CFR of 90% for the P. aeruginosa infection.
Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Piperacilina/farmacocinética , Piperacilina/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Idoso , Estado Terminal , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Método de Monte Carlo , Combinação Piperacilina e Tazobactam/farmacocinética , Combinação Piperacilina e Tazobactam/uso terapêutico , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
Sulbactam is being considered as an alternative concomitant medication with other effective antibiotics for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections. Pathophysiological changes in critically ill patients with severe sepsis, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors in determining therapeutic success. The aims of this study were (i) to examine the population PK parameters and (ii) to assess the probability of target attainment (PTA) for sulbactam in patients with severe sepsis caused by A. baumannii PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 4th day of drug administration in 27 patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentration remained above the MIC (T>MIC) and 60% T>MIC The central and peripheral volumes of distribution were 14.56 and 9.55 liters, respectively, and total clearances of sulbactam were 2.26 liters/h and 7.64 liters/h in patients aged >65 years and ≤65 years, respectively. The high PTAs (≥90%) for targets of 40% T>MIC and 60% T>MIC with a MIC of 4 µg/ml were observed when sulbactam was administered by a 4-h infusion of 1 g every 12 h and 1 g every 8 h, respectively. Sulbactam would be an alternative antibiotic option to coadminister with colistin for the treatment of infections caused by MDR A. baumannii However, for pathogens with MICs of >4 µg/ml, higher dosage regimens of sulbactam are required.