Modelagem PK/PD da daptomicina visando ao tratamento de bacteremias

Abstract

The main pathogens present in hospital bacteremias are Gram-positive. In this work we have obtained some limitations related to the difficulty in finding comparative studies referring to PK/PD models and the PK/PD index. The objective was to develop a pharmacokinetic/ pharmacodynamic model to describe the temporal profile of the bactericidal effect of daptomycin against different Gram-positive bacteria causing bacteremia. In vitro experiments were conducted using methicillin resistant Staphylococcus aureus strains (MRSA ATCC 33591), methicillin resistant Staphylococcus epidermidis (MRSE ATCC 29887) and vancomycin resistant Enterococcus faecium (VRE ATCC 700221). Pharmacodynamic studies were conducted by determining the susceptibility of these microorganisms to daptomycin and microbial death curves as a function of time using this drug. To determine the minimum inhibitory concentration, daptomycin was used in the concentration range from 0.06 to 8 µg/mL. The time-dependent bacterial death curves for daptomycin against the three Grampositive strains were constructed by considering constant drug concentrations in the in vitro system as multiples of the minimum inhibitory concentration. For the modeling of the data obtained with the death curves, different PK/PD models were used. With the pharmacodynamic parameters calculated by the modeling and the pharmacokinetic parameters of daptomycin obtained from the literature from the population pharmacokinetic model, simulations of treatment outcomes for bacteremias were performed in the clinical setting for daptomycin doses of 6, 8 and 10 mg/kg (simulated time of 18 days) and probability of reaching the therapeutic target (PTA), considering the covariable creatinine clearance in both approaches. The minimum inhibitory concentration determined for MRSA and MRSA staphylococci was 0.5 µg/mL, whereas for VRE was 2.0 µg/mL. Microbial death curves for staphylococci were suitably modeled with the modified Emax PK/PD model predicting delay in growth time and death of the microorganism. The PK/PD parameters obtained were: k0 of 0.4343 ± 0.029 h-1and 0.218 ± 0.136 h-1, Nmax of 17.071 ± 0.169 CFU/mL and 8.425 ± 0.154 CFU/mL, EC50 of 0.504 ± 0.247 µg/mL and 0.434 ± 0.215 µg/mL and kmax of 0.530 ± 0.218 h1 and 0.312 ± 0.282 h-1 for MRSA and MRSA respectively. Already for the VRE was employed model Emax with Hill coefficient only. The parameters obtained with this model were: k0 of 0.168 ± 0.005 h-1 , Nmax of 8.596 ± 0.450 CFU / mL, EC50 of 1.031 ± 0.246 µg/mL and kmax of 0.086 ± 0.044 h-1 . Different strains between the strains for the treatment of bacteremia with daptomycin were observed. The results of the Monte Carlo simulations suggest that daptomycin can be used in cases of MRSA-complicated bacteremia at doses of 6 16 to 10 mg/kg/day for any range of creatinine clearance, including at 48 h intervals with clearance between 15 at 29 mL/min/1.73m2 . For MRSE, the data suggest that doses of 6 to 10 mg/kg/day can be employed, without adjusting the dose for clearance between 15 and 29 mL/min/1.73m2 . Doses of 6 to 10 mg/kg/day for any range of creatinine clearance may be employed to treat VRE-complicated bacteremias. Thus, in scenarios of individuals with loss of renal function with indication of dose adjustment every 48 hours, it is suggested to choose antimicrobial associations or increase the dose (> 10 mg/kg). The lack of consensus on the fASC/MIC target values for MRSA, MRSE and VRE distances the expected results from the PTA approach of the microbiological outcomes observed by the Monte Carlo simulation in the reduction of CFU/mL over the treatment period. [resumo fornecido pelo autor]