PHARMACODYNAMIC-BASED DOSAGE REGIMENS FOR IMIPENEM, MEROPENEM AND DORIPENEM TO TREAT MELIOIDOSIS: A MONTE CARLO SIMULATION

Melioidosis, caused by Burkholderia pseudomallei (BP), is treated with ceftazi-dime or carbapenems. We aimed to determine the optimal pharmacodynamic-based dosage regimens and infusion times for imipenem (IMP), meropenem (MER) and doripenem (DOR) to treat melioidosis in order to inform treatment protocols for melioidosis. For this study, we used the Monte Carlo simulation to determine both conventional and prolonged infusion regimens for IMP, MER and DOR involving 10,000 simulated patients based on the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) of the studied drugs for this organism, the probability of attaining (PTA) a JT>MIC and the cumulative fraction of response (CFR) of the studied organism to the studied antimicrobials, which was calculated as the proportion of %PTA of T>MIC for each MIC according to the MIC distribution. The optimal pharmacokinetic-pharmacodynamic (PK /PD) target for this study was 40% of the fT>MIC. This percentage correlates with the in vivo efficacy for carbapenems. The pharmacokinetic parameters for the studies carbapenems were obtained from the published literature. The minimum inhibitory concentrations (MICs) for IMP, MER and DOR used for this study were derived from 100 BP clinical isolates obtained from hospitalized patients at Siriraj Hospital, Thailand. The MICs to inhibit 50% of each isolate (MIC50) for IMP, MER and DOR were 0.5 mu g / ml, 1 mu g / ml and 1.5 mu g / ml. MICs to inhibit 90% of each isolate (MIC90) for IMP, MER and DOR were 0.75 mu g / ml, 1.5 mu g / ml and 3 mu g / ml. Susceptibilities were determined according to the Clinical and Laboratory Standards Institute (CLSI). The percentage of the isolates susceptible to IMP, MER and DOR were 96%, 96% and 85%, respectively. IMP at a regimen of 0.5 g every 6 hours (0.5 hour infusion time), 0.5 g every 8 hours 0.5 g every 6 hours and 1 g every 8 hours (3 hour infusion time). all achieved CFR 90%. All MER regimens achieved on optimal CFR (98.21-100%). The DOR regimens to achieved >90% CFR were 0.5 g, 1 g and 2 g every 8 hours (4 hour infusion time). Our results show the best carbapenem drug regimens to treat melioidosis. In vivo studies are needed to determine if these regimens improve outcome compared to currently used regimens to treat melioidosis in the study population.