Population Pharmacokinetics And Pharmacodynamics Of Linezolid In Chinese

[OBJECTIVES] To investigate the in vitro sensitivity of clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics. To analyze the population pharmacokinetic and pharmacodynamic profiles of linezolid in Chinese healthy volunteers and critically ill patients. To investigate the application of linezolid in respiratory intensive care unit (RICU), and assess its efficacy and safety. On the whole, to provide some laboratory evidences for the rational use of linezolid in clinic.[METHODS] (1) A agar plate dilution method was applied to determine the MIC of linezolid against 98 strains of clinically isolated MRSA. (2) A checkerboard method that adhered to the recommendations of Clinical Laboratory Standards Institute (CLSI) was applied to assess the synergism effect of minocycline and fosidic acid on 98 strains of MRSA. The Fraction Inhibitory Concentration Index (FICI) was calculated according to the results. (3) High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK/PPD profiles of linezolid in Chinese healthy volunteers and critically ill patients. (4) A single-centre, prospective, non-controlled descriptive study was performed to assess the efficacy and safety of linezolid in critically ill patients that proven or highly suspected of multi-resistant gram-positive cocci (MR-GPC) infection in RICU.[RESULTS] (1) The MIC range of linezolid against 98 strains of MRSA was 0.5-2μg/mL, and the MIC50, as well as MIC90 was 2μg/mL. (2) The MIC50 of minocycline and fosidic acid against 98 strains of MRSA was significantly decreased when the two antibiotics were combined in vitro. The percentage of FICI≤0.5 was 57.14%,0.5< FICI≤4 was 42.86%, FICI> 4 was 0. (3) Single dose of linezolid was administrated to Chinese healthy volunteers. A 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic (PK) model. The population typical value of apparent volume (V) of central compartment was 26.99 L, V of peripheral compartment was 22.22 L, apparent clearance (CL) of central compartment was 7.99 L/h, and CL of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value,0.617 L of V of peripheral compartment was correlated. (4) Multiple doses of linezolid were administered to Chinese critically ill patients to achieve steady state. A 1-compartment with linear elimination model was the most appropriate structural PK model. The population typical value of apparent volume (V) was 38.85 L, apparent clearance (CL) was 4.70 L/h. For each 1 kg deviation of weight from the mean value,0.79 L of V, as well as 0.04 L/h of CL was correlated. For each 1 year deviation of age from the mean value,-0.045 L/h of CL was correlated. When linezolid was administrated intravenously or orally, the percentage of t>MIC was 100%, and the ratio of AUC0-24h/MIC90 was>100 for most MR-GPC in RICU. (5) Compared with intravenous or orally administration, nasal feeding of ground linezolid resulted in an obvous increase of V, thus, the maximal plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were decreased significantly. (6) When linezolid was administrated to patients with MR-GPC infection in RICU, the cure rate was approximately 85.7%, the bacterial elimination (actual and presumable) rate was 85.7%, and the rate of thrombocytopenia was 26.9%.[CONCLUSION] (1) The sensitivity of 98 strain of clinically isolated MRSA to linezolid is 100%. (2) The in vitro combination of minocycline and fosidic acid mainly presents synergistic effect on MRSA. (3) The PK profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to V. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to V and CL, the age is linearly negative-correlated to CL. The typical value of V and CL of Chinese population is significantly lower than that of Western population. Compared with intravenous or orally administration, nasal feeding of ground linezolid results in an obvous increase of apparent volume. (4) Linezolid has satisfying efficacy in treating patients with MR-GPC infection in RICU. Nevertheless, the rate of thrombocytopenia is high, which is correlated to the duration of therapy.