Study Of PK/PD Parameters To Predict The Efficacy And Inhibition Of Resistant Mutation Of Staphylococcus Aureus Infection

[OBJECTIVE]To determine MIC and MPC of linezolid and vancmycin agaist MRSA and compare the correlation between MIC and MPC;To evaluate the potential efficacy of vancomycin and linezolid of dosage schedules by PK/PD using Monte-Carlo stimulation;T o compare the superiority of linezolid and vacomycin for the treatment of Gram-positive infections using a Meta-analysis of randomised controlled trials(RCTs);To determine the PK/PD parameters which is more dependent on the inhibition of resistant mutants using vitro pharmacodynamic model.[METHOD](1) 111 non-duplicate clinical isolates of MRSA isolated in threee hospitals in Beijing were confirmed by cefoxitin(disk diffusion) and oxacillin (disk diffusion and MIC) interpretive criteria.The MIC of vancomycin and linezolid were determined by the standard twofold agar dilution method.MPC was determined following inoculation with a high inoculum on MH 4 plates with serial dilutions of the antibiotics in 72h.Pharmacodynamic exposures,measured as the ratio of steady-state total drug area under the curve to MIC(AUC/MIC), were modelled using a 10000-patient Monte-Carlo simulation against 111 nonduplicate clinical isolates of MRSA collected from hospitals in Beijing. Pharmacodynamic targets included an AUC/MIC=82.9 for linezolid and=345 for vancomycin.An extensive search of RCTs was done to identify relevant RCTs for our Meta-analysis.The effect and safety was compared between vancomycin and linezolid with Review Manager version 4.2(Cochrane Collaboration) software. (2) Staphylococcus aureusRN450,RN450-A1 and 99 exhibiting different MPC/MIC ratios(32,64 and 8,respectively) were exposed to levofloxacin once daily for 3 days.With each organism,a series of pharmacokinetic profiles was simulated to have three different AUC₂₄/MIC.The simulated AUC₂₄/MIC ratios were designed to provide levofloxacin concentrations within the MSW over most of the dosing interval or over the MSW over the entire dosing interval.In all simulations,levofloxacin-resistant staphylococci were enriched and were determined the MIC to compare the increase of MIC and were analyzed for nucleotide changes within the quinolone resistance-determining regions(QRDRs) of grlA and gyrA.The correlation of PK/PD parameters and the enrichment of resistant mutants at antibiotic concentrations within the mutant selection window (MSW) was compared.[RESULTS](1) Most MRSA isolates were resistant toβ-lactam,aminoglycosides,macrolides and FQNS(＞90%).All MRSA isolates were sensitive to vancomycin,linezolid and tigecycline.MIC₉₀ and MPC₉₀ of linezolid an vancomycin was 2,16 and 1,8ug/ml and there is low correlation between MIC and MPC.Serum Cmax of linezolid was lower than MPC,Serum Cmax of vancomycin is 6-fold of MPC.Using 10000 patients Monte-Carlo stimulation,the cumulative fractions of response(CFRs) against all S.aureus isolates were 78.5%, 88.5%,96.5%for linezolid 600 mg every 12 h,vancomycin 1000 mg every 12 h in young population and vancomycin 1000 mg every 12 h in old population. Probility of target attainment(PTA) of linezolid and vancomycin with MIC≤1ug/ml was above 90%and with MIC＞2ug/ml was below 20%. 10 RCTs,including 2549 patients were included in Meta-analysis.Linezolid was more effective than vancomycin in patients with skin and soft-tissue infections. There was no difference in adverse effects associated with vacomycin and linezolid.(2) For RN450,AUC stimulated was 23,43,76;for RN450—A1, AUC was 52,108,228 and for S.aureus 99,AUC was 17,19,30,t_1/2 was 7.8±0.4h.For low and middle AUC,bacteria number decreased at first and then recover,and levofloxacin-resistant staphylococci was enriched,MIC of bacteria at 72h was higher than bacteria at 0h,MICf/MICi of Staphylococcus aureus RN450,RN450-A1 and 99 were 4-5,32 and 4 respectively;for high AUC,bacteria number decreased at first and then recover,and levofloxacin-resistant staphylococci was enriched;for high AUC,bacteria number decreased,and levofloxacin-resistant staphylococci was eradiated and MICf/MICi was 1.The mutant site of levofloxacin-resistant staphylococci was Glu84→Lys or Ser80→Phe in grlA.The enrichment of resistant mutants at antibiotic concentrations within the mutant selection window(MSW) was more dependent with AUC/MPC than with AUC/MIC.[CONCLUSION]111 MRSA were sensitive to vancomycin and linezolid.PTA of linezolid and vancomycin with MIC≤1ug/ml was above 90%and with MIC＞2ug/ml was below 20%.AUC/MIC was more accurate than MIC to predict the clinial therapeutic effect.The inhibition of resistant mutants was more dependent with PK/PD parameters based on MPC than with that based on MIC.