Optimization The Clinical Dosage Of Cefepime Based On PK/PD Theory

ObjectiveAccording to the principle of pharmacokinetics/pharmacodynamics?PK/PD?,Monte Carlo simulation was used to optimize the dosing regimen of cefepime.Methods1.The MIC values of cefepime,cephradine,cefuroxime and ceftriaxone against eight clinically isolated strains were determined by two-fold dilution method of trace broth,the pharmacodynamic parameters such as MIC₅₀ and MIC₉₀ were analyzed,and the antibacterial effects was compared;2.To establish an immunosuppressive neutropenic mouse thigh model and determine the number of CFU in mice after administration of cefepime,and to determine the blood concentration in mice by HPLC.The antibacterial effect was evaluated,which laid the foundation for the Monte Carlo simulation study in the next phase;3.Based on the theory of PK/PD,Monte Carlo simulation was performed using a crystal ball software to combine pharmacokinetics and pharmacodynamic parameters with 10,000 simulations,the cumulative response score and the target probability of six commonly used cefepime clinical doses?ie,1.5g q12h,2g q12h,1g q8h,0.75g q6h,1g q6h,2g q8h?were calculated.Using%fT>MIC?50 as the target for expected clinical efficacy,and obtaining CFR?90%or achieving the highest PTA value as a reasonable choice for empirical treatment of antimicrobial agents,ie,the optimal clinical therapeutic dosing regimen.Results1.Eight clinically common isolates had different degrees of resistance to four cephalosporins,but the resistance to cefepime was relatively low.The resistance rate of Staphylococcus aureus to four drugs was relatively high,which was 62.86%-90%.The resistance rate of other strains to cephradine was 55.97%-72.86%,the resistance rate to cefuroxime was 47.31%-71.82%,and the resistance rate to ceftriaxone was32.86%-65.67%,The drug resistance rate to cefepime was 15.52%-30.47%.The main pharmacodynamic parameters of cefepime are:the MIC₅₀,MIC₉₀ and MIC_range of E.coli were 4,32 and 0.125-64?g/mL,respectively;For Enterobacter cloacae,MIC₅₀,MIC₉₀,and MIC_range were 1,64,and 0.064-64?g/mL,respectively;For Klebsiella pneumoniae,MIC₅₀,MIC₉₀,and MIC_range were 4,64,and 0.064-64?g/mL,respectively;For Acinetobacter baumannii,MIC₅₀,MIC₉₀,and MIC_range were 4,32,and 0.125-64?g/mL,respectively;For Citrobacter,MIC₅₀,MIC₉₀,and MIC_range were1,16,and 0.032-64?g/mL,respectively;For Staphylococcus aureus,MIC₅₀,MIC₉₀,and MIC_range were 16,64,and 1-64?g/mL,respectively;For Streptococcus pneumonia,the MIC₅₀,MIC₉₀,and MIC_range were 2,32,and 0.25-64?g/mL,respectively;For P.aeruginosa,MIC₅₀,MIC₉₀,and MIC_range were 2,32,and 0.25-64?g/mL,respectively.2.The results of antibacterial experiments in vivo showed that after 24 hours of treatment with cefepime,the logCFU values at intervals of 8 h of Enterobacter cloacae were 6.50±0.202,5.5±0.087,and 4.62±0.231,respectively;The logCFU values of S.pneumoniae at intervals of 8 h were 6.33±0.24,5.39±0.138,and4.74±0.172,respectively.It can be seen that the number of colonies decreased significantly,with very significant differences.The logCFU values of E.cloacae isolates at intervals 12 h were 6.49±0.288,5.75±0.083,5.45±0.123,and the logCFU values of colonies at intervals 12 h for S.pneumoniae were 6.64±0.073,5.72±0.041,and 5.25±0.151,respectively.The logCFU of colonies decreased with the increase of the dose,and there was a significant difference in the medium and high dose groups?P<0.01?.The experimental results showed that the trend of the number of bacterial colonies in the mouse thigh muscle and the results of in vitro antibacterial experiments were generally consistent.3.The Monte Carlo simulation's PTA results:The six doses of cefepime that PTA values were different for the different MIC of the bacteria.When the MIC was less than 8?g/mL,the PTA for the six dosing regimens of cefepime was over 90%.Therefore,when the MIC value of the susceptibility test of bacteria is?8?g/mL,the treatment effect is good;when the MIC was equal to 16?g/mL,the probability of reaching the target of the 1.5g q12h dosing regimens decreased to 64.34%;when the MIC is 32?g/mL,The probability of%fT>MIC values of the 2g q12h,1.5g q12h,and 1g q8h dosing regimens reached 50 were less than 90%;when the MIC?64?g/mL,the probability of%fT>MIC values of the six dosing regimens reached 50were less than 90%.Cumulative response scores for Monte Carlo simulations:cumulative response scores for four dosing regimens of all six doses of cefepime in 10,000 simulations against Escherichia coli,Pseudomonas aeruginosa,and Streptococcus pneumoniae were higher than 90%,which were 1g q8h,0.75g q6h,1g q6h,and 2g q8h.The results of Simulations for Acinetobacter baumannii showed that the CFRs of 0.75g q6h,1g q6h,and 2g q8h reached 90%.The three dosing regimens can achieve better results.The CFRs of the 1g q6h and 2g q8h in the simulation results for Enterobacter cloacae and Klebsiella pneumoniae were higher than 90%,indicating that the antibacterial effect was good.In the simulation results of the six cefepime administration for Citrobacter,only the regime of 1.5 g q12h,the CFR was less than90%,indicating that the other five regimens have better therapeutic effects on Citrobacter.Only the regime of 2 g q8h,the CFR was higher than 90%for Staphylococcus aureus.Conclusions1.There are multiple options for Escherichia coli,Pseudomonas aeruginosa,and Streptococcus pneumoniae,suggesting that increasing the number of administrations and decreasing the dose can achieve the same effect.But from the cost-effective point of view,1g q8h is recommend.2.The regime of 1g q6h and 2g q8h of Cefepime are effective for Enterobacter cloacae and Klebsiella pneumoniae.But from the perspective of daily dose and reducing drug resistance,daily dose of 4 g is preferentially selected.And,considering the number of administrations,the recommended dosage regimen is 1g q6h.3.The CFRs of the five regime of cefepime all reached 90%.According to the guiding principle of antibiotics for clinical medication,the treatment plan of 1g q8h is preferentially recommended.4.For Acinetobacter baumannii,CFRs of 0.75g q6h,1g q6h,2g q8h all reached90%,the regimen of 0.75g q6h is preferentially recommended.5.For the staphylococcus aureus,in addition to the cefepime 2g q8h dosing regimen,the CFRs of other dosing regimens were less than 90%,suggesting that the therapeutic effect of increasing the dose and number was not significant,and if necessary,the combination therapy may be considered.In addition,when adjusting and optimizing the dosing regimen,it should pay attention to the adverse reactions of cefepime and regulate the rational use of drugs.