Optimization Of Tigecycline Dosage Regimen In Special Populations And In Vitro Combination Medication Against Resistant Bacteria

OBJECTIVE:1.To evaluate and optimize dosing regimens of tigecycline against common bacterial infections in patients with cirrhosis.2.To evaluate and optimize dosing regimens of tigecycline against common bacterial infections in patients with various degrees of Renal Function.3.To evaluate the synergistic activity of tigecycline when combined with antibacterial drugs with different mechanisms of action.METHODS:1.Estimate tigecycline dosing regimens against common bacterial infections in patients with cirrhosis.Using pharmacokinetic(PK)parameters,pharmacodynamic(PD)data and pharmacokinetic/pharmacodynamic(PK/PD)parameters,Monte Carlo simulations(MCSs)were conducted to evaluate the cumulative fraction response(CFR)of different doses of tigecycline against common bacterial infections in patients with cirrhosis and to recommend the optimal dosing regimen..2.Estimate tigecycline dosing regimens against common bacterial infections in patients with various degrees of renal function.The above method was used to calculate the PTA and CFR values of different dosage regimens of tigecycline against common bacterial infections in patients with different renal functions and to recommend the optimal dosing regimen.3.Analysis the synergistic activity of tigecycline when combined with antibacterial drugs with different mechanisms of action.The E test strips of two antibacterial drugs were placed on the MH agar with a90°angle at their respective MICs for the organism.After the plate was incubated at35 ° C for 18 hours,the MIC value after the combination was read and the FICI was calculated.RESULTS:1.Dosing regimens optimization of tigecycline against common bacterial infections in patients with cirrhosis.For hospital-acquired pneumonia(HAP)or complicated intra-abdominal infections(cIAI)caused by Enterococcus faecalis,Enterococcus faecium and S.pneumoniae,all maintenance dosage regimens achieved CFR values of >90%.For HAP caused by E.coli,MRSA and MSSA,all dosage regimens achieved CFR values of >90%,and For cIAI caused by E.coli,MRSA and MSSA,dosage regimens except for 25 mg q12 h achieved CFR values of >90%.For all patients with Klebsiella pneumoniae and Enterobacter cloacae infections and Child Pugh A and B patients infected with Klebsiella oxytoca,CFR values of all maintenance dosage regimens is <90%.For complicated skin and skin structure infections(cSSSI)caused by A.baumannii,Enterobacter cloacae,Klebsiella oxytoca and Klebsiella pneumoniae,all maintenance dosage regimens achieved CFR values of < 90%.2.Dosing regimens optimization of tigecycline against common bacterial infections in patients with various degrees of renal function.For HAP or cIAI caused by Enterococcus faecalis,Enterococcus faecium,MSSA,and Streptococcus pneumoniae in patients with varying degrees of renal function,all maintenance dose of tigecycline achieved CFR values of >90%.For HAP caused by Escherichia coli and MRSA,all maintenance dose regimens of tigecycline achieved CFR values of >90%.For infections with Klebsiella pneumoniae,Enterobacter cloacae,and Klebsiella oxytoca,dosage regimens except for 25 mg q12 h achieved CFR values of > 90%.For cSSSI caused by A.baumannii,Enterobacter cloacae,Klebsiella oxytoca,and Klebsiella pneumoniae,all tigecycline maintenance doses achieved CFR values of < 90%.3.Evaluation activity of tigecycline when combined with antibacterial drugs with different mechanisms of action against CRKPTigecycline and trimethoprim/sulfamethoxazole were sensitive to CRKP with a MIC of 0.25 g/mL.Fosfomycin,piperacillin/tazobactam,levofloxacin and tobramycin were resistant for CRKP.Tigecycline combined with trimethoprim/sulfamethoxazole showed a partial synergistic effect on CRKP,while other regimens of tigecycline combination susceptibility show no related effect on CRKP.CONCLUSION:1.The tigecycline maintenance dosage of 25 mg q12 h achieved a good therapeutic effects for patients with cirrhosis for HAP caused by Gram-positive bacteria or E.coli.The maintenance dose of tigecycline should be increased for cIAI caused by most Gram-negative bacteria,especially in patients with Child Pugh A and B.2.The tigecycline maintenance dosage of 25 mg q12 h is effective for HAP caused by common Gram-positive bacteria or E.coli in patients with different renal functions.For HAP caused by Enterobacter cloacae,the maintenance dose of tigecycline does not need to be adjusted in severe renal impairment patients and the maintenance dose of tigecycline should be increased in other patients.For cSSSI caused by Acinetobacter baumannii,all tigecycline doses were ineffective in all patients and other drugs or combination therapy were recommended.3.Tigecycline combined with trimethoprim/sulfamethoxazole showed a partial synergistic effect on CRKP,while other regimens of tigecycline combination susceptibility show no related effect on CRKP.However,the results in this study were only in vitro.Whether they have the same therapeutic effect in vivo remains to be confirmed by more clinical studies in order to provide reference for in vivo studies.