Efficacy And Optimal Dosage Regimens Of Antifungal Agents In Treatment Of Patients With Invasive Fungal Infection

Objective: 1.To compare the efficacy of voriconazole,caspofungin and micafungin,and to investigate the influence effects in anti-infection efficacy in hematological malignancies patients with invasive fungal infection(IFI).2.To estimate and evaluate various voriconazole dosing regimens against 6 Candida spp.and 6 Aspergillus spp.in immunocompromised children,adolescents,and adults.3.To estimate and evaluate various echinocandins dosing regimens against Candida spp.in pediatric patients with IFI.Methods: 1.Efficacy comparison and influence factors analysis of voriconazole,caspofungin and micafungin in hematological malignancies patients with IFI.Measure K+,Na+,ALP,TP,Alb,TBil,ALT,AST,Urea,Cr,WBC,RBC,PLT,neutrophil,CRP and G-test for inpatients in haematology department before anti-infection treatment,which were confirmed,clinically diagnosed,suspected or need anti-infection therapy but not for sure in Tianjin First Central Hospital from January 2015 to April 2016.Compare the efficacy of each antifungal agent according clinical criteria,imaging or microorganism results,and perform simple factor analysis and multiply regression analysis.2.Estimate voriconazole dosing regimens against Candida spp.and Aspergillus spp.in immunocompromised children,adolescents and adults.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 dosing strategies against 6 Candida spp.and 6 Aspergillus spp.in different patients.3.Estimate echinocandins dosing regimens against Candida spp.in pediatric patients with IFI.Using PK parameters,PD data and PK/PD targets of echinocandins,MCSs were performed to evaluate the CFR of different regimens against Candida spp.for pediatric patients.Results: 1.Efficacy comparison and influence factors analysis of voriconazole,caspofungin and micafungin in treatment of hematological malignancies patients with IFI.The efficacy rates of voriconazole,caspofungin and micafungin in treatment of hematological malignancies patients with IFI were 66.7%,60%,and 65%,respectively.The differences were not statistically significant in three groups.The lasting days of agranulocytosis and lasting days of therapy were the influence effects in anti-infection efficacy.2.The CFRs of voriconazole in children,adolescents and adults.All of the voriconazole dosage regimens achieved CFR values of ?90% in children,adolescents and adults against C.albicans,C.parapsilosis and C.orthopsilosis.Regarding immunocompromised children(2 to <12 years old)and young adolescents(12 to 14 years old,weighing <50 kg),only a voriconazole dosage regimen of 8 mg/kg i.v.q12 h achieved CFR value of ?90% against C.tropicalis,A.fumigatus and A.nidulans.In immunocompromised adolescents(12 to <17 years old),both 4 mg/kg i.v.q12 h and 300 mg p.o.q12 h achieved CFR values of ?90% against C.tropicalis,and 4 mg/kg i.v.q12 h achieved CFR value of ?90% against A.fumigatus.In adults,4 mg/kg i.v.q12 h and 300 mg orally q12 h achieved CFRs ?90% against Candida spp.and Aspergillus spp.(expect of A.versicolor).However,the CFRs of all the dosage regimens were less than90% against A.niger for immunocompromised children and adolescents.The CFR expectation values were ?90% of all dosing regimens against A.versicolor.3.The CFRs of echinocandin against Candida spp.in pediatric patients.In pediatric patients,caspofungin regimens achieved CFR values of ?90% against C.albicans and C.glabrata.1.0 mg/kg(fungistatic target,first dose),0.5 mg/kg(fungistatic target,qd),1.5 mg/kg(fungicidal target,first dose),and 1.5 mg/kg(fungicidal target,qd)of micafungin achieved CFR values of ?90% against C.glabrata.Larger dose(3.0mg/kg,fungistatic target)was needed when receiving micafungin against C.albicans in terms of CFR ?90%.None of the dosage regimens of anidulafungin obtained a expected CFR value of?90% against Candida spp..All of the echinocandin regimens achieved low CFR values against C.parapsilosis.Conclusion: 1.In this study,the efficacy rates of voriconazole,caspofungin and micafungin in treatment of hematological malignancies patients with IFI were similar.The lasting days of agranulocytosis and lasting days of therapy were the influence effects in anti-infection efficacy.The shorter of lasting days of agranulocytosisand and longer of lasting days of therapy,the better the efficacy of antifungal agents will be.2.Clinical dosage regimens of voriconazole were all sufficient for immunocompromised children,adolescents and adults to treat fungal infections by C.albicans,C.parapsilosis and C.orthopsilosis.In children and adolescents,high doses should be recommended to achieve better clinical efficacy against A.fumigatus and A.nidulans.None of the simulated voriconazole dosage regimens were effective against A.niger.For adults,dosing regimens of 4 mg/kg i.v.q12 h and 300 mg p.o.q12 h were sufficient against Candida spp.and Aspergillus spp.(expect of A.versicolor).None of the current dosage regimens achieved optimal activity against A.versicolor.3.Clinical caspofungin recommended regimens(50 mg/m2)and high dosing regimens of micafungin have good efficacy against C.albicans and C.glabrata.However,the dosing regimens of anidulafungin may not be effective to Candida spp..For Candida parapsilosis,all of three echinocandins may be not sufficient to achieve optimal activity.