A Network Meta-analysis Of Different Antifungal Agents For The Prevention Of Invasive Fungal Infection In Patients After Transplantation

Background:Invasive fungal infection(IFI)is an important cause of morbidity and mortality in patients with immunodeficiency such as hematopoietic stem cell transplantation and solid organ transplantation.In recent years,the incidence of transplantation-related IFI increased due to the increase of transplantation-related operations.Prophylactic use of antifungal agents in high-risk patients can effectively reduce the incidence of IFI,but different antifungal agents have different efficacy and safety.This study aimed to compare the efficacy and safety of seven antifungal drugs in preventing IFI in patients after transplantation.They included fluconazole,itraconazole,posaconazole,voriconazole,micafungin,caspofungin,amphotericin B or its liposomes.At the same time,seven antifungal drugs were ranked according to the outcome indicator,so as to guide clinical decision-making.Methods: We searched Pub Med,Cochrane Library,EMbase,Web of Science databases to collect randomized controlled trials(RCT)related to the prevention of IFI from the inception of databases to November 2019,including placebo-controlled trials and head-to-head comparative trials of seven antifungal agents.Two researchers independently screened the literature,extracted data,and evaluated the studies’ risk of bias using the tool for the risk of bias assessment of RCT recommended by the Cochrane Handbook.The outcome indicators included the overall incidence of IFI,the incidence of invasive Candida infection,the incidence of invasive Aspergillus infection,the overall incidence of adverse reaction of antifungal drugs and the rates of withdrawal due to adverse drug reaction.We used the odds ratio(OR)and 95% confidence interval(CI)as statistics of the effect.The surface under the cumulative ranking curve area(SUCRA)was drawn by Stata14.0 software to show the ranking of different interventions in different outcome indicators.This study was registered with PROSPERO,number CRD42020158262.Results: A total of 1187 articles were initially retrieved and 22 articles were eventually included,comprising 5570 participants.In terms of the overall incidence of IFI,fluconazole,itraconazole,posaconazole,voriconazole,micafungin,amphotericin B,and amphotericin B liposomes can all reduce the overall incidence of IFI compared with placebo.Fluconazole(OR,1.78;95%CI,1.05-3.03)has a higher incidence of IFI than itraconazole.There is no significant difference between the remaining pairwise comparisons.The probability ranking of the overall incidence of IFI of the seven antifungal agents suggest that itraconazole had the best prophylactic effect,followed by voriconazole and posaconazole.In terms of the incidence of invasive Candida infection and the incidence of invasive Aspergillus infection,fluconazole,itraconazole,and amphotericin B can all reduce the incidence of invasive Candida infection compared with placebo.The probability ranking of the incidence of invasive Candida infection of the seven antifungal agents suggest that itraconazole has the lowest incidence of invasive Candida infection,followed by voriconazole.Compared with placebo,itraconazole,posaconazole,voriconazole and micafungin can all reduce the incidence of invasive Aspergillus infection.The incidence of invasive Aspergillus infection of micafungin(OR,0.32;95%CI,0.13-0.75),posaconazole(OR,0.32;95%CI,0.13-0.75),itraconazole(OR,0.46;95%CI,0.23-0.91)is lower than fluconazole.There is no significant difference between the remaining pairwise comparisons.The probability ranking of the incidence of invasive Aspergillus infection of the seven antifungal agents suggest that micafungin has the lowest incidence of invasive Aspergillus infection,followed by posaconazole and itraconazole.In terms of the overall incidence of adverse reaction of antifungal drugs,itraconazole(OR,4.94;95% CI,2.78-8.79)and amphotericin B(OR,37.56;95%CI,4.79-294.46)increase the incidence of adverse effect compared with placebo.The incidence of adverse reactions of fluconazole(OR,0.27;95% CI,0.18-0.41)is lower than that of itraconazole.The overall incidence of adverse reactions of itraconazole is higher than that of posaconazole(OR,4.18;95% CI,2.46-7.11)and micafungin(OR,3.92;95% CI,2.49-6.16).Amphotericin B(OR,29.78;95% CI,3.86-229.62)has significantly higher incidence of adverse reactions than that of micafungin.Compared with amphotericin B,the overall incidence of adverse reactions of posaconazole(OR,0.03;95% CI,0.00-0.24)is significantly reduced.There is no significant difference between the remaining pairwise comparisons.The probability ranking of the overall incidence of adverse reaction of various antifungal agents suggest that posaconazole has the lowest incidence of adverse reactions,followed by micafungin,and amphotericin B has the highest incidence of adverse reactions.In terms of the rates of withdrawal due to adverse drug reaction,the probability ranking suggest that itraconazole has the lowest withdrawal rate,followed by posaconazole.Conclusions: 1.Fluconazole,itraconazole,posaconazole,voriconazole,micafungin,amphotericin B and amphotericin B liposomes can all reduce the overall incidence of IFI for patients after transplantation.Itraconazole and voriconazole have the best prophylactic effect on invasive Candida infection for patients after transplantation,and micafungin and posaconazole have the best prophylactic effect on invasive Aspergillus infection for patients after transplantation,but the selection of specific drugs should be based on the characteristics of the transplanted organ.2.The overall incidence of adverse reaction of various antifungal agents is ranked as follows from the lowest to the highest: posaconazole,micafungin,fluconazole,amphotericin B liposomes,itraconazole,amphotericin B.Posaconazole has the best safety and tolerance,while amphotericin B has the worst.