Randomized trial of micafungin for the prevention of invasive fungal infection in high-risk liver transplant recipients

Faouzi Saliba, Andreas Pascher, Olivier Cointault, Pierre-François Laterre, Carlos Cervera, Jan J De Waele, Umberto Cillo, Róbert M Langer, Manuela Lugano, Bo Göran-Ericzon, Stephen Phillips, Lorraine Tweddle, Andreas Karas, Malcolm Brown, Lutz Fischer, TENPIN (Liver Transplant European Study Into the Prevention of Fungal Infection) Investigators, TENPIN Liver Transplant European Study Into the Prevention of Fungal Infection Investigators, Johann Pratschke, Johan Decruyenaere, Jan J De Waele, Pierre-François Laterre, Christophe Moreno, Peter Michielsen, Olivier Cointault, Lutz Fischer, Peter Neuhaus, Andreas Pascher, Peter Schemmer, Carlos Cervera, Evaristo Varo, Miguel Montejo, Emilio Bouza, Marino Blanes, Julián De La Torre, Jesus Fortun, Faouzi Saliba, Lionel Rostaing, Catherine Paugam-Burtz, Daniel Eyraud, Tahir Shah, Nigel Heaton, Róbert M Langer, Aiden McCormick, Umberto Cillo, Mauro Salizzoni, Manuela Lugano, Andrea De Gasperi, Luís Tomé, Jorge Daniel, Irinel Popescu, Yan G Moysyuk, Alexey V Chzhao, Vladimir E Zagaynov, Bo-Göran Ericzon, Faouzi Saliba, Andreas Pascher, Olivier Cointault, Pierre-François Laterre, Carlos Cervera, Jan J De Waele, Umberto Cillo, Róbert M Langer, Manuela Lugano, Bo Göran-Ericzon, Stephen Phillips, Lorraine Tweddle, Andreas Karas, Malcolm Brown, Lutz Fischer, TENPIN (Liver Transplant European Study Into the Prevention of Fungal Infection) Investigators, TENPIN Liver Transplant European Study Into the Prevention of Fungal Infection Investigators, Johann Pratschke, Johan Decruyenaere, Jan J De Waele, Pierre-François Laterre, Christophe Moreno, Peter Michielsen, Olivier Cointault, Lutz Fischer, Peter Neuhaus, Andreas Pascher, Peter Schemmer, Carlos Cervera, Evaristo Varo, Miguel Montejo, Emilio Bouza, Marino Blanes, Julián De La Torre, Jesus Fortun, Faouzi Saliba, Lionel Rostaing, Catherine Paugam-Burtz, Daniel Eyraud, Tahir Shah, Nigel Heaton, Róbert M Langer, Aiden McCormick, Umberto Cillo, Mauro Salizzoni, Manuela Lugano, Andrea De Gasperi, Luís Tomé, Jorge Daniel, Irinel Popescu, Yan G Moysyuk, Alexey V Chzhao, Vladimir E Zagaynov, Bo-Göran Ericzon

Abstract

Background: Invasive fungal infection (IFI) following liver transplant is associated with significant morbidity and mortality. Antifungal prophylaxis is rational for liver transplant patients at high IFI risk.

Methods: In this open-label, noninferiority study, patients were randomized 1:1 to receive intravenous micafungin 100 mg or center-specific standard care (fluconazole, liposomal amphotericin B, or caspofungin) posttransplant. The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at end of prophylaxis (EOP). Noninferiority (10% margin) of micafungin vs standard care was assessed in the per protocol and full analysis sets. Safety assessments included adverse events and liver and kidney function tests.

Results: The full analysis set comprised 344 patients (172 micafungin; 172 standard care). Mean age was 51.2 years; 48.0% had a Model for End-Stage Liver Disease score ≥20. At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care (Δ standard care - micafungin [95% confidence interval], 0.7% [-2.7% to 4.4%]) in the per protocol set and 96.5% and 93.6%, respectively (-2.9% [-8.0% to 1.9%]), in the full analysis set. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care-treated patients.

Conclusions: Micafungin was noninferior to standard care as antifungal prophylaxis in liver transplant patients at high risk for IFI. Adverse event profiles and liver function at EOP were similar, although kidney function was better with micafungin.

Clinical trials registration: NCT01058174.

Keywords: antifungal therapy; infection; liver transplant; micafungin; prophylaxis.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Disposition of patients. *All randomized patients with at least 1 dose of study drug. †All randomized patients with at least 1 dose of study drug and without an invasive fungal infection (IFI) at baseline. ‡All patients who completed the study without major protocol deviations or violations. §Patients from the full analysis set who discontinued; for every patient, only the primary reason for discontinuation was collected.
Figure 2.
Figure 2.
Fungal-free survival in micafungin and standard care treatment groups during long-term follow-up (full analysis set). Abbreviation: IFI, invasive fungal infection.
Figure 3.
Figure 3.
Mean glomerular filtration rate (A) and mean creatinine clearance (B) in patients not requiring renal replacement therapy, according to specific study drug. Abbreviations: EOP, end of prophylaxis; EOS, end of study.

References

    1. Vera A, Contreras F, Guevara F. Incidence and risk factors for infections after liver transplant: single-center experience at the University Hospital Fundacion Santa Fe de Bogota, Colombia. Transpl Infect Dis. 2011;13:608–15.
    1. Raghuram A, Restrepo A, Safadjou S, et al. Invasive fungal infections following liver transplantation: incidence, risk factors, survival, and impact of fluconazole-resistant Candida parapsilosis (2003–2007) Liver Transpl. 2012;18:1100–9.
    1. Zicker M, Colombo AL, Ferraz-Neto BH, Camargo LF. Epidemiology of fungal infections in liver transplant recipients: a six-year study of a large Brazilian liver transplantation centre. Mem Inst Oswaldo Cruz. 2011;106:339–45.
    1. Yang CH, He XS, Chen J, et al. Fungal infection in patients after liver transplantation in years 2003 to 2012. Ann Transplant. 2012;17:59–63.
    1. Shi XJ, Lu SC, He L, et al. Diagnosis and treatment of fungal infection after liver transplantation. Chin Med J (Engl) 2011;124:1015–7.
    1. Pacholczyk M, Lagiewska B, Lisik W, Wasiak D, Chmura A. Invasive fungal infections following liver transplantation—risk factors, incidence and outcome. Ann Transplant. 2011;16:14–6.
    1. Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am. 2003;17:113–34. viii.
    1. Grossi PA. Clinical aspects of invasive candidiasis in solid organ transplant recipients. Drugs. 2009;69(suppl 1):15–20.
    1. Eschenauer GA, Lam SW, Carver PL. Antifungal prophylaxis in liver transplant recipients. Liver Transpl. 2009;15:842–58.
    1. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clin Infect Dis. 2010;50:1101–11.
    1. Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2010;12:220–9.
    1. Saliba F, Delvart V, Ichai P, et al. Fungal infections after liver transplantation: outcomes and risk factors revisited in the MELD era. Clin Transplant. 2013;27:E454–61.
    1. Lichtenstern C, Hochreiter M, Zehnter VD, et al. Pretransplant model for end stage liver disease score predicts posttransplant incidence of fungal infections after liver transplantation. Mycoses. 2013;56:350–7.
    1. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18:44–69.
    1. Singh N, Husain S the AST Infectious Diseases Community of Practice. Invasive aspergillosis in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S180–91.
    1. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35.
    1. Pappas PG, Silveirab FP the AST Infectious Diseases Community of Practice. Candida in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S173–9.
    1. Arendrup MC. Epidemiology of invasive candidiasis. Curr Opin Crit Care. 2010;16:445–52.
    1. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect. 2002;50:243–60.
    1. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother. 2002;49(suppl 1):37–41.
    1. Sun HY, Cacciarelli TV, Singh N. Micafungin versus amphotericin B lipid complex for the prevention of invasive fungal infections in high-risk liver transplant recipients. Transplantation. 2013;96:573–8.
    1. Glockner A. Treatment and prophylaxis of invasive candidiasis with anidulafungin, caspofungin and micafungin: review of the literature. Eur J Med Res. 2011;16:167–79.
    1. Singh N, Wagener MM, Cacciarelli TV, Levitsky J. Antifungal management practices in liver transplant recipients. Am J Transplant. 2008;8:426–31.
    1. Cornely OA, Bassetti M, Calandra T, et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect. 2012;18(suppl 7):19–37.
    1. Gavalda J, Meije Y, Fortun J, et al. Invasive fungal infections in SOT recipients. Clin Microbiol Infect. 2014;20(suppl 7):27–48.
    1. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46:1813–21.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med. 2010;152:726–32.
    1. Astellas Pharma Europe B.V. Mycamine: summary of product characteristics. Available at: . Accessed 26 February 2014.
    1. Astellas Pharma US Inc. Mycamine prescribing information. Available at: . Accessed 26 February 2014.
    1. van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39:1407–16.
    1. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007;20:133–63.
    1. Pfizer Ltd. Diflucan: summary of product characteristics. Available at: . Accessed 26 February 2014.
    1. Pittrow L, Penk A. Dosage adjustment of fluconazole during continuous renal replacement therapy (CAVH, CVVH, CAVHD, CVVHD) Mycoses. 1999;42:17–9.
    1. Muhl E, Martens T, Iven H, Rob P, Bruch HP. Influence of continuous veno-venous haemodiafiltration and continuous veno-venous haemofiltration on the pharmacokinetics of fluconazole. Eur J Clin Pharmacol. 2000;56:671–8.
    1. Moen MD, Lyseng-Williamson KA, Scott LJ. Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs. 2009;69:361–92.
    1. Eschenauer GA, DePestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag. 2007;3:71–97.
    1. Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs. 2011;71:11–41.
    1. Beyda ND, Lewis RE, Garey KW. Echinocandin resistance in Candida species: mechanisms of reduced susceptibility and therapeutic approaches. Ann Pharmacother. 2012;46:1086–96.
    1. Perlin DS. Echinocandin resistance, susceptibility testing and prophylaxis: implications for patient management. Drugs. 2014;74:1573–85.
    1. Alexander BD, Johnson MD, Pfeiffer CD, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56:1724–32.
    1. Merck Sharp & Dohme Ltd. Cancidas: summary of product characteristics. Available at: . Accessed 26 February 2014.
    1. Hebert MF, Townsend RW, Austin S, et al. Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol. 2005;45:954–60.
    1. Inoue Y, Saito T, Ogawa K, et al. Drug interactions between micafungin at high doses and cyclosporine A in febrile neutropenia patients after allogeneic hematopoietic stem cell transplantation. Int J Clin Pharmacol Ther. 2012;50:831–7.
    1. Hebert MF, Blough DK, Townsend RW, et al. Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol. 2005;45:1018–24.
    1. Fukuoka N, Imataki O, Ohnishi H, et al. Micafungin does not influence the concentration of tacrolimus in patients after allogeneic hematopoietic stem cell transplantation. Transplant Proc. 2010;42:2725–30.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel