Efficacy and safety of triazoles versus echinocandins in the treatment of invasive aspergillosis: A meta-analysis
Abstract
Backgroun/Aim. Although majority of guidelines recommend triazoles (voriconazole, posaconazole, itraconazole and isavuconazole) as first-line therapeutic option for treatment of invasive aspergillosis, echinocandins (caspofungin, micafungin and anidulafungin) are also used for this purpose. However, head-to-head comparison of triazoles and echinocandins for invasive aspergillosis was rarely target of clinical trials. The aim of this meta-analysis was to compare efficacy and safety of triazoles and echinocandins when used for treatment of patients with invasive aspergillosis. Methods. This meta-analysis was based on systematic search of literature and selection of high-quality evidence according to pre-set inclusion and exclusion criteria. The literature search was made for comparison of treatment with any of triazoles (isavuconazole, itraconazole, posaconazole or voriconazole) versus any of echinocandins (caspofungin, anidulafungin or micafungin). The effects of triazoles (itraconazole, posaconazole or voriconazole) and echinocandins (caspofungin, anidulafungin or micafungin) were summarized using RevMan 5.3.5 software, and heterogeneity assessed by the Cochrane Q test and I² values. Several types of bias were assessed, and publication bias was shown by the funnel plot and Egger’s regression. Results. Two clinical trials and three cohort studies were included in this meta-analysis. Mortality in patients with invasive aspergillosis who were treated with triazoles was significantly lower than in patients treated with echinocandins [odds ratio 0.29 (0.13, 0.67)], and rate of favorable response (overall treatment success) 12 weeks after the therapy onset was higher in patients treated with triazoles [3.05 (1.52, 6.13)]. On the other hand, incidence of adverse events was higher with triazoles than with echinocandins in patients treated for invasive aspergillosis [3.75 (0.89, 15.76)], although this difference was not statistically significant. Conclusion.Triazoles (voriconazole in the first place) could be considered as more effective and somewhat less safe therapeutic option than echinocandins for invasive aspergillosis: However, due to poor quality of studies included in this meta-analysis, definite conclusion should await results of additional, well designed clinical trials.
References
Del Bono V, Mikulska M, Viscoli C. Invasive aspergillosis: di-agnosis, prophylaxis and treatment. Curr Opin Hematol 2008; 15(6): 586‒93.
Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of Aspergillosis: Clinical Prac-tice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46(3): 327‒60.
Pappas PG, Alexander BD, Andres DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infection among organ trans-plant recipients: results of the Transplant- Associated Infec-tion Surveillance Network (TRANSNET). Clin Infect Dis 2010; 50(8): 1101‒11.
Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal in-fections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection, Surveillance Network (TRANSNET) Database. Clin Infect Dis 2010; 50(8): 1091‒100.
Chamilos G, Kontoyiannis DP. Defining the diagnosis of invasive aspergillosis. Med Mycol 2006; 44(9): S163‒72.
De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, 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 My-coses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46(12): 1813‒21.
Patterson TF, Thompson GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63(4): e1‒e60.
Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, et al. ECIL-6 guidelines for the treatment of invasive candidi-asis, aspergillosis and mucormycosis in leukemia and hemato-poietic stem cell transplant patients. Haematologica. 2017; 102(3): 433‒44.
Grover ND. Echinocandins: A ray of hope in antifungal drug therapy. Indian J Pharmacol 2010; 42: 9‒11.
Patil A, Majumdar S. Echinocandins in antifungal pharma-cotherapy. J Pharm Pharmacol 2017; 69(12): 1635‒60.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629‒34.
Gioacchino L. Meta-analysis in medical research: the handbook for the understanding and practice of meta-analysis. 1st ed. Malden, USA: Blackwell Publishing Ltd; 2005.
Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
Raad I, El Zakhem A, El Helou G, Jiang Y, Kontoyiannis DP, Hachem R. Clinical experience of the use of voriconazole, cas-pofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies. Int J An-timicrob Agents 2015; 45(3): 283‒8.
van Burik JA, Perfect J, Louie A, Graybill JR, Pedicone L, Raad II. Efficacy of posaconazole (POS) vs standard therapy and safe-ty of POS in hematopoietic stem cell transplant (HSCT) re-cipients vs other patients with aspergillosis., Biol Blood Mar-row Transplant 2006; 12(Suppl 1): 137.
Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin In-fect Dis 2007; 44(1): 2‒12.
Cornely OA, Meems L, Herbrecht R, Viscoli C, van Amsterdam RG, Ruhnke M. Randomised, multicentre trial of micafungin vs. an institutional standard regimen for salvage treatment of invasive aspergillosis. Mycoses 2015; 58(1): 58‒64.
Rabagliati R, Siri L, Fuentes G, Aedo I, Labarca J. Comparison between Voriconazole versus Caspofungin for Invasive Asper-gillosis among Immunocompromised patients. In: Abstract Book. 4th Trends in Medical Mycology. Santiago, Chile; As-pergillus & Aspergillosis Website; 2009. p. 179.
Panackal AA. Combination antifungal therapy for invasive as-pergillosis revisited. Med Mycol Open Access 2016; 2(2). pii: 12.
Panackal AA, Parisini E, Proschan M. Salvage combination anti-fungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis. Int J Infect Dis 2014; 28: 80‒94.
Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of pa-tients. Infection 2017; 45(6): 737‒79.
Lestrade PP, van der Velden WJ, Bouwman F, Stoop FJ, Blijlevens NM, Melchers WJ, et al. Epidemiology of invasive aspergillosis and triazole-resistant Aspergillus fumigatus in patients with haematological malignancies: a single-centre, retrospective co-hort study. J Antimicrob Chemother 2018; 73(5): 1389‒94.
Gheith S, Saghrouni F, Bannour W, Ben Youssef Y, Khelif A, Nor-mand AC, et al. In vitro susceptibility to amphotericin B, itra-conazole, voriconazole, posaconazole and caspofungin of As-pergillus spp. isolated from patients with haematological, ma-lignancies in Tunisia. Springerplus 2014; 3: 19.
Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf 2017; 16(2): 149‒65.
Amsden JR, Gubbins PO. Pharmacogenomics of triazole anti-fungal agents: implications for safety, tolerability and efficacy. Expert Opin Drug Metab Toxicol 2017; 13(11): 1135‒46.
Girmenia C, Iori AP. An update on the safety and interactions of antifungal drugs in stem cell transplant recipients. Expert Opin Drug Saf 2017; 16(3): 329‒39.