Semin Respir Crit Care Med 2024; 45(01): 061-068
DOI: 10.1055/s-0043-1776776
Review Article

Antifungal Therapies for Aspergillus spp.: Present and Future

Gregory A. Eschenauer
1   Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan
› Author Affiliations

Abstract

Currently available and recommended options for the treatment of pulmonary aspergillosis include the triazoles, echinocandins, and amphotericin B products. These therapies have significant limitations. Only the azoles are available orally, but their use is often limited by toxicities, drug–drug interactions, pharmacokinetic variability, and emerging resistance. While the echinocandins are safe agents and may have a role in combination therapy, they are unproven as monotherapy. Amphotericin B preparations are toxic and require intensive monitoring. Finally, aspergillosis continues to be a disease conferring substantial morbidity and mortality, and clinical trials have not identified a therapeutic approach clearly associated with improved outcomes. As a result, there is a great need for new options in the treatment of invasive aspergillosis. Ideally, such options would be safe, have high oral bioavailability, have favorable pharmacokinetics to sequestered sites and retain activity against azole-resistant isolates. Reassuringly, there is a robust pipeline of novel therapies in development. Rezafungin (a once-weekly dosed echinocandin) and ibrexafungerp (oral agent with same mechanism of action as echinocandins) will likely be reserved for combination therapy or refractory/intolerance scenarios with no other options. Inhaled opelconazole is an attractive option for combination therapy and prophylaxis of pulmonary aspergillosis. Development of an oral form of amphotericin B that avoids nephrotoxicity and electrolyte disturbances is an exciting development. Finally, olorofim and fosmanogepix, two agents with novel mechanisms of action and oral formulations, hold significant potential to challenge the triazole antifungals place as preferred therapies. However, many questions remain regarding these novel agents, and at the time of this writing, none of these agents have been robustly studied in Phase III studies of aspergillosis, and so their promise remains investigational.



Publication History

Article published online:
27 December 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Patterson TF, Thompson III GR, Denning DW. 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 (04) e1-e60
  • 2 Herbrecht R, Denning DW, Patterson TF. et al; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347 (06) 408-415
  • 3 Walsh TJ, Finberg RW, Arndt C. et al; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999; 340 (10) 764-771
  • 4 Cornely OA, Maertens J, Bresnik M. et al; AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44 (10) 1289-1297
  • 5 Pappas PG, Kauffman CA, Andes DR. et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62 (04) e1-e50
  • 6 Viscoli C, Herbrecht R, Akan H. et al; Infectious Disease Group of the EORTC. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients. J Antimicrob Chemother 2009; 64 (06) 1274-1281
  • 7 Marr KA, Schlamm HT, Herbrecht R. et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162 (02) 81-89
  • 8 Ullmann AJ, Aguado JM, Arikan-Akdagli S. et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect 2018; 24 (Suppl. 01) e1-e38
  • 9 Maertens JA, Raad II, Marr KA. et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387 (10020): 760-769
  • 10 Maertens JA, Rahav G, Lee DG. et al; study investigators. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet 2021; 397 (10273): 499-509
  • 11 Klatt ME, Eschenauer GA. Review of pharmacologic considerations in the use of azole antifungals in lung transplant recipients. J Fungi (Basel) 2021; 7 (02) 76
  • 12 Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy 2010; 30 (08) 842-854
  • 13 Benitez LL, Carver PL. Adverse effects associated with long-term administration of azole antifungal agents. Drugs 2019; 79 (08) 833-853
  • 14 Baxter CG, Marshall A, Roberts M, Felton TW, Denning DW. Peripheral neuropathy in patients on long-term triazole antifungal therapy. J Antimicrob Chemother 2011; 66 (09) 2136-2139
  • 15 Kosmidis C, Otu A, Moore CB, Richardson MD, Rautemaa-Richardson R. Isavuconazole therapeutic drug monitoring during long-term treatment for chronic pulmonary aspergillosis. Antimicrob Agents Chemother 2020; 65 (01) e01511-20
  • 16 Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46 (02) 201-211
  • 17 Luong ML, Al-Dabbagh M, Groll AH. et al. Utility of voriconazole therapeutic drug monitoring: a meta-analysis. J Antimicrob Chemother 2016; 71 (07) 1786-1799
  • 18 Park WB, Kim NH, Kim KH. et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 2012; 55 (08) 1080-1087
  • 19 Veringa A, Brüggemann RJ, Span LFR. et al; Voriconazole ZonMw Study Group. Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial. Int J Antimicrob Agents 2023; 61 (02) 106711
  • 20 De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs 2001; 61 (Suppl. 01) 27-37
  • 21 Johnson MD, Hamilton CD, Drew RH, Sanders LL, Pennick GJ, Perfect JR. A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J Antimicrob Chemother 2003; 51 (02) 453-457
  • 22 Lindsay J, Mudge S, Thompson III GR. Effects of food and omeprazole on a novel formulation of super bioavailability itraconazole in healthy subjects. Antimicrob Agents Chemother 2018; 62 (12) e01723-18
  • 23 Lindsay J, Sandaradura I, Wong K. et al. Serum levels, safety and tolerability of new formulation SUBA-itraconazole prophylaxis in patients with haematological malignancy or undergoing allogeneic stem cell transplantation. J Antimicrob Chemother 2017; 72 (12) 3414-3419
  • 24 Wiederhold NP, Schwartz IS, Patterson TF, Thompson III GR. Variability of hydroxy-itraconazole in relation to itraconazole bloodstream concentrations. Antimicrob Agents Chemother 2021; 65 (04) e02353-20
  • 25 Walsh TJ, Raad I, Patterson TF. et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007; 44 (01) 2-12
  • 26 Nguyen MH, Davis MR, Wittenberg R. et al. Posaconazole serum drug levels associated with pseudohyperaldosteronism. Clin Infect Dis 2020; 70 (12) 2593-2598
  • 27 Desai AV, Kovanda LL, Hope WW. et al. Exposure-response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi. Antimicrob Agents Chemother 2017; 61 (12) e01034-17
  • 28 Kaindl T, Andes D, Engelhardt M, Saulay M, Larger P, Groll AH. Variability and exposure-response relationships of isavuconazole plasma concentrations in the phase 3 SECURE trial of patients with invasive mould diseases. J Antimicrob Chemother 2019; 74 (03) 761-767
  • 29 Rybak JM, Fortwendel JR, Rogers PD. Emerging threat of triazole-resistant Aspergillus fumigatus . J Antimicrob Chemother 2019; 74 (04) 835-842
  • 30 Lestrade PP, Bentvelsen RG, Schauwvlieghe AFAD. et al. Voriconazole resistance and mortality in invasive aspergillosis: a multicenter retrospective cohort study. Clin Infect Dis 2019; 68 (09) 1463-1471
  • 31 Heo ST, Tatara AM, Jiménez-Ortigosa C. et al. Changes in in vitro susceptibility patterns of aspergillus to triazoles and correlation with aspergillosis outcome in a tertiary care cancer center, 1999-2015. Clin Infect Dis 2017; 65 (02) 216-225
  • 32 Cornely OA, Maertens J, Winston DJ. et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356 (04) 348-359
  • 33 Ullmann AJ, Lipton JH, Vesole DH. et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356 (04) 335-347
  • 34 Patel TS, Eschenauer GA, Stuckey LJ, Carver PL. Antifungal prophylaxis in lung transplant recipients. Transplantation 2016; 100 (09) 1815-1826
  • 35 Lionakis MS, Lewis RE, Kontoyiannis DP. Breakthrough invasive mold infections in the hematology patient: current concepts and future directions. Clin Infect Dis 2018; 67 (10) 1621-1630
  • 36 Denning DW, Cadranel J, Beigelman-Aubry C. et al; European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J 2016; 47 (01) 45-68
  • 37 Lamoth F, Lewis RE, Kontoyiannis DP. Investigational antifungal agents for invasive mycoses: a clinical perspective. Clin Infect Dis 2022; 75 (03) 534-544
  • 38 Wiederhold NP. Pharmacodynamics, mechanisms of action and resistance, and spectrum of activity of new antifungal agents. J Fungi (Basel) 2022; 8 (08) 857
  • 39 Johnson MD. Antifungals in clinical use and the pipeline. Infect Dis Clin North Am 2021; 35 (02) 341-371
  • 40 Brexafemme (ibrexafungerp) [package insert]. Jersey City, NJ: Scynexis, Inc; 2021
  • 41 Boulware DR, Atukunda M, Kagimu E. et al. Oral lipid nanocrystal amphotericin B for cryptococcal meningitis: a randomized clinical trial. Clin Infect Dis 2023; 77 (12) 1659-1667
  • 42 Colley T, Alanio A, Kelly SL. et al. In vitro and in vivo antifungal profile of a novel and long-acting inhaled azole, PC945, on Aspergillus fumigatus infection. Antimicrob Agents Chemother 2017; 61 (05) e02280-16
  • 43 Cornelissen KN, Rex JH, Puri A. An open-label study in healthy volunteers to evaluate the effect of itraconazole and rifampicin upon the pharmacokinetics of a single oral dose of olorofim. 31st European Congress of Clinical Microbiology and Infectious Diseases. 2021
  • 44 Kennedy T, Allen G, Steiner J. et al. An open-label study in healthy volunteers to evaluate the potential for cytochrome P450 3A4 inhibition by F901318 using oral midazolam as a probe. 27th European Congress of Clinical Microbiology and Infectious Diseases. Vienna, Austria 2017
  • 45 Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther 2006; 79 (04) 362-370
  • 46 Pappas PG, Vazquez JA, Oren I. et al. Clinical safety and efficacy of novel antifungal, fosmanogepix, for the treatment of candidaemia: results from a Phase 2 trial. J Antimicrob Chemother 2023; 78 (10) 2471-2480