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01-04-2024 | Amphotericin B | Review

Aerosolized Antifungals for the Treatment of Pulmonary Fungal Diseases

Authors: Valliappan Muthu, Inderpaul Singh Sehgal, Ritesh Agarwal

Published in: Current Fungal Infection Reports

Abstract

Purpose of Review

Inhaled antifungals achieve high lung concentrations with minimal systemic adverse events. Despite being available for over five decades, data supporting their use outside the mold-active prophylaxis setting are lacking. Herein, we review the recent evidence on inhaled antifungals in treating pulmonary aspergillosis (allergic, chronic, and invasive) and mucormycosis.

Recent Findings

Several antifungals have recently been evaluated, including repurposed and newer inhaled agents (opelconazole). Inhaled amphotericin B deoxycholate (in pulmonary mucormycosis) and liposomal formulation (in invasive aspergillosis) were safely used in two recent randomized trials. However, both these small trials failed to demonstrate added benefit with adjunctive inhaled amphotericin. In allergic bronchopulmonary aspergillosis, nebulized amphotericin B may prolong the time-to-exacerbation when used in patients experiencing frequent exacerbations.

Summary

The last decade has witnessed considerable progress in inhaled antifungals. Ongoing trials will likely offer hope for managing allergic and invasive pulmonary mycoses in the future.

Agarwal R, Sehgal IS, Dhooria S, Aggarwal AN. Challenging cases in fungal asthma. Med Mycol. 2019;57:S110-s117. https://doi.org/10.1093/mmy/myy063.CrossRefPubMed

Agarwal R, Denning DW, Chakrabarti A. Estimation of the burden of chronic and allergic pulmonary aspergillosis in India. PLoS ONE. 2014;9: e114745. https://doi.org/10.1371/journal.pone.0114745.CrossRefPubMedPubMedCentral

Muthu V, Agarwal R, Dhooria S, et al. Has the mortality from pulmonary mucormycosis changed over time? A systematic review and meta-analysis. Clin Microbiol Infect. 2021;27:538–49. https://doi.org/10.1016/j.cmi.2020.12.035.CrossRefPubMed

Cornely OA, Böhme A, Buchheidt D, et al. Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematologica. 2009;94:113–22. https://doi.org/10.3324/haematol.11665.CrossRefPubMed

Rijnders BJ, Cornelissen JJ, Slobbe L, et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008;46:1401–8. https://doi.org/10.1086/586739.CrossRefPubMed

Groll AH, Lyman CA, Petraitis V, et al. Compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations. Antimicrob Agents Chemother. 2006;50:3418–23. https://doi.org/10.1128/aac.00241-06.CrossRefPubMedPubMedCentral

Vogelsinger H, Weiler S, Djanani A, et al. Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J Antimicrob Chemother. 2006;57:1153–60. https://doi.org/10.1093/jac/dkl141.CrossRefPubMed

Hoenigl M, Sprute R, Egger M, et al. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs. 2021;81:1703–29. https://doi.org/10.1007/s40265-021-01611-0.CrossRefPubMedPubMedCentral

Barzen G, Beyer J, Farshidfar G, Kramp W, Richter W. Felix R [Prophylactic inhalation of amphotericin B in invasive aspergillosis: a distribution study]. Nuklearmedizin. 1993;32:82–6.CrossRefPubMed

10.

Niki Y, Bernard EM, Schmitt HJ, Tong WP, Edwards FF, Armstrong D. Pharmacokinetics of aerosol amphotericin B in rats. Antimicrob Agents Chemother. 1990;34:29–32. https://doi.org/10.1128/aac.34.1.29.CrossRefPubMedPubMedCentral

11.

Kilburn KH. The innocuousness and possible therapeutic use of aerosol amphotericin-B. Am Rev Respir Dis. 1959;80:441–2. https://doi.org/10.1164/arrd.1959.80.3.441.CrossRefPubMed

12.

Eisenberg RS, Oatway WH. Nebulization of amphotericin B. Am Rev Respir Dis. 1971;103:289–92. https://doi.org/10.1164/arrd.1971.103.2.289.CrossRefPubMed

13.

Mc KG, Medlock JM. Pulmonary moniliasis treated with nystatin aerosol. Lancet. 1958;1:621–2. https://doi.org/10.1016/s0140-6736(58)90872-9.CrossRef

14.

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: https://doi.org/10.1128/aac.02280-16.

15.

Kimura G, Nakaoki T, Colley T, et al. In vivo biomarker analysis of the effects of intranasally dosed PC945, a novel antifungal triazole, on Aspergillus fumigatus infection in immunocompromised mice. Antimicrob Agents Chemother. 2017; 61: https://doi.org/10.1128/aac.00124-17.

16.

Ito K. Inhaled antifungal therapy: benefits, challenges, and clinical applications. Expert Opin Drug Deliv. 2022;19:755–69. https://doi.org/10.1080/17425247.2022.2084530.CrossRefPubMed

17.•

Huggins JP, Pease R, Stanly K, Workman A, Reynolds J, Alexander BD. Safety of inhaled amphotericin B lipid complex as antifungal prophylaxis in lung transplant recipients. Antimicrob Agents Chemother. 2022;66: e0028322. https://doi.org/10.1128/aac.00283-22. A large study demonstrating the safety of amphotericin B lipid complex in lung transplant recipients.CrossRefPubMed

18.

Mikami M, Nakamura S, Kawakami M. Pulmonary aspergilloma successfully treated with long-term intermittent inhalation therapy with miconazole. Intern Med. 1993;32:247–50. https://doi.org/10.2169/internalmedicine.32.247.CrossRefPubMed

19.

Holle J, Leichsenring M, Meissner PE. Nebulized voriconazole in infections with Scedosporium apiospermum–case report and review of the literature. J Cyst Fibros. 2014;13:400–2. https://doi.org/10.1016/j.jcf.2013.10.014.CrossRefPubMed

20.

Solé A, García-Robles AA, Jordá C, et al. Salvage therapy with topical posaconazole in lung transplant recipients with invasive Scedosporium infection. Am J Transplant. 2018;18:504–9. https://doi.org/10.1111/ajt.14580.CrossRefPubMed

21.

Safdar A, O’Brien S, Kouri IF. Efficacy and feasibility of aerosolized amphotericin B lipid complex therapy in caspofungin breakthrough pulmonary zygomycosis. Bone Marrow Transplant. 2004;34:467–8. https://doi.org/10.1038/sj.bmt.1704552.CrossRefPubMed

22.

Gómez-Ganda L, Terradas-Campanario S, Campany-Herrero D. Physicochemical characterization of micafungin and anidulafungin for its nebulized administration. Farm Hosp. 2019;43:163–5. https://doi.org/10.7399/fh.11226.CrossRefPubMed

23.

Los-Arcos I, Berastegui C, Martín-Gómez MT, et al. Nebulized micafungin treatment for scopulariopsis/microascus tracheobronchitis in lung transplant recipients. Antimicrob Agents Chemother. 2021; 65: https://doi.org/10.1128/aac.02174-20.

24.

Yu IG, O’Brien SE, Ryckman DM. Pharmacokinetic and pharmacodynamic comparison of intravenous and inhaled caspofungin. J Aerosol Med Pulm Drug Deliv. 2021;34:197–203. https://doi.org/10.1089/jamp.2020.1645.CrossRefPubMed

25.••

Muthu V, Gogineni RR, Agarwal R, et al. Treatment of pulmonary mucormycosis with adjunctive nebulized amphotericin B (MUCONAB trial): results of an open-label randomized controlled trial. Mycoses. 2023;66:688–96. https://doi.org/10.1111/myc.13591. Randomized controlled trial comparing standard of care treatment with or without adjunctive nebulized amphotericin B in pulmonary mucormycosis. First RCT exclusively in pulmonary mucormycosis.CrossRefPubMed

26.

Agarwal R, Singh Sehgal I, Muthu V, et al. Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying, and treating allergic bronchopulmonary aspergillosis/mycoses. Eur Respir J. 2024; In press: https://doi.org/10.1183/13993003.00061-2024.

27.•

Fortun J, Gomez-García-de-la-Pedrosa E, Martínez-Lorca A, et al. A phase I/IIa prospective, randomized, open-label study on the safety and efficacy of nebulized liposomal amphotericin for invasive pulmonary aspergillosis. J Fungi (Basel). 2024;10:191. https://doi.org/10.3390/jof10030191. First randomized trial evaluating aersolized antifungal for invasive pulmonary aspergillosis in hemato-oncology patients.CrossRefPubMed

28.••

Godet C, Couturaud F, Marchand-Adam S, et al. Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial. Eur Respir J. 2022;59:2102218. https://doi.org/10.1183/13993003.02218-2021. A large single-blind multicenter randomized controlled trial evaluating maintenance therapy with nebulized liposomal amphotericin B in ABPA.CrossRefPubMed

29.

Currie DC, Lueck C, Milburn HJ, et al. Controlled trial of natamycin in the treatment of allergic bronchopulmonary aspergillosis. Thorax. 1990;45:447–50.CrossRefPubMedPubMedCentral

30.

A randomized, double blind, placebo-controlled, prospective, multicentre, phase 2, dose-finding study of itraconazole administered as a dry powder for inhalation (PUR1900) in adult subjects with asthma and allergic bronchopulmonary aspergillosis (ABPA). https://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NzY5MzY=&Enc=&userName=CTRI/2022/12/048206 Last accessed 5th March 2024.

31.

Hilberg O, Andersen CU, Henning O, Lundby T, Mortensen J, Bendstrup E. Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis. Eur Respir J. 2012;40:271–3. https://doi.org/10.1183/09031936.00163511.CrossRefPubMed

32.•

Murray A, Cass L, Ito K, et al. PC945, a novel inhaled antifungal agent, for the treatment of respiratory fungal infections. J Fungi (Basel). 2020; 6: https://doi.org/10.3390/jof6040373. Efficacy of a purpose-designed novel triazole (opelconazole) in two post-lung transplant patients with invasive pulmonary aspergillosis.

33.

Singh S, Moore LSP, Mughal N, Ho M, Armstrong-James D, Singh S. Novel inhaled antifungal for pseudomembranous Aspergillus tracheobronchitis complicating connective tissue disease. Thorax. 2023;78:110–1. https://doi.org/10.1136/thorax-2021-218375.CrossRefPubMed

34.

Singh D, Ravi A, Kane K, Schmalbach T, Hava DL. The pharmacokinetics, pharmacodynamics and tolerability of PUR0200, a novel tiotropium formulation, in chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2018;84:2097–105. https://doi.org/10.1111/bcp.13645.CrossRefPubMedPubMedCentral

35.•

Hava DL, Tan L, Johnson P, et al. A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics. Br J Clin Pharmacol. 2020;86:723–33. https://doi.org/10.1111/bcp.14166. Phase 1 study of inhalational itraconazole.CrossRefPubMedPubMedCentral

36.

Tolman JA, Nelson NA, Son YJ, et al. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution. Eur J Pharm Biopharm. 2009;72:199–205. https://doi.org/10.1016/j.ejpb.2008.12.014.CrossRefPubMed

37.

Rudramurthy SM, Colley T, Abdolrasouli A, et al. In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris. J Antimicrob Chemother. 2019;74:2943–9. https://doi.org/10.1093/jac/dkz280.CrossRefPubMedPubMedCentral

38.

Pagani N, Armstrong-James D, Reed A. Successful salvage therapy for fungal bronchial anastomotic infection after -lung transplantation with an inhaled triazole anti-fungal PC945. J Heart Lung Transplant. 2020;39:1505–6. https://doi.org/10.1016/j.healun.2020.09.015.CrossRefPubMed

39.

Cass L, Murray A, Davis A, et al. Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent. Pharmacol Res Perspect. 2021;9: e00690. https://doi.org/10.1002/prp2.690.CrossRefPubMed

40.

Ito K, Kizawa Y, Kimura G, et al. Relationship between anti-fungal effects and lung exposure of PC945, a novel inhaled antifungal agent, in Aspergillus fumigatus infected mice: Pulmonary PK-PD analysis of anti-fungal PC945. Eur J Pharm Sci. 2021;163: 105878. https://doi.org/10.1016/j.ejps.2021.105878.CrossRefPubMed

41.

Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:588–99. https://doi.org/10.1046/j.1365-2125.2003.01892.x.CrossRefPubMedPubMedCentral

42.

Le J, Schiller DS. Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep. 2010;4:96–102. https://doi.org/10.1007/s12281-010-0011-0.CrossRefPubMedPubMedCentral

43.

Le J, Ashley ED, Neuhauser MM, et al. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010;30:562–84. https://doi.org/10.1592/phco.30.6.562.CrossRefPubMed

44.

Otu AA, Langridge P, Denning DW. An evaluation of nebulised amphotericin B deoxycholate (Fungizone(®) ) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre. Mycoses. 2019;62:1049–55. https://doi.org/10.1111/myc.12996.CrossRefPubMed

45.

Umemura K, Katada Y, Nakagawa S, et al. Comparison of the safety and cost-effectiveness of nebulized liposomal amphotericin B and amphotericin B deoxycholate for antifungal prophylaxis after lung transplantation. J Infect Chemother. 2024. https://doi.org/10.1016/j.jiac.2024.02.010.CrossRefPubMed

46.

Marinelli T, Davoudi S, Foroutan F, Orchanian-Cheff A, Husain S. Antifungal prophylaxis in adult lung transplant recipients: uncertainty despite 30 years of experience A systematic review of the literature and network meta-analysis. Transpl Infect Dis. 2022;24:e13832. https://doi.org/10.1111/tid.13832.CrossRefPubMed

47.

Hagiya H, Nishimura Y, Otsuka F. Safety and usefulness of nebulized liposomal amphotericin B: systematic scoping review. Pulm Pharmacol Ther. 2023;82: 102233. https://doi.org/10.1016/j.pupt.2023.102233.CrossRefPubMed

48.

Muthu V, Agarwal R, Patel A, et al. Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India. Lancet Infect Dis. 2022;22:e240–53. https://doi.org/10.1016/s1473-3099(22)00124-4.CrossRefPubMedPubMedCentral

49.

Pulle MV, Puri HV, Asaf BB, Bishnoi S, Sharma S, Kumar A. Outcomes of early anti-fungal therapy with aggressive surgical resection in pulmonary mucormycosis. Lung India. 2021;38:314–20. https://doi.org/10.4103/lungindia.lungindia_758_20.CrossRefPubMedPubMedCentral

50.

Patel A, Kaur H, Xess I, et al. A multicentre observational study on the epidemiology, risk factors, management and outcomes of mucormycosis in India. Clin Microbiol Infect. 2020;26(944):e949-944.e915. https://doi.org/10.1016/j.cmi.2019.11.021.CrossRef

51.•

Ray A, Manikanta J, Singh K, et al. An open-label non-inferiority randomised control trial comparing nebulised amphotericin B with oral itraconazole in patients with pulmonary aspergilloma. Mycoses. 2021;64:1038–44. https://doi.org/10.1111/myc.13329. A small randomized trial comparing nebulized amphotericin B with oral itraconazole in chronic pulmonary aspergillosis.CrossRefPubMed

52.

Ram B, Aggarwal AN, Dhooria S, et al. A pilot randomized trial of nebulized amphotericin in patients with allergic bronchopulmonary aspergillosis. J Asthma. 2016;53:517–24. https://doi.org/10.3109/02770903.2015.1127935.CrossRefPubMed

53.

Damaraju V, Agarwal R, Dhooria S, et al. Isolated tracheobronchial mucormycosis: report of a case and systematic review of literature. Mycoses. 2023;66:5–12. https://doi.org/10.1111/myc.13519.CrossRefPubMed

54.

Al Yazidi LS, Huynh J, Britton PN, et al. Endobronchial fusariosis in a child following bilateral lung transplant. Med Mycol Case Rep. 2019;23:77–80. https://doi.org/10.1016/j.mmcr.2019.01.002.CrossRefPubMedPubMedCentral

55.

Pruthi H, Muthu V, Bhujade H, et al. Pulmonary artery pseudoaneurysm in COVID-19-associated pulmonary mucormycosis: case series and systematic review of the literature. Mycopathologia. 2022;187:31–7. https://doi.org/10.1007/s11046-021-00610-9.CrossRefPubMed

56.

Sehgal IS, Dhooria S, Muthu V, et al. Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India. Lancet Infect Dis. 2022;22:1052–61. https://doi.org/10.1016/s1473-3099(22)00057-3.CrossRefPubMed

57.

Sehgal IS, Dhooria S, Prasad KT, et al. Anti-fungal agents in the treatment of chronic pulmonary aspergillosis: systematic review and a network meta-analysis. Mycoses. 2021;64:1053–61. https://doi.org/10.1111/myc.13324.CrossRefPubMed

58.

Maeda T. A case of chronic necrotizing pulmonary aspergillosis effectively treated with miconazole inhalation. Nihon Kyobu Shikkan Gakkai Zasshi. 1994;32:168–73.PubMed

59.

Sato A, Nakatani K, Matsushita Y, et al. Chronic necrotizing pulmonary aspergillosis treated with itraconazole and inhaled amphotericin B. Nihon Kyobu Shikkan Gakkai Zasshi. 1995;33:1141–5.PubMed

60.

Diot P, Rivoire B, Le Pape A, et al. Deposition of amphotericin B aerosols in pulmonary aspergilloma. Eur Respir J. 1995;8:1263–8. https://doi.org/10.1183/09031936.95.08081263.CrossRefPubMed

61.

Agarwal R, Muthu V, Sehgal IS, Dhooria S, Prasad KT, Aggarwal AN. Allergic bronchopulmonary aspergillosis. Clin Chest Med. 2022;43:99–125. https://doi.org/10.1016/j.ccm.2021.12.002.CrossRefPubMed

62.•

Agarwal R, Aggarwal AN, Dhooria S, et al. A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Eur Respir J. 2016;47:490–8. https://doi.org/10.1183/13993003.01475-2015. Randomized trial evaluating the efficacy and safety of two glucocorticoid protocols in ABPA.CrossRefPubMed

63.••

Agarwal R, Dhooria S, Singh Sehgal I, et al. A randomized trial of itraconazole vs prednisolone in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Chest. 2018;153:656–64. https://doi.org/10.1016/j.chest.2018.01.005. First RCT comparing itraconazole monotherapy and prednisolone in ABPA.CrossRefPubMed

64.

Henderson AH, Pearson JE. Treatment of bronchopulmonary aspergillosis with observations on the use of natamycin. Thorax. 1968;23:519–23. https://doi.org/10.1136/thx.23.5.519.CrossRefPubMedPubMedCentral

65.

Slavin RG, Stanczyk DJ, Lonigro AJ, Broun GO. Allergic bronchopulmonary aspergillosis–a North American Rarity. Clinical and immunologic characteristics. Am J Med. 1969;47:306–13. https://doi.org/10.1016/0002-9343(69)90156-9.CrossRefPubMed

66.

Sehgal IS, Agarwal R. Role of inhaled amphotericin in allergic bronchopulmonary aspergillosis. J Postgrad Med. 2014;60:41–5. https://doi.org/10.4103/0022-3859.128806.CrossRefPubMed

67.

Chishimba L, Langridge P, Powell G, Niven RM, Denning DW. Efficacy and safety of nebulised amphotericin B (NAB) in severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). J Asthma. 2015;52:289–95. https://doi.org/10.3109/02770903.2014.958853.CrossRefPubMed

68.

Godet C, Goudet V, Laurent F, et al. Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review. Mycoses. 2015;58:173–80. https://doi.org/10.1111/myc.12294.CrossRefPubMed

69.

Muthu V, Dhooria S, Sehgal IS, et al. Nebulized amphotericin B for preventing exacerbations in allergic bronchopulmonary aspergillosis: a systematic review and meta-analysis. Pulm Pharmacol Ther. 2023;81: 102226. https://doi.org/10.1016/j.pupt.2023.102226.CrossRefPubMed

Title: Aerosolized Antifungals for the Treatment of Pulmonary Fungal Diseases
Authors: Valliappan Muthu
Inderpaul Singh Sehgal
Ritesh Agarwal
Publication date: 01-04-2024
Publisher: Springer US
Keywords: Amphotericin B
Itraconazole
Aspergillosis
Voriconazole
Published in: Current Fungal Infection Reports
Print ISSN: 1936-3761
Electronic ISSN: 1936-377X
DOI: https://doi.org/10.1007/s12281-024-00495-3

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