We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Off-label treatments as potential accelerators in the search for the ideal antifungal treatment of cryptococcosis

    Vinicius Alves

    Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941902, Brazil

    ,
    Glauber RS Araújo

    Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941902, Brazil

    &
    Susana Frases

    *Author for correspondence: Tel.: +55 213 938 6593;

    E-mail Address: susanafrases@biof.ufrj.br

    Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941902, Brazil

    Published Online:https://doi.org/10.2217/fmb-2022-0122

    Cryptococcosis is an opportunistic mycosis that mainly affects immunosuppressed patients. The treatment is a combination of three antifungal agents: amphotericin B, 5-flucytosine and fluconazole. However, these drugs have many disadvantages, such as high nephrotoxicity, marketing bans in some countries and fungal resistance. One of the solutions to find possible new drugs is pharmacological repositioning. This work presents repositioned drugs as an alternative for new antifungal therapies for cryptococcosis. All the studies here were performed in vitro or in animal models, except for sertraline, which reached phase III in humans. There is still no pharmacological repositioning approval for cryptococcosis in humans, though this review shows the potential of repurposing as a rapid approach to finding new agents to treat cryptococcosis.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Almeida F, Rodrigues ML, Coelho C. The still underestimated problem of fungal diseases worldwide. Front. Microbiol. 10, 214–216 (2019). • The authors suggest the urgent need for more attention to the biology and pathogenesis of fungi worldwide, with special attention to diseases affecting developing countries, as a safeguard for preventing agricultural losses, environmental losses and harm to human health.
    • 2. Gnat S, Łagowski D, Nowakiewicz A, Dyląg M. A global view on fungal infections in humans and animals: infections caused by dimorphic fungi and dermatophytoses. J. Appl. Microbiol. 131(6), 2688–2704 (2021).
    • 3. Borba HHL, Steimbach LM, Riveros BS et al. Cost–effectiveness of amphotericin B formulations in the treatment of systemic fungal infections. Mycoses 61(10), 754–763 (2018).
    • 4. Wasilczuk K, Korzeniewski K. Immunocompromised travellers. Int. Marit. Health 68(4), 229–237
    • 5. Segrelles-Calvo G, de S Araújo GR, Frases S. Systemic mycoses: a potential alert for complications in COVID-19 patients. Future Microbiol. 15(14), 1405–1413 (2020).
    • 6. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA 324(13), 1330–1341 (2020). • This analysis shows the importance of immunosuppression in the treatment of COVID-19 as a perfect scenario for the development of opportunistic mycoses
    • 7. Sinha P, Matthay MA, Calfee CS. Is a ‘cytokine storm’ relevant to COVID-19? JAMA Intern. Med. 180(9), 1152 (2020).
    • 8. Segrelles‐Calvo G, Araújo GRS, Llopis‐Pastor E et al. Prevalence of opportunistic invasive aspergillosis in COVID‐19 patients with severe pneumonia. Mycoses 64(2), 144–151 (2021).
    • 9. Idnurm A, Bahn Y-S, Nielsen K, Lin X, Fraser JA, Heitman J. Deciphering the model pathogenic fungus Cryptococcus neoformans. Nat. Rev. Microbiol. 3(10), 753–764 (2005).
    • 10. Chayakulkeeree M, Perfect J. Cryptococcosis. Infectious Disease: Diagnosis and Treament of Human Mycoses. © Springer Nature Switzerland AG., 255–276 (2008).
    • 11. Tsiodras S, Papageorgiou S, Meletiadis J et al. Rhodotorula mucilaginosa associacted meningitis: a subacute entity with high mortality. Case report and review. Med. Mycol. Case Rep. 6, 46–50 (2014).
    • 12. Reboli AC, Shorr AF, Rotstein C et al. Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome. BMC Infect. Dis. 11(1), 261 (2011).
    • 13. Rajasingham R, Smith RM, Park BJ et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect. Dis. 17(8), 873–881 (2017).
    • 14. Idnurm A, Bahn Y-S, Nielsen K, Lin X, Fraser JA, Heitman J. Deciphering the model pathogenic fungus Cryptococcus neoformans. Nat. Rev. Microbiol. 3(10), 753–764 (2005).
    • 15. Krysan DJ. Toward improved anti-cryptococcal drugs: novel molecules and repurposed drugs. Fungal Genet. Biol. 78, 93–98 (2015). •• The article presents the features of an ideal anticryptococcal agent and review current advance for identifying both novel and repurposed drugs as potential new therapies.
    • 16. Micallef C, Aliyu SH, Santos R, Brown NM, Rosembert D, Enoch DA. Introduction of an antifungal stewardship programme targeting high-cost antifungals at a tertiary hospital in Cambridge, England. J. Antimicrob. Chemother. 70(6), 1908–1911 (2015).
    • 17. Sloan DJ, Dedicoat MJ, Lalloo DG. Treatment of cryptococcal meningitis in resource limited settings. Curr. Opin. Infect. Dis. 22(5), 455–463 (2009).
    • 18. Chang Y-L, Yu S-J, Heitman J, Wellington M, Chen Y-L. New facets of antifungal therapy. Virulence 8(2), 222–236 (2017). • The authors show an analysis performed to guide optimal treatment of cryptococcal meningitis within resource constraints.
    • 19. World Health Organization. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva, Switzerland (2018). •• Official guide for managing cryptococcal disease.
    • 20. Oprea TI, Mestres J. Drug repurposing: far beyond new targets for old drugs. AAPS J. 14(4), 759–763 (2012).
    • 21. Ribeiro NQ, Santos APN, Emídio ECP et al. Pioglitazone as an adjuvant of amphotericin B for the treatment of cryptococcosis. Int. J. Antimicrob. Agents 54(3), 301–308 (2019).
    • 22. Ribeiro N de Q, Costa MC, Magalhães TFF et al. Atorvastatin as a promising anticryptococcal agent. Int. J. Antimicrob. Agents 49(6), 695–702 (2017).
    • 23. Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob. Agents Chemother. 56(7), 3758–3766 (2012).
    • 24. Delattin N, de brucker K, Vandamme K et al. Repurposing as a means to increase the activity of amphotericin B and caspofungin against Candida albicans biofilms. J. Antimicrob. Chemother. 69(4), 1035–1044 (2014).
    • 25. Butts A, Krysan DJ. Antifungal drug discovery: something old and something new. PLoS Pathog. 8(9), e1002870 (2012).
    • 26. Ogundeji AO, Pohl CH, Sebolai OM. Repurposing of aspirin and ibuprofen as candidate anti-Cryptococcus drugs. Antimicrob. Agents Chemother. 60(8), 4799–4808 (2016).
    • 27. Ribeiro N de Q, Costa MC, Magalhães TFF et al. Atorvastatin as a promising anticryptococcal agent. Int. J. Antimicrob. Agents 49(6), 695–702 (2017).
    • 28. Fuchs BB, RajaMuthiah R, Souza ACR et al. Inhibition of bacterial and fungal pathogens by the orphaned drug auranofin. Future Med. Chem. 8(2), 117–132 (2016).
    • 29. Oliveira EAM, Ferreira GF, Lang KL. Drug repositioning of benzimidazole anthelmintics in the treatment of cryptococcosis: a review. Med. Chem. Res. 31(1), 26–39 (2022).
    • 30. Joffe LS, Schneider R, Lopes W et al. The anti-helminthic compound mebendazole has multiple antifungal effects against Cryptococcus neoformans. Front. Microbiol. 8, 535 (2017).
    • 31. Magalhães TFF, Costa MC, Holanda RA et al. N-acetylcysteine reduces amphotericin B deoxycholate nephrotoxicity and improves the outcome of murine cryptococcosis. Med. Mycol. 58(6), 835–844 (2020).
    • 32. Ogundeji AO, Pohl CH, Sebolai OM. The repurposing of anti-psychotic drugs, quetiapine and olanzapine, as anti-Cryptococcus drugs. Front. Microbiol. 8, 815–826 (2017).
    • 33. Brilhante RSN, Caetano EP, de Oliveira JS et al. Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species. Braz. J. Infect. Dis. 19(5), 459–465 (2015).
    • 34. Hai TP, Van AD, Ngan NTT et al. The combination of tamoxifen with amphotericin B, but not with fluconazole, has synergistic activity against the majority of clinical isolates of Cryptococcus neoformans. Mycoses 62(9), 818–825 (2019).
    • 35. Ko H-T, Hsu L-H, Yang S-Y, Chen Y-L. Repurposing the thrombopoietin receptor agonist eltrombopag as an anticryptococcal agent. Med. Mycol. 58(4), 493–504 (2019).
    • 36. Butts A, Koselny K, Chabrier-Roselló Y et al. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio 5(1), e00765–13 (2014).
    • 37. Rollini MMM. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl. Microbiol. Biotechnol. 58(5), 555–564 (2002).
    • 38. Hilal-DandanR, KnollmannB, BruntonL. Goodman and Gilman's the Pharmacological Basis of Therapeutics (13th Edition). McGraw Hill, NY, USA (2017).
    • 39. Manzoni M, Rollini M. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl. Microbiol. Biotechnol. 58(5), 555–564 (2002).
    • 40. Jia M, Huang W, Li L, Xu Z, Wu L. Statins reduce mortality after non-severe but not after severe pneumonia: a systematic review and meta-analysis. J. Pharm. Pharm. Sci. 18(3), 286–302 (2015).
    • 41. Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sørensen HT. Preadmission use of statins and outcomes after hospitalization with pneumonia population-based cohort study of 29,900 patients. Arch. Intern. Med. 168(19), 2081–2087 (2008).
    • 42. Cruz MC, Bartlett MS, Edlind TD. In vitro susceptibility of the opportunistic fungus Cryptococcus neoformans to anthelmintic benzimidazoles. Antimicrob. Agents Chemother. 38(2), 378–380 (1994).
    • 43. Bai RY, Staedtke V, Wanjiku T et al. Brain penetration and efficacy of different mebendazole polymorphs in a mouse brain tumor model. Clin. Cancer Res. 21(15), 3462–3470 (2015).
    • 44. Cruz MC, Edlind T. β-Tubulin genes and the basis for benzimidazole sensitivity of the opportunistic fungus Cryptococcus neoformans. Microbiology (NY) 143(6), 2003–2008 (1997).
    • 45. Palacio JR, Markert UR, Martínez P. Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm. Res. 60(7), 695–704 (2011).
    • 46. Uraz S, Tahan G, Aytekin H, Tahan V. N-acetylcysteine expresses powerful anti-inflammatory and antioxidant activities resulting in complete improvement of acetic acid-induced colitis in rats. Scand. J. Clin. Lab. Invest. 73(1), 61–66 (2013).
    • 47. Jones AL. Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review. J. Toxicol. Clin. Toxicol. 36(4), 277–285 (1998).
    • 48. Bachert C, Hörmann K, Mösges R et al. An update on the diagnosis and treatment of sinusitis and nasal polyposis. Allergy 58(3), 176–191 (2003).
    • 49. Casadevall A, Coelho C, Cordero RJB et al. The capsule of Cryptococcus neoformans. Virulence 10(1), 822–831 (2019).
    • 50. Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev. Iberoam. Micol. 26(4), 223–227 (2009).
    • 51. Aberg-Wistedt A. The antidepressant effects of 5-HT uptake inhibitors. Br. J. Psychiatry 155(Suppl. 8), 32–40 (1989).
    • 52. Young TJ, Oliver GP, Pryde D, Perros M, Parkinson T. Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity. J. Antimicrob. Chemother. 51(4), 1045–1047 (2003).
    • 53. Rainey MM, Korostyshevsky D, Lee S, Perlstein EO. The antidepressant sertraline targets intracellular vesiculogenic membranes in yeast. Genetics 185(4), 1221–1233 (2010).
    • 54. Spitzer M, Griffiths E, Blakely KM et al. Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol. Syst. Biol. 7(499), 1–14 (2011).
    • 55. Nayak R, Xu J. Effects of sertraline hydrochloride and fluconazole combinations on Cryptococcus neoformans and Cryptococcus gattii. Mycology 1(2), 99–105 (2010).
    • 56. Katende A, Mbwanji G, Faini D et al. Short-course amphotericin B in addition to sertraline and fluconazole for treatment of HIV-associated cryptococcal meningitis in rural Tanzania. Mycoses 62(12), 1127–1132 (2019).
    • 57. Villanueva-Lozano H, Treviño-Rangel R de J, González GM et al. Clinical evaluation of the antifungal effect of sertraline in the treatment of cryptococcal meningitis in HIV patients: a single Mexican center experience. Infection 46(1), 25–30 (2018).
    • 58. Rhein J, Huppler Hullsiek K, Tugume L et al. Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. Lancet Infect. Dis. 19(8), 843–851 (2019).
    • 59. Dolan K, Montgomery S, Buchheit B, DiDone L et al. Antifungal activity of tamoxifen: in vitro and in vivo activities and mechanistic characterization. Antimicrob. Agents Chemother. 53(8), 3337–3346 (2009).
    • 60. Cheng G. Eltrombopag, a thrombopoietin-receptor agonist in the treatment of adult chronic immune thrombocytopenia: a review of the efficacy and safety profile. Ther. Adv. Hematol. 3(3), 155–164 (2012).
    • 61. Dihazi H, Kessler R, Eschrich K. High osmolarity glycerol (HOG) pathway-induced phosphorylation and activation of 6-phosphofructo-2-kinase are essential for glycerol accumulation and yeast cell proliferation under hyperosmotic stress. J. Biol. Chem. 279(23), 23961–23968 (2004).
    • 62. Silva-Abreu M, Espinoza L, Rodríguez-Lagunas M et al. Human skin permeation studies with PPARγ agonist to improve its permeability and efficacy in inflammatory processes. Int. J. Mol. Sci. 18(12), 2548 (2017).
    • 63. Serghides L, McDonald CR, Lu Z et al. PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria. PLoS Pathog. 10(3), e1003980 (2014).
    • 64. Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2(10), 748–759 (2002).
    • 65. Schlottfeldt S, Fernandes M, Martins M, Fonseca D et al. Prevention of amphotericin B nephrotoxicity through use of phytotherapeutic medication. Rev. Esc. Enferm. USP doi:10.1590/S0080-623420150000700011 (2015).
    • 66. Gardner DM. Modern antipsychotic drugs: a critical overview. Can. Med. Assoc. J. 172(13), 1703–1711 (2005).
    • 67. Suarez-Almazor ME, Spooner CH, Belseck E, Shea B. Auranofin versus placebo in rheumatoid arthritis. Cochrane Database Syst. Rev. 1(2), CD002048–CD002077 (2000).