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RESEARCH ARTICLE

Insights into the global emergence of antifungal drug resistance

Kylie Boyce A D , Orla Morrissey B , Alexander Idnurm C and Ian Macreadie A
+ Author Affiliations
- Author Affiliations

A School of Science, RMIT University, Bundoora, Vic. 3083, Australia

B Department of Infectious Diseases, The Alfred Hospital, Melbourne, Vic. 3004, Australia

C School of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia

D Tel: +61 3 9925 7101, Email: kylie.boyce@rmit.edu.au

Microbiology Australia 40(2) 87-91 https://doi.org/10.1071/MA19024
Published: 18 April 2019

Abstract

The global prevalence of fungal diseases has escalated in the last several decades. Currently, it is estimated that fungi infect 1.7 billion people annually and result in 1.5 million deaths every year1. Deaths due to fungal infections are increasing, with mortality often exceeding 50%, further increasing to 100% if treatment is delayed1. Despite these staggering figures, the contribution of fungal infections to the global burden of disease remains under-recognised. In Australia, over a 5-year period fungal infections cost Australia an estimated $583 million2. The median cost for one invasive fungal disease (IFD) is AU$30957, increasing to AU$80291 if the patient is admitted to an intensive care unit3. Treatment of fungal infections poses significant challenges due to the small number of safe and effective antifungal drugs available and emerging antifungal drug resistance. Resistance to every class of antifungal drugs has been described and for some drug classes is extremely common4,5.


References

[1]  Brown, G.D. et al. (2012) Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv13.
Hidden killers: human fungal infections.Crossref | GoogleScholarGoogle Scholar | 23253612PubMed |

[2]  Slavin, M. et al. (2004) Burden of hospitalization of patients with Candida and Aspergillus infections in Australia. Int. J. Infect. Dis. 8, 111–120.
Burden of hospitalization of patients with Candida and Aspergillus infections in Australia.Crossref | GoogleScholarGoogle Scholar | 14732329PubMed |

[3]  Ananda-Rajah, M.R. et al. (2011) Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach. Antimicrob. Agents Chemother. 55, 1953–1960.
Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach.Crossref | GoogleScholarGoogle Scholar | 21357302PubMed |

[4]  Beardsley, J. et al. (2018) Responding to the emergence of antifungal drug resistance: perspectives from the bench and the bedside. Future Microbiol. 13, 1175–1191.
Responding to the emergence of antifungal drug resistance: perspectives from the bench and the bedside.Crossref | GoogleScholarGoogle Scholar | 30113223PubMed |

[5]  Gamaletsou, M.N. et al. (2018) Invasive fungal infections in patients with hematological malignancies: Emergence of resistant pathogens and new antifungal therapies. Turk. J. Haematol. 35, 1–11.
Invasive fungal infections in patients with hematological malignancies: Emergence of resistant pathogens and new antifungal therapies.Crossref | GoogleScholarGoogle Scholar | 29391334PubMed |

[6]  Rhodes, J. et al. (2018) Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris. Emerg. Microbes Infect. 7, 43.
| 29593275PubMed |

[7]  Heath, C.H. et al. (2019) Candida auris sternal osteomyelitis in a man from Kenya visiting Australia, 2015. Emerg. Infect. Dis. 25, 192–194.
Candida auris sternal osteomyelitis in a man from Kenya visiting Australia, 2015.Crossref | GoogleScholarGoogle Scholar | 30561310PubMed |

[8]  Slavin, M.A. and Chakrabarti, A. (2012) Opportunistic fungal infections in the Asia-Pacific region. Med. Mycol. 50, 18–25.
Opportunistic fungal infections in the Asia-Pacific region.Crossref | GoogleScholarGoogle Scholar | 21905945PubMed |

[9]  Selmecki, A. et al. (2008) An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol. Microbiol. 68, 624–641.
An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1.Crossref | GoogleScholarGoogle Scholar | 18363649PubMed |

[10]  Sionov, E. et al. (2010) Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 6, e1000848.
Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes.Crossref | GoogleScholarGoogle Scholar | 20368972PubMed |

[11]  Almeida, A.M. et al. (2007) Molecular typing and antifungal susceptibility of clinical sequential isolates of Cryptococcus neoformans from Sao Paulo State, Brazil. FEMS Yeast Res. 7, 152–164.
Molecular typing and antifungal susceptibility of clinical sequential isolates of Cryptococcus neoformans from Sao Paulo State, Brazil.Crossref | GoogleScholarGoogle Scholar | 17311593PubMed |

[12]  Morrow, C.A. and Fraser, J.A. (2013) Ploidy variation as an adaptive mechanism in human pathogenic fungi. Semin. Cell Dev. Biol. 24, 339–346.
Ploidy variation as an adaptive mechanism in human pathogenic fungi.Crossref | GoogleScholarGoogle Scholar | 23380396PubMed |

[13]  Sanguinetti, M. et al. (2015) Antifungal drug resistance among Candida species: mechanisms and clinical impact. Mycoses 58, 2–13.
Antifungal drug resistance among Candida species: mechanisms and clinical impact.Crossref | GoogleScholarGoogle Scholar | 26033251PubMed |

[14]  Rodero, L. et al. (2003) G484S amino acid substitution in lanosterol 14-α demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrob. Agents Chemother. 47, 3653–3656.
G484S amino acid substitution in lanosterol 14-α demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate.Crossref | GoogleScholarGoogle Scholar | 14576140PubMed |

[15]  Morio, F. et al. (2010) Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn. Microbiol. Infect. Dis. 66, 373–384.
Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature.Crossref | GoogleScholarGoogle Scholar | 20226328PubMed |

[16]  Chowdhary, A. et al. (2014) Azole-resistant Aspergillus fumigatus with the environmental TR46/Y121F/T289A mutation in India. J. Antimicrob. Chemother. 69, 555–557.
Azole-resistant Aspergillus fumigatus with the environmental TR46/Y121F/T289A mutation in India.Crossref | GoogleScholarGoogle Scholar | 24084639PubMed |

[17]  Chowdhary, A. et al. (2013) Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog. 9, e1003633.
Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health.Crossref | GoogleScholarGoogle Scholar | 24204249PubMed |

[18]  Gsaller, F. et al. (2016) Sterol biosynthesis and azole tolerance is governed by the opposing actions of SrbA and the CCAAT binding complex. PLoS Pathog. 12, e1005775.
Sterol biosynthesis and azole tolerance is governed by the opposing actions of SrbA and the CCAAT binding complex.Crossref | GoogleScholarGoogle Scholar | 27973537PubMed |

[19]  Whaley, S.G. and Rogers, P.D. (2016) Azole resistance in Candida glabrata. Curr. Infect. Dis. Rep. 18, 41.
Azole resistance in Candida glabrata.Crossref | GoogleScholarGoogle Scholar | 27761779PubMed |

[20]  Yamada, T. et al. (2017) Terbinafine resistance of Trichophyton clinical isolates caused by specific point mutations in the squalene epoxidase gene. Antimicrob. Agents Chemother. 61, e00115-17.
Terbinafine resistance of Trichophyton clinical isolates caused by specific point mutations in the squalene epoxidase gene.Crossref | GoogleScholarGoogle Scholar | 28416557PubMed |

[21]  Kelly, S.L. et al. (1994) Resistance to amphotericin B associated with defective sterol delta 8-->7 isomerase in a Cryptococcus neoformans strain from an AIDS patient. FEMS Microbiol. Lett. 122, 39–42.
Resistance to amphotericin B associated with defective sterol delta 8-->7 isomerase in a Cryptococcus neoformans strain from an AIDS patient.Crossref | GoogleScholarGoogle Scholar | 7958776PubMed |

[22]  Maligie, M.A. and Selitrennikoff, C.P. (2005) Cryptococcus neoformans resistance to echinocandins: (1,3)β-glucan synthase activity is sensitive to echinocandins. Antimicrob. Agents Chemother. 49, 2851–2856.
Cryptococcus neoformans resistance to echinocandins: (1,3)β-glucan synthase activity is sensitive to echinocandins.Crossref | GoogleScholarGoogle Scholar | 15980360PubMed |

[23]  Chapman, B. et al. (2017) Changing epidemiology of candidaemia in Australia. J. Antimicrob. Chemother. 72, 1270.
Changing epidemiology of candidaemia in Australia.Crossref | GoogleScholarGoogle Scholar | 28204502PubMed |

[24]  Bongomin, F. et al. (2017) Global and multi-national prevalence of fungal diseases—estimate precision. J. Fungi (Basel) 3, 57.
Global and multi-national prevalence of fungal diseases—estimate precision.Crossref | GoogleScholarGoogle Scholar |

[25]  Meis, J.F. et al. (2016) Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20150460..
| 28080986PubMed |

[26]  Verweij, P.E. et al. (2009) Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect. Dis. 9, 789–795.
Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use?Crossref | GoogleScholarGoogle Scholar | 19926038PubMed |

[27]  Bidaud, A.L. et al. (2018) Candida auris: an emerging drug resistant yeast – a mini-review. J. Mycol. Med. 28, 568–573.
Candida auris: an emerging drug resistant yeast – a mini-review.Crossref | GoogleScholarGoogle Scholar | 30030072PubMed |

[28]  Healey, K.R. et al. (2016) Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat. Commun. 7, 11128.
Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.Crossref | GoogleScholarGoogle Scholar | 27020939PubMed |

[29]  Boyce, K.J. et al. (2017) Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans. MBio 8, e00595-17.
Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans.Crossref | GoogleScholarGoogle Scholar | 28559486PubMed |

[30]  Singh, A. et al. (2018) Absence of azole or echinocandin resistance in Candida glabrata isolates in India despite background prevalence of strains with defects in the DNA mismatch repair pathway. Antimicrob. Agents Chemother. 62, e00195-e18.
Absence of azole or echinocandin resistance in Candida glabrata isolates in India despite background prevalence of strains with defects in the DNA mismatch repair pathway.Crossref | GoogleScholarGoogle Scholar | 30082281PubMed |

[31]  Dellière, S. et al. (2016) Fluconazole and echinocandin resistance of Candida glabrata correlates better with antifungal drug exposure rather than with MSH2 mutator genotype in a French cohort of patients harboring low rates of resistance. Front. Microbiol. 7, 2038.
Fluconazole and echinocandin resistance of Candida glabrata correlates better with antifungal drug exposure rather than with MSH2 mutator genotype in a French cohort of patients harboring low rates of resistance.Crossref | GoogleScholarGoogle Scholar | 28066361PubMed |

[32]  Byun, S.A. et al. (2018) Multilocus sequence typing (MLST) genotypes of Candida glabrata bloodstream isolates in Korea: association with antifungal resistance, mutations in mismatch repair gene (Msh2), and clinical outcomes. Front. Microbiol. 9, 1523.
Multilocus sequence typing (MLST) genotypes of Candida glabrata bloodstream isolates in Korea: association with antifungal resistance, mutations in mismatch repair gene (Msh2), and clinical outcomes.Crossref | GoogleScholarGoogle Scholar | 30057573PubMed |

[33]  Shor, E. et al. (2019) A novel, drug resistance-independent, fluorescence-based approach to measure mutation rates in microbial pathogens. MBio 10, e00120-19.
A novel, drug resistance-independent, fluorescence-based approach to measure mutation rates in microbial pathogens.Crossref | GoogleScholarGoogle Scholar | 30808701PubMed |

[34]  Rhodes, J. et al. (2017) A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection. G3 (Bethesda) 7, 1165–1176.
A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection.Crossref | GoogleScholarGoogle Scholar | 28188180PubMed |