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Antifungal azoles and azole resistance in the environment: current status and future perspectives—a review

Abstract

Following their extensive use, azole antifungals may enter the environment through the discharge of domestic, industrial and hospital wastewaters, agricultural runoffs and as leachates in waste-disposal sites. The presence of the azole antifungals poses potential toxicity risks to non-target organisms and plays a critical role in the evolution and/or selection of azole resistant fungal strains in the environment. Toxicities such as inhibition of algal growth, endocrine disruption in fish, CYP450-effected steroidogenesis, modulating sex differentiation in frogs, and reduction of larval body mass and growth rate have been related to azole antifungals. In addition, the isolation of azole resistant fungi such as Aspergillus fumigatus in both the environment and clinic retaining similar mode of molecular drug resistance mechanism has drawn the attention of many researchers. Therefore, the investigation of the occurrence and distribution of azole antifungals as well as azole resistant environmental isolates of fungi is becoming a trendy research venue. Here we review the occurrence of antifungal azoles and azole resistance in the environment. The major points discussed are (1) an update on the environmental occurrence, distribution and ecological risks of the most commonly used azole antifungals in the environment including surface water and drinking water (2) environmental azole antifungal resistance, predominant molecular mechanisms of azole resistance in the environment, and the implications for human health (3) future trends and perspectives that could help reduce the ecological and human health risks of azoles and tackle the spread of azole resistance in the environment, and hence in the clinic.

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References

  1. Abastabar M et al (2019) Novel point mutations in cyp51A and cyp51B genes associated with itraconazole and posaconazole resistance in Aspergillus clavatus isolates. Microb Drug Resist 25:652–662

    CAS  Article  Google Scholar 

  2. Africa CWJ, dos Santos Abrantes PM (2016) Candida antifungal drug resistance in sub-Saharan African populations: a systematic review. F1000Res 5:2832

    Article  Google Scholar 

  3. Alastruey-Izquierdo A, Melhem MS, Bonfietti LX, Rodriguez-Tudela JL (2015) Susceptibility test for fungi: clinical and laboratorial correlations in medical mycology. Rev Inst Med Trop Sao Paulo 57:57–64

    CAS  Article  Google Scholar 

  4. Alvarez-Moreno C, Lavergne R-A, Hagen F, Morio F, Meis JF, Le Pape P (2019) Fungicide-driven alterations in azole-resistant Aspergillus fumigatus are related to vegetable crops in Colombia, South America. Mycologia 111:217–224

    CAS  Article  Google Scholar 

  5. Anderson JB (2005) Evolution of antifungal-drug resistance: mechanisms and pathogen fitness nature. Rev Microbiol 3:547–556

    CAS  Google Scholar 

  6. Ankley GT et al (2007) Ketoconazole in the fathead minnow (Pimephales promelas): reproductive toxicity and biological compensation. Environ Toxicol Chem 26:1214–1223. https://doi.org/10.1897/06-428r.1

    CAS  Article  Google Scholar 

  7. Ankley GT et al (2012) A time-course analysis of effects of the steroidogenesis inhibitor ketoconazole on components of the hypothalamic-pituitary-gonadal axis of fathead minnows. Aquat Toxicol 114–115:88–95. https://doi.org/10.1016/j.aquatox.2012.02.012

    CAS  Article  Google Scholar 

  8. Ashfaq M, Noor N, Saif-Ur-Rehman M, Sun Q, Mustafa G, Faizan Nazar M, Yu CP (2017) Determination of commonly used pharmaceuticals in hospital waste of Pakistan and evaluation of their ecological risk assessment. Clean: Soil, Air, Water 45:1500392

    Google Scholar 

  9. Ashu EE, Hagen F, Chowdhary A, Meis JF, Xu J (2017) Global population genetic analysis of Aspergillus fumigatus. mSphere. https://doi.org/10.1128/mSphere.00019-17

    Article  Google Scholar 

  10. Assress HA, Selvarajan R, Nyoni H, Ntushelo K, Mamba BB, Msagati TAM (2019) Diversity, co-occurrence and implications of fungal communities in wastewater treatment plants. Sci Rep 9:1–5. https://doi.org/10.1038/s41598-019-50624-z

    CAS  Article  Google Scholar 

  11. Assress HA, Nyoni H, Mamba BB, Msagati TAM (2020) Occurrence and risk assessment of azole antifungal drugs in water and wastewater. Ecotoxicol Environ Saf 187:109868. https://doi.org/10.1016/j.ecoenv.2019.109868

    CAS  Article  Google Scholar 

  12. Azevedo M-M, Faria-Ramos I, Cruz LC, Pina-Vaz C, Goncalves Rodrigues A (2015) Genesis of azole antifungal resistance from agriculture to clinical settings. J Agric Food Chem 63:7463–7468

    CAS  Article  Google Scholar 

  13. Barron L, Tobin J, Paull B (2008) Multi-residue determination of pharmaceuticals in sludge and sludge enriched soils using pressurized liquid extraction, solid phase extraction and liquid chromatography with tandem mass spectrometry. J Environ Monit 10:353–361

    CAS  Article  Google Scholar 

  14. Beardsley J, Halliday CL, Chen SC, Sorrell TC (2018) Responding to the emergence of antifungal drug resistance: perspectives from the bench and the bedside. Future Microbiol 13:1175–1191

    CAS  Article  Google Scholar 

  15. Beijer K, Abrahamson A, Brunström B, Brandt I (2010) CYP1A inhibition in fish gill filaments: a novel assay applied on pharmaceuticals and other chemicals. Aquat Toxicol 96:145–150. https://doi.org/10.1016/j.aquatox.2009.10.018

    CAS  Article  Google Scholar 

  16. Beijer K, Jönsson M, Shaik S, Behrens D, Brunström B, Brandt I (2018) Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol 198:73–81. https://doi.org/10.1016/j.aquatox.2018.02.016

    CAS  Article  Google Scholar 

  17. Bellmann R, Smuszkiewicz P (2017) Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. Infect 45:737–779. https://doi.org/10.1007/s15010-017-1042-z

    CAS  Article  Google Scholar 

  18. Bengtsson-Palme J, Larsson DJ (2016) Concentrations of antibiotics predicted to select for resistant bacteria: proposed limits for environmental regulation. Environ Int 86:140–149

    CAS  Article  Google Scholar 

  19. Berg C, Gyllenhammar I, Kvarnryd M (2009) Xenopus tropicalis as a test system for developmental and reproductive toxicity. J Toxicol Environ Health Part A 72:219–225

    CAS  Article  Google Scholar 

  20. Berger S, El Chazli Y, Babu AF, Coste AT (2017) Azole resistance in Aspergillus fumigatus: a consequence of antifungal use in agriculture? Front Microbiol 8:1024

    Article  Google Scholar 

  21. Berthod L, Roberts G, Sharpe A, Whitley D, Greenwood R, Mills G (2016) Effect of sewage sludge type on the partitioning behaviour of pharmaceuticals: a meta-analysis. Environ Sci Water Res Technol 2:154–163

    CAS  Article  Google Scholar 

  22. Beyda ND, Chuang SH, Alam MJ, Shah DN, Ng TM, McCaskey L, Garey KW (2013) Treatment of Candida famata bloodstream infections: case series and review of the literature. J Antimicrob Chemother 68:438–443

    CAS  Article  Google Scholar 

  23. Boxall AB (2004) The environmental side effects of medication. EMBO Rep 5:1110–1116

    CAS  Article  Google Scholar 

  24. Brauer VS et al (2019) Antifungal agents in agriculture: friends and foes of public health. Biomolecules 9:521

    CAS  Article  Google Scholar 

  25. Brilhante RS et al (2016) Azole resistance in Candida spp. isolated from Catú Lake, Ceará, Brazil: an efflux-pump-mediated mechanism. Braz J Microbiol 47:33–38

    CAS  Article  Google Scholar 

  26. Bromley MJ, Van Muijlwijk G, Fraczek MG, Robson G, Verweij PE, Denning DW, Bowyer P (2014) Occurrence of azole-resistant species of Aspergillus in the UK environment. J Glob Antimicrob Resist 2:276–279

    Article  Google Scholar 

  27. Brown AR et al (2011) Are toxicological responses in laboratory (Inbred) Zebrafish representative of those in outbred (Wild) populations?: A case study with an endocrine disrupting chemical. Environ Sci Technol 45:4166–4172. https://doi.org/10.1021/es200122r

    CAS  Article  Google Scholar 

  28. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. Sci Transl Med 4: 165rv113–165rv113

  29. Burkina V, Zlabek V, Zamaratskaia G (2013) Clotrimazole, but not dexamethasone, is a potent in vitro inhibitor of cytochrome P450 isoforms CYP1A and CYP3A in rainbow trout. Chemosphere 92:1099–1104. https://doi.org/10.1016/j.chemosphere.2013.01.050

    CAS  Article  Google Scholar 

  30. Campoy S, Adrio JL (2017) Antifungals. Biochem Pharmacol 133:86–96. https://doi.org/10.1016/j.bcp.2016.11.019

    CAS  Article  Google Scholar 

  31. Camps SM et al (2012) Molecular epidemiology of Aspergillus fumigatus isolates harboring the TR34/L98H azole resistance mechanism. J Clin Microbiol 50:2674–2680

    Article  Google Scholar 

  32. Caracciolo AB, Topp E, Grenni P (2015) Pharmaceuticals in the environment: biodegradation and effects on natural microbial communities. A Review J Pharm Biomed Anal 106:25–36

    Article  CAS  Google Scholar 

  33. Cardoso O, Porcher J-M, Sanchez W (2014) Factory-discharged pharmaceuticals could be a relevant source of aquatic environment contamination: review of evidence and need for knowledge. Chemosphere 115:20–30

    CAS  Article  Google Scholar 

  34. Carrillo-Munoz A, Giusiano G, Ezkurra P, Quindós G (2006) Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter 19:130–139

    CAS  Google Scholar 

  35. Casadevall A (2018) Fungal diseases in the 21st century: the near and far horizons. Pathog Immun 3:183–196. https://doi.org/10.20411/pai.v3i2.249

    Article  Google Scholar 

  36. Casado J, Rodríguez I, Ramil M, Cela R (2014) Selective determination of antimycotic drugs in environmental water samples by mixed-mode solid-phase extraction and liquid chromatography quadrupole time-of-flight mass spectrometry. J Chromatogr A 1339:42–49

    CAS  Article  Google Scholar 

  37. Castelli MV, Butassi E, Monteiro MC, Svetaz LA, Vicente F, Zacchino SA (2014) Novel antifungal agents: a patent review (2011–present). Expert OPin Ther Pat 24:323–338

    CAS  Article  Google Scholar 

  38. Caston-Osorio J, Rivero A, Torre-Cisneros J (2008) Epidemiology of invasive fungal infection. Int J Antimicrob Agents 32:S103–S109

    CAS  Article  Google Scholar 

  39. Castro G, Casado J, Rodríguez I, Ramil M, Ferradás A, Cela R (2016) Time-of-flight mass spectrometry assessment of fluconazole and climbazole UV and UV/H 2 O 2 degradability: kinetics study and transformation products elucidation. Water Res 88:681–690

    CAS  Article  Google Scholar 

  40. CDC (2013) Antibiotic resistance threats in the United States, 2013. Centers for disease control and prevention, Atlanta, GA. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf

  41. Charuaud L, Jardé E, Jaffrézic A, Liotaud M, Goyat Q, Mercier F, Le Bot B (2019) Veterinary pharmaceutical residues in water resources and tap water in an intensive husbandry area in France. Sci Total Environ 664:605–615

    CAS  Article  Google Scholar 

  42. Chen SC, Sorrell TC (2007) Antifungal agents. Med J Aust 187:404

    Article  Google Scholar 

  43. Chen Z-F, Ying G-G (2015) Occurrence, fate and ecological risk of five typical azole fungicides as therapeutic and personal care products in the environment: a review. Environ Int 84:142–153

    CAS  Article  Google Scholar 

  44. Chen Z-F, Ying G-G, Ma Y-B, Lai H-J, Chen F, Pan C-G (2013a) Occurrence and dissipation of three azole biocides climbazole, clotrimazole and miconazole in biosolid-amended soils. Sci Total Environ 452:377–383

    Article  CAS  Google Scholar 

  45. Chen Z-F, Ying G-G, Ma Y-B, Lai H-J, Chen F, Pan C-G (2013b) Typical azole biocides in biosolid-amended soils and plants following biosolid applications. J Agric Food Chem 61:6198–6206

    CAS  Article  Google Scholar 

  46. Chen Z-F et al (2014a) Photodegradation of the azole fungicide fluconazole in aqueous solution under UV-254: kinetics, mechanistic investigations and toxicity evaluation. Water Res 52:83–91. https://doi.org/10.1016/j.watres.2013.12.039

    CAS  Article  Google Scholar 

  47. Chen Z-F et al (2014b) Triclosan as a surrogate for household biocides: an investigation into biocides in aquatic environments of a highly urbanized region. Water Res 58:269–279

    CAS  Article  Google Scholar 

  48. Chitescu CL, Oosterink E, de Jong J, Stolker AAML (2012) Accurate mass screening of pharmaceuticals and fungicides in water by U-HPLC–Exactive Orbitrap MS. Anal Bionanal Chem 403:2997–3011

    CAS  Article  Google Scholar 

  49. Chowdhary A, Meis JF (2018) Emergence of azole resistant Aspergillus fumigatus and one health: time to implement environmental stewardship. Environ Microbiol 20:1299–1301

    Article  Google Scholar 

  50. Chowdhary A, Sharma C, van den Boom M, Yntema JB, Hagen F, Verweij PE, Meis JF (2014) Multi-azole-resistant Aspergillus fumigatus in the environment in Tanzania. J Antimicrob Chemother 69:2979–2983

    CAS  Article  Google Scholar 

  51. Chowdhary A, Sharma C, Kathuria S, Hagen F, Meis JF (2015) Prevalence and mechanism of triazole resistance in Aspergillus fumigatus in a referral chest hospital in Delhi, India and an update of the situation in Asia. Front Microbiol 6:428

    Article  Google Scholar 

  52. CLSI (2010) Method for antifungal disk diffusion susceptibility testing of nondermatophyte filamentous fungi; approved guideline. CLSI document M51-A. Clinical and Laboratory Standards Institute Wayne, PA

  53. CLSI (2017) Performance standards for antifungal susceptibility testing of yeasts; Clinical and Laboratory Standards Institute: CLSI supplement M60. Wayne, PA

  54. CLSI (2018) Method for antifungal disk diffusion susceptibility testing of yeasts. 3rd edition. CLSI guideline M44. vol CLSI guideline M44. Clinical Laboratory Standards Institute Wayne, PA

  55. Corcoran J, Lange A, Cumming RI, Owen SF, Ball JS, Tyler CR, Winter MJ (2014) Bioavailability of the imidazole antifungal agent clotrimazole and its effects on key biotransformation genes in the common carp (Cyprinus carpio). Aquat Toxicol 152:57–65. https://doi.org/10.1016/j.aquatox.2014.03.016

    CAS  Article  Google Scholar 

  56. Cowen LE, Sanglard D, Howard SJ, Rogers PD, Perlin DS (2015) Mechanisms of antifungal drug resistance. Cold Spring Harb Perspect Med 5:a019752

    Article  CAS  Google Scholar 

  57. Crowley PD, Gallagher HC (2014) Clotrimazole as a pharmaceutical: past, present and future. J Appl Microbiol 117:611–617. https://doi.org/10.1111/jam.12554

    CAS  Article  Google Scholar 

  58. Cuenca-Estrella M, Rodriguez-Tudela JL (2010) The current role of the reference procedures by CLSI and EUCAST in the detection of resistance to antifungal agents in vitro. Expert Rev Anti Infect Ther 8:267–276

    CAS  Article  Google Scholar 

  59. Cuenca-Estrella M, Gomez-Lopez A, Alastruey-Izquierdo A, Bernal-Martinez L, Cuesta I, Buitrago MJ, Rodriguez-Tudela JL (2010) Comparison of the Vitek 2 antifungal susceptibility system with the clinical and laboratory standards institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) Broth Microdilution Reference Methods and with the Sensititre YeastOne and Etest techniques for in vitro detection of antifungal resistance in yeast isolates. J Clin Microbiol 48:1782–1786. https://doi.org/10.1128/jcm.02316-09

    Article  Google Scholar 

  60. Dalhoff A (2018) Does the use of antifungal agents in agriculture and food foster polyene resistance development? A reason for concern. J Glob Antimicrob Resist 13:40–48. https://doi.org/10.1016/j.jgar.2017.10.024

    Article  Google Scholar 

  61. Denning D (1995) Can we prevent azole resistance in fungi? The Lancet 346:454–455

    CAS  Article  Google Scholar 

  62. DiDomenico B (1999) Novel antifungal drugs. Curr Opin Microbiol 2:509–515

    CAS  Article  Google Scholar 

  63. Dunne K, Hagen F, Pomeroy N, Meis JF, Rogers TR (2017) Intercountry transfer of triazole-resistant Aspergillus fumigatus on plant bulbs. Clin Infect Dis 65:147–149. https://doi.org/10.1093/cid/cix257

    Article  Google Scholar 

  64. Eliopoulos GM, Perea S, Patterson TF (2002) Antifungal resistance in pathogenic fungi. Clin Infecti Dis 35:1073–1080

    Article  Google Scholar 

  65. Eslami A et al (2015) Occurrence of non-steroidal anti-inflammatory drugs in Tehran source water, municipal and hospital wastewaters, and their ecotoxicological risk assessment. Environ Monit Assess 187:734

    Article  CAS  Google Scholar 

  66. Espinel-Ingroff A, Turnidge J (2016) The role of epidemiological cutoff values (ECVs/ECOFFs) in antifungal susceptibility testing and interpretation for uncommon yeasts and moulds. Rev Iberoam Micol 33:63–75

    Article  Google Scholar 

  67. Etest (2013) Antifungal susceptibility testing. Biomerieux. https://techlib.biomerieux.com/wcm/techlib/techlib/documents/docLink/Package_Insert/35904001-35905000/Package_Insert_-_9305056_-_D_-_en_-_Etest_-_AFST_WW.pdf. (Accessed 17 Dec 2019)

  68. Faria-Ramos I et al (2014) Environmental azole fungicide, prochloraz, can induce cross-resistance to medical triazoles in Candida glabrata. FEMS Yeast Res 14:1119–1123. https://doi.org/10.1111/1567-1364.12193

    CAS  Article  Google Scholar 

  69. Fisher MC, Hawkins NJ, Sanglard D, Gurr SJ (2018) Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Sci 360:739–742. https://doi.org/10.1126/science.aap7999

    CAS  Article  Google Scholar 

  70. Flowers SA, Colón B, Whaley SG, Schuler MA, Rogers PD (2015) Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans. Antimicrob Agents Chemother 59:450–460

    Article  CAS  Google Scholar 

  71. Frédéric O, Yves P (2014) Pharmaceuticals in hospital wastewater: their ecotoxicity and contribution to the environmental hazard of the effluent. Chemosphere 115:31–39

    Article  CAS  Google Scholar 

  72. Garcia-Rubio R, Cuenca-Estrella M, Mellado E (2017) Triazole resistance in Aspergillus species: an emerging problem. Drugs 77:599–613

    CAS  Article  Google Scholar 

  73. Garcia-Rubio R, Monteiro MC, Mellado E (2020) Azole antifungal drugs: mode of action and resistance. In: Reference module in life sciences. pp 1–10. https://doi.org/10.1016/B978-0-12-809633-8.20731-0

  74. Ghannoum M (2016) Azole resistance in dermatophytes: prevalence and mechanism of action. J Am Podiatr Med Assoc 106:79–86

    Article  Google Scholar 

  75. Ghannoum MA, Rice LB (1999) Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev 12:501–517

    CAS  Article  Google Scholar 

  76. Gharaghani M, Taghipour S, Mahmoudabadi AZ (2020) Molecular identification, biofilm formation and antifungal susceptibility of Rhodotorula spp. Mol Biol Rep 47:8903–8909

    CAS  Article  Google Scholar 

  77. Gomez-Lopez A, Mellado E, Rodriguez-Tudela JL, Cuenca-Estrella M (2005) Susceptibility profile of 29 clinical isolates of Rhodotorula spp. and literature review. J Antimicrob Chemother 55:312–316

    CAS  Article  Google Scholar 

  78. Gonçalves SS, Souza ACR, Chowdhary A, Meis JF, Colombo AL (2016) Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus. Mycoses 59:198–219

    Article  CAS  Google Scholar 

  79. González-Ortegón E, Blasco J, Le Vay L, Giménez L (2013) A multiple stressor approach to study the toxicity and sub-lethal effects of pharmaceutical compounds on the larval development of a marine invertebrate. J Hazard Mater 263:233–238

    Article  CAS  Google Scholar 

  80. Gottschall N et al (2012) Pharmaceutical and personal care products in groundwater, subsurface drainage, soil, and wheat grain, following a high single application of municipal biosolids to a field. Chemosphere 87:194–203

    CAS  Article  Google Scholar 

  81. Gubbins PO, Anaissie EJ (2009) Chapter 7 - Antifungal therapy. In: Anaissie EJ, McGinnis MR, Pfaller MA (eds) Clinical mycology.2nd edn., Churchill Livingstone, Edinburgh, pp 161–165. https://doi.org/10.1016/B978-1-4160-5680-5.00007-4

  82. Guevara-Suarez M et al (2016) Identification and antifungal susceptibility of penicillium-like fungi from clinical samples in the United States. J Clin Microbiol 54:2155–2161

    CAS  Article  Google Scholar 

  83. Hamdy RF, Zaoutis TE, Seo SK (2017) Antifungal stewardship considerations for adults and pediatrics. Virulence 8:658–672. https://doi.org/10.1080/21505594.2016.1226721

    Article  Google Scholar 

  84. Hanamoto S, Nakada N, Yamashita N, Tanaka H (2013) Modeling the photochemical attenuation of down-the-drain chemicals during river transport by stochastic methods and field measurements of pharmaceuticals and personal care products. Environ Sci Technol 47:13571–13577

    CAS  Article  Google Scholar 

  85. Hanna N et al (2018) Presence of antibiotic residues in various environmental compartments of Shandong province in eastern China: its potential for resistance development and ecological and human risk. Environ Int 114:131–142

    CAS  Article  Google Scholar 

  86. Hare RK et al (2019) In Vivo Selection of a unique tandem repeat mediated azole resistance mechanism (TR120) in Aspergillus fumigatus cyp51A. Denmark Emerg Infect Dis 25:577

    CAS  Article  Google Scholar 

  87. Hashimoto A, Hagiwara D, Watanabe A, Yahiro M, Yikelamu A, Yaguchi T, Kamei K (2017) Drug sensitivity and resistance mechanism in Aspergillus section Nigri strains from Japan. Antimicrob Agents Chemother 61:e02583-e12516. https://doi.org/10.1128/aac.02583-16

    CAS  Article  Google Scholar 

  88. Hasselberg L, Westerberg S, Wassmur B, Celander MC (2008) Ketoconazole, an antifungal imidazole, increases the sensitivity of rainbow trout to 17α-ethynylestradiol exposure. Aquat Toxicol 86:256–264

    CAS  Article  Google Scholar 

  89. Herkert PF et al (2019) Molecular characterization and antifungal susceptibility of clinical Fusarium species from Brazil. Front Microbiol 10:737

    Article  Google Scholar 

  90. Hof H (2001) Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother 45:2987–2990

    CAS  Article  Google Scholar 

  91. Hof H (2008) Is there a serious risk of resistance development to azoles among fungi due to the widespread use and long-term application of azole antifungals in medicine? Drug Resist Updat 11:25–31

    CAS  Article  Google Scholar 

  92. Hokken MW, Zwaan B, Melchers W, Verweij P (2019) Facilitators of adaptation and antifungal resistance mechanisms in clinically relevant fungi. Fungal Genet Biol 132:103254

    CAS  Article  Google Scholar 

  93. Holmes AR et al (2016) Targeting efflux pumps to overcome antifungal drug resistance. Future Med Chem 8:1485–1501. https://doi.org/10.4155/fmc-2016-0050

    CAS  Article  Google Scholar 

  94. Howard SJ, Harrison E, Bowyer P, Varga J, Denning DW (2011) Cryptic species and azole resistance in the Aspergillus niger complex. Antimicrob Agents Chemother 55:4802–4809. https://doi.org/10.1128/aac.00304-11

    CAS  Article  Google Scholar 

  95. Huang Q, Yu Y, Tang C, Peng X (2010) Determination of commonly used azole antifungals in various waters and sewage sludge using ultra-high performance liquid chromatography–tandem mass spectrometry. J Chromatogr A 1217:3481–3488

    CAS  Article  Google Scholar 

  96. Huang Q, Zhang K, Wang Z, Wang C, Peng X (2012) Enantiomeric determination of azole antifungals in wastewater and sludge by liquid chromatography–tandem mass spectrometry. Anal Bional Chem 403:1751–1760

    CAS  Article  Google Scholar 

  97. Huang Q, Wang Z, Wang C, Peng X (2013) Chiral profiling of azole antifungals in municipal wastewater and recipient rivers of the Pearl River Delta, China. Environ Sci Pollut Res 20:8890–8899

    CAS  Article  Google Scholar 

  98. Huang Q et al (2018) Development of ultrasound-assisted extraction of commonly used azole antifungals in soils. Anal Methods 10:5265–5272

    CAS  Article  Google Scholar 

  99. Isoherranen N, Lutz JD, Chung SP, Hachad H, Levy RH, Ragueneau-Majlessi I (2012) Importance of multi-p450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data. Chem Res Toxicol 25:2285–2300. https://doi.org/10.1021/tx300192g

    CAS  Article  Google Scholar 

  100. Ida Skaar AA, Cecile TA, Maiken CA, Jorgen VB, Ellen C, Hege HD, Andrea F, Peter G, Einar S, Henning S, Paul EV (2019) Azole resistance in a one health perspective. Norwegian Veterinary Institute

  101. Jamiu A, Albertyn J, Sebolai O, Pohl C (2021) Update on Candida krusei, a potential multidrug-resistant pathogen. Med Mycol 59:14–30

    CAS  Article  Google Scholar 

  102. Jeanvoine A, Rocchi S, Bellanger A, Reboux G, Millon L (2019) Azole-resistant Aspergillus fumigatus: a global phenomenon originating in the environment? Med Mal Infect 50:389–395

    Article  Google Scholar 

  103. Jerker Fick RHL, Lennart Kaj, Eva Brorstrom-Lunden (2011) Results from the Swedish national screening programme 2010

  104. Ji K, Seo J, Kho Y, Choi K (2019) Co-exposure to ketoconazole alters effects of bisphenol A in Danio rerio and H295R cells. Chemosphere 237:124414

    CAS  Article  Google Scholar 

  105. Kahle M, Buerge IJ, Hauser A, Muller MD, Poiger T (2008) Azole fungicides: occurrence and fate in wastewater and surface waters. Environ Sci Technol 42:7193–7200

    CAS  Article  Google Scholar 

  106. Kahlmeter G, Brown D (2017) Are breakpoints for phenotypic susceptibility testing no longer needed? Clin Microbiol Infect 23:1

    CAS  Article  Google Scholar 

  107. Khadka S et al (2017) Isolation, speciation and antifungal susceptibility testing of Candida isolates from various clinical specimens at a tertiary care hospital. Nepal BMC Res Notes 10:1–5

    Article  CAS  Google Scholar 

  108. Kim J-W et al (2009) Acute toxicity of pharmaceutical and personal care products on freshwater crustacean (Thamnocephalus platyurus) and fish (Oryzias latipes). J Toxicol Sci 34:227–232

    CAS  Article  Google Scholar 

  109. Kjærstad MB, Taxvig C, Nellemann C, Vinggaard AM, Andersen HR (2010) Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reprod Toxicol 30:573–582. https://doi.org/10.1016/j.reprotox.2010.07.009

    CAS  Article  Google Scholar 

  110. Kołaczkowska A, Kołaczkowski M (2016) Drug resistance mechanisms and their regulation in non-albicans Candida species. J Antimicrob Chemother 71:1438–1450

    Article  CAS  Google Scholar 

  111. Krasulova K, Dvorak Z, Anzenbacher P (2019) In vitro analysis of itraconazole cis-diastereoisomers inhibition of nine cytochrome P450 enzymes: stereoselective inhibition of CYP3A. Xenobiotica 49:36–42

    CAS  Article  Google Scholar 

  112. Krishnan-Natesan S, Chandrasekar PH, Alangaden GJ, Manavathu EK (2008) Molecular characterisation of cyp51A and cyp51B genes coding for P450 14α-lanosterol demethylases A (CYP51Ap) and B (CYP51Bp) from voriconazole-resistant laboratory isolates of Aspergillus flavus. Int J Antimicrob Agents 32:519–524

    CAS  Article  Google Scholar 

  113. Krishnasamy L, Krishnakumar S, Kumaramanickavel G, Saikumar C (2018) Molecular mechanisms of antifungal drug resistance in Candida species. J Clin Diagn Res 12:1–6

    Article  Google Scholar 

  114. Kryczyk-Poprawa A, Żmudzki P, Maślanka A, Piotrowska J, Opoka W, Muszyńska B (2019) Mycoremediation of azole antifungal agents using in vitro cultures of Lentinula edodes. 3 Biotech 9:207

    Article  Google Scholar 

  115. Ksiezopolska E, Gabaldón T (2018) Evolutionary emergence of drug resistance in Candida opportunistic pathogens. Genes 9:461

    Article  CAS  Google Scholar 

  116. Kunkel U, Radke M (2012) Fate of pharmaceuticals in rivers: deriving a benchmark dataset at favorable attenuation conditions. Water Res 46:5551–5565

    CAS  Article  Google Scholar 

  117. Lacey C, McMahon G, Bones J, Barron L, Morrissey A, Tobin J (2008) An LC–MS method for the determination of pharmaceutical compounds in wastewater treatment plant influent and effluent samples. Talanta 75:1089–1097

    CAS  Article  Google Scholar 

  118. Lacey C, Basha S, Morrissey A, Tobin JM (2012) Occurrence of pharmaceutical compounds in wastewater process streams in Dublin, Ireland. Environ Monit Assess 184:1049–1062

    CAS  Article  Google Scholar 

  119. Lago M, Aguiar A, Natário A, Fernandes C, Faria M, Pinto E (2014) Does fungicide application in vineyards induce resistance to medical azoles in Aspergillus species? Environ Monit Assess 186:5581–5593

    CAS  Article  Google Scholar 

  120. Lepesheva GI, Waterman MR (2007) Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochim Biophys Acta Gen Subj 1770:467–477

    CAS  Article  Google Scholar 

  121. Levine SL, Czosnyka H, Oris JT (1997) Effect of the fungicide clotrimazole on the bioconcentration of benzo [a] pyrene in gizzard shad (Dorosoma cepedianum): in vivo and in vitro inhibition of cytochrome P4501A activity. Environ Toxicol Chem 16:306–311

    CAS  Article  Google Scholar 

  122. Li Y, Wang H, Zhao Y-P, Xu Y-C, Hsueh P-R (2020) Antifungal susceptibility of clinical isolates of 25 genetically confirmed Aspergillus species collected from Taiwan and Mainland China. J Microbiol, Immunol Infect 53:125–132. https://doi.org/10.1016/j.jmii.2018.04.003

    CAS  Article  Google Scholar 

  123. Lieberman A, Curtis L (2018) Severe adverse reactions following ketoconazole fluconazole, and environmental exposures: a case report. Drug Safety Case Rep 5:18. https://doi.org/10.1007/s40800-018-0083-2

    Article  Google Scholar 

  124. Lindberg RH, Fick J, Tysklind M (2010) Screening of antimycotics in Swedish sewage treatment plants–waters and sludge. Water Res 44:649–657

    CAS  Article  Google Scholar 

  125. Lindberg RH, Östman M, Olofsson U, Grabic R, Fick J (2014) Occurrence and behaviour of 105 active pharmaceutical ingredients in sewage waters of a municipal sewer collection system. Water Res 58:221–229

    CAS  Article  Google Scholar 

  126. Liu J, Lu G, Yang H, Yan Z, Wang Y, Wang P (2016a) Bioconcentration and metabolism of ketoconazole and effects on multi-biomarkers in crucian carp (Carassius auratus). Chemosphere 150:145–151

    CAS  Article  Google Scholar 

  127. Liu N, Wang C, Su H, Zhang W, Sheng C (2016b) Strategies in the discovery of novel antifungal scaffolds. Future Med Chem 8:1435–1454

    CAS  Article  Google Scholar 

  128. Liu W-R et al (2017) Biocides in wastewater treatment plants: mass balance analysis and pollution load estimation. J Hazard Mater 329:310–320. https://doi.org/10.1016/j.jhazmat.2017.01.057

    CAS  Article  Google Scholar 

  129. Lockhart SR, Berkow EL (2019) Antifungal susceptibility testing: the times they are a-changing. Clin Microbiol Newsl 41:85–90

    Article  Google Scholar 

  130. Lockhart SR, Ghannoum MA, Alexander BD (2017) Establishment and use of epidemiological cutoff values for molds and yeasts by use of the clinical and laboratory standards institute M57 standard. J Clin Microbiol 55:1262. https://doi.org/10.1128/jcm.02416-16

    Article  Google Scholar 

  131. Loeffler J, Stevens DA (2003) Antifungal drug resistance. Clin Infect Dis 36:S31–S41

    CAS  Article  Google Scholar 

  132. Lohberger A, Coste AT, Sanglard D (2014) Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence. Eukaryot Cell 13:127–142

    CAS  Article  Google Scholar 

  133. Martinez R (2006) An update on the use of antifungal agents. J Bras Pneumol 32:449–460

    Article  Google Scholar 

  134. Martinez-Rossi NM, Peres NT, Rossi A (2008) Antifungal resistance mechanisms in dermatophytes. Mycopathologia 166:369

    Article  Google Scholar 

  135. Mellado E, Diaz-Guerra T, Cuenca-Estrella M, Rodriguez-Tudela J (2001) Identification of two different 14-α sterol demethylase-related genes (cyp51A and cyp51B) in Aspergillus fumigatus and other Aspergillus species. J Clin Microbiol 39:2431–2438

    CAS  Article  Google Scholar 

  136. Meredith TA (2006) Chapter 133 - Vitrectomy for infectious endophthalmitis. In: Ryan SJ, Hinton DR, Schachat AP, Wilkinson CP (eds) Retina. 4th edn.,. Mosby, Edinburgh, pp 2255–2275. https://doi.org/10.1016/B978-0-323-02598-0.50139-7

  137. Metzger JW (2004) Drugs in municipal landfills and landfill leachates. In: Kümmerer K (ed) Pharmaceuticals in the Environment: Sources, Fate, Effects and Risks. Springer, Berlin, pp 133–137. https://doi.org/10.1007/978-3-662-09259-0_10

  138. Miller RA (2018) A case for antifungal stewardship. Curr Fungal Infect Rep 12:33–43

    Article  Google Scholar 

  139. Monapathi M, Bezuidenhout C, Rhode O (2018) Efflux pumps genes of clinical origin are related to those from fluconazole-resistant Candida albicans isolates from environmental water. Water Sci Technol 77:899–908

    CAS  Article  Google Scholar 

  140. Monteiro C, Pinheiro D, Maia M, Faria MA, Lameiras C, Pinto E (2019) Aspergillus species collected from environmental air samples in Portugal-molecular identification, antifungal susceptibility and sequencing of cyp51A gene on A-fumigatus sensu stricto itraconazole resistant. J Appl Microbiol 126:1140–1148. https://doi.org/10.1111/jam.14217

    CAS  Article  Google Scholar 

  141. Munkboel CH, Rasmussen TB, Elgaard C, Olesen M-LK, Kretschmann AC, Styrishave B (2019) The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicol 425:152247. https://doi.org/10.1016/j.tox.2019.152247

    CAS  Article  Google Scholar 

  142. Nabili M et al (2016) High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue? J Med Microbiol 65:468–475

    CAS  Article  Google Scholar 

  143. Nett JE, Andes DR (2016) Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am 30:51–83. https://doi.org/10.1016/j.idc.2015.10.012

    Article  Google Scholar 

  144. Niwa T, Inoue-Yamamoto S, Shiraga T, Takagi A (2005) Effect of antifungal drugs on cytochrome P450 (CYP) 1A2, CYP2D6, and CYP2E1 activities in human liver microsomes. Biol Pharm Bull 28:1813–1816

    CAS  Article  Google Scholar 

  145. Odds FC, Brown AJ, Gow NA (2003) Antifungal agents: mechanisms of action. Trends Microbiol 11:272–279

    CAS  Article  Google Scholar 

  146. Osińska A et al (2020) Small-scale wastewater treatment plants as a source of the dissemination of antibiotic resistance genes in the aquatic environment. J Hazard Mater 381:121221. https://doi.org/10.1016/j.jhazmat.2019.121221

    CAS  Article  Google Scholar 

  147. Östman M, Lindberg RH, Fick J, Björn E, Tysklind M (2017) Screening of biocides, metals and antibiotics in Swedish sewage sludge and wastewater. Water Res 115:318–328

    Article  CAS  Google Scholar 

  148. Paul R, Rudramurthy S, Meis J, Mouton J, Chakrabarti A (2015) A novel Y319H substitution in CYP51C associated with azole resistance in Aspergillus flavus. Antimicrob Agents Chemother 59:6615–6619

    CAS  Article  Google Scholar 

  149. Paul RA et al (2018) Magnitude of voriconazole resistance in clinical and environmental isolates of Aspergillus flavus and investigation into the role of multidrug efflux pumps. Antimicrob Agents Chemother 62:e01022-e11018

    Article  Google Scholar 

  150. Peng X, Huang Q, Zhang K, Yu Y, Wang Z, Wang C (2012) Distribution, behavior and fate of azole antifungals during mechanical, biological, and chemical treatments in sewage treatment plants in China. Sci Total Environ 426:311–317

    CAS  Article  Google Scholar 

  151. Peng X, Ou W, Wang C, Wang Z, Huang Q, Jin J, Tan J (2014) Occurrence and ecological potential of pharmaceuticals and personal care products in groundwater and reservoirs in the vicinity of municipal landfills in China. Sci Total Environ 490:889–898

    CAS  Article  Google Scholar 

  152. Pfaller MA (2012a) Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Amer J Med 125:S3–S13

    CAS  Article  Google Scholar 

  153. Pfaller MA (2012b) Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 125:S3–S13. https://doi.org/10.1016/j.amjmed.2011.11.001

    CAS  Article  Google Scholar 

  154. Pfaller M, Messer S, Boyken L, Rice C, Tendolkar S, Hollis R, Diekema D (2008) In vitro survey of triazole cross-resistance among more than 700 clinical isolates of Aspergillus species. J Clin Microbiol 46:2568–2572

    CAS  Article  Google Scholar 

  155. Pfaller M et al (2010) Results from the ARTEMIS DISK global antifungal surveillance study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J Clin Microbiol 48:1366–1377

    CAS  Article  Google Scholar 

  156. Pfaller M et al (2011) Comparison of the broth microdilution (BMD) method of the European Committee on Antimicrobial Susceptibility Testing with the 24-hour CLSI BMD method for testing susceptibility of Candida species to fluconazole, posaconazole, and voriconazole by use of epidemiological cutoff values. J Clin Microbiol 49:845–850

    CAS  Article  Google Scholar 

  157. Pianalto KM, Alspaugh JA (2016) New Horizons in antifungal therapy. J Fungi 2:26

    Article  CAS  Google Scholar 

  158. Porsbring T, Blanck H, Tjellström H, Backhaus T (2009) Toxicity of the pharmaceutical clotrimazole to marine microalgal communities. Aquat Toxicol 91:203–211. https://doi.org/10.1016/j.aquatox.2008.11.003

    CAS  Article  Google Scholar 

  159. Posteraro B, Sanguinetti M (2014) The future of fungal susceptibility testing. Future Microbiol 9:947–967

    CAS  Article  Google Scholar 

  160. Prasad R, Nair R, Banerjee A (2019) Multidrug transporters of Candida species in clinical azole resistance. Fungal Genet Biol 132:103252

    CAS  Article  Google Scholar 

  161. Prasad R, Shah AH, Rawal MK (2016) Antifungals: mechanism of action and drug resistance. In: Yeast Membrane Transport. Springer, pp 327–349

  162. Prigitano A, Esposto MC, Romanò L, Auxilia F, Tortorano AM (2019) Azole-resistant Aspergillus fumigatus in the Italian environment. J Glob Antimicrob Resist 16:220–224

    Article  Google Scholar 

  163. Pristov KE, Ghannoum MA (2019) Resistance of Candida to azoles and echinocandins worldwide. Clin Microbiol Infect 25:792–798

    CAS  Article  Google Scholar 

  164. Rajendran M, Khaithir TMN, Santhanam J (2016) Determination of azole antifungal drug resistance mechanisms involving Cyp51A gene in clinical isolates of Aspergillus fumigatus and Aspergillus niger. Malays J Microbiol 12:205–210

    CAS  Google Scholar 

  165. Reis EO et al (2019) Occurrence, removal and seasonal variation of pharmaceuticals in Brasilian drinking water treatment plants. Environ Pollut 250:773–781. https://doi.org/10.1016/j.envpol.2019.04.102

    CAS  Article  Google Scholar 

  166. Revie NM, Iyer KR, Robbins N, Cowen LE (2018) Antifungal drug resistance: evolution, mechanisms and impact. Curr Opin Microbiol 45:70–76

    CAS  Article  Google Scholar 

  167. Riat A, Plojoux J, Gindro K, Schrenzel J, Sanglard D (2018) Azole resistance of environmental and clinical Aspergillus fumigatus isolates from Switzerland. Antimicrob Agents Chemother 62:e02088-e12017

    CAS  Article  Google Scholar 

  168. Richardson M, Rautemaa-Richardson R (2019) Exposure to Aspergillus in Home and Healthcare facilities’ water environments: focus on biofilms. Microorganisms 7:7. https://doi.org/10.3390/microorganisms7010007

    CAS  Article  Google Scholar 

  169. Rocha MFG et al (2016) Cross-resistance to fluconazole induced by exposure to the agricultural azole tetraconazole: an environmental resistance school? Mycoses 59:281–290

    CAS  Article  Google Scholar 

  170. Rochette F, Engelen M, Vanden Bossche H (2003) Antifungal agents of use in animal health–practical applications. J Vet Pharmacol Ther 26:31–53

    CAS  Article  Google Scholar 

  171. Roemer T, Krysan DJ (2014) Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med 4:a019703

    Article  CAS  Google Scholar 

  172. Rossmann J, Schubert S, Gurke R, Oertel R, Kirch W (2014) Simultaneous determination of most prescribed antibiotics in multiple urban wastewater by SPE-LC–MS/MS. J Chromatogr B 969:162–170

    CAS  Article  Google Scholar 

  173. Rybak JM, Doorley LA, Nishimoto AT, Barker KS, Palmer GE, Rogers PD (2019) Abrogation of triazole resistance upon deletion of CDR1 in a clinical isolate of Candida auris. Antimicrob Agents Chemother 63:e00057-e119

    CAS  Article  Google Scholar 

  174. Sabourin L et al (2009) Runoff of pharmaceuticals and personal care products following application of dewatered municipal biosolids to an agricultural field. Sci Total Environ 407:4596–4604

    CAS  Article  Google Scholar 

  175. Salsé M et al (2019) Multicentre study to determine the Etest epidemiological cut-off values of antifungal drugs in Candida spp. and Aspergillus fumigatus species complex. Clin Microbiol Infect 25:1546–1552

    Article  Google Scholar 

  176. Sandoval-Denis M, Gené J, Sutton D, Wiederhold N, Cano-Lira J, Guarro J (2016) New species of Cladosporium associated with human and animal infections. Persoonia Mol Phylogeny Evol Fungi 36:281

    CAS  Article  Google Scholar 

  177. Sanglard D (2002) Resistance of human fungal pathogens to antifungal drugs. Curr Opin Microbiol 5:379–385

    CAS  Article  Google Scholar 

  178. Sanglard D (2003) Resistance and tolerance mechanisms to antifungal drugs in fungal pathogens. Mycologist 17:74–78

    Article  Google Scholar 

  179. Sanglard D (2016) Emerging threats in antifungal-resistant fungal pathogens. Front Med 3:11. https://doi.org/10.3389/fmed.2016.00011

    Article  Google Scholar 

  180. Sanguinetti M, Posteraro B (2017) New approaches for antifungal susceptibility testing. Clin Microbiol Infect 23:931–934

    CAS  Article  Google Scholar 

  181. Sanguinetti M, Posteraro B (2018) Susceptibility testing of fungi to antifungal drugs. J Fungi (basel) 4:110. https://doi.org/10.3390/jof4030110

    CAS  Article  Google Scholar 

  182. Sanguinetti M, Posteraro B, Lass-Flörl C (2015) Antifungal drug resistance among Candida species: mechanisms and clinical impact. Mycoses 58:2–13

    Article  Google Scholar 

  183. Sav H et al (2018) Biofilm formation and resistance to fungicides in clinically relevant members of the fungal genus fusarium. J Fungi 4:16

    Article  CAS  Google Scholar 

  184. Schinabeck M, Ghannoum M (2003) Human hyalohyphomycoses: a review of human infections due to Acremonium spp., Paecilomyces spp., Penicillium spp., and Scopulariopsis spp. J Chemother 15:5–15

    Article  Google Scholar 

  185. Seifi Z, Zarei Mahmoudabadi A, Hydrinia S (2013) Isolation, identification and susceptibility profile of Rhodotorula species isolated from two educational hospitals in Ahvaz. Jundishapur J Microbiol 6(6):e8935. https://doi.org/10.5812/jjm.8935

    Article  Google Scholar 

  186. Seyedmousavi S, Guillot J, Arné P, de Hoog GS, Mouton JW, Melchers WJG, Verweij PE (2015) Aspergillus and aspergilloses in wild and domestic animals: a global health concern with parallels to human disease. Med Mycol 53:765–797. https://doi.org/10.1093/mmy/myv067

    Article  Google Scholar 

  187. Sharma C, Kumar R, Kumar N, Masih A, Gupta D, Chowdhary A (2018) Investigation of multiple resistance mechanisms in voriconazole-resistant Aspergillus flavus clinical isolates from a chest hospital surveillance in Delhi, India. Antimicrob Agents Chemother 62:e01928-e11917. https://doi.org/10.1128/aac.01928-17

    CAS  Article  Google Scholar 

  188. Sharma C, Nelson-Sathi S, Singh A, Radhakrishna Pillai M, Chowdhary A (2019) Genomic perspective of triazole resistance in clinical and environmental Aspergillus fumigatus isolates without cyp51A mutations. Fungal Genet Biol 132:103265. https://doi.org/10.1016/j.fgb.2019.103265

    CAS  Article  Google Scholar 

  189. Shi H, Sun Z, Liu Z, Xue Y (2012) Effects of clotrimazole and amiodarone on early development of amphibian (Xenopus tropicalis). Toxicol Environ Chem 94:128–135

    CAS  Article  Google Scholar 

  190. Shoham S, Groll AH, Petraitis V, Walsh TJ (2017) Systemic antifungal agents. In: Infectious diseases. Elsevier, pp 1333–1344. e1334

  191. Shrestha SK, Garzan A, Garneau-Tsodikova S (2017) Novel alkylated azoles as potent antifungals. Eur J Med Chem 133:309–318

    CAS  Article  Google Scholar 

  192. Singer AC, Shaw H, Rhodes V, Hart A (2016) Review of antimicrobial resistance in the environment and its relevance to environmental regulators. Front Microbiol 7:1728

    Article  Google Scholar 

  193. Siqueira RA et al (2018) Evaluation of two commercial methods for the susceptibility testing of Candida species: Vitek 2® and Sensititre YeastOne®. Rev Iberoam Micol 35:83–87. https://doi.org/10.1016/j.riam.2017.11.001

    Article  Google Scholar 

  194. Snelders E et al (2008) Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med 5:e219

    Article  CAS  Google Scholar 

  195. Snelders E, Rijs AJ, Kema GH, Melchers WJ, Verweij PE (2009) Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol 75:4053–4057

    CAS  Article  Google Scholar 

  196. Snelders E et al (2012) Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS ONE 7:e31801

    CAS  Article  Google Scholar 

  197. Sychev DA et al (2018) The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo. Drug Des Devel Ther 12:1147–1156. https://doi.org/10.2147/dddt.s149069

    CAS  Article  Google Scholar 

  198. Taboada J, Grooters AM (2008) Chapter 9 - Systemic antifungal therapy. In: Maddison JE, Page SW, Church DB (eds) Small animal clinical pharmacology, 2nd edn., W.B. Saunders, Edinburgh, pp 186–197. https://doi.org/10.1016/B978-070202858-8.50011-7

  199. Talbot JJ et al (2019) cyp51A mutations, extrolite profiles, and antifungal susceptibility in clinical and environmental isolates of the Aspergillus viridinutans species complex. Antimicrob Agents Chemother 63:e00632-e1619

    CAS  Article  Google Scholar 

  200. Tangwattanachuleeporn M et al (2016) Prevalence of azole-resistant Aspergillus fumigatus in the environment of Thailand. Med Mycol 55:429–435. https://doi.org/10.1093/mmy/myw090

    CAS  Article  Google Scholar 

  201. Terças AL, Marques SG, Moffa EB, Alves MB, de Azevedo CM, Siqueira WL, Monteiro CA (2017) Antifungal drug susceptibility of Candida species isolated from HIV-positive patients recruited at a public hospital in São Luís, Maranhão. Brazil Front Microbiol 8:298

    Google Scholar 

  202. Thapa U, Hanigan D (2020) Waterless urinals remove select pharmaceuticals from urine by phase partitioning. Environ Sci Technol 54:6344–6352. https://doi.org/10.1021/acs.est.9b06205

    CAS  Article  Google Scholar 

  203. Trösken ER, Bittner N, Völkel W (2005) Quantitation of 13 azole fungicides in wine samples by liquid chromatography–tandem mass spectrometry. J Chromatogr A 1083:113–119

    Article  CAS  Google Scholar 

  204. Tsao S, Rahkhoodaee F, Raymond M (2009) Relative contributions of the Candida albicans ABC transporters Cdr1p and Cdr2p to clinical azole resistance. Antimicrob Agents Chemother 53:1344–1352

    CAS  Article  Google Scholar 

  205. Van De Steene JC, Lambert WE (2008) Validation of a solid-phase extraction and liquid chromatography–electrospray tandem mass spectrometric method for the determination of nine basic pharmaceuticals in wastewater and surface water samples. J Chromatogr A 1182:153–160

    Article  CAS  Google Scholar 

  206. Van Der Linden JW, Warris A, Verweij PE (2011) Aspergillus species intrinsically resistant to antifungal agents. Medl Mycol 49:S82–S89

    Article  Google Scholar 

  207. Van der Linden J et al (2015) Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg Infect Dis 21:1041

    Article  CAS  Google Scholar 

  208. Vandeputte P, Ferrari S, Coste AT (2011) Antifungal resistance and new strategies to control fungal infections. Int J Microbiol 2012:1–26

    Article  CAS  Google Scholar 

  209. Velpandian T, Halder N, Nath M, Das U, Moksha L, Gowtham L, Batta SP (2018) Un-segregated waste disposal: an alarming threat of antimicrobials in surface and ground water sources in Delhi. Environ Sci Pollut Res 25:29518–29528. https://doi.org/10.1007/s11356-018-2927-9

    Article  Google Scholar 

  210. Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ (2009) Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis 9:789–795

    CAS  Article  Google Scholar 

  211. Vestel J et al (2016) Use of acute and chronic ecotoxicity data in environmental risk assessment of pharmaceuticals. Environ Toxicol Chem 35:1201–1212

    CAS  Article  Google Scholar 

  212. Walters E, McClellan K, Halden RU (2010) Occurrence and loss over three years of 72 pharmaceuticals and personal care products from biosolids–soil mixtures in outdoor mesocosms. Water Res 44:6011–6020

    CAS  Article  Google Scholar 

  213. Wang HC et al (2018) Prevalence, mechanisms and genetic relatedness of the human pathogenic fungus Aspergillus fumigatus exhibiting resistance to medical azoles in the environment of Taiwan. Environ Microbiol 20:270–280

    Article  CAS  Google Scholar 

  214. Warnock DW (2007) Trends in the epidemiology of invasive fungal infections. Nippon Ishinkin Gakkai Zasshi 48:1–12

    Article  Google Scholar 

  215. White TC, Marr KA, Bowden RA (1998) Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 11:382–402

    CAS  Article  Google Scholar 

  216. Wiederhold NP (2017) Antifungal resistance: current trends and future strategies to combat. Infect Drug Resist 10:249–259. https://doi.org/10.2147/idr.s124918

    CAS  Article  Google Scholar 

  217. Wightwick AM et al (2012) Environmental fate of fungicides in surface waters of a horticultural-production catchment in southeastern Australia. Arch Environ Contam Toxicol 62:380–390

    CAS  Article  Google Scholar 

  218. Wirth F, Goldani LZ (2012) Epidemiology of Rhodotorula: an emerging pathogen. Interdiscip Perspect Infect Dis 2012:1–7

    Article  Google Scholar 

  219. Wishart DS et al (2018) DrugBank 5.0: a major update to the DrugBank database for 2018. Nucl Acids Res 46:D1074–D1082. https://doi.org/10.1093/nar/gkx1037

    CAS  Article  Google Scholar 

  220. Wu X, Lu Y, Zhou S, Chen L, Xu B (2016) Impact of climate change on human infectious diseases: empirical evidence and human adaptation. Environ Int 86:14–23. https://doi.org/10.1016/j.envint.2015.09.007

    Article  Google Scholar 

  221. Xie JL, Polvi EJ, Shekhar-Guturja T, Cowen LE (2014) Elucidating drug resistance in human fungal pathogens. Future Microbiol 9:523–542

    CAS  Article  Google Scholar 

  222. Yamagishi T, Horie Y, Tatarazako N (2017) Synergism between macrolide antibiotics and the azole fungicide ketoconazole in growth inhibition testing of the green alga Pseudokirchneriella subcapitata. Chemosphere 174:1–7. https://doi.org/10.1016/j.chemosphere.2017.01.071

    CAS  Article  Google Scholar 

  223. Yamamoto H et al (2009) Persistence and partitioning of eight selected pharmaceuticals in the aquatic environment: laboratory photolysis, biodegradation, and sorption experiments. Water Res 43:351–362

    CAS  Article  Google Scholar 

  224. Yan Z, Lu G, Wu D, Ye Q, Xie Z (2013) Interaction of 17β-estradiol and ketoconazole on endocrine function in goldfish (Carassius auratus). Aquat Toxicol 132:19–25

    Article  CAS  Google Scholar 

  225. Yang Y-L et al (2012) Comparison of human and soil Candida tropicalis isolates with reduced susceptibility to fluconazole. PLoS ONE 7:e34609–e34609. https://doi.org/10.1371/journal.pone.0034609

    CAS  Article  Google Scholar 

  226. Zarn JA, Brüschweiler BJ, Schlatter JR (2003) Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase. Environ Health Perspect 111:255

    CAS  Article  Google Scholar 

  227. Zarrin M, Faramarzi S (2018) Study of azole-resistant and Cyp51a gene in Aspergillus fumigatus. Maced J Med Sci 6:747

    Article  Google Scholar 

  228. Zavrel M, Esquivel BD, White TC (2014) The ins and outs of azole antifungal drug resistance: molecular mechanisms of transport. Handbook of antimicrobial resistance, pp 1–27

  229. Zavrel M, Esquivel BD, White TC (2017) The ins and outs of azole antifungal drug resistance: molecular mechanisms of transport. Handbook of antimicrobial resistance, pp 423–452

  230. Zgoła-Grześkowiak A, Grześkowiak T (2013) Application of dispersive liquid–liquid microextraction followed by HPLC–MS/MS for the trace determination of clotrimazole in environmental water samples. J Sep Sci 36:2514–2521

    Article  CAS  Google Scholar 

  231. Zheng H et al (2019) In vitro susceptibility of dematiaceous fungi to nine antifungal agents determined by two different methods. Mycoses 62:384–390

    CAS  Article  Google Scholar 

  232. Zonios DI, Bennett JE (2008) Update on azole antifungals. Semin Respir Crit Care Med 29(2):198–210. https://doi.org/10.1055/s-2008-1063858

    Article  Google Scholar 

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Acknowledgements

The authors are thankful to Institute for Nanotechnology and Water Sustainability, UNISA, South Africa for funding. The first author is thankful to Addis Ababa University, Ethiopia, for granting him a study leave.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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HAA: Conceptualized, wrote the manuscript, and prepared all figures. All authors read, commented and approved the manuscript.

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Correspondence to Titus A. M. Msagati.

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Assress, H.A., Selvarajan, R., Nyoni, H. et al. Antifungal azoles and azole resistance in the environment: current status and future perspectives—a review. Rev Environ Sci Biotechnol 20, 1011–1041 (2021). https://doi.org/10.1007/s11157-021-09594-w

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Keywords

  • Occurrence
  • Azole antifungal drugs
  • Azole resistance
  • Future perspectives
  • Fungi
  • Environment