Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd
Sponsored Links
This presentation is the property of its rightful owner.
1 / 25

Agricultural triazole fungicides should be withdrawn – PRO Katrien Lagrou , PharmD , PhD PowerPoint PPT Presentation

  • Uploaded on
  • Presentation posted in: General

Agricultural triazole fungicides should be withdrawn – PRO Katrien Lagrou , PharmD , PhD. University Hospitals Leuven and KU Leuven , BELGIUM. Emerging environmental azole resistance. Few sporadic resistant isolates in Sweden, Spain, France and UK.

Download Presentation

Agricultural triazole fungicides should be withdrawn – PRO Katrien Lagrou , PharmD , PhD

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript

Agricultural triazole fungicides should be withdrawn – PROKatrien Lagrou, PharmD, PhD

University Hospitals Leuven and KU Leuven, BELGIUM

Emerging environmental azole resistance

Few sporadic resistant isolates in Sweden, Spain, France and UK

  • Series of Dutch patients – including azole naïve patients- with invasive aspergillosis due to pan-azole-resistant strains

  • Resistance attributed to one predominant resistance mechanism, TR34/L98H

  • Verweij, NEJM 2007

Isolates with TR34/L98H reported from Denmark, Norway, Belgium, UK, Spain, France, Germany, Italy, China, India and Iran

Itraconazole resistance in 2 cases

Denning, AAC 1997






Emerging environmental azole resistance

  • New environmental CYP51A-mediated resistance mechanism in the Netherlands, TR46/Y121F/T289A associated with voriconazole therapy failure

  • High-grade voriconazole resistance, variable itraconazole MICs

  • Van der Linden, CID 2013

Isolates with TR46/Y121F/T289A reported from Belgium, India and Germany






Routes of resistancedevelopment

Triazole fungicides in agriculture





Long-term triazole treatment for aspergilloma or cavitary lungdisease

Variety of resistancemechanisms


%agricultural fungicide use






CR Stensvold et al. CurrFungal Infect Rep 2012, 6: 141-153.

Most identical docking with medical triazoles

1998: first TR34/L98H isolate cultured

Evolution analysis of microsatellite genotypes:

TR34/L98H developed from a single ancestor that emerged around 1997

PublishedMarch 1, 2012

Clinical implications of azole resistance in A. fumigatus

  • Prospective nationwide multicenter study (2007-2009)

  • 2062 isolates from 1385 patients

  • Prevalence itraconazole resistance in A. fumigatus = 5,3 %

  • Patients with hematologic or oncologic disease more likely to harbor azole resistant isolate

  • 64% azole naive

  • Case fatality rate 88%

J. Van der Linden et al, EID 2011, 17: 1846-1854.

People affected worldwide by A. fumigatus

D. Denning and P. Bowyer, CID 2013, 57: 521-523.

Stockholm, February 2013

Evidence for the environmental route

  • Azole resistance observed in azole naïve patients.

  • No isogenic isolates with a wild-type phenotype has been recovered from patients infected with an Aspergillus isolate with TR34/L98H or TR46/Y121F/T289A.

  • Dominant resistance mechanisms with two or three genomic changes.

  • Isolates with the same resistance mechanisms are found in the environment.

  • Several triazole fungicides used in agriculture have a similar molecular structure to medical triazoles.

Nucleic acids synthesis

Mitosis and cell division


Amino acids and protein synthesis/ Signal transduction

Lipid synthesis and membrane integrity

Sterol synthesis in membranes

Cell wall biosynthesis/melanin synthesis in cell wall

Host plant defense induction

Unknown mode of action

Azole resistance: also a problem in agriculture!

Antifungal agents available to treat invasive fungal infections


High degree of correlation between ISA and VORI MICs.

L. Gregson et al., AAC 2013, 57: 5778-5780

Problems – problems – problems …..

  • Isolate is only available in about 50% of patients for susceptibility testing.

  • Triazole resistance severely limits treatment options.

    • Treatment of central nervous system aspergillosis: better outcome with voriconazole compared to other drugs. (Schwartz et al., Blood, 2005, 106: 2641-2645).

    • Treatment of chronic Aspergillus diseases: azoles are only class that can be administered orally.

  • Pan-azole resistance or voriconazole highly resistant.

  • Resistant isolates with cyp51A mutations are not less virulent.

  • New resistant mechanisms evolve and spread.

Withdraw agricultural triazole fungicides before resistance in Aspergillus is widespread

  • Login