Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd
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Agricultural triazole fungicides should be withdrawn – PRO Katrien Lagrou , PharmD , PhD.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.

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Agricultural triazole fungicides should be withdrawn – PRO Katrien Lagrou , PharmD , PhD

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Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

Agricultural triazole fungicides should be withdrawn – PROKatrien Lagrou, PharmD, PhD

University Hospitals Leuven and KU Leuven, BELGIUM


Emerging environmental azole resistance

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

1995

2000

2005

2010

2015


Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

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

1995

2000

2005

2010

2015


Routes of resistance development

Routes of resistancedevelopment

Triazole fungicides in agriculture

ENVIRONMENT

TR34/L98H

TR46/Y121F/T289A

PATIENT

Long-term triazole treatment for aspergilloma or cavitary lungdisease

Variety of resistancemechanisms


Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

TR34/L98H

%agricultural fungicide use

TR46/Y121F/T289A

37%

9%

24%

22%

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


Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

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

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

People affected worldwide by A. fumigatus

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


Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

Stockholm, February 2013


Evidence for the environmental route

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

Nucleic acids synthesis


Mitosis and cell division

Mitosis and cell division


Respiration

Respiration


Amino acids and protein synthesis signal transduction

Amino acids and protein synthesis/ Signal transduction


Lipid synthesis and membrane integrity

Lipid synthesis and membrane integrity


Sterol synthesis in membranes

Sterol synthesis in membranes


Cell wall biosynthesis melanin synthesis in cell wall

Cell wall biosynthesis/melanin synthesis in cell wall


Host plant defense induction

Host plant defense induction


Unknown mode of action

Unknown mode of action


Azole resistance also a problem in agriculture

Azole resistance: also a problem in agriculture!


Antifungal agents available to treat invasive fungal infections

Antifungal agents available to treat invasive fungal infections

X


Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

High degree of correlation between ISA and VORI MICs.

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


Problems problems problems

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.


Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

Withdraw agricultural triazole fungicides before resistance in Aspergillus is widespread


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