Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd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Agricultural triazole fungicides should be withdrawn – PRO Katrien Lagrou , PharmD , PhD.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Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd

Agricultural triazole fungicides should be withdrawn – PROKatrien Lagrou, PharmD, PhD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Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd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Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd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Agricultural triazole fungicides should be withdrawn pro katrien lagrou pharmd phd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








Cell wall biosynthesis melanin synthesis in cell wall
Cell wall biosynthesis/melanin synthesis in cell wall




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