Lagrou Azole resistance in aspergillosis 13052019 · 2019. 5. 24. · azole-resistant isolates from...
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Azole resistance in aspergillosis
Katrien Lagrou, PharmD, PhD
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Introduction
Aspergillus is ubiquitously present in the environment (air, soil, compost, water, ….)
• Broad range of diseases: acute invasive infections, chronic invasive infections, chronic non-invasive forms, allergic syndromes
• >200,000 life-threatening infections/year worldwide• Mortality rates >25%• Azoles are the preferred antifungal agents for prophylaxis and targeted
treatment
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Prevalence of triazole resistance in Aspergillus fumigatus
Image courtesy of Bram Lestrade
• No standardized methodology (all isolates/isolates from invasive aspergillosis, ..)• Total incidence of IA not available to calculate % of IA with an azole resistant isolate
A. Alanio et al, JAC 2016, 71: 2075-2078.
BUT
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Resistance development in patients
Long-term triazole treatment for aspergilloma or cavitary lung disease
Variety of resistance mechanisms
• High genetic diversity between azole-resistant isolates from unrelated patients
• Lack of sporulation and reduced growth rate may occur
Patient route
Medical azoles
Triazole resistance development: ‘patient and environmental route’
Adapted from Wageningen University and Research. Available at: www.wur.nl/upload_mm/d/7/c/7191fc8f-15cf-4b1d-984b-653a0c9db27b_Hotspot-NE-1000x1227.png. (Accessed April 2019).Verweij PE, et al. Clin Infect Dis 2016;62:362–8.
TR34/L98HTR46/Y121F/T289A
• Patients with invasive aspergillosis and chronic aspergillus diseases
• Low genetic diversity between azole-resistant isolates from unrelated patients
• No apparent fitness cost
Environmental route
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Environmental resistance modifications
ITRA VOR POS
R Garcia-Rubio et al, Drugs 2017, Feb 24
Tandem repeats in the promoter and associated point mutations in the azole target gene (cyp51A) in A. fumigatus
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Hot spot acquired single point mutations
R Garcia-Rubio et al, Drugs 2017, Feb 24
Three most commonly described single-point mutations in the azole target gene (cyp51A) in A. fumigatus
ITRA VOR POS
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Year of first recovery of TR34/L98H and TR46/Y121F/T289A resistance mechanisms in A. fumigatus
PE Verweij et al, CID 2016, 62:362-368.
TR34/L98H
1998
2004
2005 2008-2009
2008
2011
2015
2010
TR46/Y121F/T289A
20082009
2012
20132015
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2016 2017 2018No. % No. % No. %
A. fumigatusNumber of strains screened 490 100 537 100 531 100Growth on VIP Check 46 9.4 33 6.1 38 7.2Susceptibility testing
Resistant 39 8.0 26 4.8 31 5.8Susceptible 2 0.4 4 0.7 7 1.3Not performed 5 1.0 3 0.6 0 0.0
Resistance mechanismsNo CYP51A mutation 5 12.8 8 30.8 3 9.7
CYP51A gene mutationTR34/L98H 29 74.4 14 53.8 23 74.2TR34/L98H/S257T/F495I 1 2.6 0 0 0 0TR46/Y121F/T298A 4 10.3 2 7.7 3 9.7G54W 0 0 0 0 1 3.2G54E/G513A 0 0 1 3.8 0 0Other 0 0 1 3.8 1 3.2
Triazole resistance data UZ Leuven
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Triazole-resistant aspergillosis in patients with hematological malignancies: retrospective cohort study from Nijmegen
Consecutive patients during 2006-2012 (n= 432):• receiving chemotherapy for AML or MDS (n=182)• allo HSCT (n=250)
Screening of all isolates for triazole resistance
Proven/probable invasive aspergillosis (n=36)
Culture of Aspergillus fumigatus from respiratory sample (n=12)
Triazole resistance (n=2)
16.7% (HIGH !!!)
5.5%
PP. Lestrade et al. JAC 2018, 73: 1389-1394.
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Triazole resistance in hematological patients in UZ Leuven
17% resistance
A.R. Sharpe and T. Mercier et al., oral presentation, 14th Fungal Update, London.
17% resistance
3% resistance
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‘Hotspots’ for triazole resistance selection in A. fumigatus
Specific conditions and sites are thought to exist in the environment that facilitate the emergence, amplification and spread of triazole-resistant mutations in A. fumigatus (‘hotspots’)Hotspot characteristics according to experts: Ability of A. fumigatus to grow and complete its lifecycle (to achieve genetic diversity) Presence of azole residues with activity against A. fumigatus
A. fumigatus +++Azole fungicides +++Azole R: 6.2 – 24.5%
Tweede Kamer. Available at: https://www.tweedekamer.nl/kamerstukken/brieven_regering/detail?id=2017Z16992&did=2017D35356. (Accessed April 2019).
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‘Hotspots’ for triazole resistance selection in A. fumigatus
Professional green composting
A. fumigatus +++ (timing dependent)Azole fungicides +Azole R: 8.5 – 30%
A. fumigatus +++Azole fungicides +Azole R: 5.8 – 20%
Tweede Kamer. Available at: https://www.tweedekamer.nl/kamerstukken/brieven_regering/detail?id=2017Z16992&did=2017D35356. (Accessed April 2019).
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CULTURE
MOLECULAR
Detection of triazole resistance in patient samples
But >50% of cultures remain negative in invasive
aspergillosis patients
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Broth dilution
EUCAST
Azole resistance screening-agar
• Home made• VIPcheckTM
CULTURE
J. Guinea et al. CMI 2018. Epub ahead of print.
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http://www.eucast.org/clinical_breakpoints/Version 8.1, valid from 2017-03-01
A. Espinel-Ingroff et al, AAC 2011, 55: 5150-515A. Espinel-Ingroff et al, AAC 2013, 57: 3823-3828A. Espinel-Ingroff et al, JCM 2010, 48: 3251-3257
Interpretation of susceptibility testing results
A. fumigatus A. flavus A. nigerS≤ R> S≤ R> S≤ R>
Amphotericin B EUCAST 1a 2 4b 1 2CLSI 2/4 2/4 2
Itraconazole EUCAST 1 2 1 2 4CLSI 1 1 2
Voriconazole EUCAST 1 2 2 2CLSI 1 1 2
Posaconazole EUCAST 0.125 0.25 0.5 0.5CLSI 0.5 0.25 0.5
Isavuconazole EUCAST 1 1 2 4CLSI 1 1 4
a clinical breakpoint b ECV, epidemiological cutoff value
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E. Kolwijck et al. Am J Respir Crit Care Med 2016 Apr 15;
Coinfections of voriconazole-susceptible and voriconazole-resistant Aspergillus fumigatus
ICU, influenza
Kidney Tx
Kidney Tx
Voriconazole-resistant strains were genetically different from voriconazole susceptible strains precluding resistance development during therapy
Screen multiple isolates if available!
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43% were culture negative
Detection of resistance associated mutations was associated with
azole treatment failure
Resistance multiplex – L98H – TR34 – T289A – Y121F
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Mortality
Day 42
VCZ‐S 28%VCZ‐R 49%p=0.017
Day 90
VCZ‐S 37%VCZ‐R 62%p=0.0038
Impact of triazole resistance on mortality
159
37
VCZ S VCZ R
• Retrospective cohort study 2011 – 2015• 3 university medical centers, The Netherlands (Radboudumc – LUMC – Erasmus MC)• All patients with A. fumigatus culture positive invasive aspergillosis (N=196)
21%
19% triazole resistance prevalence
Lestrade P, et al. Clin Infect Dis 2018;10.1093/cid/ciy859.
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Management of patients with IA in regions with no/minimal azole resistance in the environment
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Management of patients with IA in regions with ≥ 10% environmental resistance
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Management of patients with IA in regions with ≥ 10% environmental resistance
10%
AZOLE RESISTANCE
HIGHER EFFECTIVENESS OF
VORICONAZOLE
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Dutch Working Party on Antibiotic Policy: guideline
https://www.nvmm.nl/media/1424/p-medische-microbiologie-nvmm-nvmm-richtlijnen-richtlijnen-170815-swab-richtlijn-mycosen-2017-draft-aug17.pdf
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Need for (oral) antifungal agents to treat (triazole resistant) invasive fungal infections
Binding with ergosterolAmphotericin B and lipid formulations IV
Sterol biosynthesis - triazolesFluconazoleItraconazoleVoriconazolePosaconazoleIsavuconazole
O/IV
Cell wall biosynthesisCaspofunginAnidulafungin
MicafunginIV
Nucleic acid synthesisFlucytosine O/IV
X
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Promising antifungal drugs are in the pipeline
Buil JB et al. J Antimicrob Chemother. 2017;72:2548-2552
Olorofim showed potent and consistent in vitro activity against difficult-to-treat Aspergillus spp. with intrinsic and acquired antifungal resistance due to known and unknown resistance mechanisms.
Olorofim (F901318): acts via inhibition of fungal DHODH, a key enzyme in pyrimidine biosynthesis
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Conclusions
• Epidemiology of triazole resistance is evolving in Aspergillus fumigatus
• All isolates from patients who are treated for aspergillosis should be checked for triazole resistance
• Culture is unsuccessful in many patients with aspergillosis, PCR is helpful to detect the most common resistance mechanisms directly in the samples from these patients
• Are there hotspots for triazole resistance development in Belgium?• Reassessment of the handling of organic waste focusing on conditions that
reduce the growth of Aspergillus fumigatus are recommended