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Aspergillus Resistance

Aspergillus Resistance. Don Sheppard M.D. Associate Professor, Dept of Microbiology and Immunology Director, Division of Infectious Diseases McGill University. Conflict of Interest Statement. Dr Sheppard has received research support or been a consultant for: Pfizer Canada

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Aspergillus Resistance

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  1. Aspergillus Resistance Don Sheppard M.D. Associate Professor, Dept of Microbiology and Immunology Director, Division of Infectious Diseases McGill University

  2. Conflict of InterestStatement Dr Sheppard has received research support or been a consultant for: Pfizer Canada Astellas Canada, Merck Canada

  3. Azole resistance in Aspergillus Many questions! • Should I be concerned? • How do I look for it? • How do I treat it? • Can I still use prophylaxis?

  4. Types of resistance Intrinsic • Species whose MIC distibution is elevated Acquired • Primary • Environmental acquisition of resistance in a normally sensitive strain • Linked to environmental fungicide use in Europe • Secondary • Emergence during therapy • Most commonly in chronic pulmonary aspergillosis

  5. Intrinsic resistance • Elevated azole MICs are observed in many non-fumigatus species • Usti group • A. calidoustus – MIC>8 all azoles • Often resistant to other antifungals also • Nigiri group • Some show elevated MICs • Poor correlation with species identity Seyedmousavi & Verweij, In Handbook of Antimicrobial Resistance 2015

  6. Acquired Primary (Environmentally acquired) • First described in Netherlands • Genotype clustering suggests clonal origin • Combined mutations in promotor and coding sequence of CYP51A • TR34/L98H best studied • VCZ >2, PCZ 0.5, ITRA >16 • Now reported in Europe, India and China • TR46/Y121F/T289A • Newest mutation • Spreading rapidly in Europe; Environmental strains in India • VCZ MIC >16, PCZ 0.25-2, ITRA = 4-16 Verweijj et al. Lancet ID, 2009:59(3);789-95 Van der Linden et al, CID 2013:57; 513-20

  7. Acquired Secondary (during therapy) • Most common reported in chronic infections • Incidence also increasing – up to 20% of patients in Manchester, UK • Heterogenous genotypes and mechanisms • CYP51a mutations in less than half of patients • Isolated PCZ/ITRA resistance common • G54R, P216L and G448S • Preserved susceptibility to VCZ • M220 • Variable VCZ susceptibility Howard et al. EID, 2009:15(7);1068-76 Bueid et al., JAC 2010:65; 2116–2118

  8. Epidemiology of resistance 20% in 2009 Seyedmousavi & Verweij, In Handbook of Antimicrobial Resistance 2015

  9. Challenges in diagnosis • IA now commonly diagnosed by GM or other molecular testing • Culture is insensitive (~30% for BAL) • MIC testing not available in many centres • When available, turn around time is long • Molecular based detection of resistant isolates is not standardized and rarely available • Forced to rely on local epidemiology and analysis of clinical failures

  10. Management

  11. Clinical data • High failure rate in treatment of successful strains makes clinical correlation challenging • Multiple reports of clinical failure on therapy with voriconazole • Resistance associated with increased mortality in several studies when initially treated with voriconazole • Majority of patients succesfully treated to date received L-AMB

  12. Clinical data • High failure rate in treatment of successful strains makes clinical correlation challenging • Multiple reports of clinical failure on therapy with voriconazole • Resistance associated with increased mortality in several studies when initially treated with voriconazole • Majority of patients succesfully treated to date received L-AMB

  13. Voriconazoleuse for Treatment • ƒAUC in HSCT patients: ~ 15-20 • For resistant strains (MIC = 2): ƒAUC/MIC = 7-10 • Activity < 35% of expected Mavridou et al, AAC 2010:54(11):4758-64

  14. Posaconazole: Treatment • Multiple studies have examined Pk/Pd of posaconazole in mouse models • Different endpoints – fungal burden vs survival • Target endpoints identified AUC/MIC: 167 or 100 Lewis et al, AAC 2014:58(11):6767-72 Howard et al, JID, 2011;203:1324–32

  15. Predicted Posaconazole Exposure-Response: low MIC • AUC suspension ~ 15μg/ml • AUC tablet ~ 35μg/ml Tablet Lewis et al, AAC 2014:58(11):6767-72 Howard et al, JID, 2011;203:1324–32

  16. Predicted Posaconazole Exposure-Response: Sensitive, high MIC • AUC suspension ~ 15μg/ml • AUC tablet ~ 35μg/ml Tablet Lewis et al, AAC 2014:58(11):6767-72 Howard et al, JID, 2011;203:1324–32

  17. Predicted Posaconazole Exposure-Response: Resistant • AUC suspension ~ 15μg/ml • AUC tablet ~ 35μg/ml Tablet Lewis et al, AAC 2014:58(11):6767-72 Howard et al, JID, 2011;203:1324–32

  18. What about prophylaxis? • Studies suggest cellular levels may be more important to mediate protection against infection • Tissue levels are significantly higher than serum levels • Should we be using the same targets? • Can these be achieved with tablet formulations?

  19. In vitro model of the human alveolus Simulates two compartments: • alveolar airspace • pulmonary capillary Hope (2009) Med. Mycology S291-S298

  20. Dynamic Model of Antifungal Prophylaxis Infect alveolar space with conidia Antifungal Sample media for antifungal and galactomannan concentrations Pump

  21. Dynamic in vitro model of posaconazole prophylaxis Model of human pharmacokinetics/pharmacodynamics Challenge Peak concentration of 0.45 mg/L is protective

  22. Dynamic in vitro model of posaconazole prophylaxis against an TRL98H isolate Challenge Peak concentration is protective, although sustained levels of 0.45μg/ml are required

  23. Posaconazoleprophylaxis PK/PD in mice No loss of activity noted with TRL98H strains, only with strains MIC>16 Seyedmousavi et al. AAC 2015:59(3)1487-94

  24. Prophylaxis and Treatment Pk Targets Differ Treatment targets higher than those for prophylaxis Seyedmousavi et al. AAC 2015:59(3)1487-94

  25. Posaconazoleas prophylaxis for resistant A. fumigatus Protection from high dose conidial exposure (~1x107/ mouse) MIC =0.5 Seyedmousavi et al. AAC 2015:59(3)1487-94

  26. L-AMB treatment of azole resistant strains VCZ MIC 0.25 0.5 4 16 Seyedmousavi et al. AAC 2013:57(4)1866-71

  27. When to switch empiric therapy: How effective is L-AmB ? 12 wk Survival VCZ - 70.8% AmB - 57.9% L-AMB? Bart-Jan Kullberg, 2013

  28. Overall Conclusions and Perspectives • Resistance is emerging • VCZ not drug of choice • Posa prophylaxis effective at least to MIC 0.5 • Posa role in treatment less clear – higher targets • L-AMB is probably best for treatment • When to switch empiric therapy? • Local epidemiology • Difference in efficacy between VCZ and L-AMB?

  29. Thank you !

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