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Antifungal therapy in haematology patients: Empirical or preemptive ?

3ème Atelier Thématique en Hématologie (ATHEM ) 22 novembre 2013. Antifungal therapy in haematology patients: Empirical or preemptive ?. Dr S. Alfandari Médecin Référent en antibiothérapie et Hygiéniste, CH Tourcoing Infectiologue Consultant, Service des Maladies du sang, CHRU Lille

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Antifungal therapy in haematology patients: Empirical or preemptive ?

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  1. 3ème Atelier Thématique en Hématologie (ATHEM) 22 novembre 2013 Antifungaltherapy in haematology patients:Empirical or preemptive ? Dr S. Alfandari Médecin Référent en antibiothérapie et Hygiéniste, CH Tourcoing Infectiologue Consultant, Service des Maladies du sang, CHRU Lille www.infectio-lille.com

  2. Potentialconflicts of interest • Lectures: Gilead, MSD, Novartis, Pfizer • Meetings: Gilead, MSD, Pfizer, Sanofi • French ID society administrator: Astellas- Astra Zeneca - Gilead - ViivHealthcare - Janssen Cilag - MSD - Sanofi Pasteur MSD - Pfizer - Bayer Pharma - BMS - Abbott - Roche - Novartis – Vitalaire - Biofilm control - GSK - Celestis

  3. Whattreatment are wetalking about ? • All haematology patients • No, that’sprophylaxis • Haematology patients withmycologicalevidence of IFI • No, that’stargetedtreatment • Febrileneutropenia patients • Yes, but which patients ?

  4. Empiricalantifungaltherapy in febrileneutropenia patients • Standard of care since the 2002 IDSA guidelines • Supportingstudies • Pizzo et al. AMJ 1982 • 50 patients withfever & 7 daysbroadspectrum AB randomized to • AB stop/continuing AB/ AB + amphotericin B • Infections: 9/6/2 • EORTC. AMJ 1989 • 132 patients withfever & 4 days AB randomizedw - w/o AmB • 1,5% (n=1) vs 9% IFI (n=6) • No significantdifference in overallmortality

  5. Three large trials: similarresults - few events

  6. Pro/con empirical AF therapy • Pro • Early IFI Rx • Anotherstep in antimicrobialtherapy • Mightdelayescalationtherapy to carbapenems • Psychological support: « weDO something » to treat the fever • Con • Most patients receiveunnecessaryRx: no infection/no IFI • Adverse events • Costs • New diagnostic toolsallow for earlydiagnosis

  7. Why is this a hot issue ? • Decreasing IFI risk in haematology patients • 90’s • 17-25% in AML/allograft (Bodey, EJCMID 1992, Guiot CID 1994) • 00’s • ~10% in AML (Nosary, AJH 2001, Cornely, NEJM 2007) and allograft (Ullmann, NEJM 2007) • Includingarmswithoutmould-active prophylaxisfromrandomized trials • 10’s • Unfrequenteventwithgeneralizedmould-active prophylaxis • <5% • High antifungalcosts • ~830000€/year (1M $) in Lille Haematologydepartment • ~90% of antiinfectivescosts

  8. A new strategy: preemptive therapy • Empirical • Fever driven • Pre-emptive • Diagnostic driven • Biomarkers • Imaging • Non standardizeddefinition: confusion risk in literature

  9. No consensus on the criteriafor a pre-emptive strategy • Clinical: • Pneumonia • Imaging: • Typical or not? • Biomarkers: • Galactomannan antigenemia • -D glucan • PCR • Mannan, antimannan • Combinations of several criteria ? Slidecourtesy C Cordonnier

  10. Galactomannan and CT-Based Preemptive Antifungal Therapy Maertens et al CID 2005; 41:1242–50

  11. Galactomannan and CT-Based Preemptive Antifungal Therapy • 117 febrileepisodes • 30 persistent fever / 28 relapsingfeverwhile ATB • 41 (30%) withempiricalcriteria • 9 have GM Ag + and receive AF • 32 Rx NOT given • 10 non febrileepisodeswithGM Ag + treated • Outcome: • Overallsurvival: 81,9% • 22 IFD with 3 breakthrough infections • 2 non fatal candidemias • One autopsy diagnosed zygomycosis(non febrile) Maertens et al CID 2005; 41:1242–50

  12. PCR-Based Preemptive Antifungal Therapy • 403 allo-HSCT, Day-100 fu, randomized to • AmB-L 3 mg/kg/d • A- PCR monitoring (n=196) • 1x PCR+ or persistent fever >5 d or pulminfiltrate: • B- Empiricalantifungaltherapy (n=207) • Persistent fever >5 d (w ou w/o PCR+) or pulminfiltrate Hebart et al BMT 2009;43: 553-61

  13. Multiple criteria based Preemptive Antifungal Therapy • Drug: AmB or AmB-L daily / CrCl • Empirical arm • Fever driven • Pre-emptive arm • Pneumonia, shock, skin lesions evocative of IFI, sinusitis, orbititis, hepatosplenic abscesses, grade 4 mucositis, • Aspergillus colonization, or one GM Ag + Cordonnier et al CID 2009 48:1042–51

  14. Multiple criteria based Preemptive Antifungal Therapy Cordonnier et al CID 2009 48:1042–51

  15. Multiple criteria based Preemptive Antifungal Therapy Empirical 15 Days Neutropenia Consolidation AML or Auto-HSCT Induction AML Pre-emptive IFI in Pre-emptive IFI in Empirical Cordonnier et al CID 2009 48:1042–51 Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051

  16. Clinically driven Preemptive Antifungal Therapy • Observationalstudy, 146 AL/auto-HSCT pts • 220 neutropenic episodes (NE) • Intensive diagnosis work-up if fever > 4d or recurrent fever • 3 consecutive daily GM, chest CT, etc… • AF if: proven-probable-possible IFI or persistent fever + « clinical deterioration » • AF given: 48 / 159 (30.2%) • 84 / 159 (52.8%) if followingusualguidelines • IFI Proven/probable: 14% (25% high risk patients) Girmenia et al., J Clin Oncol, 2010;28:667-74

  17. Observational: Empiric versus “pre-emptive” • Data collection 397 HM patients • 190 empirical (fever driven) • 207”pre-emptive” (imaging or mycology or non specific lab tests) • More probable/proven IFI in pre-emptive arm • 23.7 vs 7.4% - p<0.001 • Increased IFI mortality in pre-emptive arm • 22.5% vs 7.1% • Limits • Non interventional, diagnostic work up not standardized, candida colonization included in preemptive Pagano et al Haematologica 2011; 96:1363-70

  18. PCR/CTscan-Based Preemptive Antifungal Therapy • 240 AML/allo-HSCT, open label, randomized study • Standard strategy: • Fever => CT scan+/-BAL • Empirical AF till resultsthen back to prophylaxis or up to targeted • Biomarkerstrategy: • PCR/GM Ag + (or persistent fever if negative) => CT scan+/-BA • Preemptive AF if typical images • No AF if atypical or no CT abnormalities Morrissey, et al. LancetID 2013;13:519

  19. PCR/CTscan-Based Preemptive Antifungal Therapy Morrissey, et al. LancetID 2013;13:519

  20. Enrolling: EORTC 65091 trial • Allo HCST/ AML/ALL induction chemo • Fluconazoleprophylaxis for all patients • One (sponsored) drug: caspofungin • Assesment of PCR/GM/BDG • Empirical arm • 4-d fever (or recurringfeverafter 2-d apyrexia) • Pre-emptive arm • GM Ag >0.5 or • Aspergillus sputum culture or • New infiltrate on chest X-ray or • Dense limitedlesion on CT scan

  21. Whatwe use in Lille: best of bothworlds ! • Widespreadposaconazoleprophylaxis • Switched to: • Empiricaltherapy: Fever based &/or • Preemptivetherapy: Biomarkers/imagingbased • Switched back to posaconazoleprophylaxis • For fever/biomarkersbasedRx and no nodules on CT scan

  22. Patterns of IFI in practice Maertens et al. Haematologica 2012;97:325-327.

  23. Conclusion: • Preemptivetherapypromising • AF sparing • IFI mortalityseemslowerthen in empiricalRx • More proven/probable IFI diagnosed • Weneed • A standardizeddefinition of preemptivetherapy • Better diagnostic tools • Standardized PCR • GM assayswith = sensitivity in patients w or w/o posa proph • Shorterdelays for CT scan access (< 48h ?)

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