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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 - PowerPoint PPT Presentation
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3ème Atelier Thématique en Hématologie (ATHEM)22 novembre 2013
Dr S. AlfandariMédecin Référent en antibiothérapie et Hygiéniste, CH TourcoingInfectiologue Consultant, Service des Maladies du sang, CHRU Lillewww.infectio-lille.com
Antifungal therapy in haematology patients:Empirical or preemptive ?
Lectures: Gilead, MSD, Novartis, Pfizer Meetings: Gilead, MSD, Pfizer, Sanofi French ID society administrator:
Astellas - Astra Zeneca - Gilead - Viiv Healthcare - Janssen Cilag - MSD - Sanofi Pasteur MSD - Pfizer - Bayer Pharma - BMS - Abbott - Roche - Novartis – Vitalaire - Biofilm control - GSK - Celestis
Potential conflicts of interest
All haematology patients◦ No, that’s prophylaxis
Haematology patients with mycological evidence of IFI◦ No, that’s targeted treatment
Febrile neutropenia patients◦ Yes, but which patients ?
What treatment are we talking about ?
Standard of care since the 2002 IDSA guidelines Supporting studies ◦ Pizzo et al. AMJ 1982
50 patients with fever & 7 days broad spectrum AB randomized to AB stop/continuing AB/ AB + amphotericin B
Infections: 9/6/2◦ EORTC. AMJ 1989
132 patients with fever & 4 days AB randomized w - w/o AmB 1,5% (n=1) vs 9% IFI (n=6) No significant difference in overall mortality
Empirical antifungal therapy in febrile neutropenia patients
Three large trials: similar results - few events
Pro◦ Early IFI Rx◦ Another step in antimicrobial therapy
Might delay escalation therapy to carbapenems Psychological support: « we DO something » to treat the fever
Con◦Most patients receive unnecessary Rx: no infection/no IFI◦ Adverse events◦ Costs◦ New diagnostic tools allow for early diagnosis
Pro/con empirical AF therapy
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) Including arms without mould-active prophylaxis from randomized trials
◦ 10’s Unfrequent event with generalized mould-active prophylaxis
<5% High antifungal costs◦ ~830000€/year (1M $) in Lille Haematology department◦ ~90% of antiinfectives costs
Why is this a hot issue ?
Empirical◦ Fever driven
Pre-emptive◦ Diagnostic driven
Biomarkers Imaging
◦ Non standardized definition: confusion risk in literature
A new strategy: preemptive therapy
Clinical:◦ Pneumonia
Imaging:◦ Typical or not?
Biomarkers:◦ Galactomannan antigenemia◦ -D glucan◦ PCR◦Mannan, antimannan
Combinations of several criteria ?
No consensus on the criteriafor a pre-emptive strategy
Slide courtesy C Cordonnier
Galactomannan and CT-Based Preemptive Antifungal Therapy
Maertens et al CID 2005; 41:1242–50
117 febrile episodes 30 persistent fever / 28 relapsing fever while ATB
◦ 41 (30%) with empirical criteria◦ 9 have GM Ag + and receive AF
32 Rx NOT given 10 non febrile episodes with GM Ag + treated Outcome:◦ Overall survival: 81,9%◦ 22 IFD with 3 breakthrough infections
2 non fatal candidemias One autopsy diagnosed zygomycosis (non febrile)
Galactomannan and CT-Based Preemptive Antifungal Therapy
Maertens et al CID 2005; 41:1242–50
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 pulm infiltrate:
B- Empirical antifungal therapy (n=207)◦ Persistent fever >5 d (w ou w/o PCR+) or pulm infiltrate
PCR-Based Preemptive Antifungal Therapy
Hebart et al BMT 2009;43: 553-61
PCR Empirical p
N treated 112 (57.1%) 76 (36.7%) 0.003
N proven/probable IFI 16 17 NS
N death D30 4 (1.5%) 13 (6.3%) 0.015
N total death D100 32 34 NS
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 +
Multiple criteria based Preemptive Antifungal Therapy
Cordonnier et al CID 2009 48:1042–51
Multiple criteria based Preemptive Antifungal Therapy
Empirical (N=150) Preemptive (N=143) P
Fever before ATF (d) 7 13 <.01Duration of fever (d) 18.3 18.3 NSPatients with ATF % 62.7 39.2 <10-4
Days of ATF 7.4 4.5 <.01Survival 97% 95% NSProven/probable IFI 2,7% 9% <0.02
Cordonnier et al CID 2009 48:1042–51
Empirical
Pre-emptive
IFI in Pre-emptive
IFI in Empirical
Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051
15 Days Neutropenia
Induction AML
Consolidation AMLor
Auto-HSCT
Multiple criteria based Preemptive Antifungal Therapy
Cordonnier et al CID 2009 48:1042–51
Observational study, 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 following usual guidelines
IFI Proven/probable: 14% (25% high risk patients)
Clinically driven Preemptive Antifungal Therapy
Girmenia et al., J Clin Oncol, 2010;28:667-74
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
Observational: Empiric versus “pre-emptive”
Pagano et al Haematologica 2011; 96:1363-70
240 AML/allo-HSCT, open label, randomized study Standard strategy:
Fever => CT scan+/-BAL Empirical AF till results then back to prophylaxis or up to targeted
Biomarker strategy: PCR/GM Ag + (or persistent fever if negative) => CT scan+/-BA Preemptive AF if typical images No AF if atypical or no CT abnormalities
PCR/CTscan-Based Preemptive Antifungal Therapy
Morrissey , et al. Lancet ID 2013;13:519
PCR/CTscan-Based Preemptive Antifungal Therapy
Morrissey , et al. Lancet ID 2013;13:519
Standard group (n=122)
Biomarker group (n=118)
p
AF use 39 (32%) 18 (15%) 0·002
MortalityAll-cause 18 (15%) 12 (10%) 0·31IA-related 6 (5%) 3 (3%) 0·5Other IFI-related 0 2 (2%) 0·24
IA incidenceProven 1 (1%) 1 (1%) 1·0Probable 0 16 (14%) <0·0001Possible 0 6 (5%) 0·013
Other IFI incidenceProven 4 (3%) 5 (4%) 0·75Probable 0 1 (1%) 0·49
Allo HCST/ AML/ALL induction chemo◦ Fluconazole prophylaxis for all patients◦ One (sponsored) drug: caspofungin◦ Assesment of PCR/GM/BDG
Empirical arm◦ 4-d fever (or recurring fever after 2-d apyrexia)
Pre-emptive arm◦ GM Ag >0.5 or◦ Aspergillus sputum culture or ◦ New infiltrate on chest X-ray or◦ Dense limited lesion on CT scan
Enrolling: EORTC 65091 trial
Widespread posaconazole prophylaxis Switched to:◦ Empirical therapy: Fever based &/or◦ Preemptive therapy: Biomarkers/imaging based
Switched back to posaconazole prophylaxis◦ For fever/biomarkers based Rx and no nodules on CT scan
What we use in Lille: best of both worlds !
Maertens et al. Haematologica 2012;97:325-327.
Patterns of IFI in practice
Conclusion:
Preemptive therapy promising◦ AF sparing◦ IFI mortality seems lower then in empirical Rx◦More proven/probable IFI diagnosed
We need◦ A standardized definition of preemptive therapy◦ Better diagnostic tools
Standardized PCR GM assays with = sensitivity in patients w or w/o posa proph
◦ Shorter delays for CT scan access (< 48h ?)