Empirical or preemptive - Infectio

Report
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
www.infectio-lille.com
Potential conflicts of interest



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
What treatment are we talking about ?

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 ?
Empirical antifungal therapy in febrile
neutropenia patients


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
Three large trials:
similar results - few events
Pro/con empirical AF therapy

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
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)
 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
A new strategy: preemptive therapy

Empirical
◦ Fever driven

Pre-emptive
◦ Diagnostic driven
 Biomarkers
 Imaging
◦ Non standardized definition: confusion risk in literature
No consensus on the criteria
for a pre-emptive strategy

Clinical:
◦ Pneumonia

Imaging:
◦ Typical or not?

Biomarkers:
◦
◦
◦
◦

Galactomannan antigenemia
-D glucan
PCR
Mannan, antimannan
Combinations of several criteria ?
Slide courtesy C Cordonnier
Galactomannan and CT-Based
Preemptive Antifungal Therapy
Maertens et al CID 2005; 41:1242–50
Galactomannan and CT-Based
Preemptive Antifungal Therapy

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)
Maertens et al CID 2005; 41:1242–50
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 pulm infiltrate:

B- Empirical antifungal therapy (n=207)
◦ Persistent fever >5 d (w ou w/o PCR+) or pulm infiltrate
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
Hebart et al BMT 2009;43: 553-61
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
Multiple criteria based Preemptive
Antifungal Therapy
Empirical (N=150)
Preemptive (N=143)
P
Fever before ATF (d)
7
13
<.01
Duration of fever (d)
18.3
18.3
NS
Patients with ATF %
62.7
39.2
<10-4
Days of ATF
7.4
4.5
<.01
Survival
97%
95%
NS
Proven/probable IFI
2,7%
9%
<0.02
Cordonnier et al CID 2009 48:1042–51
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, Clin Infect Dis, 2009; 48: 1042-1051
Cordonnier et al CID 2009 48:1042–51
Clinically driven Preemptive Antifungal
Therapy

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)
Girmenia et al., J Clin Oncol, 2010;28:667-74
Observational: Empiric versus “preemptive”

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
PCR/CTscan-Based Preemptive
Antifungal Therapy


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
Morrissey , et al. Lancet ID 2013;13:519
PCR/CTscan-Based Preemptive Antifungal
Therapy
AF use
Mortality
All-cause
IA-related
Other IFI-related
IA incidence
Proven
Probable
Possible
Other IFI incidence
Proven
Probable
Standard group Biomarker group p
(n=122)
(n=118)
39 (32%)
18 (15%)
0·002
18 (15%)
6 (5%)
0
12 (10%)
3 (3%)
2 (2%)
0·31
0·5
0·24
1 (1%)
0
0
1 (1%)
16 (14%)
6 (5%)
1·0
<0·0001
0·013
4 (3%)
0
5 (4%)
1 (1%)
0·75
0·49
Morrissey , et al. Lancet ID 2013;13:519
Enrolling: EORTC 65091 trial

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
What we use in Lille:
best of both worlds !


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
Patterns of IFI in practice
Maertens et al. Haematologica 2012;97:325-327.
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 ?)

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