Optimal Antifungal Prophylaxis The Case for Posaconazole

1
Optimal Antifungal ProphylaxisThe Case for
Posaconazole
Oliver A. Cornely, MD, FIDSA Dep. I for Internal
Medicine Hematology - Oncology Infectious
Diseases Intensive Care Center for Clinical
Trials BMBF 01KN0706 University of Cologne
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Sources of information

• 2 RCT
• Institutional data

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Leukemia Treatment Path
Newly diagnosed Uncontrolled leukemia
Induce remission by induction chemotherapy
Remission achieved ?
Yes
Consolidate remission by consolidation
chemotherapy
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Fluconazole1x 400 mg or Itraconazole2x 200 mg
Posaconazole 3x 200 mg
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Number of Induction Chemotherapies
6
Time to Systemic Antifungal Use
100
75
with systemic antifungal
50
Kaplan-Meier analysis of the time to empiric
systemic antifungal use within the 100-day phase
showed a significant difference in favor of POS
(P .0235)
25
0
0
20
40
60
80
100
Time From Randomization
Posaconazole
Posaconazole censored
Other azole
Other azole censored
Censoring time is the minimum of the last contact
date and day 100
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Posaconazole Prophylaxis Effectively Prevented
Invasive Fungal Infections
P .0009
Posaconazole
12
FLU/ITZ
10
8
8
Incidence of IFIs ()
6
4
2
2
7
25
7/304
25/298
0
IFI During Prophylaxis
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Clinical Success and Reasons for Failure
Patients might have been classified as
experiencing clinical failure for more than 1
reason. Clinical failure included patients
randomly assigned but not treated (posaconazole,
7 2 standard azoles, 6 2). Chi-square
test.
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Overall Mortality Time to Death
1.00
0.75
log rank, P .035
Probability of Survival
0.50
0.25
Posaconazole
FLU/ITZ
0.00
0
20
40
60
80
100
Days after Randomization
Censoring time is last contact or day 100.
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Numbers Needed to TreatPrimary and Secondary
Endpoints in the Neutropenia Trial
All diagnostic procedures applied IFI still
under diagnosed.
Cornely OA, Ullmann AJ. Clin Inf Dis 2008.
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Posaconazole 3x 200 mg
Fluconazole1x 400 mg
Ullmann AJ et al. NEJM 2007.
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Incidence of Proven/Probable IFIs
Posaconazole
Fluconazole
30
P .074
27
25
P .004
P .006
22
20
P .001
21
Number of IFIs
17
15
16
10
7
7
5
3
0
All IFIs
Invasive Aspergillosis
All IFIs
Invasive Aspergillosis
While on treatment
Primary time period 112 days after randomization
Ullmann AJ et al. NEJM 2007.
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Posaconazole Prophylaxis in Real LifeThe Cologne
Institutional Experience
2003-2005 No changes in diagnostic and
therapeutic strategy 2006-2008 Posaconazole
Prophylaxis
? Two time periods for a historic comparison of
AML/MDS patients undergoing 1st induction
chemotherapy
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Current Approach to Febrile Neutropenia
Neutropenia gt10 Days
Rüping MJGT et al. Drugs. 2008.
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Current Approach to Febrile Neutropenia
Neutropenia gt10 Days
CT
Rüping MJGT et al. Drugs. 2008.
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Characteristics
P-test for independent samples (two-sided)
Fishers exact test (two-sided)Granulocyte
colony stimulating factor
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Endpoints
18
Other Clinical Endpoints
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Pharmacokinetic Aspects
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PK of Posaconazole AML Induction
t-test. White vs nonwhite.
Cornely et al. ICAAC 2006.
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Posaconazole Plasma Levels Were Similar in
Patients With and Without IFIs
Krishna G, et al. Pharmacotherapy.
2008281223-1232.
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Posaconazole Plasma Concentrations in
AML/MDSCologne Cohort
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Posaconazole Distribution into Pulmonary
Components Steady State Levels in Healthy
Volunteers
Alveolar cells
Pulmonary epithelial lining fluid
Posaconazole Concentration, µg/mL
10000
Plasma
MIC90 Aspergillus spp
1000
100
10
Hours Following Last Dose
1
0.1
0.01
0
2
4
6
8
10
12
14
16
18
20
22
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Conte JE et al. Antimicrob Agents Chemother.
200953703-707.
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Posaconazole Concentrations in Peripheral Blood
Compartments

• PBMC (n23), PMN (n20), RBC (n22), plasma
  (n23) p.01, unpaired t-test plt.001

Farowski F et al. TIMM-4, Athens, 2009.
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Posaconazole Prophylaxis Undefined Areas

• Patient groups outside the RCTs
• Remission consolidation chemotherapy
• Neutropenic allogeneic SCT
• Other neutropenic, e.g. aplastic anemia, CLL,
  pallative AML or MDS
• Pharmacokinetics
• Is there a cut-off plasma concentration?
• Bridging with IV during periods of e.g. nausea
• Antifungal strategy
• Persistent fever
• Possible breakthrough IFI