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Optimal Antifungal ProphylaxisThe Case for Posaconazole
Oliver A. Cornely, MD, FIDSA
Dep. I for Internal MedicineHematology - Oncology
Infectious Diseases – Intensive Care
Center for Clinical TrialsBMBF 01KN0706
University of Cologne
Sources of information
• 2 RCT
• Institutional data
Leukemia Treatment Path
Newly diagnosed = Uncontrolled leukemia
Induce remission by „induction chemotherapy“
Remission achieved ?
Yes
No
Consolidate remission by „consolidation chemotherapy“
Posaconazole3x 200 mg
Fluconazole1x 400 mg
orItraconazole2x 200 mg
Number of Induction Chemotherapies
POS(n = 304)
FLU/ITZ(n = 298)
n (%)
1 174 (57) 182 (61)
2 96 (32) 89 (30)
≥3 34 (11) 27 (9)
Time to Systemic Antifungal Use
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)
100
75
50
0
25
0 20 40 60 80 100
% w
ith
sys
tem
ic a
nti
fun
ga
l
Time From Randomization
PosaconazoleOther azole
Posaconazole – censoredOther azole – censored
Censoring time is the minimum of the last contact date and day 100
Posaconazole Prophylaxis Effectively Prevented Invasive Fungal Infections
P =.0009
7/304 25/298
2%
8%
0%
2%
4%
6%
8%
10%
12%
IFI During Prophylaxis
Inci
den
ce o
f IF
Is (
%) Posaconazole
FLU/ITZ
7 25
Clinical Response, n (%)Posaconazole
(n = 304)
Standard Azoles
(n = 298) P† 95% CI
Clinical success 195 (64) 160 (54)
Clinical failure* 109 (36) 138 (46) .009 –18.3% to –
2.6%
Proven or probable invasive fungal infection
7 (2) 25 (8) <.001 –9.7% to – 2.5%
Use of systemic antifungal for 4 consecutive days for suspected/probable/proven invasive fungal infection
68 (22) 101 (34) .002 –18.7% to –
4.3%
Related adverse event leading to study drug discontinuation
25 (8) 25 (8) 0.94 —
Use of IV study drug for 4 consecutive or 10 total days
6 (2) 12 (4) 0.14 —
Withdrawal from study for any reason and loss to follow-up
8 (3) 1 (<1) .02 0% to 4.2%
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.
Overall Mortality – Time to Death
log rank, P = .035
Pro
bab
ilit
y o
f S
urv
ival
1.00
0.75
0.50
0.00
0.25
0 20 40 60 80 100Days after Randomization
PosaconazoleFLU/ITZ
Censoring time is last contact or day 100.
Numbers Needed to TreatPrimary and Secondary Endpoints in the Neutropenia Trial
Cornely OA, Ullmann AJ. Clin Inf Dis 2008.
All diagnostic procedures applied – IFI still under diagnosed.
Posaconazole3x 200 mg
Fluconazole1x 400 mg
Ullmann AJ et al. NEJM 2007.
Incidence of Proven/Probable IFIs
0
5
10
15
20
25
30
Posaconazole Fluconazole
Nu
mb
er
of
IFIs
All IFIs Invasive Aspergillosis
P = .004
P = .001
While on treatment
7
22
3
17
All IFIs Invasive Aspergillosis
P = .074
P = .006
Primary time period112 days after randomization
27
16
7
21
Ullmann AJ et al. NEJM 2007.
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
Current Approach to Febrile Neutropenia
Neutropenia >10 Days
Fever >72h or Galactomannan positive
Posaconazole Prophylaxis
Rüping MJGT et al. Drugs. 2008.
Neutropenia >10 Days
Fever >72h or Galactomannan positive
Posaconazole Prophylaxis
Empiric Treatment
CT
BAL
Rüping MJGT et al. Drugs. 2008.
Current Approach to Febrile Neutropenia
TargetedTreatment
Characteristics
Topical polyene
(N= 82)
Posaconazole
(N= 77)
P
Age (Years) Mean
Median
Range
52 14.1
54
18 – 76
54 13.5
55
19 – 75
NS*
Female – no. (%) 32 (39.0%) 42 (54.5%) NS†
Neutropenic Days Mean
Median
Range
31.2 12.99
28
5 – 89
32.8 11.54
32
10 – 66
NS*
G-CSF‡ (no. [%]) 43 (52.4%) 27 (35.1%) 0.037†
*P-test for independent samples (two-sided) †Fisher’s exact test (two-sided)‡Granulocyte colony stimulating factor
Endpoints
100= 6.4
19.5% – 3.9%
Other Clinical Endpoints
Pharmacokinetic Aspects
PK of Posaconazole – AML InductionPatient Characteristic P Value*
Age .4637
Sex .3242
Race .0028†
Baseline body weight .1716
Baseline BSA .1157
GGT .0184
Liver enzymes .4077
Mucositis .6409
Neutropenia .4575
Diarrhea <.0001
Vomiting .5561
H2 receptor antagonist use .5887
PPI use .0010*t-test.†White vs nonwhite. Cornely et al. ICAAC 2006.
Posaconazole Plasma Levels Were Similar in Patients With and Without IFIs
Krishna G, et al. Pharmacotherapy. 2008;28:1223-1232.
Posaconazole Plasma Concentrations in AML/MDSCologne Cohort
Posaconazole Distribution into Pulmonary Components: Steady State Levels in Healthy Volunteers
0.01
0.1
1
10
100
1000
10000
0 2 4 6 8 10 12 14 16 18 20 22 24
Po
saco
naz
ole
Co
nce
ntr
atio
n,
μg
/mL
Hours Following Last Dose
Alveolar cells
Pulmonary epithelial lining fluidPlasmaMIC90 Aspergillus spp
Conte JE et al. Antimicrob Agents Chemother. 2009;53:703-707.
Posaconazole Concentrations in Peripheral Blood Compartments
Farowski F et al. TIMM-4, Athens, 2009.
PBMC PMN RBC Plasma1
10
100
1000
10000
100000
***
***
*
PS
C c
on
cen
trat
ion
[mg
/mL
]
PBMC (n=23), PMN (n=20), RBC (n=22), plasma (n=23); *p=.01, unpaired t-test; ***p<.001
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
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