optimal antifungal prophylaxis the case for posaconazole oliver a. cornely, md, fidsa dep. i for...
TRANSCRIPT
![Page 1: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/1.jpg)
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
![Page 2: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/2.jpg)
Sources of information
• 2 RCT
• Institutional data
![Page 3: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/3.jpg)
Leukemia Treatment Path
Newly diagnosed = Uncontrolled leukemia
Induce remission by „induction chemotherapy“
Remission achieved ?
Yes
No
Consolidate remission by „consolidation chemotherapy“
![Page 4: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/4.jpg)
Posaconazole3x 200 mg
Fluconazole1x 400 mg
orItraconazole2x 200 mg
![Page 5: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/5.jpg)
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)
![Page 6: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/6.jpg)
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
![Page 7: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/7.jpg)
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
![Page 8: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/8.jpg)
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.
![Page 9: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/9.jpg)
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.
![Page 10: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/10.jpg)
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.
![Page 11: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/11.jpg)
Posaconazole3x 200 mg
Fluconazole1x 400 mg
Ullmann AJ et al. NEJM 2007.
![Page 12: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/12.jpg)
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.
![Page 13: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/13.jpg)
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
![Page 14: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/14.jpg)
Current Approach to Febrile Neutropenia
Neutropenia >10 Days
Fever >72h or Galactomannan positive
Posaconazole Prophylaxis
Rüping MJGT et al. Drugs. 2008.
![Page 15: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/15.jpg)
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
![Page 16: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/16.jpg)
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
![Page 17: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/17.jpg)
Endpoints
100= 6.4
19.5% – 3.9%
![Page 18: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/18.jpg)
Other Clinical Endpoints
![Page 19: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/19.jpg)
Pharmacokinetic Aspects
![Page 20: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/20.jpg)
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.
![Page 21: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/21.jpg)
Posaconazole Plasma Levels Were Similar in Patients With and Without IFIs
Krishna G, et al. Pharmacotherapy. 2008;28:1223-1232.
![Page 22: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/22.jpg)
Posaconazole Plasma Concentrations in AML/MDSCologne Cohort
![Page 23: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/23.jpg)
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.
![Page 24: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/24.jpg)
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
![Page 25: Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases](https://reader035.vdocuments.us/reader035/viewer/2022070305/5515c38f55034689058b4669/html5/thumbnails/25.jpg)
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