ICN Victoria presents Professor Oliver Cornely, Professor of Internal Medicine and Director for Clinical Trials at University Hospital, Cologne, Germany. His research interests include invasive fungal diseases in haematology/oncology and in the ICU setting. Dr Cornely is also a clinical infectious diseases consultant at the University Hospital of Cologne. Professor Cornely gives an entertaining talk on the pervasiveness, invasiveness, diagnosis and treatment of fungal infections in ICU patients.

2. Fun-gi in ICU
Oliver A. Cornely MD, FACP, FIDSA, FAAM
Chair, Translational Research, CECAD Cluster of Excellence
Deputy Head, Division of Infectious Diseases
Director, Clinical Trials Center
University of Cologne, Germany

3. Transparency Declaration
Research Grants: 3M, Actelion, Astellas, AstraZeneca, Basilea, Bayer, Genzyme, Gilead,
GSK, Miltenyi, MSD, Pfizer, Scynexis, Viropharma
Advisory Boards: Amplyx, Anacor, Astellas, Basilea, Cidara, Da Volterra, F2G, Genentech,
Gilead, Matinas, Merck Serono, MSD, Pfizer, Sanofi Pasteur, Scynexis,
Seres, Summit, Vical, Vifor
Speaker Honoraria: Astellas, Basilea, Gilead, Merck/MSD, Pfizer
Shareholder: N/A

4. 1729 – Epidemiology

5. 1856 & 1885 – Diagnosis
Virchow R.
Archiv für Pathologische Anatomie
1856; 9 (4): 557–593.
Paltauf A.
Archiv für Pathologische Anatomie
1885; 102 (25): 543–564.
Tissue Culture Histology

6. Epidemiology

7. Pathogen Distribution of Proven IFI In ~9000
Participants In Antifungal Prophylaxis Trials
Cornely OA et al. Blood 2003.
Mucorales
6%
Fusarium
6%
Candida
48%
Aspergillus
40%

8. Attributable Mortality of IC
Attributable mortality Attributable mortality
Gudlaugsson O, et al. Clin Infect Dis 2003.

9. Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–3645.
Hospitalmortality[%]
[hour
s]
Delayed Therapy of Invasive Candidiasis
Increases Mortality

10. Reliable Diagnostic Tests Would Allow
Early Treatment to be Targeted

11. Diagnostics

12. x
Liss BJ et al. Mycoses epub.

13. β-D-Glucan – Latest News
Nucci M et al. ICAAC 2014; M-1754.
• 85 of 2148 ICU patients had all of the below:
1. CVC
2. Antibiotic treatment
3. 2 of: dialysis, surgery, pancreatitis, steroids/immunosuppression,
parenteral nutrition
4. 1 of: fever, hypothermia, hypotension, leukocytosis, acidosis, or CRP↑
• Received echinocandin treatment and
 Diagnostic screening
 Day 1 and 2: Blood culture
 Day 1, 2, and 3: β-D-Glucan

14. β-D-Glucan – Latest News
N=85
BDG pos.
BC neg.
N=57 (67%)
BC pos.
N=7 (8%)
BDG neg.
BC neg.
N=21 (25%)
Nucci M et al. ICAAC 2014; M-1754.

15. Challenges
Diagnostic tools are too few and are unreliable
 „One fungus – one name“ we welcome
 „One fungus – one test“ is no ! solution
All rely on
the same
principle!
 Aspergillus – GM: 10 years to a cut-off
 Aspergillus – PCR: 15 years to standardization
 Mannan/Anti-Mannan: Any good at all?
 ß-D-Glucan: Benefits not yet fully explored
Give up the paradigm of proving the presence of
the pathogen?

16. Promises of New Diagnostic Tools – Example
Turning to host response instead of fungal molecules
 T cells as specific diagnostic sensors for invasive fungal
infections
 Monitor mold-reactive CD154+ peripheral blood T cells
 Pilot study completed
Bacher P, Steinbach A et al. Am J Resp Crit Care Med (in press).

17. Promises of New Diagnostic Tools – Example
Bacher P, Steinbach A et al. Am J Resp Crit Care Med (in press).
Frequencies of fungus-reactive T cells

18. Promises of New Diagnostic Tools – Example
Bacher P, Steinbach A et al. Am J Resp Crit Care Med (in press).
Mold-reactive T cell frequencies and fungal burden in 2
patients with pulmonary mucormycosis

19. Promises of New Diagnostic Tools – Example
Bacher P, Steinbach A et al. Am J Resp Crit Care Med (in press).
Mold-reactive T cell frequencies and fungal burden in 3
patients with invasive mold infection

20. CT Pulmonary Angiography (CTPA) can
Differentiate Mold vs. Bacterial Pneumonia
CTPA positive,
proven mold
disease by autopsy
CTPA negative,
bacterial PNA
Stanzani et al. Clin Infect Dis. 2015;60(11):1603-10.

21. CT Pulmonary Angiography (CTPA) can
differentiate mold vs. P. aeruginosa pneumonia
53 y/o neutropenic male with AML on
consolidation chemotherapy
with fever and respiratory distress
Final diagnosis: MDR P. aeruginosa
Stanzani et al. Clin Infect Dis. 2015;60(11):1603-10.

22. Extensively-treated
lymphoma patient admitted
with persistent fever
CT Pulmonary Angiography (CTPA) can
Differentiate Mold vs. Malignancy
Final diagnosis: Pulmonary
lymphoma relapse
Stanzani et al. Clin Infect Dis. 2015;60(11):1603-10.

23. Prophylaxis

24. Trials That Yielded a Difference in Survival
Empiric Treatment
Pre-emptive w/o microbiology
Prophylaxis
Prophylaxis

25. Posaconazole Tablet Phase III
Observed Individual Cavg
Multiple dosing of 300 mg QD, BID on day 1, serial PK-evaluable cohort
3,750
2,500
1,500 1,580
1,870
1,440
300 mg
AML/MDS, n = 33
300 mg
HSCT, n = 17
300 mg
All, n = 50
500
Individuals
Arithmetic mean
Cavg,ng/ml
Cornely OA et al. J Antimicrob Chemother 2016; 71(3): 718-26.

26. Posaconazol IV Phase III
Pharmacokinetics
• 46/49 patients (94%) attained the exposure target of
Cavg ≥500 ng/mL and ≤2,500 ng/mL
• Steady state Cavg was similar in AML/MDS (1,470 ng/mL) and
allogeneic HSCT (1,560 ng/mL) patients
PK Steady State Cavg Criteria AML
n = 30
HSCT
n = 19
Total
n = 49
<500 ng/mL, n (%) 0 0 0
≥500 and 2,500 ng/mL, n (%) 28 (93) 18 (95) 46 (94)
>2,500 and 3,650 ng/mL, n (%) 2 (7) 1 (5) 3 (6)
>3,650 ng/mL, n (%) 0 0 0
Cornely OA et al. 53rd ICAAC, Denver, September 10-13, 2013.

27. Treating IFI with various Posaconazole
Formulations
Lehrnbecher T et al. EJCMID 2010.
Ramos ER et al. Oncologist 2011.
Vehreschild JJ et al. Crit Rev Microbiol 2012.
Heinz WJ et al. Mycoses 2013.
Ellenbogen JR et al. Case Rep J Clin Neurosc 2014.
Kepenekli et al. Italian J Paed 2014.
Conant MM et al. Mycoses 2015.

28. Recent Data
N=98, induction-consolidation chemotherapy, 85% prophylaxed
Doan TN et al. J Antimicrob Chemother 2016.
2/78 (2.6%)
3/14 (21.4%)

29. Early Exposure (to Antifungals) is a
Common Pattern Through all Trials
Improving Survival Rates