Fun-gi in ICU

Oliver A. Cornely MD, FACP, FIDSA, FAAM

Chair, Translational Research, CECAD Cluster of ExcellenceDeputy Head, Division of Infectious Diseases

Director, Clinical Trials CenterUniversity of Cologne, Germany

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, PfizerShareholder: N/A

1729 – Epidemiology

1856 & 1885 – Diagnosis

Virchow R.Archiv für Pathologische Anatomie1856; 9 (4): 557–593.

Paltauf A.Archiv für Pathologische Anatomie1885; 102 (25): 543–564.

Tissue Culture Histology

Epidemiology

Pathogen Distribution of Proven IFI In ~9000 Participants In Antifungal Prophylaxis Trials

Cornely OA et al. Blood 2003.

Mucorales6%

Fusarium6%

Candida48%

Aspergillus40%

Attributable Mortality of IC

Attributable mortality Attributable mortality

Gudlaugsson O, et al. Clin Infect Dis 2003.

Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–3645.

Hos

pita

l mor

talit

y [%

]

[hours]

Delayed Therapy of Invasive Candidiasis Increases Mortality

Reliable Diagnostic Tests Would Allow

Early Treatment to be Targeted

Diagnostics

x

Liss BJ et al. Mycoses epub.

β-D-Glucan – Latest News

Nucci M et al. ICAAC 2014; M-1754.

• 85 of 2148 ICU patients had all of the below:1. CVC2. Antibiotic treatment3. 2 of: dialysis, surgery, pancreatitis, steroids/immunosuppression,

parenteral nutrition4. 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

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.

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?

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).

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

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

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

CT Pulmonary Angiography (CTPA) can Differentiate Mold vs. Bacterial Pneumonia

CTPA positive, proven molddisease by autopsy

CTPA negative,bacterial PNA

Stanzani et al. Clin Infect Dis. 2015;60(11):1603-10.

CT Pulmonary Angiography (CTPA) can differentiate mold vs. P. aeruginosa pneumonia

53 y/o neutropenic male with AML on consolidation chemotherapywith fever and respiratory distress

Final diagnosis: MDR P. aeruginosa

Stanzani et al. Clin Infect Dis. 2015;60(11):1603-10.

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.

Prophylaxis

Trials That Yielded a Difference in Survival

Empiric Treatment

Pre-emptive w/o microbiology

Prophylaxis

Prophylaxis

Posaconazole Tablet Phase IIIObserved Individual Cavg

Multiple dosing of 300 mg QD, BID on day 1, serial PK-evaluable cohort

3,750

2,500

1,500 1,5801,870

1,440

300 mgAML/MDS, n = 33

300 mgHSCT, n = 17

300 mgAll, n = 50

500

IndividualsArithmetic mean

Cav

g, ng

/ml

Cornely OA et al. J Antimicrob Chemother 2016; 71(3): 718-26.

Posaconazol IV Phase IIIPharmacokinetics

• 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 AMLn = 30

HSCTn = 19

Totaln = 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.

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.

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%)

Early Exposure (to Antifungals) is a

Common Pattern Through all Trials

Improving Survival Rates