icn victoria: cornely on "being a fun-gi in icu"
TRANSCRIPT
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