Prognostic factors in 264 adults with invasive and Lomentospora infections Data from the literature and FungiScope®

Danila Seidel1, Arne Meißner1, Michaela Lackner, Ellen Piepenbrock1, Jon Salmanton-García1, Sibylle Mellinghoff1, Luisa Duran Graeff1, Maria J.G.T. Vehreschild1, Axel Hamprecht1, Hilmar Wisplinghoff2, Oliver A. Cornely1,3,4 IDweek 2018 on behalf of The FungiScope ECMM/ISHAM Working Group Poster #403 1Department I of Internal Medicine, University of Cologne, Cologne, Germany; 2Labor Wisplinghoff, Cologne, Germany; 3Clinical Trials Centre Cologne, ZKS Köln, University of Cologne, Cologne, Germany; 4Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Cologne, Germany

Background Methods and Objective Results A growing number of non-Aspergillus mold infections, such as invasive Scedosporium and Lomentospora infections, are of particular Cases of proven and probable infections according to EORTC/MSG criteria [9] related to • 208 Scedosporium spp. concern because of intrinsic resistance of such pathogens and thus limited treatment options [1]. Scedosporium spp. and L. prolificans diagnosed between 2000 and August 2017 were selected • 185 S. apiospermum from the FungiScope® registry. Respective cases were identified from the literature using the Medically most relevant pathogens causing are species of the genus Scedosporium (e.g. S. apiospermum, S. boydii) • 16 S. boydii and Lomentospora prolificans (formerly Scedosporium prolificans). Scedosporium spp. are often resistant to , but PubMed search filter “(Scedospori* OR Pseudallescheri* OR Lomentospori*) AND ((invasive OR • 7 S. aurantiacum susceptible to and , whereas L. prolificans is resistant to all available antifungals [2-5]. disseminated OR infection) AND (case OR patient OR report))”. • 56 L. prolificans Immunocompromised patients are at highest risk for these infections. Primarily those with hematological malignancy with Collected data included: demographics, fungal pathogens, underlying diseases and risk factors for prolonged profound neutropenia, hematopoietic stem cell or solid organ recipients, and patients with inherited or acquired IFD, site of infection, signs and symptoms at time of diagnosis of IFD (imaging findings, fever, • Proven 89 % immunodeficiency. Immunocompetent patients are at risk through direct inoculation of the pathogen after traumatic injury, major cough, dyspnea, neurological signs), antifungal and surgical therapy, susceptibility to antifungals • Male 60.6 % (EUCAST, CLSI), outcome, autopsy findings. surgery or aspiration of contaminated water associated with near drowning [6, 7]. Mortality rates of up to 90% despite best • Median age 57 (IQR 40 – 65) years available antifungal therapy underline the unmet medical need of an effective treatment option improving clinical management [7]. For a comprehensive assessment of the epidemiology and currently used treatments. Results

Risk factors Scedosporium L. prolificans Site of Infection Scedosporium L. prolificans L. prolificans isolates show high MICs to antifungals Treatment Scedosporium L. prolificans % spp. n=208 n=56 % spp. n=208 n=56 median spp. n=208 n=56 % % 12 Amphotericin B 32 32 32 32 32 32 16 16 16 16 16 16 16 16 8 8 4 4 4 4 4 2 1 1 0.5 0.5 0.5 0.3 % % 0 20 40 60 Prophylaxis (%) 20 (9.6) 13 (23.2) 0 20 40 60 128 128 128 128 128 128 128 64

spp. Flucytosine 16 Terbinafine 32 32 16 4 2 POS, VRC 7 (35) 10 (76.9) 24 Fluconazole 128 128 32 32 32 16 16 16 16 16 Blood 5.8 46.4 a Hematological 13.9 50.0 3 Isavuconazole 16 16 4 4 2 2 1 0.5 Other 13 (65) 3 (23.1) CNS 24.0 10.7 2 Itraconazole 64 32 16 16 16 8 8 8 2 2 2 1 1 1 1 1 0.5 0.3 Antifungal treatment Solid organ transplant 27.9 12.5 1.5 Posaconazole 32 16 4 4 2 2 2 2 2 2 1.5 1 1 1 1 0.5 0.5 0.5 0.3 0.3 0.3 Eye 0.5 Voriconazole 2 2 1 1 1 1 1 1 1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.4 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.1 Antifungal + surgery 117 (56.3) 24 (42.9) 22.6 21.4 2 Anidulafungin 4 4 2 2 2 2 1 1 Other immunocompromised 14.9 7.1 3 Caspofungin 32 16 8 4 4 2 2 2 0.3 0.3 Antifungal 87 (41.8) 31 (55.4) Sinuses 9.1 5.4 0.004 Olorofim 0 0 0 0 0 0 0 0

Scedosporium Scedosporium Surgery 2 (1) - - Heart 5.3 19.6 median No treatment 2 (1) 1 (1.8) Surgery Lung 16 Amphotericin B 32 32 32 20 16 16 16 16 16 16 16 8 8 8 4 4 4 4 2 1 Antifungal drugs (%) 8.2 12.5 24.5 39.3 128 Flucytosine 128 128 128 128 128 128 128 128 64 64 4 Terbinafine 4 4 Amphotericin B 63 (30.3) 27 (48.2) Deep Tissue 3.4 1.8 128 256 256 128 128 128 128 128 128 64 16 Trauma 8.2 8.9 Fluconazole Voriconazole 137 (65.9) 38 (67.9) 32 Isavuconazole 32 32 32 32 32 32 32 Skin 16 128 32 32 32 16 16 16 16 16 16 16 8 8 Near drowning 28.4 10.7 Itraconazole Posaconazole 15 (7.2) 8 (14.3) 5.8 0.0 32 Posaconazole 128 32 32 32 32 32 32 32 16 16 Bone/joints 14.9 12.5 8 Voriconazole 128 32 32 16 16 16 16 16 8 8 8 8 8 8 4 4 2 2 1 Itraconazole 57 (27.4) 8 (14.3) Other immunocompetent 4 Anidulafungin 16 4 4 4 4 4 1 1 0.5 Other azoles 20 (9.6) 4 (7.1)

13.5 5.4 prolificans L. Other 13.5 23.2 8 Caspofungin 16 8 4 24 Micafungin 32 32 32 32 16 4 1 0.5 Terbinafine 26 (12.5) 22 (39.3) Unknown 7.7 3.6 Disseminated 0.004 Olorofim 0 0 0 0 0 0 0 MIC µg/ml ≥8 4 2 1 ≤0.5 22.1 58.9 Echinocandin 22 (10.6) 17 (30.4)

Figure 1. Predisposing factors Figure 2. Frequent site of infection Figure 3. Minimum inhibitory concentration (MIC) against antifungals determined by Table 1. Treatment Other immunocompromised: asthma, rheumatic arthritis, chronic pulmonary disease, chronic granulomatous disease, HIV/AIDS Disseminated: includes bloodstream infections ᵃScedosporium spp.: ITRA (5), FLU (4), AMB (3), CASP (1); L. prolificans: FLU Other immunocompetent: Bronchiectasis, cystic fibrosis, chronic kidney disease/Diabetes Mellitus, contact lens, chronic EUCAST and CLSI methods. pulmonary disease, dialysis, extracorporeal membrane oxygenation, glaucoma, intravenous drug abuse, tuberculosis , viral (2), ITRA (1) pneumonia

Dissemination of the infection predicts worse outcome Usage of AMB alone is associated with worse outcome Conclusion Scedosporium spp. Scedosporium spp. L. prolificans • Scedosporium spp. and L. prolificans infections in patients Localized disease Disseminated disease not only with compromised immune status • Frequently presents as fungemia with devastating outcome • Scedosporium spp. and L. prolificans are resistant to most AMB antifungals currently available L. prolificans Scedosporium spp. overall: • Voriconazole usage is associated with improved outcome AMB compared to amphotericin B formulations alone

AMB amphotericin B-based formulation Contact: Danila Seidel, PhD University Hospital of Cologne, GER Phone +49 221 478 97343 References [1] Douglas A.P., Chen S.C., Slavin M.A., Clin Microbiol Infect, 2016. 22(8): p. 670-80. [2] Bouza E., Munoz P. Clin Microbiol Infect, 2004. 10 Suppl 1: p. 76-85. [3] Carrillo A.J., Guarro J. 2001. 45(7): p. 2151-3. [4] Cuenca-Estrella M., et al. J Antimicrob Chemother, 1999. 43(1): p. 149-51. [5] Espinel-Ingroff A. J. Clin Microbiol, 2001. 39(3): p. 954-8. [6] Panackal A.A., Marr K.A. Semin Respir Crit Care Med, 2004. 25(2): p. 171-81. [7] Katragkou A. et al. Mycoses, [email protected] 2007. 50(5): p. 412-21. [8] Blyth C.C., et al. 2014. Intern Med J, 2014. 44(12b): p. 1333-49. [9] DePauw et al. Clin Infect Dis. 2008 Jun 15;46(12):1813-21.