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Annals of Hematology

, Volume 93, Issue 9, pp 1449–1456 | Cite as

Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology

  • Daniela Tacke
  • Dieter Buchheidt
  • Meinolf Karthaus
  • Stefan W. Krause
  • Georg Maschmeyer
  • Silke Neumann
  • Helmut Ostermann
  • Olaf Penack
  • Christina Rieger
  • Markus Ruhnke
  • Michael Sandherr
  • Katharina E. Schweer
  • Andrew J. Ullmann
  • Oliver A. CornelyEmail author
Review Article

Abstract

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII).

Keywords

Invasive fungal infection Antifungal prophylaxis Itraconazole Fluconazole Posaconazole Amphotericin B Liposomal 

Notes

Conflict of interest

Dr. Tacke reports personal fees from MSD, personal fees from Gilead Sciences GmbH, peronal fees from Pfizer and personal fees from Astellas, outside the submitted work. Dr. Tacke is affiliated to the COMBACTE consortium. She has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115523; resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution.

Dr. Buchheidt reports grants and personal fees from Gilead Sciences, grants and personal fees from Pfizer, personal fees and non-financial support from Astellas, personal fees and non-financial support from Merck Sharp & Dohme/Merck, outside the submitted work.

Dr. Karthaus reports personal fees from MSD, personal fees from Astellas and personal fees from Pfizer, outside the submitted work.

Dr. Krause reports personal fees from MSD and personal fees from Gilead, outside the submitted work.

Dr. Maschmeyer reports personal fees from Gilead, personal fees from Pfizer and personal fees from MSD, outside the submitted work.

Dr. Neumann reports personal fees from Gilead and personal fees from MDS, outside the submitted work.

Dr. Ostermann reports grants and personal fees from MSD, grants and personal fees from Gilead and personal fees from Astellas, outside the submitted work.

Dr. Penack reports personal fees from MSD, personal fees from Astellas, personal fees from Gilead and grants from Pfizer, outside the submitted work.

Dr. Rieger has nothing to disclose.

Dr. Ruhnke reports grants from commercial sponsor (Pfizer, Roche Molecular Diagnostics) and personal fees from commercial sponsor (Astellas, Gilead, Pfizer), outside the submitted work.

Dr. Sandherr has nothing to disclose.

Dr. Schweer has nothing to disclose.

Dr. Ullmann reports grants and personal fees from MSD, personal fees from Gilead, personal fees from Pfizer and personal fees from Astellas, outside the submitted work.

Dr. Cornely is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1106); received research grants from 3 M, Actelion, Astellas, Basilea, Bayer, Celgene, Cubist, F2G, Genzyme, Gilead, GSK, Merck/MSD, Miltenyi, Optimer, Pfizer, Quintiles and Viropharma; a consultant to 3 M, Astellas, Basilea, Cubist, F2G, Gilead, GSK, Merck/MSD, Optimer, Pfizer, Sanofi Pasteur and Summit/Vifor; and received lecture honoraria from Astellas, Gilead, Merck/MSD and Pfizer.

Supplementary material

277_2014_2108_MOESM1_ESM.docx (248 kb)
ESM 1 (DOCX 687 kb)

References

  1. 1.
    Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, Pastore D, Picardi M, Bonini A, Chierichini A, Fanci R, Caramatti C, Invernizzi R, Mattei D, Mitra ME, Melillo L, Aversa F, Van Lint MT, Falcucci P, Valentini CG, Girmenia C, Nosari A (2006) The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 91(8):1068–1075PubMedGoogle Scholar
  2. 2.
    Pagano L, Caira M, Nosari A, Van Lint MT, Candoni A, Offidani M, Aloisi T, Irrera G, Bonini A, Picardi M, Caramatti C, Invernizzi R, Mattei D, Melillo L, de Waure C, Reddiconto G, Fianchi L, Valentini CG, Girmenia C, Leone G, Aversa F (2007) Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study—Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis 45(9):1161–1170. doi: 10.1086/522189 PubMedCrossRefGoogle Scholar
  3. 3.
    Maschmeyer G, Haas A, Cornely OA (2007) Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs 67(11):1567–1601PubMedCrossRefGoogle Scholar
  4. 4.
    Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20(1):133–163. doi: 10.1128/cmr.00029-06 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Cornely OA, Bohme A, Buchheidt D, Einsele H, Heinz WJ, Karthaus M, Krause SW, Kruger W, Maschmeyer G, Penack O, Ritter J, Ruhnke M, Sandherr M, Sieniawski M, Vehreschild JJ, Wolf HH, Ullmann AJ (2009) Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematologica 94(1):113–122. doi: 10.3324/haematol.11665 PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Thursky K, Byrnes G, Grigg A, Szer J, Slavin M (2004) Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation. Bone Marrow Transplant 34(2):115–121. doi: 10.1038/sj.bmt.1704543 PubMedCrossRefGoogle Scholar
  7. 7.
    Ruping MJ, Vehreschild JJ, Cornely OA (2008) Patients at high risk of invasive fungal infections: when and how to treat. Drugs 68(14):1941–1962PubMedCrossRefGoogle Scholar
  8. 8.
    Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, Shadduck RK, Shea TC, Stiff P, Friedman DJ et al (1992) A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 326(13):845–851. doi: 10.1056/nejm199203263261301 PubMedCrossRefGoogle Scholar
  9. 9.
    Philpott-Howard JN, Wade JJ, Mufti GJ, Brammer KW, Ehninger G (1993) Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group. J Antimicrob Chemother 31(6):973–984PubMedCrossRefGoogle Scholar
  10. 10.
    Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, Meyers JD, Bowden RA (1995) Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—a prospective, randomized, double-blind study. J Infect Dis 171(6):1545–1552PubMedCrossRefGoogle Scholar
  11. 11.
    Cornely OA, Vazquez J, De Waele J, Betts R, Rotstein C, Nucci M, Pappas PG, Ullmann AJ (2013) Efficacy of micafungin in invasive candidiasis caused by common Candida species with special emphasis on non-albicans Candida species. Mycoses. doi: 10.1111/myc.12104 Google Scholar
  12. 12.
    Tortorano AM, Peman J, Bernhardt H, Klingspor L, Kibbler CC, Faure O, Biraghi E, Canton E, Zimmermann K, Seaton S, Grillot R (2004) Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) hospital-based surveillance study. Eur J Clin Microbiol Infect Dis 23(4):317–322. doi: 10.1007/s10096-004-1103-y PubMedCrossRefGoogle Scholar
  13. 13.
    Wisplinghoff H, Ebbers J, Geurtz L, Stefanik D, Major Y, Edmond MB, Wenzel RP, Seifert H (2013) Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution, clinical features and antifungal susceptibilities. Int J Antimicrob Agents. doi: 10.1016/j.ijantimicag.2013.09.005 PubMedGoogle Scholar
  14. 14.
    van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, Bunin N, Wall DA, Hiemenz JW, Satoi Y, Lee JM, Walsh TJ (2004) Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 39(10):1407–1416. doi: 10.1086/422312 PubMedCrossRefGoogle Scholar
  15. 15.
    Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolanos-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA (2010) Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 116(24):5111–5118PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T, Asakura S, Sunami K, Tabayashi T, Miyata A, Matsuoka K, Shinagawa K, Ikeda K, Matsuo K, Tanimoto M (2008) Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation. Int J Hematol 88(5):588–595. doi: 10.1007/s12185-008-0196-y PubMedCrossRefGoogle Scholar
  17. 17.
    Girmenia C, Barosi G, Aversa F, Bacigalupo A, Barbui T, Baronciani D, Bosi A, Candoni A, Locasciulli A, Locatelli F, Menichetti F, Musso M, Viscoli C, Rambaldi A (2009) Prophylaxis and treatment of invasive fungal diseases in allogeneic stem cell transplantation: results of a consensus process by Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Clin Infect Dis 49(8):1226–1236. doi: 10.1086/605665 PubMedCrossRefGoogle Scholar
  18. 18.
    Marks DI, Pagliuca A, Kibbler CC, Glasmacher A, Heussel CP, Kantecki M, Miller PJ, Ribaud P, Schlamm HT, Solano C, Cook G (2011) Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation. Br J Haematol 155(3):318–327. doi: 10.1111/j.1365-2141.2011.08838.x PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Huang X, Chen H, Han M, Zou P, Wu D, Lai Y, Huang H, Chen X, Liu T, Zhu H, Wang J, Hu J (2012) Multicenter, randomized, open-label study comparing the efficacy and safety of micafungin versus itraconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplant. Biol Blood Marrow Transplant 18(10):1509–1516. doi: 10.1016/j.bbmt.2012.03.014 PubMedCrossRefGoogle Scholar
  20. 20.
    Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, Nichols WG, Musher B, Corey L (2004) Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 103(4):1527–1533. doi: 10.1182/blood-2003-08-2644 PubMedCrossRefGoogle Scholar
  21. 21.
    Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, Leitz GJ, Territo MC (2003) Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 138(9):705–713PubMedCrossRefGoogle Scholar
  22. 22.
    Shen Y, Huang XJ, Wang JX, Jin J, Hu JD, Yu K, Wu DP, Wang SJ, Yu L, Chen XQ, Liu T, Liang YM, Chen FP, Li Y, Shen ZX (2013) Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. Int J Clin Pharmacol Ther 51(9):738–745. doi: 10.5414/cp201880 PubMedCrossRefGoogle Scholar
  23. 23.
    Winston DJ, Bartoni K, Territo MC, Schiller GJ (2011) Efficacy, safety, and breakthrough infections associated with standard long-term posaconazole antifungal prophylaxis in allogeneic stem cell transplantation recipients. Biol Blood Marrow Transplant 17(4):507–515. doi: 10.1016/j.bbmt.2010.04.017 PubMedCrossRefGoogle Scholar
  24. 24.
    Sanchez-Ortega I, Patino B, Arnan M, Peralta T, Parody R, Gudiol C, Encuentra M, Fernandez de Sevilla A, Duarte RF (2011) Clinical efficacy and safety of primary antifungal prophylaxis with posaconazole vs itraconazole in allogeneic blood and marrow transplantation. Bone Marrow Transplant 46(5):733–739. doi: 10.1038/bmt.2010.185 PubMedCrossRefGoogle Scholar
  25. 25.
    Peterson L, Ostermann J, Rieger H, Ostermann H, Rieger CT (2013) Posaconazole prophylaxis—impact on incidence of invasive fungal disease and antifungal treatment in haematological patients. Mycoses 56(6):651–658. doi: 10.1111/myc.12086 PubMedCrossRefGoogle Scholar
  26. 26.
    Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D (2007) Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356(4):348–359. doi: 10.1056/NEJMoa061094 PubMedCrossRefGoogle Scholar
  27. 27.
    Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S (2007) Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 356(4):335–347PubMedCrossRefGoogle Scholar
  28. 28.
    Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M (2004) Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 57(2):218–222PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Lopez J, Van Iersel M, Connelly N, Waskin H (2013) Phase 3 pharmacokinetics and safety study of posaconazole tablet in patients at risk for invasive fungal infection. Paper presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), BerlinGoogle Scholar
  30. 30.
    Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B (2002) Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347(6):408–415PubMedCrossRefGoogle Scholar
  31. 31.
    Mattiuzzi GN, Cortes J, Alvarado G, Verstovsek S, Koller C, Pierce S, Blamble D, Faderl S, Xiao L, Hernandez M, Kantarjian H (2011) Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Support Care Cancer 19(1):19–26. doi: 10.1007/s00520-009-0783-3 PubMedCrossRefGoogle Scholar
  32. 32.
    Barreto JN, Beach CL, Wolf RC, Merten JA, Tosh PK, Wilson JW, Hogan WJ, Litzow MR (2013) The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole. Am J Hematol 88(4):283–288. doi: 10.1002/ajh.23388 PubMedCrossRefGoogle Scholar
  33. 33.
    Cattaneo C, Monte S, Algarotti A, Audisio E, Borlenghi E, Campiotti L, Cerqui E, Fanizza C, Giuliani R, Mico C, Rocconi R, Salvi A, Salvi F, Verga L, Levis A, Lambertenghi Deliliers G, Pogliani EM, Tognoni G, Rambaldi A, Rossi G (2011) A randomized comparison of caspofungin versus antifungal prophylaxis according to investigator policy in acute leukaemia patients undergoing induction chemotherapy (PROFIL-C study). J Antimicrob Chemother 66(9):2140–2145. doi: 10.1093/jac/dkr271 PubMedCrossRefGoogle Scholar
  34. 34.
    Mattiuzzi GN, Alvarado G, Giles FJ, Ostrosky-Zeichner L, Cortes J, O'Brien S, Verstovsek S, Faderl S, Zhou X, Raad II, Bekele BN, Leitz GJ, Lopez-Roman I, Estey EH (2006) Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother 50(1):143–147. doi: 10.1128/aac.50.1.143-147.2006 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Cornely OA, Ullmann AJ, Karthaus M (2005) Choosing a study population for the evaluation of antifungal prophylaxis. Clin Infect Dis 40(11):1699. doi: 10.1086/429823, author reply 1699-1701PubMedCrossRefGoogle Scholar
  36. 36.
    Walsh TJ, van Burik J-AH (2005) Reply to Cornely et al. Clin Infect Dis 40(11):1699–1701. doi: 10.1086/429823 CrossRefGoogle Scholar
  37. 37.
    Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Lowenberg B, Vulto A, Lugtenburg PJ, de Marie S (2008) Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis 46(9):1401–1408. doi: 10.1086/586739 PubMedCrossRefGoogle Scholar
  38. 38.
    Hullard-Pulstinger A, Holler E, Hahn J, Andreesen R, Krause SW (2011) Prophylactic application of nebulized liposomal amphotericin B in hematologic patients with neutropenia. Onkologie 34(5):254–258. doi: 10.1159/000327802 PubMedCrossRefGoogle Scholar
  39. 39.
    Chaftari AM, Hachem RY, Ramos E, Kassis C, Campo M, Jiang Y, Prince RA, Wang W, Raad II (2012) Comparison of posaconazole versus weekly amphotericin B lipid complex for the prevention of invasive fungal infections in hematopoietic stem-cell transplantation. Transplantation 94(3):302–308. doi: 10.1097/TP.0b013e3182577485 PubMedCrossRefGoogle Scholar
  40. 40.
    Penack O, Schwartz S, Martus P, Reinwald M, Schmidt-Hieber M, Thiel E, Blau IW (2006) Low-dose liposomal amphotericin B in the prevention of invasive fungal infections in patients with prolonged neutropenia: results from a randomized, single-center trial. Ann Oncol 17(8):1306–1312PubMedCrossRefGoogle Scholar
  41. 41.
    Kish MA (2001) Guide to development of practice guidelines. Clin Infect Dis 32(6):851–854. doi: 10.1086/319366 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Daniela Tacke
    • 1
    • 14
    • 17
  • Dieter Buchheidt
    • 2
  • Meinolf Karthaus
    • 3
  • Stefan W. Krause
    • 4
  • Georg Maschmeyer
    • 5
  • Silke Neumann
    • 6
  • Helmut Ostermann
    • 7
  • Olaf Penack
    • 8
  • Christina Rieger
    • 7
  • Markus Ruhnke
    • 9
  • Michael Sandherr
    • 10
  • Katharina E. Schweer
    • 1
    • 14
    • 17
  • Andrew J. Ullmann
    • 11
  • Oliver A. Cornely
    • 1
    • 12
    • 13
    • 14
    • 15
    • 16
    Email author
  1. 1.Klinik I für Innere MedizinUniklinik KölnKölnGermany
  2. 2.III. Medizinische KlinikUniversitätsmedizin MannheimMannheimGermany
  3. 3.Klinik für Hämatologie und OnkologieKlinikum NeuperlachMünchenGermany
  4. 4.Hämatologie und Internistische OnkologieUniversitätsklinikum ErlangenErlangenGermany
  5. 5.Klinik für Hämatologie, Onkologie und PalliativmedizinErnst von Bergmann KlinikumPotsdamGermany
  6. 6.Ambulantes OnkologiezentrumWolfsburgGermany
  7. 7.Medizinische Klinik und Poliklinik IIIKlinikum der Universität MünchenMünchenGermany
  8. 8.Medizinische Klinik m.S. Hämatologie, Onkologie und TumorimmunologieCharité-Universitätsmedizin Berlin Campus Virchow-KlinikumBerlinGermany
  9. 9.Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie, Charité-Universitätsmedizin Berlin, Campus Mitte BerlinBerlinGermany
  10. 10.Schwerpunktpraxis für Hämatologie und OnkologieWeilheimGermany
  11. 11.Medizinische Klinik und Poliklinik II-Schwerpunkt InfektiologieUniversitätsklinikum WürzburgWürzburgGermany
  12. 12.Zentrum für Klinische Studien (BMBF 01KN1106)Medical Fuculty, University of CologneCologneGermany
  13. 13.CECAD – Cologne Excellence Cluster on Cellular Stress Responses in Aging–Associated DiseasesMedical Faculty, University of CologneCologneGermany
  14. 14.Center for Integrated Oncology CIO Köln-Bonn, Medical FacultyUniversity of CologneCologneGermany
  15. 15.German Centre for Infection Research (DZIF), partner site Bonn-CologneCologneGermany
  16. 16.CHIR-Net, Chirurgisches Regionalzentrum Witten/Herdecke—KölnUniversität Witten/Herdecke gGmbH/Universität KölnCologneGermany
  17. 17.COMBACTE-consortium

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