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Intensive care medicine research agenda on invasive fungal infection in critically ill patients

  • Research Agenda
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Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Purpose

To describe concisely the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to Candida and Aspergillus infections in non-neutropenic patients in the ICU setting.

Methods

A systematic review of the medical literature taking account of national and international guidelines and expert opinion.

Results

Severe invasive fungal infections (IFIs) are becoming increasingly frequent in critically ill patients. Approximately 80% of IFIs are due to Candida spp. and 0.3–19% to Aspergillus spp. Recent observations emphasize the necessity of building a worldwide sentinel network to monitor the emergence of new fungal species and changes in susceptibility. Robust data on the attributable mortality are essential for the design of clinical studies with mortality endpoints. Although early antifungal therapy for Candida has been recommended in patients with risk factors, sepsis of unknown cause, and positive Candida serum biomarkers [β-1 → 3-d-glucan (BDG) and Candida albicans germ tube antibody (CAGTA)], its usefulness and influence on outcome need to be confirmed. Future studies may specifically address the optimal diagnostic and therapeutic strategies for patients with abdominal candidiasis. Better knowledge of the pharmacokinetics of antifungal molecules and tissue penetration is a key issue for intensivists. Regarding invasive aspergillosis, further investigation is needed to determine its incidence in the ICU, its relationship with influenza outbreaks, the clinical impact of rapid diagnosis, and the significance of combination treatment.

Conclusions

Fundamental questions regarding IFI have to be addressed over the next decade. The clinical studies described in this research agenda should provide a template and set priorities for the clinical investigations that need to be performed.

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Abbreviations

BDG:

β-1 → 3-d-glucan

CAGTA:

Candida albicans germ tube antibody

CCPA:

Chronic cavitary pulmonary aspergillosis

CFPA:

Chronic fibrosing pulmonary aspergillosis

CPA:

Chronic pulmonary aspergillosis

ESAT:

Empirical systemic antifungal treatment

GM:

Galactomannan

HSCT:

Halogenic stem cell transplant

IC:

Invasive candidiasis

IFI:

Invasive fungal infections

IPA:

Invasive pulmonary aspergillosis

LAmb:

Liposomal amphotericin B

LFD:

Lateral flow device

MALDI-TOF MS:

Matrix-assisted laser desorption ionization–time of flight mass spectrometry

PCT:

Procalcitonin

TDM:

Therapeutic drug monitoring

References

  1. Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, Lanternier F, Pagano L, Skiada A, Akova M et al (2014) ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect 20(Suppl 3):5–26

    Article  CAS  PubMed  Google Scholar 

  2. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z et al (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34(1):7–14

    Article  CAS  PubMed  Google Scholar 

  3. de Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–1821

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT et al (2007) Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356(4):348–359

    Article  CAS  PubMed  Google Scholar 

  5. Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D, Betts R, Wible M, Goldstein BP, Schranz J et al (2007) Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 356(24):2472–2482

    Article  CAS  PubMed  Google Scholar 

  6. Delaloye J, Calandra T (2014) Invasive candidiasis as a cause of sepsis in the critically ill patient. Virulence 5(1):161–169

    Article  PubMed  Google Scholar 

  7. Vincent J-L, Rello J, Marshall J, Silva E, Anzueto A, Martin CD et al (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302(21):2323–2329

    Article  CAS  PubMed  Google Scholar 

  8. Kett DH, Azoulay E, Echeverria PM, Vincent J-L, Extended Prevalence of Infection in ICU Study (EPIC II) Group of Investigators (2011) Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 39(4):665–670

    Article  PubMed  Google Scholar 

  9. Kullberg BJ, Arendrup MC (2015) Invasive candidiasis. N Engl J Med 373(15):1445–1456

    Article  CAS  PubMed  Google Scholar 

  10. Guery BP, Arendrup MC, Auzinger G, Azoulay E, Borges Sá M, Johnson EM et al (2009) Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: part I. Epidemiology and diagnosis. Intensive Care Med 35(1):55–62

    Article  PubMed  Google Scholar 

  11. Clancy CJ, Nguyen MH (2013) Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 56(9):1284–1292

    Article  PubMed  Google Scholar 

  12. Bassetti M, Righi E, Ansaldi F, Merelli M, Trucchi C, De Pascale G, Diaz-Martin A, Luzzati R, Rosin C, Lagunes L, Trecarichi EM, Sanguinetti M, Posteraro B, Garnacho-Montero J, Sartor A, Rello J, Rocca GD, Antonelli M, Tumbarello M (2014) A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med 40:839–845

    Article  CAS  PubMed  Google Scholar 

  13. Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, Bearden DT (2006) Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 43:25–31

    Article  CAS  PubMed  Google Scholar 

  14. Shorr AF, Chung K, Jackson WL, Waterman PE, Kollef MH (2005) Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis. Crit Care Med 33:1928–1935

    Article  CAS  PubMed  Google Scholar 

  15. Ostrosky-Zeichner L, Shoham S, Vazquez J, Reboli A, Betts R, Barron MA, Schuster M, Judson MA, Revankar SG, Caeiro JP, Mangino JE, Mushatt D, Bedimo R, Freifeld A, Nguyen MH, Kauffman CA, Dismukes WE, Westfall AO, Deerman JB, Wood C, Sobel JD, Pappas PG (2014) MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 58:1219–1226

    Article  CAS  PubMed  Google Scholar 

  16. Schuster MG, Edwards JE Jr, Sobel JD, Darouiche RO, Karchmer AW, Hadley S, Slotman G, Panzer H, Biswas P, Rex JH (2008) Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med 149:83–90

    Article  PubMed  Google Scholar 

  17. Timsit JF, Azoulay E, Schwebel C, Charles PE, Cornet M, Souweine B, Klouche K, Jaber S, Trouillet JL, Bruneel F, Argaud L, Cousson J, Meziani F, Gruson D, Paris A, Darmon M, Garrouste-Orgeas M, Navellou JC, Foucrier A, Allaouchiche B, Das V, Gangneux JP, Ruckly S, Maubon D, Jullien V, Wolff M, EMPIRICUS Trial Group (2016) Empirical micafungin treatment and survival without invasive fungal infection in adults with icu-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA 316:1555–1564

    Article  CAS  PubMed  Google Scholar 

  18. León C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J, Alvarez-Lerma F, Garnacho-Montero J, León MA, EPCAN Study Group (2006) A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 34:730–737

    Article  PubMed  Google Scholar 

  19. Nucci M, Nouér SA, Esteves P, Guimarães T, Breda G, de Miranda BG, Queiroz-Telles F, Colombo AL (2016) Discontinuation of empirical antifungal therapy in ICU patients using 1,3-β-d-glucan. J Antimicrob Chemother 71:2628–2633

    Article  CAS  PubMed  Google Scholar 

  20. Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE, Washburn RG, Scheld WM, Karchmer AW, Dine AP et al (1994) A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 331:1325–1330

    Article  CAS  PubMed  Google Scholar 

  21. León C, Ostrosky-Zeichner L, Schuster M (2014) What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Intensive Care Med 40:808–819

    Article  PubMed  Google Scholar 

  22. Kullberg BJ, Sobel JD, Ruhnke M, Pappas PG, Viscoli C, Rex JH, Cleary JD, Rubinstein E, Church LW, Brown JM, Schlamm HT, Oborska IT, Hilton F, Hodges MR (2005) Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet 366:1435–1442

    Article  CAS  Google Scholar 

  23. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J, Caspofungin Invasive Candidiasis Study Group (2002) Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 347(25):2020–2029

    Article  CAS  PubMed  Google Scholar 

  24. Kuse ER, Chetchotisakd P, Da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, Sekhon JS, Freire A, Ramasubramanian V, Demeyer I, Nucci M, Leelarasamee A, Jacobs F, Decruyenaere J, Pittet D, Ullmann AJ, Ostrosky-Zeichner L, Lortholary O, Koblinger S, Diekmann-Berndt H, Cornely OA, Micafungin Invasive Candidiasis Working Group (2007) Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 369:1519–1527

    Article  CAS  PubMed  Google Scholar 

  25. Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar D, De Waele JJ, Vazquez JA, Dupont BF, Horn DL, Ostrosky-Zeichner L, Reboli AC, Suh B, Digumarti R, Wu C, Kovanda LL, Arnold LJ, Buell DN (2007) Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 45:883–893

    Article  CAS  PubMed  Google Scholar 

  26. Taccone FS, Van den Abeele AM, Bulpa P, Misset B, Meersseman W, Cardoso T, Paiva JA, Blasco-Navalpotro M, De Laere E, Dimopoulos G, Rello J, Vogelaers D, Blot SI, AspICU Study Investigators (2015) Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care 12(19):7

    Article  Google Scholar 

  27. Garnacho-Montero J, Olaechea P, Alvarez-Lerma F, Alvarez-Rocha L, Blanquer J, Galván B, Rodriguez A, Zaragoza R, Aguado JM, Mensa J, Solé A, Barberán J (2013) Epidemiology, diagnosis and treatment of fungal respiratory infections in the critically ill patient. Rev Esp Quimioter Jun 26(2):173–188

    Google Scholar 

  28. Chun-Yu L, Wei-Lun L, Che-Chia C, Hou-Tai C, Han-Chung H, Kuo-chin K, Ning-Hung C, Ying-Jen C, Cheng-Ta Y, Chung-Chi H, Dimopoulos G (2017) Invasive fungal tracheobronchitis in mechanically ventilated critically ill patients: underlying conditions, diagnosis and outcomes. Ann Intensive Care 7:9.doi:10.1186/s13613-016-0230-9

  29. Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP et al (2017) Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 64(2):134–140

  30. Marklein G, Josten M, Klanke U, Muller E, Horre R, Maier T et al (2009) Matrix-assisted laser desorption ionization-time of flight mass spectrometry for fast and reliable identification of clinical yeast isolates. J Clin Microbiol 47(9):2912–2917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Spanu T, Posteraro B, Fiori B, D’Inzeo T, Campoli S, Ruggeri A et al (2012) Direct maldi-tof mass spectrometry assay of blood culture broths for rapid identification of Candida species causing bloodstream infections: an observational study in two large microbiology laboratories. J Clin Microbiol 50(1):176–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ling H, Yuan Z, Shen J, Wang Z, Xu Y (2014) Accuracy of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of clinical pathogenic fungi: a meta-analysis. J Clin Microbiol 52(7):2573–2582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vella A, De Carolis E, Vaccaro L, Posteraro P, Perlin DS, Kostrzewa M et al (2013) Rapid antifungal susceptibility testing by matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis. J Clin Microbiol 51(9):2964–2969

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mikulska M, Calandra T, Sanguinetti M, Poulain D, Viscoli C (2012) The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Crit Care 14(6):R222

    Article  Google Scholar 

  35. Lamoth F, Cruciani M, Mengoli C, Castagnola E, Lortholary O, Richardson M et al (2012) Beta-Glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3). Clin Infect Dis 54(5):633–643

    Article  PubMed  Google Scholar 

  36. Azoulay E, Dupont H, Tabah A, Lortholary O, Stahl JP, Francais A et al (2012) Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit Care Med 40:813–822

    Article  CAS  PubMed  Google Scholar 

  37. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster M, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD (2016) Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 62:e1–e50

    Article  PubMed  Google Scholar 

  38. Hanson KE, Pfeiffer CD, Lease ED, Balch AH, Zaas AK, Perfect JR et al (2012) (1,3)-β-d-Glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS One 7:e42282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. León C, Ruiz-Santana S, Saavedra P, Castro C, Ubeda A, Loza A et al (2012) Value of (1 → 3) β-d-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions. Intensive Care Med 38:1315–1325

    Article  PubMed  Google Scholar 

  40. Martín-Mazuelos E, Loza A, Castro C, Macías D, Zakariya I, Saavedra P et al (2015) β-d-glucan and Candida albicans germ tube antibody in ICU patients with invasive candidiasis. Intensive Care Med 41:1424–1432

    Article  PubMed  Google Scholar 

  41. Prattes J, Hoenigl M, Rabensteiner J, Raggam RB, Prueller F, Zollner-Schwetz I, Valentin T, Hönigl K, Fruhwald S, Krause R (2014) Serum 1,3-beta-d-glucan for antifungal treatment stratification at the intensive care unit and the influence of surgery. Mycoses 57:679–686

    Article  CAS  PubMed  Google Scholar 

  42. Posteraro B, Tumbarello M, De Pascale G, Liberto E, Vallecoccia MS, De Carolis E, Di Gravio V, Trecarichi EM, Sanguinetti M, Antonelli M (2016) (1,3)-β-d-glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother 71:2262–2269

    Article  CAS  PubMed  Google Scholar 

  43. Reboli AC, Shorr AF, Rotstein C, Pappas PG, Kett DH, Schlamm HT, Reisman AL, Biswas P, Walsh TJ (2011) Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome. BMC Infect Dis 11:261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang Q, Wang T, Xie J, Wang Y, Zheng X, Chen L et al (2016) Pharmacokinetic/pharmacodynamic adequacy of echinocandins against Candida spp. in intensive care unit patients and general patient populations. Int J Antimicrob Agents 47:397–402

    Article  CAS  PubMed  Google Scholar 

  45. Jullien V, Azoulay E, Schwebel C, Le Saux T, Charles PE, Cornet M et al (2017) Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation. J Antimicrob Chemother 72(1):181–189

  46. Brüggemann RJ, Middel-Baars V, de Lange DW, Colbers A, Girbes AR, Pickkers P, Swart EL (2017) Pharmacokinetics of anidulafungin in critically ill patients in the intensive care unit with suspected or proven invasive fungal infections. Antimicrob Agents Chemother. doi:10.1128/AAC.01894-16

  47. van der Elst KC, Veringa A, Zijlstra JG, Beishuizen A, Klont R, Brummelhuis-Visser P, Uges DR, Touw DJ, Kosterink JG, van der Werf TS, Alffenaar JC (2016) Low caspofungin exposure in patients in the intensive care unit. Antimicrob Agents Chemother. doi:10.1128/AAC.01582-16

  48. Schroeder M, Simon M, Katchanov J, Wijaya C, Rohde H, Christner M, Laqmani A, Wichmann D, Fuhrmann V, Kluge S (2016) Does galactomannan testing increase diagnostic accuracy for IPA in the ICU? A prospective observational study. Crit Care 20:139

    Article  PubMed  PubMed Central  Google Scholar 

  49. Steinmann J, Buer J, Rath PM (2016) Detection of Aspergillus fumigatus in blood samples from critically ill patients in intensive care units by use of the SeptiFast assay. J Clin Microbiol 54:1918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Blot S, Taccone F, Van den Abeele A, Bulpa P, Meersseman W, Brusselaers N, Dimopoulos G, Paiva JA, Misset B, Rello J, Vandewoude K, Vogelaers D, AspICU Study Investigators (2012) A clinical algorithm to diagnose invasive pulmonary aspergillosis in ICU patients. Am J Respir Crit Care Med 186(1):56–64

    Article  PubMed  Google Scholar 

  51. Falagas ME, Apostolou KE, Pappas VD (2006) Attributable mortality of candidemia: a systematic review of matched cohort and case-control studies. Eur J Clin Microbiol Infect Dis 25(7):419–425

    Article  CAS  PubMed  Google Scholar 

  52. López-Cortés LE, Almirante B, Cuenca-Estrella M, Garnacho-Montero J, Padilla B, Puig-Asensio M, Ruiz-Camps I, Rodríguez-Baño J, members of the CANDIPOP Project from GEIH-GEMICOMED (SEIMC) and REIPI (2016) Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort. Clin Microbiol Infect 22:733

    Article  PubMed  Google Scholar 

  53. Eschenauer GA, Carver PL, Lin SW, Klinker KP, Chen YC, Potoski BA, Shields RK, Clancy CJ, Nguyen MH, Lam SW (2013) Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study. J Antimicrob Chemother 68:922–926

    Article  CAS  PubMed  Google Scholar 

  54. Puig-Asensio M, Fernández-Ruiz M, Aguado JM, Merino P, Lora-Pablos D, Guinea J, Martín-Dávila P, Cuenca-Estrella M, Almirante B (2016) Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections. Antimicrob Agents Chemother 60:3291–3300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, Sobel JD, Pappas PG, Kullberg BJ, Mycoses Study Group (2012) Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 54:1110–1122

    Article  CAS  PubMed  Google Scholar 

  56. Vazquez J, Reboli AC, Pappas PG, Patterson TF, Reinhardt J, Chin-Hong P, Tobin E, Kett DH, Biswas P, Swanson R (2014) Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis 14:97

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bailly S, Leroy O, Montravers P, Constantin JM, Dupont H, Guillemot D, Lortholary O, Mira JP, Perrigault PF, Gangneux JP, Azoulay E, Timsit JF (2015) Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data. Intensive Care Med 41(11):1931–1940

    Article  CAS  PubMed  Google Scholar 

  58. Seyedmousavi S, Melchers WJ, Mouton JW, Verweij PE (2013) Pharmacodynamics and dose- response relationships of liposomal amphotericin b against different azole-resistant Aspergillus fumigatus isolates in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother 57:1866–1871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Verweij PE, Chowdhary A, Melchers WJ, Meis JF (2016) Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis 62:362–368

    Article  PubMed  Google Scholar 

  60. Lestner JM, Roberts SA, Moore CB, Howard SJ, Denning DW, Hope WW (2009) Toxicodynamics of itraconazole: implications for therapeutic drug monitoring. Clin Infect Dis 49:928–930

    Article  CAS  PubMed  Google Scholar 

  61. Dolton MJ, Ray JE, Chen SCA, Ng K, Pont LG, McLachlan AJ (2012) Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother 56:4793–4799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Walsh TJ, Raad I, Patterson TF et al (2007) Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 44:2–12

    Article  CAS  PubMed  Google Scholar 

  63. Hatipoglu N, Hatipoglu H (2013) Combination antifungal therapy for invasive fungal infections in children and adults. Expert Rev Anti Infect Ther 11:523–535

    Article  CAS  PubMed  Google Scholar 

  64. Marr KA, Schlamm HT, Herbrecht R et al (2015) Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 162:81–89

    Article  PubMed  Google Scholar 

  65. Martín-Peña A, Aguilar-Guisado M, Espigado I, Cisneros JM (2014) Antifungal combination therapy for invasive aspergillosis. Clin Infect Dis 59(10):1437–1445

    Article  PubMed  Google Scholar 

  66. Verweij PE, Ananda-Rajahb M, Andes D, Arendrup MC, Brüggemann RJ, Chowdhary A et al (2015) International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resist Updates 21–22:30–40

    Article  Google Scholar 

  67. Denning D, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, Ullman A, Dimopoulos G, Lange C, on behalf of the ESCIM and ERS (2016) Chronic pulmonary aspergillosis rationale and clinical guidelines for diagnosis and management. Eur Respir J 47(1):45–68

    Article  CAS  PubMed  Google Scholar 

  68. Tissot F, Lamoth F, Hauser PM, Orasch C, Fluckiger U, Siegemund M et al (2013) Beta-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med 188(9):1100–1109

    Article  PubMed  Google Scholar 

  69. Posteraro B, De Pascale G, Tumbarello M, Torelli R, Pennisi MA, Bello G et al (2011) Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1 to >3)-beta-d-glucan assay, Candida score, and colonization index. Crit Care 15(5):R249

    Article  PubMed  PubMed Central  Google Scholar 

  70. Angebault C, Lanternier F, Dalle F, Schrimpf C, Roupie AL, Dupuis A, Agathine A, Scemla A, Paubelle E, Caillot D, Neven B, Frange P, Suarez F, dEnfert C, Lortholary O, Bougnoux ME (2016) Prospective evaluation of serum β-glucan testing in patients with probable or proven fungal diseases. Open Forum Infect Dis 16 3(3):ofw128. doi:10.1093/ofid/ofw128

    Article  Google Scholar 

  71. Avni T, Leibovici L, Paul M (2011) PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol 49(2):665–670

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nguyen MH, Wissel MC, Shields RK, Salomoni MA, Hao B, Press EG et al (2012) Performance of Candida real-time polymerase chain reaction, beta-d-glucan assay, and blood cultures in the diagnosis of invasive candidiasis. Clin Infect Dis 54(9):1240–1248

    Article  CAS  PubMed  Google Scholar 

  73. Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, Garey KW, Alangaden GJ, Vazquez JA et al (2015) T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis 60(6):892–899

    Article  PubMed  Google Scholar 

  74. Vincent JL, Brealey D, Libert N, Abidi NE, O’Dwyer M, Zacharowski K et al (2015) Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Crit Care Med 43(11):2283–2291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Metzgar D, Frinder MW, Rothman RE, Peterson S, Carroll KC, Zhang SX et al (2016) The IRIDICA BAC BSI assay: rapid, sensitive and culture-independent identification of bacteria and Candida in blood. PLoS One 11(7):e0158186

    Article  PubMed  PubMed Central  Google Scholar 

  76. Rodríguez-Sánchez B, Sánchez-Carrillo C, Ruiz A, Marín M, Cercenado E, Rodríguez-Créixems M, Bouza E (2014) Direct identification of pathogens from positive blood cultures using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. Clin Microbiol Infect 20:O421–O427

    Article  PubMed  Google Scholar 

  77. Idelevich EA, Grünastel B, Becker K (2016) Rapid detection and identification of candidemia by direct blood culturing on solid medium using lysis-centrifugation method combined with MALDI-TOF MS. J Clin Microbiol 55(1):97–100

  78. Da Silva RM Jr, Da Silva Neto JR, Santos CS, Frickmann H, Poppert S, Cruz KS, Koshikene D, De Souza JV (2015) Evaluation of fluorescence in situ hybridisation (FISH) for the detection of fungi directly from blood cultures and cerebrospinal fluid from patients with suspected invasive mycoses. Ann Clin Microbiol Antimicrob 14:6

    Article  PubMed  PubMed Central  Google Scholar 

  79. Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, Garey KW, Alangaden GJ, Vazquez JA, Groeger JS, Judson MA, Vinagre YM, Heard SO, Zervou FN, Zacharioudakis IM, Kontoyiannis DP, Pappas PG (2015) T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis 60:892–899

    Article  PubMed  Google Scholar 

  80. Sinnollareddy MG, Roberts JA, Lipman J, Akova M, Bassetti M, De Waele JJ, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Dimopoulos G, DALI Study authors (2015) Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients study. Crit Care 19:33

    Article  PubMed  PubMed Central  Google Scholar 

  81. Lin CY, Liu WL, Chang CC, Chang HT, Hu HC, Kao KC, Chen NH, Chen YJ, Yang CT, Huang CC, Dimopoulos G (2017). Invasive fungal tracheobronchitis in mechanically ventilated critically ill patients: underlying conditions, diagnosis, and outcomes. Ann Intensive Care 7(1):9. doi:10.1186/s13613-016-0230-9

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kollef M, Micek S, Hampton N, Doherty JA, Kumar A (2012) Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 54(1):1739–1746

    Article  CAS  PubMed  Google Scholar 

  83. Eschenauer GA, Carver PL, Lin SW, Klinker KP, Chen YC, Potoski BA, Shields RK, Clancy CJ, Nguyen MH, Lam SW (2013) Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study. J Antimicrob Chemother 68:922–926

    Article  CAS  PubMed  Google Scholar 

  84. Bassetti M, Marchetti M, Chakrabarti A, Colizza S, Garnacho-Montero J, Kett DH, Munoz P, Cristini F, Andoniadou A, Viale P, Rocca GD, Roilides E, Sganga G, Walsh TJ, Tascini C, Tumbarello M, Menichetti F, Righi E, Eckmann C, Viscoli C, Shorr AF, Leroy O, Petrikos G, De Rosa FG (2013) A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts. Intensive Care Med 39(12):2092–2106

    Article  PubMed  Google Scholar 

  85. Plantinga TS, Johnson MD, Scott WK, van de Vosse E, Velez Edwards DR, Smith PB, Alexander BD, Yang JC, Kremer D, Laird GM, Oosting M, Joosten LA, van der Meer JW, van Dissel JT, Walsh TJ, Perfect JR, Kullberg BJ, Netea MG (2012) Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis 205:934–943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kumar V, Cheng SC, Johnson MD, Smeekens SP, Wojtowicz A, Giamarellos-Bourboulis E, Karjalainen J, Franke L, Withoff S, Plantinga TS, van de Veerdonk FL, van der Meer JW, Joosten LA, Sokol H, Bauer H, Herrmann BG, Bochud PY, Marchetti O, Perfect JR, Xavier RJ, Kullberg BJ, Wijmenga C, Netea MG (2014) Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia. Nat Commun 5:4675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kullberg BJ, van de Veerdonk F, Netea MG (2014) Immunotherapy: a potential adjunctive treatment for fungal infection. Curr Opin Infect Dis 27(6):511–516

    Article  CAS  PubMed  Google Scholar 

  88. Boff C, Zoppas BC, Aquino VR, Kuplich NM, Miron D, Pasqualotto AC (2013) The indoor air as a potential determinant of the frequency of invasive aspergillosis in the intensive care. Mycoses 56(5):527–531

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Infectious Diseases Clinic, Santa Maria Misericordia Hospital, University of Udine, Udine, Italy

    Matteo Bassetti

  2. Unidad Clínica de Cuidados Intensivos, Hospital Universitario Virgen Macarena and Institute of Biomedicine of Seville, IBiS/CSIC/University of Seville, seville, Spain

    Jose Garnacho-Montero

  3. Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland

    Thierry Calandra

  4. Department of Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands

    Bartjan Kullberg

  5. Department of Critical Care, University Hospital ATTIKON, National and Kapodistrian University of Athens, Athens, Greece

    George Dimopoulos

  6. Medical Intensive Care Unit, Hôpital Saint-Louis, ECSTRA Team, Biostatistics and Clinical Epidemiology, Paris Diderot Sorbonne University, Paris, France

    Elie Azoulay

  7. Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Arunaloke Chakrabarti

  8. Division of Pulmonary and Critical Care Medicine, The Leonard M. Miller School of Medicine at the University of Miami, Miami, FL, USA

    Daniel Kett

  9. Intensive Care Unit, Hospital Universitario de Valme, Universidad de Sevilla, Seville, Spain

    Cristobal Leon

  10. Division of Infectious Diseases, McGovern Medical School, UTHealth, Houston, USA

    Luis Ostrosky-Zeichner

  11. Institute of Microbiology, Università Cattolica del Sacro Cuore, Rome, Italy

    Maurizio Sanguinetti

  12. 1UMR1137-IAMETeam 5, Decision Sciences in Infectious Disease Prevention, Control and Care, Paris Diderot University-Inserm, Sorbonne Paris Cité and 2AP-HP, Medical and Infectious Diseases ICU, Bichat Hospital, Paris, France

    Jean-Francois Timsit

  13. Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

    Malcom D. Richardson

  14. Pulmonary and Critical Care Medicine, Medstar Washington Hospital Center, Washington, USA

    Andrew Shorr

  15. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (ZKS Köln), Department I of Internal Medicine, German Centre for Infection Research (DZIF), University of Cologne, Cologne, Germany

    Oliver A. Cornely

  16. Clinica Malattie Infettive, Azienda Sanitaria Universitaria Integrata, Presidio Ospedaliero Santa Maria della Misericordia, Piazzale S. Maria della Misericordia, n. 15, 33100, Udine, Italy

    Matteo Bassetti

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  1. Matteo Bassetti
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  2. Jose Garnacho-Montero
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  3. Thierry Calandra
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  15. Oliver A. Cornely
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Corresponding author

Correspondence to Matteo Bassetti.

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Conflicts of interests

No non-financial conflicts of interest exist for any of the authors.

Financial interest

MB serves on scientific advisory boards for Basilea, Gilead, Pfizer, Merck, and Astellas and has received funding for travel or speaker honoraria from Basilea, Gilead, Pfizer, Merck, and Astellas Pharma. LO has received research grants and/or speaking or consulting fees from Merck, Astellas, Pfizer, Scynexis, Cidara, Gilead, Meiji, and T2 biosystems. AS has served as a speaker for, consultant to, or received research support from Achaogen, Actavis, Astellas, AZ, Bayer, Cempra, Cidara, Entasysis, MedCo, Melinta, Merck, Paratek, Roche, Spero, Tetraphase, Theravamce, and Wockhordt. JFT serves on scientific advisory boards for Merck and Gilead and has received speaker honoraria and/or research grants from Merck, Astellas, and Pfizer. The other authors declare no conflict of interest.

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Bassetti, M., Garnacho-Montero, J., Calandra, T. et al. Intensive care medicine research agenda on invasive fungal infection in critically ill patients. Intensive Care Med 43, 1225–1238 (2017). https://doi.org/10.1007/s00134-017-4731-2

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