title: Intensive care medicine research agenda on invasive fungal infection in critically ill patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Infectious Diseases Clinic, Santa Maria Misericordia Hospital, University of Udine, Udine, Italy. mattba@tin.it.|Clinica Malattie Infettive, Azienda Sanitaria Universitaria Integrata, Presidio Ospedaliero Santa Maria della Misericordia, Piazzale S. Maria della Misericordia, n. 15, 33100, Udine, Italy. mattba@tin.it.
authors.forename: Matteo
authors.identifier: http://orcid.org/0000-0002-4406-962X
authors.initials: M
authors.lastname: Bassetti
authors.affiliation: Unidad Clínica de Cuidados Intensivos, Hospital Universitario Virgen Macarena and Institute of Biomedicine of Seville, IBiS/CSIC/University of Seville, seville, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Garnacho-Montero
authors.affiliation: Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
authors.affiliation: Department of Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Bartjan
authors.initials: B
authors.lastname: Kullberg
authors.affiliation: Department of Critical Care, University Hospital ATTIKON, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dimopoulos
authors.affiliation: Medical Intensive Care Unit, Hôpital Saint-Louis, ECSTRA Team, Biostatistics and Clinical Epidemiology, Paris Diderot Sorbonne University, Paris, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Azoulay
authors.affiliation: Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Arunaloke
authors.initials: A
authors.lastname: Chakrabarti
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Leonard M. Miller School of Medicine at the University of Miami, Miami, FL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kett
authors.affiliation: Intensive Care Unit, Hospital Universitario de Valme, Universidad de Sevilla, Seville, Spain.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Leon
authors.affiliation: Division of Infectious Diseases, McGovern Medical School, UTHealth, Houston, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Ostrosky-Zeichner
authors.affiliation: Institute of Microbiology, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.affiliation: 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.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Timsit
authors.affiliation: Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
authors.forename: Malcom D
authors.initials: MD
authors.lastname: Richardson
authors.affiliation: Pulmonary and Critical Care Medicine, Medstar Washington Hospital Center, Washington, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shorr
authors.affiliation: 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.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
mesh_terms: D000908:Antibodies, Fungal / Q000097:blood; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001230:Aspergillus / Q000276:immunology / Q000302:isolation & purification; D015415:Biomarkers / Q000097:blood; D035843:Biomedical Research; D002175:Candida / Q000276:immunology / Q000302:isolation & purification; D058387:Candidemia / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control; D016638:Critical Illness / Q000401:mortality; D014943:Global Health; D006801:Humans; D015994:Incidence; D007362:Intensive Care Units; D000072742:Invasive Fungal Infections / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control; D055744:Invasive Pulmonary Aspergillosis / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control; D017410:Practice Guidelines as Topic; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D059039:Standard of Care / Q000592:standards*
chemical_list: D000908:Antibodies, Fungal; D000935:Antifungal Agents; D015415:Biomarkers
keywords: Antifungals; Aspergillus; Beta-D-glucan; Candida; Echinocandins; Fluconazole