Advertisement

MEDical wards Invasive Candidiasis ALgorithms (MEDICAL):Consensus proposal for management

Open AccessPublished:August 02, 2016DOI:https://doi.org/10.1016/j.ejim.2016.07.007

      Highlights

      • Patient’s stratification for clinical severity and risk of IC is pivotal.
      • In symptomatic patients, a microbiological diagnosis should be pursued.
      • In stable patients, a watchful waiting approach until diagnosis is appropriate.
      • In critically ill patients, first-line therapy with an echinocandin is necessary.
      • In patients with proven infection, early antifungal therapy is warranted.

      Abstract

      Introduction

      A majority of invasive Candida infections occur in medical wards; however, evidence for management in this setting is scarce and based primarily on the intensive care or surgical setting. On behalf of the Italian Society for Anti-Infective Therapy (SITA) and the Italian Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), the MEDICAL group produced practical management algorithms for patients in internal medicine wards.

      Methods

      The MEDICAL group panel, composed of 30 members from internal medicine, infectious disease, clinical pharmacology, clinical microbiology and clinical epidemiology, provided expert opinion through the RAND/UCLA method.

      Results

      Seven clinical scenarios were constructed based on clinical severity and probability of invasive candidiasis. For each scenario, the appropriateness of 63 different diagnostic, imaging, management, or therapeutic procedures was determined in two Delphi rounds. The necessity for performing each appropriate procedure, was then determined in a third Delphi round. Results were summarized in algorithms.

      Discussion

      The proposed algorithms provide internal medicine physicians and managers with an easy to interpret tool that is exhaustive, clear and suitable for adaption to individual local settings. Attention was paid to individual patient management and resource allocation.

      Keywords

      1. Introduction

      Invasive candidiasis (IC) is increasingly recognized as a frequent problem among patients hospitalized in internal medicine wards, owing to the high prevalence of frail patients in this setting. Such patients often have risk factors, including mucosal or cutaneous barrier disruptions, invasive procedures, endovascular devices, parenteral nutrition, cancer, chronic renal failure, renal transplantation, liver disease, immunosuppressive treatments for systemic connective tissue diseases, extensive exposure to broad spectrum antibiotics and multisite Candida colonization [
      • Falcone M.
      • Concia E.
      • Iori I.
      • Lo Cascio G.
      • Mazzone A.
      • Pea F.
      • et al.
      Identification and management of invasive mycoses in internal medicine: a road-map for physicians.
      ,
      • Luzzati R.
      • Cavinato S.
      • Deiana M.L.
      • Rosin C.
      • Maurel C.
      • Borelli M.
      Epidemiology and outcome of nosocomial candidemia in elderly patients admitted prevalently in medical wards.
      ,
      • Tortorano A.M.
      • Prigitano A.
      • Lazzarini C.
      • Passera M.
      • Deiana M.L.
      • Cavinato S.
      • et al.
      A 1-year prospective survey of candidemia in Italy and changing epidemiology over one decade.
      ,
      • Briongos-Figuero L.S.
      • Hernanz-Román L.
      • Pineda-Alonso M.
      • Vega-Tejedor G.
      • Gómez-Traveso T.
      • Sañudo-García S.
      • et al.
      In-hospital mortality due to infectious disease in an Internal Medicine Department. Epidemiology and risk factors.
      ,
      • Puig-Asensio M.
      • Ruiz-Camps I.
      • Fernández-Ruiz M.
      • Aguado J.M.
      • Muñoz P.
      • Valerio M.
      • et al.
      Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain.
      ,
      • Bassetti M.
      • Taramasso L.
      • Nicco E.
      • Molinari M.P.
      • Mussap M.
      • Viscoli C.
      Epidemiology, species distribution, antifungal susceptibility and outcome of nosocomial candidemia in a tertiary care hospital in Italy.
      ,
      • Spiliopoulou A.
      • Vamvakopoulou S.
      • Bartzavali C.
      • Dimitracopoulos G.
      • Anastassiou E.D.
      • Christofidou M.
      Eleven-year retrospective survey of candidaemia in a university hospital in southwestern Greece.
      ].
      Moreover, mortality from IC in medical wards is high, often comparable to that in intensive care units (ICUs). In contrast, the level of diagnostic suspicion and timely therapy are variable and frequently inadequate [
      • Bassetti M.
      • Molinari M.P.
      • Mussap M.
      • Viscoli C.
      • Righi E.
      Candidaemia in internal medicine departments: the burden of a rising problem.
      ,
      • De Rosa F.G.
      • Corcione S.
      • Filippini C.
      • Raviolo S.
      • Fossati L.
      • Montrucchio C.
      • et al.
      The effect on mortality of fluconazole or echinocandins treatment in internal medicine wards.
      ]. These epidemiological features have contributed to defining IC as a public health problem with excess mortality, prolonged hospital stays, and significant costs [
      • Pfaller M.A.
      • Diekema D.J.
      Epidemiology of invasive candidiasis: a persistent public health problem.
      ].
      Despite attention to IC in medical wards, the evidence-base for management and treatment is primarily derived from other settings, such as ICU, transplant units, surgery or hematology wards, and most guidelines are directed towards these settings [
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • Garbino J.
      • Kullberg B.J.
      • Lortholary O.
      • et al.
      ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      ,
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.R.
      • Clancy C.J.
      • Marr K.A.
      • Ostrosky-Zeichner L.
      • et al.
      Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.
      ]. However, patients in medical wards are often more complex and have more and different comorbidities than those “traditionally” studied in earlier experiences on IC. In our opinion it is not appropriate to directly apply guidelines created for other settings to the internal medicine setting [
      • Guthrie B.
      • Payne K.
      • Alderson P.
      • McMurdo M.E.
      • Mercer S.W.
      Adapting clinical guidelines to take account of multimorbidity.
      ,
      • Tinetti M.E.
      • McAvay G.
      • Trentalange M.
      • Cohen A.B.
      • Allore H.G.
      Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study.
      ].
      To address the need for practical guidance on medical patients, based on imperfect evidence, the Italian Society for Anti-Infective Therapy (SITA) and the Italian Federation of Associations of Hospital Doctors in Internal Medicine (FADOI) have supported this consensus process to develop indications on the diagnosis, management and treatment of IC, and to support antifungal stewardship programs [
      • Muñoz P.
      • Valerio M.
      • Vena A.
      • Bouza E.
      Antifungal stewardship in daily practice and health economic implications.
      ,
      • Ruhnke M.
      Antifungal stewardship in invasive Candida infections.
      ]. This document applies to a patient admitted to a medical hospital ward who:
      • Has not received a solid organ transplant in the last 24 months
      • Does not present a surgical reason for admission (excluding post-operative medical management)
      • Does not present severe absolute neutropenia (neutrophil count < 0.5 × 109/L) [
        • De Naurois J.
        • Novitzky-Basso I.
        • Gill M.J.
        • Marti F.M.
        • Cullen M.H.
        • Roila F.
        • et al.
        Management of febrile neutropenia: ESMO Clinical Practice Guidelines.
        ]
      • Does not present with septic shock on admission to the medical ward (such patient should be managed as an ICU patient)

      2. Methods

      2.1 Project design, expert panel and literature search

      The project was managed by the MEDICAL group, a three-layer (supervisory, steering committee, expert panel), multidisciplinary team, including experts in infectious diseases and internal medicine, clinical microbiology, clinical pharmacology, and methodology (Table 1). The final project structure, composition of the expert panel, methods, Authorship criteria, and management of potential conflicts of interest were decided in two preparatory rounds. Expert opinion from the 30-member panel was elicited through a modified Delphi process (RAND/UCLA Method) [
      • Brook R.H.
      • Chassin M.R.
      • Fink A.
      • Solomon D.H.
      • Kosecoff J.
      • Park R.E.
      A method for the detailed assessment of the appropriateness of medical technologies.
      ].
      Table 1Members of the MEDICAL group.
      NameAffiliationRoleClinical specialty
      Ercole ConciaSection of Infectious Diseases, Department of Pathology and Diagnostics, Azienda Ospedaliera Universitaria Integrata, Policlinico G B Rossi, Verona, ItalySupervisorInfectious diseases
      Francesco MenichettiInfectious Disease Department, Cisanello Hospital, Pisa, ItalySupervisorInfectious diseases
      Pierluigi VialeInfectious Diseases Unit, Teaching Hospital Policlinico S. Orsola-Malpighi Alma Mater Studiorum, University of Bologna, Bologna, ItalySupervisorInfectious diseases
      Claudio ViscoliInfectious Disease Unit, University of Genova (DISSAL) and IRCCS San Martino-IST, Genoa, ItalySupervisorInfectious diseases
      Mario VendittiDepartment of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, ItalySupervisorIM/ID
      Matteo BassettiInfectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, ItalySteering committeeInfectious Diseases
      Francesco CristiniInfectious Diseases Unit, Teaching Hospital Policlinico S. Orsola-Malpighi Alma Mater Studiorum, University of Bologna, Bologna, ItalySteering committeeInfectious Diseases
      Francesco Giuseppe De RosaDepartment of Medical Sciences, University of Torino, Turin, ItalySteering committeeInfectious diseases
      Valerio Del BonoClinic of Infectious Diseases, IRCCS San Martino-IST, University of Genova, Genoa, ItalySteering committeeInfectious diseases
      Emanuele Durante-MangoniInternal Medicine Section, Department of Cardiothoracic Sciences, and Division of Infectious and Transplant Medicine, Second University of Naples at Monaldi Hospital, Naples, ItalySteering committeeInternal medicine
      Marco FalconeDepartment of Public Health and Infectious Diseases, Policlinico Umberto I, “Sapienza“ University of Rome, Rome, ItalySteering committeeIM/ID
      Antonino MazzoneInternal Medicine Department, Hospital of Legnano, Legnano, ItalySteering committeeInternal medicine
      Carlo TasciniInfectious Disease Department, Cisanello Hospital, Pisa, ItalySteering committeeInfectious diseases
      Mario TumbarelloInfectious Diseases Institute, Policlinico Gemelli, Università Cattolica del Sacro Cuore, Rome, ItalySteering committeeInfectious diseases
      Eleonora ArboscelloClinica di Medicina Interna 3, Dipartimento delle Terapie Oncologiche Integrate, IRCSS AOU San Martino-IST Genova, Genoa, ItalyExpertInternal medicine
      Salvatore CorraoDepartment of Internal Medicine, National Relevance Hospital Trust, ARNAS Civico, Di Cristina e Benfratelli, Palermo, Di.Bi.M.I.S., University of Palermo, ItalyExpertInternal medicine
      Silvano EspositoDepartment of Infectious Diseases, University of Salerno, Salerno, ItalyExpertInfectious diseases
      Gianluca Pasquale GiuriInternal Medicine Department, S. Anna Hospital, Reggio Emilia, ItalyExpertInternal medicine
      Massimo GiustiInternal Medicine, San Giovanni Bosco Hospital, Turin, ItalyExpertInternal medicine
      Marco GrandiInternal Medicine, Nuovo Ospedale Civile, Sassuolo, ItalyExpertInternal medicine
      Paolo GrossiInfectious and Tropical Diseases Unit, University of Insubria—Ospedale di Circolo e Fondazione Macchi, Varese, ItalyExpertInfectious diseases
      Roberto LuzzatiInfectious Diseases Unit Azienda Ospedaliera—Universitaria ‘Ospedali Riuniti’ di Trieste, Trieste, ItalyExpertInfectious diseases
      Nicola PetrosilloDepartment of Infectious Diseases IRCCS Istituto Nazionale per le Malattie Infettive “L. Spallanzani”, IRCCS, Rome, ItalyExpertInfectious diseases
      Filippo PieralliInternal Medicine, Careggi Hospital, Florence, ItalyExpertInternal medicine
      Claudio SantiniInternal Medicine, Vannini Hospital, Rome, ItalyExpertInternal medicine
      Luca ScaglioneDepartment of Internal Medicine, Azienda Ospedaliero-Universitaria

      Città della Salute e della Scienza di Torino, Turin, Italy
      ExpertInternal medicine
      Gaetano ServiddioCentro Universitario per la Ricerca e la Cura delle Malattie Epatiche (C.U.R.E.), Institute of Internal Medicine, University of Foggia, ItalyExpertInternal medicine
      Dino SgarabottoDepartment of Infectious and Tropical Diseases, University Hospital, Padova, ItalyExpertInfectious diseases
      Liana SignoriniClinic of Infectious Diseases Spedali Civili di Brescia, Brescia, ItalyExpertInfectious diseases
      Luigia ScudellerClinical Epidemiology and Biometry Unit - Scientific Direction- IRCCS Policlinic San Matteo Foundation, Pavia, ItalyClinical epidemiologistClinical epidemiology and infectious diseases
      The entire process, including preparatory meetings, literature search, three Delphi rounds, an interim meeting of the steering committee and the final consensus conference took place between January and October 2015.
      Evidence was collected by searching the PubMed literature database with the query terms (candid*[all fields] OR invasive fungal disease*[all fields] OR invasive fungal infection*[all fields]). In addition, the bibliographies of retrieved papers were manually scanned to identify additional evidence. Search results were updated weekly throughout the project.

      2.2 Consensus process

      The panel scored the appropriateness of 63 different diagnostic, imaging, management, or therapeutic procedures in seven clinical scenarios. Two scoring rounds were conducted by email. Appropriateness was scored on a scale of 1 (usually not appropriate) to 9 (always appropriate). Terminology for classifying the procedures is presented in Box 1 [
      • Fitch K.
      • Bernstein S.J.
      • Aguilar M.D.
      • Burnand B.
      • LaCalle J.R.
      • Lazaro P.
      • et al.
      The Rand/UCLA appropriateness method user’s manual.
      ].
      Terminology used to describe procedures
      • -
        Could be considered” refers to a procedure that is indicated only in specific clinical conditions.
      • -
        Appropriate” is used when the overall benefits of the procedure outweigh harms, and the procedure is recommended if it is available in the specific clinical setting
      • -
        Necessary“ is used when there is a reasonable chance that the procedure will benefit the patient, and it would be improper care not to offer it to a patient.
      The median score and the 30–70 interpercentile range corrected for asymmetry (IPRAS) were calculated. Procedures were classified as inappropriate, uncertain, appropriate with disagreement or appropriate without disagreement. After viewing the results of the first round, in which their own responses were highlighted, panel members were asked to review their choices in the second round. Then, in a third scoring round, experts rated the necessity (Box 1) of each procedure that had been classified “appropriate” without disagreement.
      Steering committee members drafted separate clinical management algorithms for sepsis and severe sepsis. The reader is referred to published guidelines for treatment of specific clinical localizations of IC (e.g., osteomyelitis, endophthalmitis) [
      • Scudeller L.
      • Viscoli C.
      • Menichetti F.
      • del Bono V.
      • Cristini F.
      • Tascini C.
      • et al.
      An Italian consensus for invasive candidiasis management (ITALIC).
      ]. At a consensus conference on October 1–2, 2015, the panel finalized the algorithms, taking healthcare costs into consideration, as well as benefits. Consensus was defined as ≥90% agreement.

      2.3 Operational definitions

      Invasive Candida infections are more common in certain populations, due to the higher incidence of risk factors. We identified candidate risk factors from published studies and risk scores developed and validated for ICU patients [
      • Bassetti M.
      • Molinari M.P.
      • Mussap M.
      • Viscoli C.
      • Righi E.
      Candidaemia in internal medicine departments: the burden of a rising problem.
      ,
      • Marchetti O.
      • Bille J.
      • Fluckiger U.
      • et al.
      Fungal Infection Network of Switzerland. Epidemiology of candidaemia in Swiss tertiary care Hospitals: secular trends 1991-2000.
      ,
      • Guimarães T.
      • Nucci M.
      • Mendonça J.S.
      • et al.
      Epidemiology and predictors of a poor outcome in elderly patients with candidemia.
      ,
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • Almirante B.
      • Nolla-Salas J.
      • Alvarez-Lerma F.
      • et al.
      A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.
      ,
      • Ostrosky-Zeichner L.
      • Sable C.
      • Sobel J.
      • Alexander B.D.
      • Donowitz G.
      • Kan V.
      • et al.
      Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.
      ,
      • Ben-Ami R.
      • Olshtain-Pops K.
      • Krieger M.
      • Oren I.
      • Bishara J.
      • Dan M.
      • et al.
      Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection.
      ,
      • Eggimann P.
      • Que Y.A.
      • Revelly J.P.
      • Pagani J.L.
      Preventing invasive candida infections. Where could we do better?.
      ,
      • Berdal J.E.
      • Haagensen R.
      • Ranheim T.
      • Bjørnholt J.V.
      Nosocomial candidemia; risk factors and prognosis revisited; 11 years experience from a Norwegian secondary hospital.
      ]. 5 days of antibiotic exposure, 10 days prior hospitalization, and prior candida infections were chosen as risk factor for IC following consensus procedure, based upon literature review and clinical expertise of participants. Risk factors considered relevant by ≥90% of the panel were included in the analysis (Box 2). Stable clinical conditions were defined as normal vital signs and no organ failure.
      Selected risk factors for invasive candidiasis
      Broad spectrum antibiotic treatment ongoing for at least 5 days
      Central venous catheter (CVC) or peripherally inserted central catheter (PICC)
      Parenteral nutrition
      Chemotherapy for solid and hematological tumors (including steroids)
      Hospitalization > 10 days in previous 3 months (including nursing homes/long-term care facilities)
      Prior candidemia
      Candida colonization in >1 site
      Transferred from ICU
      Dialysis
      Operational definitions were adopted also for IC (Box 3), and the concepts of sepsis, severe sepsis and septic shock [
      • Scudeller L.
      • Viscoli C.
      • Menichetti F.
      • del Bono V.
      • Cristini F.
      • Tascini C.
      • et al.
      An Italian consensus for invasive candidiasis management (ITALIC).
      ,
      • Angus D.C.
      • van der Poll T.
      Severe sepsis and septic shock.
      ,
      • Kullberg B.J.
      • Arendrup M.C.
      Invasive Candidiasis.
      ]. Persistent candidemia was defined as isolation of the same Candida species > 72 h after initiation of antifungal therapy [
      • Fernández-Ruiz M.
      • Aguado J.M.
      • Almirante B.
      • Lora-Pablos D.
      • Padilla B.
      • Puig-Asensio M.
      • et al.
      Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis bloodstream infection: a propensity score analysis.
      ,
      • Arnold C.J.
      • Johnson M.
      • Bayer A.S.
      • Bradley S.
      • Giannitsioti E.
      • Miró J.M.
      • et al.
      Candida infective endocarditis: an observational cohort study with a focus on therapy.
      ]. Surveillance cultures were defined as sampling from distinct non-blood body sites in absence of any clinical indication, performed only to determine colonization status. Fundus oculi and echocardiographic evaluations imply serial assessments, because pathological changes may not be evident in early phases of IC.
      Definition of invasive candidiasis
      Invasive candidiasis (IC) indicates either a deep-seated Candida infection or candidemia. The following categories of diagnostic certainty were used:
      • Proven IC: microbiological evidence of Candida, or yeast cells, hyphae or pseudohyphae at histology or on direct examination in a normally sterile tissue or organ (i.e., excluding urine, sputum, bronchoalveolar lavage, mucous membrane swabs and specimens from skin).
      • Probable IC: concomitant presence of an underlying disease predisposing to IC, two or more risk factors (Box 2), with signs of active infection [
        • Muth C.
        • Glasziou P.P.
        Guideline recommended treatments in complex patients with multimorbidity.
        ], and at least one positive antigen test (e.g., beta-D-glucan, mannan/antimannan).
      • Possible IC: concomitant presence of an underlying disease predisposing to IC, one risk factor (Box 2), with signs of active infection [
        • Muth C.
        • Glasziou P.P.
        Guideline recommended treatments in complex patients with multimorbidity.
        ], but without microbiological confirmation.

      2.4 Clinical scenarios

      Likelihood of IC was operationally defined as certainty (patients with microbiological diagnosis (blood culture positivity) of IC, high (patients with two or more risk factors), or low (patients with one risk factor only). Hypothetical patients were stratified into one of seven clinical scenarios (Table 2), based on both clinical severity (asymptomatic, sepsis or severe sepsis) (1) and the likelihood of having IC, as defined in Box 3.
      Table 2Clinical scenarios based on severity of sepsis and risk factors for invasive candidiasis.
      Lower IC probability

      1 risk factor
      Higher IC probability

      2 or more risk factors
      Proven IC

      Microbiological diagnosis
      AsymptomaticNot consideredScenario 1Not applicable
      SepsisScenario 2Scenario 3Scenario 4 (excluding diagnostic procedures)
      Severe sepsisScenario 5Scenario 6Scenario 7 (excluding diagnostic procedures)
      Note: septic shock/critically ill patients (with a life-threatening condition, with changes in one or more vital functions – circulation, breathing, mental status – and in need of organ support) is not within the scope of this consensus.

      3. Results

      The algorithms are presented according to clinical severity: patients with sepsis (Fig. 1) or severe sepsis (Fig. 2), each with three corresponding scenarios: lower risk of IC, higher risk for IC and proven diagnosis (defined in Box 3). Asymptomatic patients have not been included in the algorithms; their management is described in Section 3.1.
      Fig. 1
      Fig. 1Proposed algorithm for the management of a patient with sepsis in internal medicine wards. Procedures deemed necessary in the RAND/UCLA process are required.
      Fig. 2
      Fig. 2Proposed algorithm for the management of a patient with severe sepsis in internal medicine wards. Procedures deemed necessary in the RAND/UCLA process are required.

      3.1 Asymptomatic patient with risk factors for IC

      Neither therapy nor prophylaxis is recommended for this group of patients. The primary goal should be to reduce the risks of developing IC. Multiple colonization is not a risk factor per se, but, because endogenous colonization is the source for the majority of severe episodes of IC, it should be taken into account if the patient develops signs and symptoms of IC [
      • León C.
      • Ostrosky-Zeichner L.
      • Schuster M.
      What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients.
      ]. The cost/benefit ratio for colonization screening in the medical setting is not well established and should be discourage.
      The indication for peripherally or centrally infused parenteral nutrition in the medical setting should be reassessed frequently in patients with risk factors for invasive candidiasis [
      • Luzzati R.
      • Cavinato S.
      • Giangreco M.
      • Granà G.
      • Centonze S.
      • Deiana M.L.
      • et al.
      Peripheral and total parenteral nutrition as the strongest risk factors for nosocomial candidemia in elderly patients: a matched case-control study.
      ]. Patients with diabetes or concomitant C. difficile colitis might have invasive candidiasis without fever and rarely also without SIRS, patients with these comorbidities and risk factors for invasive candidiasis should undergo a diagnostic work-up for invasive candida infections, including non-cultural serologic methods, where available. The group agrees that there is no indication for empirical or pre-emptive antifungal treatment in this setting.

      3.2 Symptomatic patients

      A patient with signs and symptoms of infection must have at least two blood cultures sets performed, one from a central venous catheter (CVC), if present. Additional samples from any clinical site suspect for localization of infection should be tested. In addition, plasma levels of the C-reactive protein and procalcitonic concentrations should be evaluated, despite their low specificity and sensitivity. Beta-d-glucan (BDG) has a high negative predictive value, which may help to exclude IC. However, this test was graded as appropriate but not necessary because it is not available in all settings. The mannan-antimannan assay can also be considered, although there is less evidence on the clinical use of this test. Surveillance cultures may be performed, with the sole aim of assessing colonization, which is not per se an indication for antifungal therapy. To date, PCR and other nucleic acid-based tests are not recommended for widespread use at the clinical level.

      3.2.1 Non-critically ill patients with sepsis: Algorithm 1 (Fig. 1)

      This patient shows signs and symptoms of infection, but is in relatively stable clinical condition. Whereas the causative agent could be Candida spp., the likelihood of a Candida infection is lower if ≤1 risk factor is present (scenario 2), and higher if ≥2 risk factors are present (scenario 3). In medical wards, most patients present multiple known risk factors for IC, thus the “high-risk” scenario is probably more frequent there. The management goal is correct diagnosis of IC (and its complications) or its exclusion, and selecting the correct empirical treatment.

      3.2.2 Patients without confirmed IC infection

      A watchful waiting approach, is appropriate, with re-assessment as clinically indicated. If antifungal treatment is started, fluconazole is an acceptable choice, unless there are risk factors for infection with fluconazole-resistant strains (e.g., previous therapeutic courses of fluconazole).
      If microbiological tests do not lead to a diagnosis of Candida infection and clinical conditions do not improve, then clinical, imaging and microbiological reassessment (with device removal/replacement, if possible) are appropriate.

      3.2.3 Patients with confirmed IC infection

      In patients with a confirmed microbiological diagnosis, but relatively stable clinical condition (scenario 4), the aim of management to select the correct targeted therapy, reduce the risk of complications or relapse, and carefully screen for secondary localizations.
      Even if the patient is not critically ill, clinicians should administer antifungal therapy as early as possible, preferably an echinocandin. Early de-escalation to fluconazole is appropriate, if supported by species identification and susceptibility tests. Possible therapeutic alternatives, depending on the isolated strain and/or local epidemiology, are fluconazole, voriconazole or a lipid formulation of amphotericin B (LF-AmB), especially if already started empirically or for other reasons (e.g., treatment with an echinocandin during the previous 30 days).
      Clinical follow-up would necessarily include repeat blood culture every 48–72 h, device removal and possibly source control if imaging results reveal a suspected deep infection; an infectious disease clinician should be consulted. Screening of secondary septic localizations, including fundus oculi evaluation, echocardiograph, and ultrasound scan of neck or arm vessels at the CVC site, are necessary, especially in patients with persistently positive blood cultures.

      3.3 Critically ill patients with severe sepsis: Algorithm 2 (Fig. 2)

      This patient shows severe signs and symptoms of infection and is clinically unstable. The causative agent could be Candida spp.; the probability is lower if there are ≤1 risk factor (scenario 5), and higher if there are ≥2 risk factors (scenario 6). As noted above, scenario 5 is much more frequent in the medical ward, because of patient complexity and comorbidities. In patients with severe sepsis, but a low likelihood of IC, the aims of management are the diagnosis of IC (and its complications) and selecting the appropriate empiric treatment.

      3.3.1 Patients without confirmed IC infection

      Imaging studies upon clinical suspicion are indicated for investigating the source of sepsis. Removal of unnecessary devices is considered good practice. Infectious disease and intensive care consultations are necessary, and additional consultations (e.g., surgery, cardiac surgery, interventional cardiology, vascular surgery) should be sought according to the clinical picture.
      For patients with ≤1 risk factor, it is acceptable to not administer an antifungal treatment as first line therapy, given the low risk of IC in this scenario. If an antifungal therapy is started, the first choice is usually an echinocandin, with de-escalation to azoles as soon as the patient is clinically stable. Drug interactions should be considered, in particular when the selected therapy is an azole.
      Unstable patients with ≥2 risk factors require prompt initiation of an appropriate treatment. In these patients, early antifungal treatment with an echinocandin is recommended, with de-escalation to an azole when the patient is clinically stable. An LF-AmB can be a useful option in some patients.

      3.3.2 Patients with confirmed IC infection

      In patients with confirmed IC and severe sepsis (scenario 7), the aim of management is the prompt initiation of adequate therapy, reduction of risk of complications or relapse, and diagnosis of any secondary localizations.
      In this setting, besides the management recommendations outlined above for previous scenarios, first-line therapy with an echinocandin is necessary, with an LF-AmB being an alternative. Again, de-escalation to an azole is appropriate as soon as the patient is clinically stable.

      4. Discussion

      We propose management algorithms for IC in medical wards, envisioned as practical assessment and treatment tools. Our proposals are based on a two-way risk stratification strategy that considers both clinical severity (sepsis vs. severe sepsis) and the likelihood that Candida spp. is a causative agent. We chose a modified Delphi method (RAND/UCLA) to identify appropriate and necessary practices in this setting, because formal evidence from controlled clinical trials is lacking. Using it, we sought to combine the best available scientific evidence, also from the ICU setting, and the collective judgment of experts with extensive experience in managing IC in medical wards.

      4.1 IC is common in internal medicine wards

      IC in the medical ward setting is understudied and possibly underestimated, but there is increasing evidence of a rising incidence [
      • Luzzati R.
      • Cavinato S.
      • Deiana M.L.
      • Rosin C.
      • Maurel C.
      • Borelli M.
      Epidemiology and outcome of nosocomial candidemia in elderly patients admitted prevalently in medical wards.
      ,
      • Tortorano A.M.
      • Prigitano A.
      • Lazzarini C.
      • Passera M.
      • Deiana M.L.
      • Cavinato S.
      • et al.
      A 1-year prospective survey of candidemia in Italy and changing epidemiology over one decade.
      ,
      • Bassetti M.
      • Merelli M.
      • Ansaldi F.
      • de Florentiis D.
      • Sartor A.
      • Scarparo C.
      • et al.
      Clinical and therapeutic aspects of candidemia: a five year single centre study.
      ]. Also, IC mortality among medical patients appears higher than in other settings, possibly due to delayed diagnosis, compromised underlying clinical conditions and difficulties in adhering to guidelines that have been elaborated for less complex patients [
      • De Rosa F.G.
      • Corcione S.
      • Filippini C.
      • Raviolo S.
      • Fossati L.
      • Montrucchio C.
      • et al.
      The effect on mortality of fluconazole or echinocandins treatment in internal medicine wards.
      ,
      • Tinetti M.E.
      • McAvay G.
      • Trentalange M.
      • Cohen A.B.
      • Allore H.G.
      Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study.
      ,
      • Muth C.
      • Glasziou P.P.
      Guideline recommended treatments in complex patients with multimorbidity.
      ].
      The typical patient admitted to a general medical ward is an elderly subject with multiple comorbidities, including many of the recognized risk factors for IC [
      • Falcone M.
      • Concia E.
      • Iori I.
      • Lo Cascio G.
      • Mazzone A.
      • Pea F.
      • et al.
      Identification and management of invasive mycoses in internal medicine: a road-map for physicians.
      ]. Some IC risk factors are modifiable (e.g., prolonged antibiotic treatment, indwelling devices) and efforts should be made to avoid exposing frail patients to unnecessary risk, when still asymptomatic for infection [
      • Ben-Ami R.
      • Olshtain-Pops K.
      • Krieger M.
      • Oren I.
      • Bishara J.
      • Dan M.
      • et al.
      Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection.
      ,
      • Luzzati R.
      • Cavinato S.
      • Giangreco M.
      • Granà G.
      • Centonze S.
      • Deiana M.L.
      • et al.
      Peripheral and total parenteral nutrition as the strongest risk factors for nosocomial candidemia in elderly patients: a matched case-control study.
      ]. In any scenario, careful reassessment of parenteral nutrition or ongoing antibiotic therapy should aim at withdrawing unnecessary treatment to avoid these modifiable risks for IC (e.g., when the patient's condition stabilizes). Microbiological diagnosis should be sought if there is no response after 72–96 h of empirical therapy. Surveillance cultures might be useful to identify colonized patients, as often suggested in ICU patients [
      • Kautzky S.
      • Staudinger T.
      • Presterl E.
      Invasive Candida infections in patients of a medical intensive care unit: attempt of improving diagnosis by quantifying the colonization.
      ]. Whereas, colonization with Candida spp., per se, is not an indication for treatment, it should be taken into consideration when assessing patients who become symptomatic.

      4.2 Early diagnosis or exclusion of IC requires proper microbiological diagnosis

      Early diagnosis and treatment of invasive candidiasis are associated with improved survival [
      • Posteraro B.
      • De Pascale G.
      • Tumbarello M.
      • Torelli R.
      • Pennisi M.A.
      • Bello G.
      • et al.
      Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1?3)-ß-D-glucan assay, Candida score, and colonization index.
      ,
      • Andes D.R.
      • Safdar N.
      • Baddley J.W.
      • Playford G.
      • Reboli A.C.
      • Rex J.H.
      • et al.
      Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials.
      ]. Elderly and patients with comorbidities may have blunted inflammatory and febrile response due to impaired immune function as a direct consequence of advanced age (immune aging) [
      • Jagger A.
      • Shimojima Y.
      • Goronzy J.J.
      • Weyand C.M.
      Regulatory T cells and the immune aging process: a mini-review.
      ,
      • Fulop T.
      • Dupuis G.
      • Baehl S.
      • Le Page A.
      • Bourgade K.
      • Frost E.
      • et al.
      From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.
      ] and/or to steroid or other immune suppressive therapy, including cancer therapy. Other components of the systemic inflammatory response syndrome may be lacking, including tachycardia due to beta-blocker use, tachypnea due to muscle atrophy and hypocapnia due to chronic respiratory failure. Diabetes mellitus may impair response to infections and favor fungal growth. Afebrile patients with candidemia have been described [
      • Morrell M.
      • Fraser V.J.
      • Kollef M.H.
      Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.
      ], and in one study, up to 20% of patients with candidemia did not show SIRS criteria [
      • Wisplinghoff H.
      • Seifert H.
      • Wenzel R.P.
      • Edmond M.B.
      Inflammatory response and clinical course of adult patients with nosocomial bloodstream infections caused by Candida spp.
      ]. In the absence of fever, IC mortality may be higher than in patients with fever or pyrexia [
      • León C.
      • Ostrosky-Zeichner L.
      • Schuster M.
      What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients.
      ,
      • Weiss E.
      • Timsit J.F.
      Management of invasive candidiasis in nonneutropenic ICU patients.
      ].
      In this clinical setting, signs and symptoms of infections may be mild or absent, and detecting IC presents a difficult albeit necessary task. Considering that up to 50% of IC diagnoses are estimated to be missed, attending physicians need a high index of suspicion to hasten microbiological diagnosis and manage these potentially severe infections [
      • Clancy C.J.
      • Nguyen M.H.
      Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care.
      ]. The search for the source of infection does not differ from good practice in any clinical setting [
      • Kollef M.
      • Micek S.
      • Hampton N.
      • Doherty J.A.
      • Kumar A.
      Septic shock attributed to Candida infection: importance of empiric therapy and source control.
      ]; however, issues specific to early diagnosis or exclusion of IC (pivotal from a clinical as well as from an antimicrobial stewardship perspective) involve proper microbiological diagnosis, with proper blood culturing in all cases. More advanced diagnostic techniques (e.g., fungal antigen testing) might be reserved to high-risk patients, and centralized in referral microbiology facilities [
      • Hou T.Y.
      • Wang S.H.
      • Liang S.X.
      • Jiang W.X.
      • Luo D.D.
      • Huang D.H.
      The Screening Performance of Serum 1,3-Beta-D-Glucan in Patients with Invasive Fungal Diseases: A Meta-Analysis of Prospective Cohort Studies.
      ,
      • Sims C.R.
      • Jaijakul S.
      • Mohr J.
      • Rodriguez J.
      • Finkelman M.
      • Ostrosky-Zeichner L.
      Correlation of clinical outcomes with ß-glucan levels in patients with invasive candidiasis.
      ,
      • Nguyen M.H.
      • Wissel M.C.
      • Shields R.K.
      • Salomoni M.A.
      • Hao B.
      • Press E.G.
      • et al.
      Performance of Candida real-time polymerase chain reaction, ß-D-glucan assay, and blood cultures in the diagnosis of invasive candidiasis.
      ,
      • Eggimann P.
      • Marchetti O.
      Is (1?3)-ß-D-glucan the missing link from bedside assessment to pre-emptive therapy of invasive candidiasis?.
      ].
      In order to hasten microbiological diagnosis, blood cultures from an arterial line might reduce the time to confirmation of candidiasis especially in patients with few symptoms [
      • Tascini C.
      • Sbrana F.
      • Cardinali G.
      • Ripoli A.
      • Leonildi A.
      • Amadori F.
      • et al.
      Arterial blood culture to hasten the diagnosis of candidemia in critically ill patients.
      ]. Source identification and control are necessary in patients with severe sepsis. This may require CVC removal, as well as consultations in surgery (general, heart or vascular as clinically appropriate), radiology, intensive care and infectious diseases. In particular, removal of all potentially infected devices is pivotal, as there is strong evidence supporting improved outcomes with CVC removal in patients with IC [
      • Muth C.
      • Glasziou P.P.
      Guideline recommended treatments in complex patients with multimorbidity.
      ,
      • Andes D.R.
      • Safdar N.
      • Baddley J.W.
      • Playford G.
      • Reboli A.C.
      • Rex J.H.
      • et al.
      Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials.
      ,
      • Rodriguez D.
      • Park B.J.
      • Almirante B.
      • Cuenca-Estrella M.
      • Planes A.M.
      • Mensa J.
      • et al.
      Impact of early central venous catheter removal on outcome in patients with candidaemia.
      ,
      • Liu C.Y.
      • Huang L.J.
      • Wang W.S.
      • Chen T.L.
      • Yen C.C.
      • Yang M.H.
      • et al.
      Candidemia in cancer patients: impact of early removal of non-tunneled central venous catheters on outcome.
      ].
      The stable patient with low risk of IC has no need of aggressive management or treatment; on the other hand, an empirical antifungal treatment can be considered in patients with ≥2 risk factors, pending blood culture results, and according to clinical judgment; in this case fluconazole is an appropriate choice [
      • De Rosa F.G.
      • Corcione S.
      • Filippini C.
      • Raviolo S.
      • Fossati L.
      • Montrucchio C.
      • et al.
      The effect on mortality of fluconazole or echinocandins treatment in internal medicine wards.
      ]. In severely ill patients at high risk for IC, it is widely accepted that first-line therapy should be an echinocandin [
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • Garbino J.
      • Kullberg B.J.
      • Lortholary O.
      • et al.
      ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      ,
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.
      • Benjamin D.K.
      • Calandra T.F.
      • Edwards J.E.
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      ]. The actual choice of molecule within the echinocandin class should be based on approved indications, personal experience, known side effects, PK/PD parameters and evidence. However, to reduce costs and limit impact on local resistance patterns, de-escalation from echinocandins to fluconazole is advisable when the patient is stable, especially if the isolated Candida strain is fluconazole-susceptible [
      • Bailly S.
      • Leroy O.
      • Montravers P.
      • Constantin J.M.
      • Dupont H.
      • Guillemot D.
      • et al.
      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.
      ,
      • Van der Geest P.J.
      • Rijnders B.J.
      • Vonk A.G.
      • Groeneveld A.B.
      Echinocandin to fluconazole step-down therapy in critically ill patients with invasive, susceptible Candida albicans infections.
      ]. The correct timing of de-escalation is still matter of debate; the panel recommends reassessment at 72/96 h [
      • Ostrosky-Zeichner L.
      • Sable C.
      • Sobel J.
      • Alexander B.D.
      • Donowitz G.
      • Kan V.
      • et al.
      Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.
      ,
      • Takesue Y.
      • Ueda T.
      • Mikamo H.
      • Oda S.
      • Takakura S.
      • Kitagawa Y.
      • et al.
      Management bundles for candidaemia: the impact of compliance on clinical outcomes.
      ]. Echinocandins are the drug of choice when the diagnosis of IC is confirmed, independent of clinical severity. Once again, de-escalation is an appropriate management strategy [
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.
      • Benjamin D.K.
      • Calandra T.F.
      • Edwards J.E.
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      ,
      • Bailly S.
      • Leroy O.
      • Montravers P.
      • Constantin J.M.
      • Dupont H.
      • Guillemot D.
      • et al.
      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.
      ]. The overall duration of therapy is not established, but there is consensus that treatment should be continued until blood cultures are repeatedly negative; pursuing both clinical and microbiological cure is critical to reducing the risk of relapse.

      4.3 Limitations

      We acknowledge a number of limitations in this project. First, although risk factor selection was based on an extensive literature review, the list of risk factors is arbitrary; currently, it is not possible to assign relative weights to individual risk factors. Also, implicit in the RAND/UCLA method, most recommendations are derived from evidence obtained in other settings or from expert opinion.

      4.4 Conclusions

      Applying the correct diagnostic and therapeutic approaches to IC in the medical setting would greatly improve clinical outcomes and advance hospital cost-containment strategies [
      • Muñoz P.
      • Valerio M.
      • Vena A.
      • Bouza E.
      Antifungal stewardship in daily practice and health economic implications.
      ,
      • Ruhnke M.
      Antifungal stewardship in invasive Candida infections.
      ]. One aim of this Consensus is to raise awareness in internal medicine wards, where the risk of IC risk is increasing. Another important issue is to optimize the use of new microbiological diagnostic techniques, because early diagnosis with prompt initiation of antifungal treatment can improve survival [
      • Puig-Asensio M.
      • Ruiz-Camps I.
      • Fernández-Ruiz M.
      • Aguado J.M.
      • Muñoz P.
      • Valerio M.
      • et al.
      Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain.
      ,
      • Hsu D.I.
      • Nguyen M.
      • Nguyen L.
      • Law A.
      • Wong-Beringer A.
      A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in non-immunocompromised adult patients.
      ]. We propose two algorithms for this purpose, developed to provide hospital managers and the physicians caring for medical patients with a simple but comprehensive tool to support decision-making around the issue of IC. We believe our proposed algorithms can be adapted to different hospitals and settings.

      Learning points

      • Candida and IC are underestimated in general medical wards, but there is increasing evidence of rising incidence
      • Early diagnosis of IC with prompt and adequate treatment is associated with improved survival
      • Patients with IC may have blunted inflammatory and febrile responses, therefore it is important to recognize these patients through their risk factors, to facilitate the diagnosis of IC
      • In all symptomatic patients, at least two blood cultures (one from a CVC, if present) are mandatory to confirm Candida infection
      • High risk patients with severe sepsis are similar in severity to patients admitted to ICUs, and therefore early antifungal treatment with an echinocandin is recommended

      Disclosures

      This work, including travel and meeting expenses, was supported by an unrestricted grant from MSD Italia Srl. The sponsor had no role in selecting the participants, reviewing the literature, defining recommendations, drafting or reviewing the paper, or in the decision to submit the manuscript for publication. All views expressed are solely those of the authors. All authors have completed the International Committee of Medical Journal Editors (ICMJE) form, which is available upon request.

      Conflict of interests

      The authors state that they have no conflicts of interest

      Acknowledgements

      We thank Federico Pea and Maurizio Sanguinetti for their important contribution to discussion of the recommendations.
      Medical writing assistance was provided by Editamed srl., Turin, Italy.

      References

        • Falcone M.
        • Concia E.
        • Iori I.
        • Lo Cascio G.
        • Mazzone A.
        • Pea F.
        • et al.
        Identification and management of invasive mycoses in internal medicine: a road-map for physicians.
        Intern Emerg Med. Aug 2014; 9: 501-511
        • Luzzati R.
        • Cavinato S.
        • Deiana M.L.
        • Rosin C.
        • Maurel C.
        • Borelli M.
        Epidemiology and outcome of nosocomial candidemia in elderly patients admitted prevalently in medical wards.
        Aging Clin Exp Res. Apr 2015; 27: 131-137
        • Tortorano A.M.
        • Prigitano A.
        • Lazzarini C.
        • Passera M.
        • Deiana M.L.
        • Cavinato S.
        • et al.
        A 1-year prospective survey of candidemia in Italy and changing epidemiology over one decade.
        Infection. Jun 2013; 41: 655-662
        • Briongos-Figuero L.S.
        • Hernanz-Román L.
        • Pineda-Alonso M.
        • Vega-Tejedor G.
        • Gómez-Traveso T.
        • Sañudo-García S.
        • et al.
        In-hospital mortality due to infectious disease in an Internal Medicine Department. Epidemiology and risk factors.
        Eur Rev Med Pharmacol Sci. Feb 2015; 19: 567-572
        • Puig-Asensio M.
        • Ruiz-Camps I.
        • Fernández-Ruiz M.
        • Aguado J.M.
        • Muñoz P.
        • Valerio M.
        • et al.
        Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain.
        Clin Microbiol Infect. May 2015; 21: 491.e1-491.e10
        • Bassetti M.
        • Taramasso L.
        • Nicco E.
        • Molinari M.P.
        • Mussap M.
        • Viscoli C.
        Epidemiology, species distribution, antifungal susceptibility and outcome of nosocomial candidemia in a tertiary care hospital in Italy.
        PLoS ONE. Sep 15 2011; 6e24198
        • Spiliopoulou A.
        • Vamvakopoulou S.
        • Bartzavali C.
        • Dimitracopoulos G.
        • Anastassiou E.D.
        • Christofidou M.
        Eleven-year retrospective survey of candidaemia in a university hospital in southwestern Greece.
        Clin Microbiol Infect. Sep 2010; 16: 1378-1381
        • Bassetti M.
        • Molinari M.P.
        • Mussap M.
        • Viscoli C.
        • Righi E.
        Candidaemia in internal medicine departments: the burden of a rising problem.
        Clin Microbiol Infect. Jun 2013; 19: E281-E284
        • De Rosa F.G.
        • Corcione S.
        • Filippini C.
        • Raviolo S.
        • Fossati L.
        • Montrucchio C.
        • et al.
        The effect on mortality of fluconazole or echinocandins treatment in internal medicine wards.
        PLoS ONE. May 4 2015; 10e0125149
        • Pfaller M.A.
        • Diekema D.J.
        Epidemiology of invasive candidiasis: a persistent public health problem.
        Clin Microbiol Rev. Jan 2007; 20: 133-163
        • Cornely O.A.
        • Bassetti M.
        • Calandra T.
        • Garbino J.
        • Kullberg B.J.
        • Lortholary O.
        • et al.
        ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
        Clin Microbiol Infect. Dec 2012; 18: 19-37
        • Pappas P.G.
        • Kauffman C.A.
        • Andes D.R.
        • Clancy C.J.
        • Marr K.A.
        • Ostrosky-Zeichner L.
        • et al.
        Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.
        Clin Infect Dis. Dec 16 2015;
        • Guthrie B.
        • Payne K.
        • Alderson P.
        • McMurdo M.E.
        • Mercer S.W.
        Adapting clinical guidelines to take account of multimorbidity.
        BMJ. Oct 4 2012; 345e6341
        • Tinetti M.E.
        • McAvay G.
        • Trentalange M.
        • Cohen A.B.
        • Allore H.G.
        Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study.
        BMJ. Oct 2 2015; 351: h4984
        • Muñoz P.
        • Valerio M.
        • Vena A.
        • Bouza E.
        Antifungal stewardship in daily practice and health economic implications.
        Mycoses. Jun 2015; 58: 14-25
        • Ruhnke M.
        Antifungal stewardship in invasive Candida infections.
        Clin Microbiol Infect. Jun 2014; 20: 11-18
        • De Naurois J.
        • Novitzky-Basso I.
        • Gill M.J.
        • Marti F.M.
        • Cullen M.H.
        • Roila F.
        • et al.
        Management of febrile neutropenia: ESMO Clinical Practice Guidelines.
        Ann Oncol. May 2010; 21: v252-v256
        • Brook R.H.
        • Chassin M.R.
        • Fink A.
        • Solomon D.H.
        • Kosecoff J.
        • Park R.E.
        A method for the detailed assessment of the appropriateness of medical technologies.
        Int J Technol Assess Health Care. 1986; 2: 53-63
        • Fitch K.
        • Bernstein S.J.
        • Aguilar M.D.
        • Burnand B.
        • LaCalle J.R.
        • Lazaro P.
        • et al.
        The Rand/UCLA appropriateness method user’s manual.
        ([accessed 14.01.15])
        • Scudeller L.
        • Viscoli C.
        • Menichetti F.
        • del Bono V.
        • Cristini F.
        • Tascini C.
        • et al.
        An Italian consensus for invasive candidiasis management (ITALIC).
        Infection. Apr 2014; 42: 263-279
        • Marchetti O.
        • Bille J.
        • Fluckiger U.
        • et al.
        Fungal Infection Network of Switzerland. Epidemiology of candidaemia in Swiss tertiary care Hospitals: secular trends 1991-2000.
        Clin Infect Dis. 2004; 38: 311-320
        • Guimarães T.
        • Nucci M.
        • Mendonça J.S.
        • et al.
        Epidemiology and predictors of a poor outcome in elderly patients with candidemia.
        Int J Infect Dis. 2012; 16: e442-e447
        • Leon C.
        • Ruiz-Santana S.
        • Saavedra P.
        • Almirante B.
        • Nolla-Salas J.
        • Alvarez-Lerma F.
        • et al.
        A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.
        Crit Care Med. 2006; 34: 730-737
        • Ostrosky-Zeichner L.
        • Sable C.
        • Sobel J.
        • Alexander B.D.
        • Donowitz G.
        • Kan V.
        • et al.
        Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.
        Eur J Clin Microbiol Infect Dis. 2007; 26: 271-276
        • Ben-Ami R.
        • Olshtain-Pops K.
        • Krieger M.
        • Oren I.
        • Bishara J.
        • Dan M.
        • et al.
        Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection.
        Antimicrob Agents Chemother. May 2012; 56: 2518-2523
        • Eggimann P.
        • Que Y.A.
        • Revelly J.P.
        • Pagani J.L.
        Preventing invasive candida infections. Where could we do better?.
        J Hosp Infect. Apr 2015; 89: 302-308
        • Berdal J.E.
        • Haagensen R.
        • Ranheim T.
        • Bjørnholt J.V.
        Nosocomial candidemia; risk factors and prognosis revisited; 11 years experience from a Norwegian secondary hospital.
        PLoS ONE. Jul 31 2014; 9e103916
        • Angus D.C.
        • van der Poll T.
        Severe sepsis and septic shock.
        N Engl J Med. Nov 21 2013; 369: 2063
        • Kullberg B.J.
        • Arendrup M.C.
        Invasive Candidiasis.
        N Engl J Med. Oct 8 2015; 373: 1445-1456
        • Fernández-Ruiz M.
        • Aguado J.M.
        • Almirante B.
        • Lora-Pablos D.
        • Padilla B.
        • Puig-Asensio M.
        • et al.
        Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis bloodstream infection: a propensity score analysis.
        Clin Infect Dis. May 2014; 58: 1413-1421
        • Arnold C.J.
        • Johnson M.
        • Bayer A.S.
        • Bradley S.
        • Giannitsioti E.
        • Miró J.M.
        • et al.
        Candida infective endocarditis: an observational cohort study with a focus on therapy.
        Antimicrob Agents Chemother. Apr 2015; 59: 2365-2373
        • Muth C.
        • Glasziou P.P.
        Guideline recommended treatments in complex patients with multimorbidity.
        BMJ. Oct 2 2015; 351: h5145
        • León C.
        • Ostrosky-Zeichner L.
        • Schuster M.
        What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients.
        Intensive Care Med. Jun 2014; 40: 808-819
        • Luzzati R.
        • Cavinato S.
        • Giangreco M.
        • Granà G.
        • Centonze S.
        • Deiana M.L.
        • et al.
        Peripheral and total parenteral nutrition as the strongest risk factors for nosocomial candidemia in elderly patients: a matched case-control study.
        Mycoses. Nov 2013; 56: 664-671
        • Bassetti M.
        • Merelli M.
        • Ansaldi F.
        • de Florentiis D.
        • Sartor A.
        • Scarparo C.
        • et al.
        Clinical and therapeutic aspects of candidemia: a five year single centre study.
        PLoS ONE. May 26 2015; 10e0127534
        • Kautzky S.
        • Staudinger T.
        • Presterl E.
        Invasive Candida infections in patients of a medical intensive care unit: attempt of improving diagnosis by quantifying the colonization.
        Wien Klin Wochenschr. Feb 2015; 127: 132-142
        • Posteraro B.
        • De Pascale G.
        • Tumbarello M.
        • Torelli R.
        • Pennisi M.A.
        • Bello G.
        • et al.
        Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1?3)-ß-D-glucan assay, Candida score, and colonization index.
        Crit Care. Oct 22 2011; 15: R249
        • Andes D.R.
        • Safdar N.
        • Baddley J.W.
        • Playford G.
        • Reboli A.C.
        • Rex J.H.
        • et al.
        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. Apr 2012; 54: 1110-1122
        • Jagger A.
        • Shimojima Y.
        • Goronzy J.J.
        • Weyand C.M.
        Regulatory T cells and the immune aging process: a mini-review.
        Gerontology. 2014; 60: 130-137
        • Fulop T.
        • Dupuis G.
        • Baehl S.
        • Le Page A.
        • Bourgade K.
        • Frost E.
        • et al.
        From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.
        Biogerontology. Oct 2015; 15
        • Morrell M.
        • Fraser V.J.
        • Kollef M.H.
        Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.
        Antimicrob Agents Chemother. Sep 2005; 49: 3640-3645
        • Wisplinghoff H.
        • Seifert H.
        • Wenzel R.P.
        • Edmond M.B.
        Inflammatory response and clinical course of adult patients with nosocomial bloodstream infections caused by Candida spp.
        Clin Microbiol Infect. Feb 2006; 12: 170-177
        • Weiss E.
        • Timsit J.F.
        Management of invasive candidiasis in nonneutropenic ICU patients.
        Ther Adv Infect Dis. Oct 2014; 2: 105-115
        • Clancy C.J.
        • Nguyen M.H.
        Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care.
        Clin Infect Dis. May 2013; 56: 1284-1292
        • Kollef M.
        • Micek S.
        • Hampton N.
        • Doherty J.A.
        • Kumar A.
        Septic shock attributed to Candida infection: importance of empiric therapy and source control.
        Clin Infect Dis. Jun 2012; 54: 1739-1746
        • Hou T.Y.
        • Wang S.H.
        • Liang S.X.
        • Jiang W.X.
        • Luo D.D.
        • Huang D.H.
        The Screening Performance of Serum 1,3-Beta-D-Glucan in Patients with Invasive Fungal Diseases: A Meta-Analysis of Prospective Cohort Studies.
        PLoS ONE. Jul 6 2015; 10e0131602
        • Sims C.R.
        • Jaijakul S.
        • Mohr J.
        • Rodriguez J.
        • Finkelman M.
        • Ostrosky-Zeichner L.
        Correlation of clinical outcomes with ß-glucan levels in patients with invasive candidiasis.
        J Clin Microbiol. Jun 2012; 50: 2104-2106
        • Nguyen M.H.
        • Wissel M.C.
        • Shields R.K.
        • Salomoni M.A.
        • Hao B.
        • Press E.G.
        • et al.
        Performance of Candida real-time polymerase chain reaction, ß-D-glucan assay, and blood cultures in the diagnosis of invasive candidiasis.
        Clin Infect Dis. May 2012; 54: 1240-1248
        • Eggimann P.
        • Marchetti O.
        Is (1?3)-ß-D-glucan the missing link from bedside assessment to pre-emptive therapy of invasive candidiasis?.
        Crit Care. Dec 5 2011; 15: 1017
        • Tascini C.
        • Sbrana F.
        • Cardinali G.
        • Ripoli A.
        • Leonildi A.
        • Amadori F.
        • et al.
        Arterial blood culture to hasten the diagnosis of candidemia in critically ill patients.
        Intensive Care Med. Jul 2014; 40: 1059-1060
        • Rodriguez D.
        • Park B.J.
        • Almirante B.
        • Cuenca-Estrella M.
        • Planes A.M.
        • Mensa J.
        • et al.
        Impact of early central venous catheter removal on outcome in patients with candidaemia.
        Clin Microbiol Infect. Aug 2007; 13: 788-793
        • Liu C.Y.
        • Huang L.J.
        • Wang W.S.
        • Chen T.L.
        • Yen C.C.
        • Yang M.H.
        • et al.
        Candidemia in cancer patients: impact of early removal of non-tunneled central venous catheters on outcome.
        J Infect. Feb 2009; 58: 154-160
        • Pappas P.G.
        • Kauffman C.A.
        • Andes D.
        • Benjamin D.K.
        • Calandra T.F.
        • Edwards J.E.
        • et al.
        Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
        Clin Infect Dis. Mar 1 2009; 48: 503-535
        • Bailly S.
        • Leroy O.
        • Montravers P.
        • Constantin J.M.
        • Dupont H.
        • Guillemot D.
        • et al.
        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. Nov 2015; 41: 1931-1940
        • Van der Geest P.J.
        • Rijnders B.J.
        • Vonk A.G.
        • Groeneveld A.B.
        Echinocandin to fluconazole step-down therapy in critically ill patients with invasive, susceptible Candida albicans infections.
        Mycoses. Mar 2016; 59: 179-185
        • Takesue Y.
        • Ueda T.
        • Mikamo H.
        • Oda S.
        • Takakura S.
        • Kitagawa Y.
        • et al.
        Management bundles for candidaemia: the impact of compliance on clinical outcomes.
        J Antimicrob Chemother. Feb 2015; 70: 587-593
        • Hsu D.I.
        • Nguyen M.
        • Nguyen L.
        • Law A.
        • Wong-Beringer A.
        A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in non-immunocompromised adult patients.
        J Antimicrob Chemother. Aug 2010; 65: 1765-1770