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Uncertainty about the evidence on untargeted antifungal treatment

  • Andrea Cortegiani
    Correspondence
    Corresponding author at: Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anesthesia Analgesia Intensive Care and Emergency, Policlinico P. Giaccone, University of Palermo, Via del vespro 129, 90127 Palermo, Italy.
    Affiliations
    Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anesthesia Analgesia Intensive Care and Emergency, Policlinico P. Giaccone, University of Palermo, Italy
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  • Vincenzo Russotto
    Affiliations
    Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anesthesia Analgesia Intensive Care and Emergency, Policlinico P. Giaccone, University of Palermo, Italy
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  • Santi Maurizio Raineri
    Affiliations
    Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anesthesia Analgesia Intensive Care and Emergency, Policlinico P. Giaccone, University of Palermo, Italy
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  • Cesare Gregoretti
    Affiliations
    Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anesthesia Analgesia Intensive Care and Emergency, Policlinico P. Giaccone, University of Palermo, Italy
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  • Antonino Giarratano
    Affiliations
    Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anesthesia Analgesia Intensive Care and Emergency, Policlinico P. Giaccone, University of Palermo, Italy
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Published:August 30, 2016DOI:https://doi.org/10.1016/j.ejim.2016.08.029
      We read with great interest the narrative review by Antinori et al. about candidaemia and invasive candidiasis in adults [
      • Antinori S.
      • Milazzo L.
      • Sollima S.
      • Galli M.
      • Corbellino M.
      Candidemia and invasive candidiasis in adults: a narrative review.
      ]. We focused our attention on the description of main results from three recent studies investigating the effect of untargeted antifungal treatment, namely the administration of antifungal drugs before definitive microbiological evidence of fungal infection. The authors reported that these studies failed to demonstrate any outcome benefit. However, untargeted antifungal strategies have been widely investigated for 30 years and the evidence about its efficacy is complex. We recently published a Cochrane systematic review of randomized controlled trials (RCTs) comparing untargeted antifungal treatment to placebo or no intervention in non-neutropenic patients [
      • Cortegiani A.
      • Russotto V.
      • Maggiore A.
      • Attanasio M.
      • Naro A.R.
      • Raineri S.M.
      • et al.
      Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients.
      ]. Notably, the term ‘untargeted antifungal treatment’ encompasses three antifungal strategies: 1) prophylaxis: the administration of antifungal drugs in patients without proven or suspected fungal infection but with risk factors for its development 2) pre-emptive: treatment trigger by microbiological evidence of infection without definitive microbiological proof, e.g. positive surrogate marker [
      • Posteraro B.
      • Tumbarello M.
      • De Pascale G.
      • Liberto E.
      • Vallecoccia M.S.
      • De Carolis E.
      • et al.
      (1,3)-Beta-d-glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study.
      ,
      • Cortegiani A.
      • Russotto V.
      • Montalto F.
      • Foresta G.
      • Accurso G.
      • Palmeri C.
      • et al.
      Procalcitonin as a marker of Candida species detection by blood culture and polymerase chain reaction in septic patients.
      ] 3) empiric: treatment triggered by signs and symptoms of infection in patients at risk for invasive fungal infections [
      • Cuenca-Estrella M.
      • Verweij P.E.
      • Arendrup M.C.
      • Arikan-Akdagli S.
      • Bille J.
      • Donnelly J.P.
      • et al.
      ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures.
      ]. The Cochrane systematic review included 22 RCTs and 2761 patients. There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce total all-cause mortality (Relative Risk 0.93, 95% CI 0.79 to 1.09, P value = 0.36). However, there was a low grade evidence that these strategies significantly reduce by about 45% the incidence of proven invasive fungal infections, defined as clinical illness consistent with the diagnosis and either histopathological evidence of IFI or a positive fungal culture from sterile site specimens (Relative Risk 0.57, 95% CI 0.39 to 0.83. P value = 0.0001). Most of studies investigated antifungal prophylaxis and empiric treatment. Only one RCT investigated pre-emptive treatment driven by beta-d-glucan. Among included studies, there was a predominance of RCTs using azoles (14) rather than echinocandins (4) or other antifungals (4). From these global data, a paradox may arise from high crude mortality of invasive infections by Candida spp. and the absence of effects in terms of overall mortality by untargeted antifungal treatment, despite the reduction of invasive fungal infections rate [
      • Cortegiani A.
      • Russotto V.
      • Raineri S.M.
      • Giarratano A.
      The paradox of the evidence about invasive fungal infection prevention.
      ,
      • Cortegiani A.
      • Russotto V.
      • Raineri S.M.
      • Giarratano A.
      Antifungal prophylaxis: update on an old strategy.
      ]. ESCMID 2012 guideline supports the use of fluconazole prophylaxis in patients who recently underwent abdominal surgery and had reoperations for perforation or anastomotic leakage [
      • Cuenca-Estrella M.
      • Verweij P.E.
      • Arendrup M.C.
      • Arikan-Akdagli S.
      • Bille J.
      • Donnelly J.P.
      • et al.
      ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures.
      ]. On the contrary, empiric treatment and the use of beta-D-glucan to guide therapy are not supported. IDSA 2015 guideline describes antifungal prophylaxis with fluconazole or echinocandins as a therapeutic option in high-risk patients (weak recommendation) [
      • 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.
      ]. A strong recommendation supports empiric treatment in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever. Notably, IDSA guideline described well the conflicting results of studies investigating this type of antifungal treatment, especially from RCTs. Moreover, it could not take into consideration the evidence from Knitsch et al. (last RCT to date on this topic) and the Cochrane systematic review [
      • Knitsch W.
      • Vincent J.-L.
      • Utzolino S.
      • François B.
      • Dinya T.
      • Dimopoulos G.
      • et al.
      A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections.
      ].

      Keywords

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      References

        • Antinori S.
        • Milazzo L.
        • Sollima S.
        • Galli M.
        • Corbellino M.
        Candidemia and invasive candidiasis in adults: a narrative review.
        Eur J Intern Med. 2016; 34: 21-28
        • Cortegiani A.
        • Russotto V.
        • Maggiore A.
        • Attanasio M.
        • Naro A.R.
        • Raineri S.M.
        • et al.
        Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients.
        Cochrane Database Syst Rev. 2016; 1CD004920
        • Posteraro B.
        • Tumbarello M.
        • De Pascale G.
        • Liberto E.
        • Vallecoccia M.S.
        • De Carolis E.
        • et al.
        (1,3)-Beta-d-glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study.
        J Antimicrob Chemother. 2016; 71: 2262-2269
        • Cortegiani A.
        • Russotto V.
        • Montalto F.
        • Foresta G.
        • Accurso G.
        • Palmeri C.
        • et al.
        Procalcitonin as a marker of Candida species detection by blood culture and polymerase chain reaction in septic patients.
        BMC Anesthesiol. 2014; 14: 9
        • Cuenca-Estrella M.
        • Verweij P.E.
        • Arendrup M.C.
        • Arikan-Akdagli S.
        • Bille J.
        • Donnelly J.P.
        • et al.
        ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures.
        Clin Microbiol Infect. 2012; 18: 9-18
        • Cortegiani A.
        • Russotto V.
        • Raineri S.M.
        • Giarratano A.
        The paradox of the evidence about invasive fungal infection prevention.
        Crit Care. 2016; 20: 114
        • Cortegiani A.
        • Russotto V.
        • Raineri S.M.
        • Giarratano A.
        Antifungal prophylaxis: update on an old strategy.
        Eur J Clin Microbiol Infect Dis. 2016 Jun 25; https://doi.org/10.1007/s10096-016-2699-4
        • 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. 2016; 62: e1-e50
        • Knitsch W.
        • Vincent J.-L.
        • Utzolino S.
        • François B.
        • Dinya T.
        • Dimopoulos G.
        • et al.
        A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections.
        Clin Infect Dis. 2015; 61: 1671-1678
        • Cortegiani A.
        • Russotto V.
        • Raineri S.M.
        • Giarratano A.
        Is it time to combine untargeted antifungal strategies to reach the goal of “early” effective treatment?.
        Crit Care. 2016; 20: 241