Guideline sources The following summarized guidelines for the evaluation and management of invasive candidiasis are prepared by our editorial team based on guidelines from the European Society of Intensive Care Medicine (ESICM/ESCMID 2019) and the Infectious Diseases Society of America (IDSA 2016). 1 2 3 3 4 4 5 Definition Invasive candidiasis refers to bloodstream infection (candidemia) caused by Candida species that can lead to deep-seated infections including intra-abdominal abscess, peritonitis, and osteomyelitis. 3 Epidemiology Invasive candidiasis is most frequently caused by C. albicans. Candidemia pathways include long- term use of antibiotics, gastrointestinal and cutaneous perforation (chemotherapy, gastric surgery, venous catheters, ), and immunosuppressive medication. 4 Pathophysiology The incidence of invasive candidiasis in the United States is estimated at 8 per 100,000 population per year, with peak rates at the extremes of age. Half of all invasive candidiasis cases occur in the ICU setting. 4 https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 1/6 6/24/23, 2:34 PM Invasive candidiasis Pathway Disease course Clinical manifestations include unexplained fever nonresponsive to antibacterial treatment. Complications of candidemia can lead to ocular involvement (choroiditis, retinitis, endophthalmitis, and blindness), abdominal cavity (abdominal abscess, pancreatitis, peritonitis), bone (osteomyelitis, spondylodiscitis), brain (brain abscess, meningoencephalitis), heart (endocarditis), kidneys (candiduria, pyelonephritis, pyonephrosis, renal abscess), liver and spleen (chronic disseminated candidiasis, focal abscess), and lung (focal abscess). The disease decreases the quality of life. 3 Prognosis and risk of recurrence Invasive candidiasis in the ICU setting is associated with a high mortality rate of 35-80%. 5 Guidelines 1. Diagnostic investigations Fungal culture: as per IDSA 2016 guidelines, obtain serial blood cultures (every day or every other day) in patients under treatment for candidemia, in order to establish the time point at which candidemia has been cleared. B Antifungal susceptibility testing: obtain testing for azole susceptibility for all bloodstream and other clinically relevant Candida isolates. Consider testing for echinocandin susceptibility in patients who have had prior treatment with an echinocandin and among those who have infection with C. glabrata or Candida parapsilosis. B Ophtalmological examination: obtain a dilated ophthalmological examination, preferably performed by an ophthalmologist, in all non-neutropenic patients with candidemia within the first week after diagnosis, and within the first week after recovery from neutropenia in neutropenic patients, since ophthalmological findings of choroidal and vitreal infection are minimal until recovery from neutropenia. B 2. Medical management Antifungal therapy, echinocandins: as per IDSA 2016 guidelines, administer any of the following echinocandins as initial therapy in patients with invasive candidiasis: Situation Guidance Loading dose 70 mg, then 50 mg daily Caspofungin 100 mg daily Micafungin Loading dose 200 mg, then 100 mg daily. A Anidulafungin https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 2/6 6/24/23, 2:34 PM Invasive candidiasis Pathway Updated evidence: ReSTORE In adult patients with systemic signs and mycological confirmation of candidemia or invasive candidiasis, rezafungin was noninferior to caspofungin with respect to global cure at day 14. George R Thompson rd et al. Lancet. 2023 Jan 7. Antifungal therapy, triazoles: As per IDSA 2016 guidelines: Administer fluconazole IV or PO, 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily as an acceptable alternative to an echinocandin as initial therapy in selected patients with invasive candidiasis, including non-critically ill patients and patients unlikely to have a fluconazole-resistant Candida species. A Consider administering voriconazole 400 mg (6 mg/kg) BID for 2 doses, then 200 mg (3 mg/kg) BID in patients with invasive candidiasis, recognizing that it offers little advantage over fluconazole as initial therapy. B Antifungal therapy, amphotericin: as per IDSA 2016 guidelines, recognize that lipid formulations of amphotericin B is an effective but less attractive alternative because of the potential for toxicity. B Show 2 more Step-down therapy: as per IDSA 2016 guidelines, switch from an echinocandin to fluconazole usually within 5-7 days in clinically stable patients, patients with isolates susceptible to fluconazole, and in patients with negative repeat blood cultures following initiation of antifungal therapy. B Duration of therapy: As per IDSA 2016 guidelines: Complete 2 weeks of antifungal treatment after documented resolution of candidemia and associated symptoms in non-neutropenic patients. B Complete 2 weeks of antifungal treatment after documented resolution of candidemia and associated symptoms in neutropenic patients, provided neutropenia has resolved. B 3. Therapeutic procedures Catheter removal: remove central venous catheters as early as possible in patients with candidemia, when the source is presumed to be the central venous catheter and the catheter can be removed safely. B Granulocyte transfusion: consider administering G-CSF-mobilized granulocyte transfusions in cases of persistent candidemia with anticipated protracted neutropenia. C Abdominal drainage/debridement: perform drainage and/or debridement in order to achieve source control in patients with intra-abdominal candidiasis. B https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 3/6 6/24/23, 2:34 PM Invasive candidiasis Pathway 4. Specific circumstances Neonatal patients (prophylaxis in NICU): administer IV or PO fluconazole prophylaxis, 3-6 mg/kg twice weekly for 6 weeks, in neonates with birth weights < 1,000 g in nurseries with high rates (> 10%) of invasive candidiasis. A Show 2 more Neonatal patients (invasive candidiasis and candidemia): perform a lumbar puncture and a dilated retinal examination in neonatal patients with cultures positive for Candida species from blood and/or urine. B Show 7 more Neonatal patients (CNS candidiasis): administer amphotericin B deoxycholate 1 mg/kg/day IV as initial treatment, or liposomal amphotericin B 5 mg/kg/y as an alternative regimen, in neonatal patients with Candida infection of the CNS. B Show 4 more Critically ill patients: Consider initiating empiric antifungal therapy in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever, guided by a clinical assessment of risk factors, surrogate markers for invasive candidiasis, and/or culture data from non-sterile sites. (strong recommendation; moderate-quality evidence. Initiate empiric antifungal therapy as soon as possible in patients with risk factors for invasive candidiasis and having clinical signs of septic shock. B Patients with neutropenia: administer an echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily) as initial therapy in patients with neutropenia. B Show 5 more Patients with esophageal candidiasis: initiate systemic antifungal therapy with oral fluconazole 200-400 mg (3-6 mg/kg) daily for 14-21 days in all patients with esophageal candidiasis. Administer a diagnostic trial of antifungal therapy before performing an endoscopic examination. A Show 8 more Patients with chronic disseminated candidiasis: administer initial therapy with lipid formulation amphotericin B or an echinocandin, for several weeks, followed by oral fluconazole in patients unlikely to have a fluconazole-resistant isolate. B Patients with intra-abdominal candidiasis: consider initiating empiric antifungal therapy in patients with clinical evidence of intra-abdominal infection and significant risk factors for candidiasis, including recent abdominal surgery, anastomotic leaks, or necrotizing pancreatitis. B Patients with respiratory tract candidiasis: avoid initiating routine antifungal therapy in patients with growth of Candida from respiratory secretions, as this is typically indicative of colonization. D https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 4/6 6/24/23, 2:34 PM Invasive candidiasis Pathway Patients with cardiovascular system infection: administer a lipid formulation of amphotericin B 3-5 mg/kg/day, with or without flucytosine 25 mg/kg QID, or high-dose echinocandin (caspofungin 150 mg/day, micafungin 150 mg/day, or anidulafungin 200 mg/day) as initial therapy in patients with native valve endocarditis. B Show 7 more Patients with central nervous system candidiasis: administer liposomal amphotericin B (with or without oral flucytosine) as initial therapy in patients with CNS candidiasis. B Patients with osteoarticular candidiasis: initiate fluconazole 400 mg (6 mg/kg) daily for 6-12 months or an echinocandin (caspofungin 50-70 mg/day, micafungin 100 mg/day, or anidulafungin 100 mg/day) for at least 2 weeks, followed by fluconazole 400 mg (6 mg/kg) daily for 6-12 months in patients with Candida osteomyelitis. B Show 7 more Patients with endophtalmitis: plan antifungal treatment and surgical intervention in conjunction with an ophthalmologist and an infectious diseases physician in patients with Candida endophtalmitis. B Show 4 more 5. Preventative measures Primary prevention in ICU patients: As per IDSA 2016 guidelines: Consider administering prophylactic fluconazole (12 mg/kg loading dose, then 6 mg/kg daily), in high-risk adult patients admitted to the ICU with a high rate of invasive candidiasis. C Consider performing daily chlorhexidine bathing in patients admitted to the ICU, to decrease the incidence of bloodstream infections including candidemia. C References 1. Ignacio Martin-Loeches, Massimo Antonelli, Manuel Cuenca-Estrella et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019 Jun;45 6 789 805. Open 2. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62 4):e1 50. Open 3. Peter G Pappas, Michail S Lionakis, Maiken Cavling Arendrup et al. Invasive candidiasis. 2018 May 11;4 18026.2018 May 11;4 18026. Open 4. Nur Yapar. Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag. 2014 Feb 13;10 95 105. Open 5. Zengli Xiao, Qi Wang, Fengxue Zhu et al. Epidemiology, species distribution, antifungal susceptibility and mortality risk factors of candidemia among critically ill patients: a retrospective study from 2011 to 2017 in https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 5/6 6/24/23, 2:34 PM Invasive candidiasis Pathway a teaching hospital in China. 2019 May 29;8 89.2019 May 29;8 89. Open 6. Peter G Pappas, Michail S Lionakis, Maiken Cavling Arendrup et al. Invasive candidiasis. Nat Rev Dis Primers. 2018 May 11;4 18026. Open 7. Zengli Xiao, Qi Wang, Fengxue Zhu et al. Epidemiology, species distribution, antifungal susceptibility and mortality risk factors of candidemia among critically ill patients: a retrospective study from 2011 to 2017 in a teaching hospital in China. Antimicrob Resist Infect Control. 2019 May 29;8 89. Open 8. Nur Yapar. Epidemiology and risk factors for invasive candidiasis. 2014 Feb 13;10 95 105.2014 Feb 13;10 95 105. Open 9. Jean-Francois Timsit, Elie Azoulay, Carole Schwebel et al. 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. 2016 Oct 18;316 15 1555 1564. Open 10. Guillaume Leroy, Fabien Lambiotte, Didier Th venin et al. Evaluation of "Candida score" in critically ill patients: a prospective, multicenter, observational, cohort study. Ann Intensive Care. 2011 Nov 30;1 1 50. Open 11. Andrew H Limper, Kenneth S Knox, George A Sarosi et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183 1 96 128. Open 12. Frank Bloos, J rgen Held, Stefan Kluge et al. 1 3 -D Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial. Intensive Care Med. 2022 Jul;48 7 865 875. Open 13. George R Thompson rd, Alex Soriano, Oliver A Cornely et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis ReSTORE a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet. 2023 Jan 7;401 10370 49 59. Open https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 6/6