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Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial

Abstract

Purpose

The aim of this study was to determine the impact of a biomarker-based strategy on early discontinuation of empirical antifungal treatment.

Methods

Prospective randomized controlled single-center unblinded study, performed in a mixed ICU. A total of 110 patients were randomly assigned to a strategy in which empirical antifungal treatment duration was determined by (1,3)-β-d-glucan, mannan, and anti-mannan serum assays, performed on day 0 and day 4; or to a routine care strategy, based on international guidelines, which recommend 14 days of treatment. In the biomarker group, early stop recommendation was determined using an algorithm based on the results of biomarkers. The primary outcome was the percentage of survivors discontinuing empirical antifungal treatment early, defined as a discontinuation strictly before day 7.

Results

A total of 109 patients were analyzed (one patient withdraw consent). Empirical antifungal treatment was discontinued early in 29 out of 54 patients in the biomarker strategy group, compared with one patient out of 55 in the routine strategy group [54% vs 2%, p < 0.001, OR (95% CI) 62.6 (8.1–486)]. Total duration of antifungal treatment was significantly shorter in the biomarker strategy compared with routine strategy [median (IQR) 6 (4–13) vs 13 (12–14) days, p < 0.0001). No significant difference was found in the percentage of patients with subsequent proven invasive Candida infection, mechanical ventilation-free days, length of ICU stay, cost, and ICU mortality between the two study groups.

Conclusions

The use of a biomarker-based strategy increased the percentage of early discontinuation of empirical antifungal treatment among critically ill patients with suspected invasive Candida infection. These results confirm previous findings suggesting that early discontinuation of empirical antifungal treatment had no negative impact on outcome. However, further studies are needed to confirm the safety of this strategy. This trial was registered at ClinicalTrials.gov, NCT02154178.

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References

  1. Kett DH, Azoulay E, Echeverria PM, Vincent J-L (2011) Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 39:665–670. doi:10.1097/CCM.0b013e318206c1ca

    Article  PubMed  Google Scholar 

  2. Paiva J-A, Pereira JM, Tabah A et al (2016) Characteristics and risk factors for 28-day mortality of hospital acquired fungemias in ICUs: data from the EUROBACT study. Crit Care 20:53. doi:10.1186/s13054-016-1229-1

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lortholary O, Renaudat C, Sitbon K et al (2014) Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010). Intensive Care Med 40:1303–1312. doi:10.1007/s00134-014-3408-3

    Article  PubMed  PubMed Central  Google Scholar 

  4. Colombo AL, Guimarães T, Sukienik T et al (2014) Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter studies sequentially conducted over a 9-year period. Intensive Care Med 40:1489–1498. doi:10.1007/s00134-014-3400-y

    Article  PubMed  PubMed Central  Google Scholar 

  5. Leroy O, Bailly S, Gangneux J-P et al (2016) Systemic antifungal therapy for proven or suspected invasive candidiasis: the AmarCAND 2 study. Ann Intensive Care 6:2. doi:10.1186/s13613-015-0103-7

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kollef M, Micek S, Hampton N et al (2012) Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 54:1739–1746. doi:10.1093/cid/cis305

    CAS  Article  PubMed  Google Scholar 

  7. Ostrosky-Zeichner L (2012) Invasive mycoses: diagnostic challenges. Am J Med 125:S14–S24. doi:10.1016/j.amjmed.2011.10.008

    Article  PubMed  Google Scholar 

  8. Leroy O, Gangneux J-P, Montravers P et al (2009) Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006). Crit Care Med 37:1612–1618. doi:10.1097/CCM.0b013e31819efac0

    Article  PubMed  Google Scholar 

  9. Cornely O, Bassetti M, Calandra T et al (2012) ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 18:19–37. doi:10.1111/1469-0691.12039

    CAS  Article  PubMed  Google Scholar 

  10. Rhodes A, Evans LE, Alhazzani W et al (2017) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377. doi:10.1007/s00134-017-4683-6

    Article  PubMed  Google Scholar 

  11. Pappas PG, Kauffman CA, Andes DR et al (2016) Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 62:e1–e50. doi:10.1093/cid/civ933

    Article  PubMed  Google Scholar 

  12. Bailly S, Bouadma L, Azoulay E et al (2015) Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients. Am J Respir Crit Care Med 191:1139–1146. doi:10.1164/rccm.201409-1701OC

    CAS  Article  PubMed  Google Scholar 

  13. Timsit J-F, Azoulay E, Schwebel C et al (2016) Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure. JAMA 316:1555. doi:10.1001/jama.2016.14655

    CAS  Article  PubMed  Google Scholar 

  14. Azoulay E, Dupont H, Tabah A et al (2012) Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit Care Med 40:813–822. doi:10.1097/CCM.0b013e318236f297

    CAS  Article  PubMed  Google Scholar 

  15. Bailly S, Leroy O, Montravers P et al (2015) Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data. Intensive Care Med 41:1931–1940. doi:10.1007/s00134-015-4053-1

    CAS  Article  PubMed  Google Scholar 

  16. León C, Ostrosky-Zeichner L, Schuster M (2014) What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Intensive Care Med 40:808–819. doi:10.1007/s00134-014-3281-0

    Article  PubMed  Google Scholar 

  17. Karageorgopoulos DE, Vouloumanou EK, Ntziora F et al (2011) β-d-Glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 52:750–770. doi:10.1093/cid/ciq206

    CAS  Article  PubMed  Google Scholar 

  18. Poissy J, Sendid B, Damiens S et al (2014) Presence of Candida cell wall derived polysaccharides in the sera of intensive care unit patients: relation with candidaemia and Candida colonisation. Crit Care 18:R135. doi:10.1186/cc13953

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hanson KE, Pfeiffer CD, Lease ED et al (2012) β-d-Glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS One 7:e42282. doi:10.1371/journal.pone.0042282

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Posteraro B, De Pascale G, Tumbarello M et al (2011) Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1 → 3)-β-d-glucan assay, Candida score, and colonization index. Crit Care 15:R249. doi:10.1186/cc10507

    Article  PubMed  PubMed Central  Google Scholar 

  21. Martínez-Jiménez MC, Muñoz P, Valerio M et al (2015) Combination of Candida biomarkers in patients receiving empirical antifungal therapy in a Spanish tertiary hospital: a potential role in reducing the duration of treatment. J Antimicrob Chemother 70:3107–3115. doi:10.1093/jac/dkv241

    Article  PubMed  Google Scholar 

  22. Posteraro B, Tumbarello M, De Pascale G et al (2016) (1,3)-β-d-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother 71:2262–2269. doi:10.1093/jac/dkw112

    CAS  Article  PubMed  Google Scholar 

  23. Ostrosky-Zeichner L, Sable C, Sobel J et al (2007) 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 26:271–276. doi:10.1007/s10096-007-0270-z

    CAS  Article  PubMed  Google Scholar 

  24. De Pauw B, Walsh TJ, Donnelly JP et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813–1821. doi:10.1086/588660

    Article  PubMed  PubMed Central  Google Scholar 

  25. Arendrup MC, Cuenca-Estrella M, Lass-Flörl C, Hope WW (2013) Breakpoints for antifungal agents: an update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat 16:81–95. doi:10.1016/j.drup.2014.01.001

    Article  PubMed  Google Scholar 

  26. Zein M, Parmentier-Decrucq E, Kalaoun A et al (2014) Factors predicting prolonged empirical antifungal treatment in critically ill patients. Ann Clin Microbiol Antimicrob. doi:10.1186/1476-0711-13-11

    PubMed  PubMed Central  Google Scholar 

  27. Velasquez T, Mackey G, Lusk J et al (2016) (2016) ESICM LIVES 2016: part three. Intensive Care Med Exp 41(4):28. doi:10.1186/S40635-016-0100-7

    Article  Google Scholar 

  28. Maubon D, Garnaud C, Calandra T et al (2014) Resistance of Candida spp. to antifungal drugs in the ICU: where are we now? Intensive Care Med 40:1241–1255. doi:10.1007/s00134-014-3404-7

    CAS  Article  PubMed  Google Scholar 

  29. Lortholary O, Desnos-Ollivier M, Sitbon K et al (2011) Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother 55:532–538. doi:10.1128/AAC.01128-10

    CAS  Article  PubMed  Google Scholar 

  30. Bailly S, Maubon D, Fournier P et al (2016) Impact of antifungal prescription on relative distribution and susceptibility of Candida spp.—Trends over 10 years. J Infect 72:103–111. doi:10.1016/j.jinf.2015.09.041

    Article  PubMed  Google Scholar 

  31. Alexander BD, Johnson MD, Pfeiffer CD et al (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56:1724–1732. doi:10.1093/cid/cit136

    Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  33. Held J, Kohlberger I, Rappold E et al (2013) Comparison of (1 → 3)-β-d-glucan, mannan/anti-mannan antibodies, and Cand-Tec Candida antigen as serum biomarkers for candidemia. J Clin Microbiol 51:1158–1164. doi:10.1128/JCM.02473-12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Azoulay E, Guigue N, Darmon M et al (2016) (1, 3)-β-d-Glucan assay for diagnosing invasive fungal infections in critically ill patients with hematological malignancies. Oncotarget 7:21484–21495. doi:10.18632/oncotarget.7471

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

Authors

Consortia

Contributions

Study concept and design: AR, JP, BS, and SN. Acquisition, analysis, and interpretation of data: all authors. Drafting the manuscript: AR and SN. Statistical and cost-effectiveness analyses: BD and SN. Critical revision of the manuscript: all authors. Study supervision: SN

Corresponding author

Correspondence to Saad Nseir.

Ethics declarations

Conflicts of interest

SN: Bayer, MSD, Ciel Medical, and Medtrocic (advisory board, and lecture); other authors: none.

Funding source

University Hospital of Lille received a grant from MSD to support this study in part. MSD had no role in the design, conduct of the study, nor in the analysis or interpretation of study results.

Additional information

Take-home message: The use of a biomarker-based strategy is helpful for early discontinuation of empirical antifungal treatment in critically ill patients with suspected invasive Candida infection, with no negative impact on outcome.

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Rouzé, A., Loridant, S., Poissy, J. et al. Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial. Intensive Care Med 43, 1668–1677 (2017). https://doi.org/10.1007/s00134-017-4932-8

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  • DOI: https://doi.org/10.1007/s00134-017-4932-8

Keywords

  • Antifungal
  • Empirical
  • (1,3)-β-d-Glucan
  • Mannan
  • Candida
  • Critical illness