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PCR-Based Methods for the Diagnosis of Invasive Candidiasis: Are They Ready for Use in the Clinic?

  • Advances in Diagnosis of Invasive Fungal Infections (S Chen, Section Editor)
  • Published:
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Abstract

Purpose of Review

We review the performance of Candida PCR and the T2Candida panel (T2Biosystems, Lexington, MA) in diagnosing invasive candidiasis, consider how these tests may be incorporated into patient care, and determine if they are ready to be used in the clinic.

Recent Findings

PCR and T2Candida sensitivity/specificity for diagnosing candidemia are ~ 90%/90% and ~ 90%/98%, respectively. Limited data for intra-abdominal candidiasis suggest PCR sensitivity of ~ 85–90%, but specificity has varied from 33 to 97%. T2Candida data are lacking for infections other than candidemia.

Summary

PCR and T2Candida will have the greatest value if their use is restricted to cases in which positive and negative predictive values differ in a clinically meaningful way from the pre-test likelihood. Studies are needed to establish that patient care and stewardship strategies incorporating Candida PCR or T2Candida improve patients’ outcomes, reduce unnecessary antifungal usage, limit emergence of resistance, and are cost-effective. The development and validation of standardized PCR assays is a top priority.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Clancy CJ, Nguyen MH. Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis. 2013;56(9):1284–92. https://doi.org/10.1093/cid/cit006.

    Article  PubMed  Google Scholar 

  2. Vergidis P, Clancy CJ, Shields RK, Park SY, Wildfeuer BN, Simmons RL, et al. Intra-abdominal candidiasis: the importance of early source control and antifungal treatment. PloS One. 2016;11(4):e0153247. https://doi.org/10.1371/journal.pone.0153247.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, 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. 2012;54(8):1110–22. https://doi.org/10.1093/cid/cis021.

    Article  PubMed  CAS  Google Scholar 

  4. Clancy CJ, Nguyen MH. The end of an era in defining the optimal treatment of invasive candidiasis. Clin Infect Dis. 2012;54(8):1123–5. https://doi.org/10.1093/cid/cis023.

    Article  PubMed  Google Scholar 

  5. Fortun J, Meije Y, Buitrago MJ, Gago S, Bernal-Martinez L, Peman J, et al. Clinical validation of a multiplex real-time PCR assay for detection of invasive candidiasis in intensive care unit patients. J Antimicrob Chemother. 2014;69(11):3134–41. https://doi.org/10.1093/jac/dku225.

    Article  PubMed  CAS  Google Scholar 

  6. Leon C, Ruiz-Santana S, Saavedra P, Castro C, Loza A, Zakariya I, et al. Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions. Crit Care. 2016;20(1):149. https://doi.org/10.1186/s13054-016-1324-3.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mikulska M, Calandra T, Sanguinetti M, Poulain D, Viscoli C. The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Crit Care. 2010;14(6):R222. https://doi.org/10.1186/cc9365.

    Article  PubMed  PubMed Central  Google Scholar 

  8. He S, Hang JP, Zhang L, Wang F, Zhang DC, Gong FH. A systematic review and meta-analysis of diagnostic accuracy of serum 1,3-beta-d-glucan for invasive fungal infection: focus on cutoff levels. J Microbiol Immunol Inf = Wei mian yu gan ran za zhi. 2014; https://doi.org/10.1016/j.jmii.2014.06.009.

  9. Karageorgopoulos DE, Vouloumanou EK, Ntziora F, Michalopoulos A, Rafailidis PI, Falagas ME. beta-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis. 2011;52(6):750–70. https://doi.org/10.1093/cid/ciq206.

    Article  PubMed  CAS  Google Scholar 

  10. Onishi A, Sugiyama D, Kogata Y, Saegusa J, Sugimoto T, Kawano S, et al. Diagnostic accuracy of serum 1,3-beta-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol. 2012;50(1):7–15. https://doi.org/10.1128/JCM.05267-11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Colombo AL, de Almeida Junior JN, Slavin MA, Chen SC, Sorrell TC. Candida and invasive mould diseases in non-neutropenic critically ill patients and patients with haematological cancer. Lancet Infect Dis. 2017;17(11):e344–e56. https://doi.org/10.1016/S1473-3099(17)30304-3.

    Article  PubMed  CAS  Google Scholar 

  12. •• Clancy CJ PP, Vazquez J, Judson MA, Kontoyiannis DP, Thompson GR, Garey KW, Reboli A, Greenberg RN, Apewokin S, Lyons GM, Ostrosky-Zeichner L, Wu AHB, Tobin E, Nguyen MH, Caliendo AM. Detecting infections rapidly and easily for Candidemia Trial-2 (DIRECT2): a prospective, multicenter study of the T2Candida Panel Clin Infect Dis. 2018:(in press). DIRECT2 is a multi-center clinical trial that validated the clinical sensitivity of the T2Candida panel for the diagnosis of candidemia using patient samples and demonstrated that T2Candida is more likely to remain positive than blood cultures among patients with candidemia who are being treated with antifungal agents.

  13. • Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, Garey KW, Alangaden GJ, Vazquez JA, et al. T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis. 2015;60(6):892–9. https://doi.org/10.1093/cid/ciu959. DIRECT is a multi-center clinical trial that used spiked samples and whole blood from patients in whom blood cultures were negative to demonstrate sensitivity and specificity of T2Candida for candidemia of 91 and 98%, respectively; turn-around time of T2Candida was 4.4 ±1.0 h.

    Article  PubMed  CAS  Google Scholar 

  14. Avni T, Leibovici L, Paul M. PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol. 2011;49(2):665–70. https://doi.org/10.1128/JCM.01602-10.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Nguyen MH, Wissel MC, Shields RK, Salomoni MA, Hao B, Press EG, et al. Performance of Candida real-time polymerase chain reaction, beta-D-glucan assay, and blood cultures in the diagnosis of invasive candidiasis. Clin Infect Dis. 2012;54(9):1240–8. https://doi.org/10.1093/cid/cis200.

    Article  PubMed  CAS  Google Scholar 

  16. Pfaller MA, Messer SA, Moet GJ, Jones RN, Castanheira M. Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal agents in intensive care unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008–2009). Int J Antimicrob Agents. 2011;38(1):65–9. https://doi.org/10.1016/j.ijantimicag.2011.02.016.

    Article  PubMed  CAS  Google Scholar 

  17. Jung DS, Farmakiotis D, Jiang Y, Tarrand JJ, Kontoyiannis DP. Uncommon Candida species fungemia among cancer patients, Houston, Texas. USA. Emerg Infect Dis. 2015;21(11):1942–50. https://doi.org/10.3201/eid2111.150404.

    Article  PubMed  CAS  Google Scholar 

  18. Mylonakis E CC, Ostrosky-Zeichner L, Garey KW, Alangaden GJ, Vazquez JA, Groeger SJ, Judson MA, Vinagre YM, Heard SO, Zervou FN, Zacharioudakis IM, Kontoyiannis DP, Pappas PG. T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial CID. 2014.

  19. Clancy CJ, Nguyen MH. Undiagnosed invasive candidiasis: incorporating non-culture diagnostics into rational prophylactic and preemptive antifungal strategies. Expert Rev Anti Infect Ther. 2014;12(7):731–4. https://doi.org/10.1586/14787210.2014.919853.

    Article  PubMed  CAS  Google Scholar 

  20. Clancy CJ, Nguyen MH. Diagnostic methods for detection of blood-borne Candidiasis. Methods Mol Biol. 2016;1356:215–38. https://doi.org/10.1007/978-1-4939-3052-4_16.

    Article  PubMed  CAS  Google Scholar 

  21. Blumberg HM, Jarvis WR, Soucie JM, Edwards JE, Patterson JE, Pfaller MA, et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis. 2001;33(2):177–86. https://doi.org/10.1086/321811.

    Article  PubMed  CAS  Google Scholar 

  22. Ng K, Schorr C, Reboli AC, Zanotti S, Tsigrelis C. Incidence and mortality of sepsis, severe sepsis, and septic shock in intensive care unit patients with candidemia. Infect Dis (Lond). 2015;47(8):584–7. https://doi.org/10.3109/23744235.2015.1028100.

    Article  PubMed  Google Scholar 

  23. Boogaerts M, Winston DJ, Bow EJ, Garber G, Reboli AC, Schwarer AP, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med. 2001;135(6):412–22.

    Article  PubMed  CAS  Google Scholar 

  24. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;340(10):764–71. https://doi.org/10.1056/NEJM199903113401004.

    Article  PubMed  CAS  Google Scholar 

  25. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346(4):225–34. https://doi.org/10.1056/NEJM200201243460403.

    Article  PubMed  CAS  Google Scholar 

  26. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391–402. https://doi.org/10.1056/NEJMoa040446.

    Article  PubMed  CAS  Google Scholar 

  27. Leon C, Ruiz-Santana S, Saavedra P, Galvan B, Blanco A, Castro C, et al. Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study. Crit Care Med. 2009;37(5):1624–33. https://doi.org/10.1097/CCM.0b013e31819daa14.

    Article  PubMed  Google Scholar 

  28. Magill SS, Swoboda SM, Johnson EA, Merz WG, Pelz RK, Lipsett PA, et al. The association between anatomic site of Candida colonization, invasive candidiasis, and mortality in critically ill surgical patients. Diagn Microbiol Infect Dis. 2006;55(4):293–301. https://doi.org/10.1016/j.diagmicrobio.2006.03.013.

    Article  PubMed  Google Scholar 

  29. Ostrosky-Zeichner L, Sable C, Sobel J, Alexander BD, 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(4):271–6. https://doi.org/10.1007/s10096-007-0270-z.

    Article  PubMed  CAS  Google Scholar 

  30. Aslam S, Hernandez M, Thornby J, Zeluff B, Darouiche RO. Risk factors and outcomes of fungal ventricular-assist device infections. Clin Infect Dis. 2010;50(5):664–71. https://doi.org/10.1086/650454.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shoham S, Shaffer R, Sweet L, Cooke R, Donegan N, Boyce S. Candidemia in patients with ventricular assist devices. Clin Infect Dis. 2007;44(2):e9–12. https://doi.org/10.1086/509640.

    Article  PubMed  Google Scholar 

  32. Ostrosky-Zeichner L, Shoham S, Vazquez J, Reboli A, Betts R, Barron MA, et al. MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis. 2014;58(9):7. https://doi.org/10.1093/cid/ciu074.

    Article  CAS  Google Scholar 

  33. • Playford EG, Lipman J, Jones M, Lau AF, Kabir M, Chen SC, et al. Problematic dichotomization of risk for intensive care unit (ICU)-acquired invasive candidiasis: results using a risk-predictive model to categorize 3 levels of risk from a multicenter prospective cohort of Australian ICU patients. Clin Infect Dis. 2016;63(11):1463–9. https://doi.org/10.1093/cid/ciw610. In this multi-study from Australia, investigators developed a prediction model for invasive candidiasis in ICU pts that assigns three levels of risk; the model should be amenable to incorporating non-culture diagnostic test results, thereby further stratifying the groups.

    Article  PubMed  Google Scholar 

  34. • Timsit JF, Azoulay E, Schwebel C, Charles PE, Cornet M, Souweine B, 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: J Am Med Assoc. 2016;316(15):1555–64. https://doi.org/10.1001/jama.2016.14655. EMPIRICUS is a multi-center trial that showed a benefit of empiric micafungin in decreasing new invasive fungal infections (IFIs) among ICU patients with a 12% incidence of infection, but failed to show a benefit in survival.

    Article  CAS  Google Scholar 

  35. Hall AM, Poole LA, Renton B, Wozniak A, Fisher M, Neal T, et al. Prediction of invasive candidal infection in critically ill patients with severe acute pancreatitis. Crit Care. 2013;17(2):R49. https://doi.org/10.1186/cc12569.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Matuszkiewicz-Rowinska J. Update on fungal peritonitis and its treatment. Perit Dial Int. 2009;29(Suppl 2):S161–5.

    PubMed  CAS  Google Scholar 

  37. Knitsch W, Vincent JL, Utzolino S, Francois 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(11):1671–8. https://doi.org/10.1093/cid/civ707.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Calandra T, Bille J, Schneider R, Mosimann F, Francioli P. Clinical significance of Candida isolated from peritoneum in surgical patients. Lancet. 1989;2(8677):1437–40.

    Article  PubMed  CAS  Google Scholar 

  39. Tissot F, Lamoth F, Hauser PM, Orasch C, Fluckiger U, Siegemund M, et al. beta-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med. 2013;188(9):1100–9. https://doi.org/10.1164/rccm.201211-2069OC.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Scaife Hall 867, 3550 Terrace St., Pittsburgh, PA, 15261, USA

    M. Hong Nguyen & Cornelius J. Clancy

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  1. M. Hong Nguyen
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  2. Cornelius J. Clancy
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Correspondence to M. Hong Nguyen.

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Conflict of Interest

Drs. Clancy and Nguyen have served as principal investigators for clinical trials sponsored by T2 Biosystems and ViraCor Eurofins. Dr. Clancy has spoken at symposia sponsored by T2 Biosystems.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Nguyen, M.H., Clancy, C.J. PCR-Based Methods for the Diagnosis of Invasive Candidiasis: Are They Ready for Use in the Clinic?. Curr Fungal Infect Rep 12, 71–77 (2018). https://doi.org/10.1007/s12281-018-0313-1

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