T2Candida: Comparison
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Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Lea Monday.
Invasive candidiasis is a common healthcare-associated infection with high mortality and is difficult to diagnose due to nonspecific symptoms and limitations of culture based diagnostic methods. T2Candida, based on T2 magnetic resonance technology, is FDA approved for the diagnosis of candidemia and can rapidly detect the five most commonly isolated Candida sp. in approximately 5 h directly from whole blood. We discuss the preclinical and clinical studies of T2Candida for the diagnosis of candidemia and review the current literature on its use in deep-seated candidiasis, its role in patient management and prognosis, clinical utility in unique populations and non-blood specimens, and as an antifungal stewardship tool. Lastly, we summarize the strengths and limitations of this promising nonculture-based diagnostic test.

Invasive candidiasis is a common healthcare-associated infection with high mortality and is difficult to diagnose due to nonspecific symptoms and limitations of culture based diagnostic methods. T2Candida, based on T2 magnetic resonance technology, is FDA approved for the diagnosis of candidemia and can rapidly detect the five most commonly isolated Candida sp. in approximately 5 h directly from whole blood. We discuss the preclinical and clinical studies of T2Candida for the diagnosis of candidemia and review the current literature on its use in deep-seated candidiasis, its role in patient management and prognosis, clinical utility in unique populations and non-blood specimens, and as an antifungal stewardship tool. Lastly, we summarize the strengths and limitations of this promising nonculture-based diagnostic test.

  • T2Candida
  • candidemia
  • invasive candidiasis
  • fungemia

1. Introduction

Candida

 is the most common cause of invasive fungal infections and associated mortality in the United States [1]. Invasive candidiasis includes both candidemia and deep-seated 

Candida infections at submucosal sites that may occur with or without associated bloodstream infection. The prevalence of invasive candidiasis has steadily increased in a broad variety of clinical settings. The increase is in part due increased survival with advances in life support techniques in the intensive care unit (ICU), expanding use of therapeutic modalities including immunosuppressive therapies, complex surgical procedures, hematopoietic stem cell and solid organ transplantation and others. Between 1970 and 2000, the annual number of sepsis cases due to fungal organisms increased by 207% in the United States [2]. Invasive candidiasis has significant attributable mortality and early antifungal treatment is associated improved outcomes [3,4]. Despite recognition of risk factors, the diagnosis and consequently treatment of invasive candidiasis is frequently delayed. Cultures of blood and specimens from deep-seated sites of infection have sensitivity of approximately 50% and slow turnaround times [5,6,7]. Furthermore, blood cultures will not identify deep-seated invasive candidiasis unless it is associated with candidemia.

 infections at submucosal sites that may occur with or without associated bloodstream infection. The prevalence of invasive candidiasis has steadily increased in a broad variety of clinical settings. The increase is in part due increased survival with advances in life support techniques in the intensive care unit (ICU), expanding use of therapeutic modalities including immunosuppressive therapies, complex surgical procedures, hematopoietic stem cell and solid organ transplantation and others. Between 1970 and 2000, the annual number of sepsis cases due to fungal organisms increased by 207% in the United States [2]. Invasive candidiasis has significant attributable mortality and early antifungal treatment is associated improved outcomes [3][4]. Despite recognition of risk factors, the diagnosis and consequently treatment of invasive candidiasis is frequently delayed. Cultures of blood and specimens from deep-seated sites of infection have sensitivity of approximately 50% and slow turnaround times [5][6][7]. Furthermore, blood cultures will not identify deep-seated invasive candidiasis unless it is associated with candidemia.

These diagnostic limitations leave clinicians struggling to balance the benefits of early empiric antifungal therapy (EAT) with the risks of antifungal resistance and healthcare costs associated with unnecessary antifungal use. Rapid and sensitive non-culture based diagnostic methods for detecting invasive candidiasis are needed to improve outcomes through early initiation of targeted antifungal therapy [5,6,7]. In this review, we discuss T2Candida, the novel technology of this automated non-culture based diagnostic platform using whole blood specimens, and preclinical and clinical studies that evaluated the performance characteristics of this test for detection of candidemia. We also examine the role of T2Candida for the diagnosis of deep-seated candidiasis (with and without candidemia), its potential as a prognostic and management tool for invasive candidiasis, and its use as a stewardship resource to de-escalate antifungal therapy. Lastly, we discuss the clinical utility of this test in unique patient populations and testing of non-blood clinical specimens.

These diagnostic limitations leave clinicians struggling to balance the benefits of early empiric antifungal therapy (EAT) with the risks of antifungal resistance and healthcare costs associated with unnecessary antifungal use. Rapid and sensitive non-culture based diagnostic methods for detecting invasive candidiasis are needed to improve outcomes through early initiation of targeted antifungal therapy [5][6][7]. In this review, we discuss T2Candida, the novel technology of this automated non-culture based diagnostic platform using whole blood specimens, and preclinical and clinical studies that evaluated the performance characteristics of this test for detection of candidemia. We also examine the role of T2Candida for the diagnosis of deep-seated candidiasis (with and without candidemia), its potential as a prognostic and management tool for invasive candidiasis, and its use as a stewardship resource to de-escalate antifungal therapy. Lastly, we discuss the clinical utility of this test in unique patient populations and testing of non-blood clinical specimens.

2. T2 Candida Panel

T2Candida is a non-culture-based platform approved by the US Food and Drug Administration (FDA) in 2014 for the diagnosis of candidemia [8]. Whole blood specimens are collected in K2EDTA tubes and inserted into the fully automated T2Dx instrument (T2Biosystems, Inc., Wilmington, MA, USA). T2Dx lyses the 

Candida

 cells by mechanical bead beating then amplifies their DNA using a thermostable DNA polymerase and primers for the 

Candida ribosomal DNA operon [9,10]. The amplified 

 ribosomal DNA operon [9][10]. The amplified 

Candida

 DNA product is detected using amplicon-induced agglomeration of super magnetic particles and T2 Magnetic Resonance (T2MR) measurement [9]. An internal control is processed with each specimen to monitor the integrity of the results. The resulting product is reported as positive or negative for identification of the 5 common 

Candida

 species (

C. albicans, C. tropicalis, C. parapsilosis, C. krusei, and C. glabrata) which account for >95% of candidemia at most centers [9,10,11,12]. The results are grouped on the basis of susceptibility to antifungals (primarily fluconazole) and are reported as 

) which account for >95% of candidemia at most centers [9][10][11][12]. The results are grouped on the basis of susceptibility to antifungals (primarily fluconazole) and are reported as 

C. albicans/C. tropicalis, C. parapsilosis, and C. krusei/C. glabrata). The T2Candida Panel has a limit of detection as low as 1 colony-forming unit (CFU)/mL of whole blood and has a mean turn-around-time of < 5 h [8,9,10,11,12].

). The T2Candida Panel has a limit of detection as low as 1 colony-forming unit (CFU)/mL of whole blood and has a mean turn-around-time of < 5 h [8][9][10][11][12].

3. T2Candida for the Diagnosis of Deep-Seated Candida Infection

Invasive candidiasis as a disease spectrum includes not only candidemia (with or without deep-seated infection), but also isolated deep-seated candidiasis without candidemia [5]. Deep-seated 

Candida

 infection is difficult to study because it includes a heterogenous group of conditions ranging from direct local inoculation (e.g., 

Candida

 peritonitis in peritoneal dialysis, spinal infection from contaminated steroid injections), to hematogenous metastatic seeding of 

Candida sp. (e.g., infective endocarditis, hematogenous fungal endophthalmitis) [22]. Intra-abdominal candidiasis (IAC) usually refers to peritonitis and abdominal abscess in patients with recent abdominal surgery, anastomotic leak, or gastrointestinal perforation [22,23,24].

 sp. (e.g., infective endocarditis, hematogenous fungal endophthalmitis) [13]. Intra-abdominal candidiasis (IAC) usually refers to peritonitis and abdominal abscess in patients with recent abdominal surgery, anastomotic leak, or gastrointestinal perforation [13][14][15].

The usefulness of positive T2Candida results despite negative blood cultures for the identification of IAC has been noted in a few cases. These included patients with IAC and positive T2Candida result concordant with 

Candida sp. isolated from cultures of peritoneal fluid, infected bile16, and explanted liver tissue [25]. Building on these preliminary case reports, a 2019 ICU study examined T2Candida performance in a real-world patient population with suspected invasive candidiasis including IAC [26]. Blood cultures, T2Candida, and 

 sp. isolated from cultures of peritoneal fluid, infected bile16, and explanted liver tissue [16]. Building on these preliminary case reports, a 2019 ICU study examined T2Candida performance in a real-world patient population with suspected invasive candidiasis including IAC [17]. Blood cultures, T2Candida, and 

Candida Mannan antigen (MAg) were performed on 126 ICU patients at high-risk for invasive candidiasis with sepsis despite 3 days of empiric broad-spectrum antibiotics. Paired samples were obtained twice weekly (334 sets) and patients were classified as having proven, likely, or possible invasive candidiasis based on culture results, imaging, and expert review [26]. At enrollment, 77% were on antifungal therapy. In all, 28 of 126 (22%) had proven, likely, or possible invasive candidiasis and IAC was the most common manifestation in 57% of these cases. Five of the 11 proven cases had 

 Mannan antigen (MAg) were performed on 126 ICU patients at high-risk for invasive candidiasis with sepsis despite 3 days of empiric broad-spectrum antibiotics. Paired samples were obtained twice weekly (334 sets) and patients were classified as having proven, likely, or possible invasive candidiasis based on culture results, imaging, and expert review [17]. At enrollment, 77% were on antifungal therapy. In all, 28 of 126 (22%) had proven, likely, or possible invasive candidiasis and IAC was the most common manifestation in 57% of these cases. Five of the 11 proven cases had 

Candida

 sp. isolated on blood cultures and T2Candida detected all except a 

C. kefyr that is not included on the panel. Overall, the sensitivity of T2Candida, blood culture and MAg in proven cases of invasive candidiasis was 55%, 45% and 36% [26]. The addition of T2Candida to blood culture or MAg resulted in the best diagnostic performance. All three tests had negative predictive value of >90% [26]. A later study compared T2Candida with blood cultures and cultures from deep-seated infection [27]. In total, 133 samples were taken from 32 patients with candidemia and 22 patients with deep-seated invasive culture proven candidiasis. T2Candida was positive in 27% of the patients with deep-seated invasive candidiasis [27]. Of note, only 88% patients with candidemia had positive T2Candida result at any time point, which is lower than rates reported in the early clinical trials [27]. Lastly, a 2020 study compared performance of T2Candida to BDG and blood cultures for the diagnosis IAC [28]. Patients were enrolled if they were at risk for IAC based on recent gastrointestinal tract perforation, necrotizing pancreatitis, or abdominal surgery as well as concurrent 

 that is not included on the panel. Overall, the sensitivity of T2Candida, blood culture and MAg in proven cases of invasive candidiasis was 55%, 45% and 36% [17]. The addition of T2Candida to blood culture or MAg resulted in the best diagnostic performance. All three tests had negative predictive value of >90% [17]. A later study compared T2Candida with blood cultures and cultures from deep-seated infection [18]. In total, 133 samples were taken from 32 patients with candidemia and 22 patients with deep-seated invasive culture proven candidiasis. T2Candida was positive in 27% of the patients with deep-seated invasive candidiasis [18]. Of note, only 88% patients with candidemia had positive T2Candida result at any time point, which is lower than rates reported in the early clinical trials [18]. Lastly, a 2020 study compared performance of T2Candida to BDG and blood cultures for the diagnosis IAC [19]. Patients were enrolled if they were at risk for IAC based on recent gastrointestinal tract perforation, necrotizing pancreatitis, or abdominal surgery as well as concurrent 

Candida

 colonization from a nonsterile site. Of 48 patients enrolled, 38% had proven IAC defined as 

Candida isolated by perioperative intra-abdominal culture [28]. In patients with proven IAC, blood cultures and T2Candida were positive in 11% and 33%, respectively [28]. Two patients had IAC with species not included on the T2Candida panel (

 isolated by perioperative intra-abdominal culture [19]. In patients with proven IAC, blood cultures and T2Candida were positive in 11% and 33%, respectively [19]. Two patients had IAC with species not included on the T2Candida panel (

C. kefyr

 and 

C. lusitaniae) [28]. Overall, T2Candida sensitivity/specificity were 33%/93% and PPV/NPV 71%/74% for diagnosing IAC. The above studies provide limited data that T2Candida may serve as a surrogate marker for deep-seated candidiasis and IAC, especially in cases with negative blood cultures or when invasive procedures cannot be performed to obtain specimens for testing from deep-seated sites of infection.

) [19]. Overall, T2Candida sensitivity/specificity were 33%/93% and PPV/NPV 71%/74% for diagnosing IAC. The above studies provide limited data that T2Candida may serve as a surrogate marker for deep-seated candidiasis and IAC, especially in cases with negative blood cultures or when invasive procedures cannot be performed to obtain specimens for testing from deep-seated sites of infection.

References

  1. Pfaller, M.A.; Diekema, D.J. Epidemiology of Invasive Candidiasis: A Persistent Public Health Problem. Clin. Microbiol. Rev. 2007, 20, 133–163.
  2. Martin, G.S.; Mannino, D.M.; Eaton, S.; Moss, M. The Epidemiology of Sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 2003, 348, 1546–1554.
  3. Andes, D.R.; Safdar, N.; Baddley, J.W.; Playford, G.; Reboli, A.C.; Rex, J.H.; Sobel, J.D.; Pappas, P.G.; Kullberg, B.J. 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, 1110–1122.
  4. Garey, K.W.; Rege, M.; Pai, M.P.; Mingo, D.E.; Suda, K.J.; Turpin, R.S.; Bearden, D.T. Time to Initiation of Fluconazole Therapy Impacts Mortality in Patients with Candidemia: A Multi-Institutional Study. Clin. Infect. Dis. 2006, 43, 25–31.
  5. Clancy, C.J.; Nguyen, M.H. Finding the “missing 50%” of invasive candidiasis: How nonculture diagnostics will improve un-derstanding of disease spectrum and transform patient care. Clin. Infect. Dis. 2013, 56, 1284–1292.
  6. Clancy, C.J.; Nguyen, M.H. The end of an era in defining the optimal treatment of invasive candidiasis. Clin. Infect. Dis. 2012, 54, 1123–1125.
  7. Kidd, S.E.; Chen, S.C.-A.; Meyer, W.; Halliday, C.L. A New Age in Molecular Diagnostics for Invasive Fungal Disease: Are We Ready? Front. Microbiol. 2020, 10, 2903.
  8. Zervou, F.N.; Zacharioudakis, I.M.; Kurpewski, J.; Mylonakis, E. T2 Magnetic Resonance for Fungal Diagnosis. Adv. Struct. Saf. Stud. 2016, 1508, 305–319.
  9. Beyda, N.D.; Alam, M.J.; Garey, K.W. Comparison of the T2Dx instrument with T2Candida assay and automated blood culture in the detection of Candida species using seeded blood samples. Diagn. Microbiol. Infect. Dis. 2013, 77, 324–326.
  10. Neely, L.A.; Audeh, M.; Phung, N.A.; Min, M.; Suchocki, A.; Plourde, D.; Blanco, M.; Demas, V.; Skewis, L.R.; Anagnostou, T.; et al. T2 Magnetic Resonance Enables Nanoparticle-Mediated Rapid Detection of Candidemia in Whole Blood. Sci. Transl. Med. 2013, 5, 182ra54.
  11. Zacharioudakis, I.M.; Zervou, F.N.; Mylonakis, E. T2 Magnetic Resonance Assay: Overview of Available Data and Clinical Implications. J. Fungi 2018, 4, 45.
  12. Pfaller, M.A.; Wolk, D.M.; Lowery, T.J. T2MR and T2Candida: Novel technology for the rapid diagnosis of candidemia and inva-sive candidiasis. Future Microbiol. 2016, 11, 103–117.
  13. Zacharioudakis, I.M.; Zervou, F.N.; Mylonakis, E. Use of T2MR in invasive candidiasis with and without candidemia. Future Microbiol. 2018, 13, 1165–1173.
  14. Pappas, P.G.; Kauffman, C.A.; Andes, D.R.; Clancy, C.J.; Marr, K.A.; Ostrosky-Zeichner, L.; Reboli, A.C.; Schuster, M.G.; Vazquez, J.A.; Walsh, T.J.; 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.
  15. Carneiro, H.A.; Mavrakis, A.; Mylonakis, E. Candida Peritonitis: An Update on the Latest Research and Treatments. World J. Surg. 2011, 35, 2650–2659.
  16. Fortun, J.; Gioia, F.; Munoz, P.; Graus, J.; de la Pedrosa, E.G.-G.; Martín-Dávila, P.; Saiz, A.; Vena, A.; Moreno, S. T2 magnetic resonance for the diagnosis of deep-seated invasive candidiasis in a liver re-cipient without candidemia. Rev. Iberoam. Microl. 2018, 35, 159–161.
  17. Arendrup, M.C.; Andersen, J.S.; Holten, M.K.; Krarup, K.B.; Reiter, N.; Schierbeck, J.; Helleberg, M. Diagnostic Performance of T2Candida Among ICU Patients With Risk Factors for Invasive Candidiasis. Open Forum Infect. Dis. 2019, 6, ofz136.
  18. Zurl, C.; Prattes, J.; Zollner-Schwetz, I.; Valentin, T.; Rabensteiner, J.; Wunsch, S.; Hoenigl, M.; Krause, R. T2Candida magnetic resonance in patients with invasive candidiasis: Strengths and limitations. Med. Mycol. 2019, 58, 632–638.
  19. Lamoth, F.; Clancy, C.J.; Tissot, F.; Squires, K.; Eggimann, P.; Flückiger, U.; Siegemund, M.; Orasch, C.; Zimmerli, S.; Calandra, T.; et al. Performance of the T2Candida Panel for the Diagnosis of Intra-abdominal Candidiasis. Open Forum Infect. Dis. 2020, 7, ofaa075.
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