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.
Candida
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.
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.
Candida
cells by mechanical bead beating then amplifies their DNA using a thermostable DNA polymerase and primers for theCandida ribosomal DNA operon [9][10]. The amplified
ribosomal DNA operon [9,10]. The amplifiedCandida
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 commonCandida
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 asC. 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].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 ofCandida 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].
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]. 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 withCandida 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
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, andCandida 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
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 hadCandida
sp. isolated on blood cultures and T2Candida detected all except aC. 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% [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
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 concurrentCandida
colonization from a nonsterile site. Of 48 patients enrolled, 38% had proven IAC defined asCandida 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 (
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 (C. kefyr
andC. lusitaniae) [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.
) [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.