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Key reasons underlying the demand for noninvasive and reliable fungal diagnostic tools

Test diagnostic del 1,3- b -D-glucano Maurizio Sanguinetti Istituto di Microbiologia Fondazione Policlinico Universitario «A. Gemelli» Università Cattolica del Sacro Cuore. Key reasons underlying the demand for noninvasive and reliable fungal diagnostic tools.

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Key reasons underlying the demand for noninvasive and reliable fungal diagnostic tools

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  1. Test diagnostic del 1,3-b-D-glucanoMaurizio SanguinettiIstituto di MicrobiologiaFondazione Policlinico Universitario «A. Gemelli» Università Cattolica del Sacro Cuore

  2. Key reasons underlying the demand for noninvasive and reliable fungal diagnostic tools • Earlydiagnosis and identification of fungalinfection(to improve the survival of affectedpatients) • Accurate estimates of fungal disease burden (to sustain long-term surveillance programs for fungal diseases)

  3. New diagnostics are needed to complement cultures, in particular to identify the “missing 50%” of patients who are blood culture-negative.

  4. Chandrasekar, Eur J Haematol 2010;84:281-90

  5. b-1,3-D-Glucan testing – 4 kits Obayashi Clin Infect Dis 2008:46:1864

  6. Limitations of antigen assays in the diagnosis of invasive fungal disease aIncluding ampicillin, amoxicillin/clavulanate, and piperacillin/tazobactam.

  7. The findings of this meta-analysis suggest that the BG assay is a useful screening tool with high sensitivity and specificity for discriminating between patients with and without IFDs. In clinical practice, BG assay results should be evaluated together with clinical and microbiological findings.

  8. Risk stratification and the predictive value of culture-independent diagnostic test for candidiasis aKarageorgopulos, CID, 2011 bMikulska, Crit. Care, 2010 cChang, PLoS ONE, 2013 dMylonakis, CID, 2015

  9. In unselected patientswith factors known to affect serum BG, a single BG assay at ICU admission makes only a modest contribution to the diagnosis of IFI • However, the good NPV of the BG assay suggests a possible role in guiding decisions to antifungal agent de-escalate in high-risk patients with low pre-test probability of IFI • Future studies are needed to assess whether prophylactic/pre-emptive antifungals can be withdrawn safely 10% IFI prevalence PPV 21% NPV 94%

  10. 10% IFI prevalence PPV 21% NPV 94%

  11. Sensitivity/specificity of 2 consecutive BG ≥80 pg/ml was 65%/78%. In recurrent GI tract perforation it was 75%/77% vs. 90%/38% (Candida score ≥3), 79%/34% (colonization index ≥0.5), and 54%/63% (corrected colonization index ≥0.4). • BG positivity anticipated IAC diagnosis (5 days) and antifungal therapy (6 days). • Severe sepsis/septic shock and death occurred in 10/11 (91%) and 4/11 (36%) patients with beta-glucan ≥400 pg/ml vs. 5/18 (28%, P = 0.002) and 1/18 (6%, P = 0.05) with beta-glucan <400 pg/ml. • Beta-glucan decreased in IAC responding to therapy and increased in nonresponse.

  12. The BDG assay is useful in diagnosing and therapeutically monitoring Candida and Aspergillus CNS infections in pediatric patients

  13. Objectives: • To determine the effects of a strategy that uses (1,3)-β-D-glucan (BDG) results for antifungal treatment of ICU patients at high risk of invasive candidiasis. • Methods: • Patients were included in the analysis if they exhibited sepsis at the time of BDG testing, and they met Candida-score components (i.e., severe sepsis, total parenteral nutrition, surgery, or multifocal Candida colonization) to reach a ≥3 value. • Results: • 198 patients were studied • Of 63 BDG-positive patients, 47 with candidemia and 16 with probable Candida infection, all received antifungal therapy • Of 135 BDG-negative patients, 110 (55.5%) did not receive antifungal therapy, whereas 25 (12.6%) were initially treated. In 14 of these 25 patients antifungals were discontinued as negative BDG results were notified. Candidemia was subsequently diagnosed only in one patient who did not receive prior antifungal therapy • The median antifungal therapy duration in candidemic patients differed from that in non-candidemic patients (14 days [IQR, 6–18 d] vs 4 days [IQR, 3–7 d]; p <0.001) • Thus, unnecessary antifungal therapy was avoided in ~73% of potentially treatable patients and it was shortened in another ~20%

  14. To the best of our knowledge, this study is the first to investigate the outcome of incorporating BDG into the clinical and therapeutic management of strictly selected ICU patients. • By studying a cohort of 198 critically ill patients at high risk for candidemia, we show the usefulness of positive and negative BDG results as a guidance not only for triggering but, more interestingly, discontinuing antifungal therapy. • A rough cost analysis showed also that adopting a BDG-based therapeutic approach might lead to a not negligible cost reduction by saving approximately €3500 per patient. • In summary, a BDG-driven management of ICU patients could reduce the overall population of severely ill patients exposed to empirical antifungal agents.

  15. This study aimed to assess the combined performance of serum (1,3)-β-D-glucan (BDG) and procalcitonin (PCT) for the differential diagnosis between candidaemia and bacteraemia in three intensive care units (ICUs) in two large teaching hospitals in Italy. • From June 2014 to December 2015, all adult patients admitted to the ICU who had a culture proven candidaemia or bacteraemia, as well as BDG and PCT measured closely to the time of the index culture, were included in the study. The diagnostic performance of BDG and PCT, used either separately or in combination, was assessed by calculating the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV). • 166 patients were included, 73 with candidaemia (44%) and 93 with bacteraemia (56%). When both markers indicated candidaemia (BDG ≥80 pg/ml and PCT <2 ng/ml) they showed higher PPV (96%) compared to 79% and 66% for BDG or PCT alone, respectively. When both markers indicated bacteraemia (BDG <80 pg/ml and PCT ≥2 ng/ml), their NPV for candidaemia was similar to that of BDG used alone (95% vs. 93%). • The combined use of PCT and BDG could be helpful in the diagnostic workflow for critically ill patients with suspected candidaemia.

  16. Positive predictive value (PPV) and negative predictive value (NPV) for candidaemia of (1,3)-β-D-glucan (BDG) and procalcitonin (PCT) considered both separately and in combination (BDG+PCT). The reported PPV for candidaemia (also readable as NPV for bacteraemia) was obtained when both markers were concordant in indicating candidaemia (BDG ≥80 pg/ml and PCT <2 ng/ml), while the reported NPV for candidaemia (also readable as PPV for bacteraemia) was obtained when both markers when concordant in indicating bacteraemia (BDG <80 pg/ml and PCT ≥2 ng/ml)

  17. Prospective study of 176 non-neutropenic patients, with SAC at ICU admission, and expected to stay at least 7 days. • Surveillance cultures and BDG, CAGTA, CRP, and PCT levels were performed. • Patients were grouped into invasive candidiasis (IC), Candida colonization, and neither colonized/nor infected. • BDG with a positive test for CAGTA accurately differentiated Candida colonization from IC in patients with SAC,whereas CRP and PCT did not.

  18. 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.

  19. In the biomarker strategy group, the laboratory recommendation according to the fungal biomarker measurements was to stop empirical antifungal treatment in 32 patients (59%). The recommendation to stop empirical antifungal treatment did not concern any of the patients diagnosed with proven invasive Candida infection, except one patient with a positive culture for Candida in peritoneal fluid. This recommendation was followed in 29 out of 32 patients (91%).

  20. The primary endpoint of this study was the percentage of patients receiving early discontinuation of empirical antifungal treatment, defined as a discontinuation, for reasons other than death, strictly before day 7 after empirical antifungal treatment initiation. 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. 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.

  21. Concluding remarks • Cost-benefit analyses that include a faster initiation of antifungal therapy and limiting the administration of unnecessary antifungals should further optimize the use of rapid fungal diagnostics • As rapid (i.e. β-glucan) detection tests will likely supplement traditional culture-based identification tests, studies that evaluate the real-world utility of rapid diagnostic techniques are ever more required • In the meantime, hospitals and health care executives should be encouraged to establish and support antifungal stewardship programs that incorporate rapid diagnostics

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