Hull York Medical School University of Hull University of York University of Liverpool Hull University Teaching Hospital NHS Trust King's College Hospital NHS Foundation Trust

BioDrive Antifungal Stewardship

Turnaround Time: Toolkit Introduction

Welcome!

Welcome and many thanks for participating in this short educational package on the turnaround time for infection biomarkers.

In the following video, Dr Gavin Barlow introduces the BioDriveAFS trial, including the incentive behind the trial and its context within the surrounding literature.

Introduction

This package aims to share our prism of experiences in improving the turnaround time (TAT) for infection biomarkers through setting up the BioDriveAFS trial.

This learning has been established around our experiences emerging from setting up the trial, including discussions with regional and national laboratories and many others. However, many of these identified principles are generic and may have application to other clinical or research situations.

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Every year, approximately 5000 adults are diagnosed with acute myeloid leukaemia (AML), high-risk myelodysplastic syndrome (HRMDS) or acute lymphoblastic leukaemia (ALL). Out of these patients being treated with intensive chemotherapy (IC), 4 to 11 percent will develop invasive fungal infection (IFI), most commonly invasive aspergillosis (IA), as shown in the image below. However, antifungal agents prescribed to treat IFIs, such as posaconazole, can be associated with toxicity, drug-drug interactions, selection of resistant fungal species, and significant financial expenditure.

A chest X-ray of a patient with invasive Aspergillosis (IA).

Chest x-ray of an IA patient.

Antifungal stewardship (AFS) programmes are key to optimising antifungal use and improving outcomes in patients with IFI. A 2022 study found that diagnostics-driven interventions, in particular, can potentially improve AFS including antifungal consumption, cost, mortality, and length of stay (Chakrabarti et al., 2022). Click here to view a graphical summary of this study.

One such diagnostic-driven intervention is improving TAT for biomarkers of fungal infection.

Fungal biomarkers are a biological product, made from the structure of the fungus or yeast, that are able to be detected by ‘unconventional’ techniques and allow (sometimes) an early diagnosis of IFI in patients. Their detection contributes to reducing unnecessary antifungal use and improving AFS measures (Maertens et al., 2005).

BD Vacutainer Serum tubes, typically used for testing both biomarkers.

Fungal biomarkers have higher predictive accuracy when used in combination, however, they may perform less well when the patient is already receiving an antifungal. Therefore, they could be used to detect IFI in patients not receiving prophylaxis, with those identified as a risk targeted for therapy.

There has been a considerable amount of work on the use of fungal biomarkers prior to the BioDriveAFS Trial, particularly comparing the use of antifungals with a diagnostics-driven strategy to a standard practice, ’empirical’ strategy.

A 2022 trial by Maertens et al., available here, is particularly important in relation to BiodriveAFS because the general approach is similar.

In this trial, both patient groups received antifungal prophylaxis in the form of fluconazole (non-mould acting). The diagnostics arm only received antifungal therapy with caspofungin (mould acting) if one or more diagnostic tests were positive, whereas the empiric therapy arm received caspofungin based on traditional clinical criteria. Galactomannan (which is mainly a test for aspergillosis) was the only biomarker used, whereas in BioDriveAFS beta-D-glucan will also be used (this can detect Candida species and some other IFIs too). You can view the lay summary of this trial here.

In summary, this trial demonstrated that a diagnostic-driven strategy safely and considerably reduced antifungal use. The BioDriveAFS trial will follow up this study with a hot debate in recent literature, which has been shown below. The results of the two trials together should identify the optimal approach to prevent and manage fungal infections in acute leukaemia patients.

 

‘Can we safely replace antifungal prophylaxis with
regular biomarker blood tests and a diagnostics approach?’

 

This question has been raised in a 2022 review by Harrison and Partridge, available here. The opposing sides of this debate are as follows:

For: 

Taynton et al., available here, argues that fungal biomarker surveillance in the absence of primary antifungal chemoprophylaxis is a safe alternative that could reduce antifungal use and the development of resistance. Biomarker surveillance for IFI without antifungal prophylaxis could safely reduce antifungal use in acute leukaemia.

Against:

Howard et al., available here, argues in favour of continuing chemoprophylaxis in patients with acute leukaemia receiving systemic chemotherapy, citing the multiple randomised control trials and meta-analyses that demonstrate its efficacy. Serum biomarker monitoring should not replace primary antifungal chemoprophylaxis in patients with acute leukaemia receiving systemic anti-cancer therapy.

The BioDriveAFS trial investigates the use of a diagnostics approach to the prevention and management of IFI by comparing a biomarker-based AFS strategy, using galactomannan and beta-D-glucan, with a prophylactic AFS strategy including existing standard of care.

The aim is to investigate whether the former is superior to the latter in reducing antifungal therapy use in acute leukaemia patients undergoing IC, without impacting health-related quality of life at 12 months.

Click here to view an outline of the BioDriveAFS trial design.

 

  1. Chakrabarti, A., et al. (2022). The Role of Diagnostics-Driven Antifungal Stewardship in the Management of Invasive Fungal Infections: A Systematic Literature Review. In Open Forum Infectious Diseases, Vol. 9, No 7, p. ofac234. Here: https://doi.org/10.1093/ofid/ofac234
  2. Harrison, T. and Partridge, D. (2022). Should serum biomarker monitoring replace primary antifungal chemoprophylaxis in patients with acute leukaemia receiving systemic anti-cancer therapy? A PRO/CON debate. JAC-Antimicrobial Resistance, 4(4), p.dlac075. Here: https://doi.org/10.1093/jacamr/dlac075
  3. Howard, A. and Hope, W. (2022). CON: Serum biomarker monitoring should not replace primary antifungal chemoprophylaxis in patients with acute leukaemia receiving systemic anti-cancer therapy. JAC-Antimicrobial Resistance, 4(4), p.dlac081. Here: https://doi.org/10.1093/jacamr/dlac081
  4. Maertens, J., et al. (2005). Galactomannan and computed tomography–based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clinical Infectious Diseases41(9), pp.1242-1250. Here: https://doi.org/10.1086/496927
  5. Maertens, J., et al. (2023). Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer. Clinical Infectious Diseases, 76(4), pp.674–682. Here: https://doi.org/10.1093/cid/ciac623
  6. Taynton, T., et al. (2022). PRO: Biomarker surveillance for invasive fungal infections without antifungal prophylaxis could safely reduce antifungal use in acute leukaemia. JAC-Antimicrobial Resistance, 4(4), p.dlac074. Here: https://doi.org/10.1093/jacamr/dlac074