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:

The Clinical Need

Current UK antifungal strategy

The current approach to the prevention and management of fungal infections in acute leukaemia, based on our trial surveys and experiences to date, is summarised in the 3 key areas below. The wide variation in practice we have identified strongly suggests that clinical teams do not have confidence in the existing evidence-base.

Diagnostics including systematic monitoring of ≥1 IFI biomarker without antifungal prophylaxis.

No high-quality trials comparing this with either of the two other approaches.

A small minority of centres appear to use this approach.

Antifungal prophylaxis plus diagnostics, including systematic monitoring of ≥1 IFI biomarker.

A recent trial, here, suggests that a diagnostics approach using non-mould acting antifungal prophylaxis (fluconazole) is not inferior to an empiric therapy approach using a mould acting agent (caspofungin) plus fluconazole prophylaxis when regular blood galactomannan testing is used and results in less antifungal use.

A larger minority of centres appear to use this approach.

Antifungal prophylaxis with reactive or no use of diagnostics.

A historic trial, here, suggests fluconazole (non-mould acting antifungal) reduces Candida infections versus a  placebo group, but it did not impact overall mortality. Posaconazole was previously shown, here, to be more effective than fluconazole or itraconazole in preventing IFI and overall mortality.

Most centres appear to use this approach.

The clinical need

The clinical need for the BioDriveAFS trial has been summarised in the following six key areas. Click below to view each in more detail:

Patients at risk of IFI

Patients with acute leukaemia undergoing intensive chemotherapy (IC) are known to be at risk of IFI, mainly with Aspergillus species (left).

Approximately 4 to 11% of patients will develop an IFI, depending on whether they are taking prophylaxis or not (van de Peppell et al., 2018). However, most of these are ‘probable’ rather than proven infections. Furthermore, a much higher proportion of patients still get empiric therapy despite taking prophylaxis – this number varies between studies, but is approximately one-quarter to one-half of all patients.

All-cause mortality may not be affected by using prophylaxis based on systematic reviews (Wong et al., 2020). Antifungal and diagnostic stewardship is, therefore, essential to optimise both antifungal and biomarker use, as well as patient outcomes.

Effects of antifungal prophylaxis

Antifungal prophylaxis has adverse effects for patients. These range from common symptoms such as nausea or dizziness, to even very rare symptoms like cardiac arrest or stroke.

More information on side effects of posaconazole is available on the British National Formulary here.

Patient preferences

Because of the above symptoms, patients generally prefer to take less medications.

In the video, two members from the BioDriveAFS Patient Advisory Group share their experiences from diagnosis to their involvement in the BioDriveAFS trial. To view the full length version of this discussion, please click here.

 

Drug-drug interactions

Antifungal prophylaxis often interacts with other drugs the patient may need, including certain chemotherapy agents.

In the video, former Lead Pharmacist in Infectious Diseases and current Regional Antimicrobial Stewardship Lead for London, Dr Laura Whitney, shares her perspective of antifungal drug interactions.

To read more about specific interactions, please see the British National Formulary here.

Antifungal resistance

Antifungal resistance is emerging, including in Aspergillosis.

For example, a recent study of patients with IA, here, found that 19% of isolates were voriconazole resistant – a first line agent for therapy – and mortality was lower in those who received appropriate initial antifungal therapy. In comparison to antibacterial agents, we have far fewer antifungal drug classes and overall antifungal drugs. See this study for more information.

In the video, Neil Stone, Consultant in Infectious Diseases and Microbiology, discusses the importance of emerging resistance to antifungals.

Cost of antifungal prophylaxis

Antifungal prophylaxis is costly.

There are several new antifungals that are likely to come onto the market over the next few years. These are likely to be costly to the NHS, therefore, it is important that we only use them when we really need to.

A UK based study of a diagnostics-led AFS programme, here, with haematology-oncology as the highest prescribers, found that 40% of antifungal use was empiric, with 82% without evidence of IFI. This study, using NHS England data, also revealed that national antifungal expenditure increased significantly from £64.1 million to £94.2 million during the 5 year period 2011–16 (left). This programme reduced antifungal-associated costs compared to national prevailing trends without negatively impacting mortality.

References

  1. Hendrickson, J.A., et al. (2019). Antifungal Resistance: a Concerning Trend for the Present and Future. Current Infectious Diseases Reports, 21(47), pp.1-8. Here: https://doi.org/10.1007/s11908-019-0702-9
  2. Lestrade, P.P., et al. (2019).  Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study. Clinical Infectious Diseases68(9), pp.1463–1471. Here: https://doi.org/10.1093/cid/ciy859
  3. 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
  4. Rotstein, C., et al. (1999). Randomized Placebo-Controlled Trial of Fluconazole Prophylaxis for Neutropenic Cancer Patients: Benefit Based on Purpose and Intensity of Cytotoxic Therapy. Clinical Infectious Diseases, 28(2), pp.331–340. Here: https://doi.org/10.1086/515128
  5. van de Peppel, R.J., et al. (2018). The burden of Invasive Aspergillosis in patients with haematological malignancy: A meta-analysis and systematic review. Journal of Infection76(6), pp.550-562. Here: https://doi.org/10.1016/j.jinf.2018.02.012
  6. Whitney, L., et al. (2019). Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010–16. Journal of Antimicrobial Chemotherapy, 74(1), pp.234–241. Here: https://doi.org/10.1093/jac/dky389
  7. Wong, T.Y., et al. (2020). Efficacy and safety of posaconazole for the prevention of invasive fungal infections in immunocompromised patients: a systematic review with meta-analysis and trial sequential analysis. Scientific Reports10(1), p.14575. Here: https://doi.org/10.1038/s41598-020-71571-0