Antifungal Stewardship in Healthcare Systems

1. Antifungal stewardship Rosemary A Barnes Emeritus Professor of Medical Microbiology and Infectious Diseases Cardiff University School of Medicine

2. Antimicrobial stewardship • coordinated interventions designed to improve and measure the appropriate use of antimicrobials • promotes selection of the optimal: • drug regimen • dose • duration of therapy • route of administration • Aims • optimise clinical outcomes • minimize toxicity and adverse events • reduce costs • Limit selection for resistance Dellit TH et al Clin Infect Dis (2007) 44 (2): 159-77. DOI:https://doi.org/10.1086/510393

3. Differs from antibacterial stewardship • Antibacterial • Clear relationship between antimicrobial usage and resistance • Clear relationship between clinical failure and resistance • Focus on • “start smart then focus” • Antifungal • Focuses mainly on • Targeting treatment • Identifying IFD • Reducing empiric treatment • Using diagnostics • Optimising treatment • TDM • Controlling costs It’s all about the patient https://www.gov.uk/government/publications/antimicrobial-stewardship-start-smart-then-focus Agrawal S, et al J Antimicrob Chemother 2016;71:37-42.

4. Problems Total UK antifungal expenditure c £112 million Rising by 9% pa • How can you discuss antifungal stewardship • You cannot diagnose the condition you are interested in • No formal surveillance is ongoing • Antifungal expenditure continues to rise • completely out of proportion with the scale of the problem • Incidence of invasive fungal disease in ICU <0.1% • Aspergillus infection in haematological malignancy (0.5-12%) • Aspergillus in solid organ transplant <5% • Plethora of “Guidelines” • based on low quality evidence Harrison D et al Health Technol Assess 2013; 17(3):1-156 Pagano L et al. Haematologica 2006; 91: 1068-1075 Pagano L et al. Clin Infect Dis 2007; 45: 1161-1170

5. Candidaemiaper 100,00 population (England) Health Protection Report Vol10 No. 32–23 September 2016 https://www.gov.uk/government/publications/candidaemia-annual-data-from-voluntary-surveillance.

6. Clancy et al Clin Infect Dis. 2013;56:1284-1292

7. How we use antifungal drugs Prophylaxis Empirical Targeted Definitive

8. Areas where antifungal use is inappropriate/irrational • Prophylaxis of low risk patients • Empirical therapy • Treating patients who do not have fungal infection • Haematology, Intensive care • Treating patients already on prophylaxis • Unnecessary prolongation of treatment • When to stop • When to switch iv to oral

9. Reasons • Infection associated with significant morbidity and mortality • Delays in treatment associated with poorer outcome • Signs and symptoms of systemic infection are nonspecific • Conventional diagnostic techniques traditionally were suboptimal • FEAR led us to use empirical antifungals despite lack of evidence of efficacy

10. Aim of a diagnostic strategy include all patients likely to have invasive fungal infection and treat them with the safest and most effective drug exclude all patients unlikely to have invasive fungal disease and adopt a WAIT-and-SEE policy

11. Diagnosis depends on: • Specific clinical signs • Biomarkers • Antigen tests • Galactomannan (aspergillus), mannan (cCandida) • Beta D glucan (fungal cell wall) • Crytpococcal antigen test • Molecular • Species specific • Panfungal • Commercial • Next generation sequencing In 85% biomarkers preceded specific clinical signs Really good at ruling out invasive disease

12. Using diagnostic tests Example 54 year old man with acute myeloid leukeamia Develops fever during chemotherapy No response to ‘big gun’ antibiotics Still has temperature after 48 hours Clinical team add broad spectrum antifungal agent and delay next course of chemotherapy Stewardship team arrive: Review clinical status (stable) Review laboratory investigations and radiololgy – no abnormalities Stop antifungal drugs • Enable the diagnosis to be excluded so antifungal drugs do not need to used empirically • Can establish accurate diagnosis • right drug, right time, right dose, right duration • Guide therapeutic drug monitoring • identify optimal time to • Switch from intravenous to oral • Stop therapy

13. Impact of biomarker diagnosis Aguado J M et al Clin Infect Dis. 2014 Morrissey CO et al Lancet 2013 RogersT R et al B J Haem 2013 Barnes RA J Infect 2013 Springer J et al J CIin Micro 2013

14. What about resistancecan stewardship make a difference? From: Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clin Infect Dis. 2015;62(3):362-368. doi:10.1093/cid/civ885

15. Resistance • Antifungal use in patients dwarfed by: • Veterinary usage • Agricultural and horticultural usage • c50% of the total acreage of European cereal and grapevine production is treated at least once a year • Every tulip bulb is dipped in azoles • Without it food production could be cut by up to 30% • Spoilage increases massively • effect on global poverty • Economic impacts O’Neill report: “Antimicrobials in Agriculture and the environment”

17. Conclusions • Antifungal stewardship can improve outcomes • Requires a coordinated team approach • Relies heavily on • Diagnostic testing • Understanding what you want of your test • Knowing when to stop • Resistance may impact on our choice of agents • Unlikely that stewardship can control it