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): DOI:

3. Differs from antibacterial stewardship
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
Agrawal S, et al J Antimicrob Chemother 2016;71:37-42.

4. Problems How can you discuss antifungal stewardship
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:
Pagano L et al. Clin Infect Dis 2007; 45:

5. Candidaemia per 100,00 population (England)
Health Protection Report Vol10 No. 32–23 September 2016

6. Impact of nonculture diagnostics on identifying different types of invasive candidiasis. The 3 entities that must be considered when diagnosing invasive candidiasis are shown from left to right in the Venn diagrams. At present, data suggest that the 3 groups are roughly similar in size (top Venn diagram). A reasonable estimate from the literature is that blood cultures are approximately 50% sensitive in diagnosing invasive candidiasis, missing roughly half of the deep-seated candidiasis in the second group and all cases in the third group. Moving from left to right across the groups, the relative impact of nonculture diagnostics on identifying previously unrecognized invasive candidiasis is increased. Nonculture diagnostics, for the most part, will identify new cases of deep-seated candidiasis (bottom Venn diagram), primarily by detecting Candida nucleic acid and cellular components that persist in the blood or that are released from deep tissue sites. By identifying previously unrecognized infections, nonculture diagnostics will improve our understanding of the clinical spectrum of invasive candidiasis.
Clancy et al Clin Infect Dis. 2013;56:

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
Morrissey
Barnes
Rogers
Springer
empirical therapy NA
Earlier diagnosis 
antifungal usage
Proven probable disease
Decrease mortality from IFD
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 resistance can stewardship make a difference?
Figure 1. Shaded areas show countries that have reported the TR₃₄/L98H and TR₄₆/Y121F/T289A resistance mechanism in clinical or environmental Aspergillus fumigatus isolates.
From: Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clin Infect Dis. 2015;62(3): doi: /cid/civ885 14

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