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

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

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 https://www.gov.uk/government/publications/antimicrobial-stewardship-start-smart-then-focus Agrawal S, et al J Antimicrob Chemother 2016;71:37-42.

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: 1068-1075 Pagano L et al. Clin Infect Dis 2007; 45: 1161-1170

Candidaemia per 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.

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;56:1284-1292

How we use antifungal drugs Prophylaxis Empirical Targeted Definitive

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

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

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

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

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

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

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):362-368. doi:10.1093/cid/civ885 14

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”

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