1. Dr. Shawn R. Lockhart, PhD D(ABMM)
Antifungal Susceptibility Testing committee’s perspective on the development and use of ECVs
Dr. Shawn R. Lockhart, PhD D(ABMM)
Mycotic Diseases Branch, Centers for Disease Control and Prevention
CLSI, Spring 2018
1/27/2017

2. Objectives:
The mindset of the antifungal susceptibility testing committee
Data collection
Data presentation
Use

3. Some initial thoughts…
ECVs could promote more susceptibility testing because they will allow MIC values to be put into context
Right now, too many times we have to say “We can test that, but we won’t know what the numbers mean”

4. Why would we develop ECVS if nobody knows how to use them?
How will anyone know how to use them if we don’t develop them?

5. Why not?
Antifungal susceptibility testing is not routine, especially in the US
Most of the data comes from just a few labs
New antifungals are few and far between

6. Will they come?

8. Definition
The minimal inhibitory concentration/minimal effective concentration value that separates fungal populations into those with and without acquired and/or mutational resistance based on their phenotypes (MICs)

9. CLSI Rules for establishing an ECV
Only data generated using the protocol in CLSI document M27 can be used
Species identification must be molecular or MALDI-TOF
The iterative statistical method with a 97.5% cutoff is used for ECV determination

10. 100, 3, 50% 100 isolates of a species must be tested
The isolates have to come from at least 3 different labs
No more than 50% of the data from a single lab

11. Differences between breakpoints and ECVs
Require an MIC distribution, pharmakokinetic/pharmacodynamics data, and clinical treatment and outcome data
Require an MIC distribution
Can be used to predict clinical success
Does not necessarily predict clinical success
Can be used to identify isolates that may harbor a mutation
Extremely difficult to generate as treatment and outcome data are rare
Can be generated against any species as long as enough isolates exist

12. Points of emphasis in the document
ECVs do not allow us to determine whether a given bug/drug combination is likely to work only whether a particular MIC value is “normal” (wild type) or “not normal” (non-wild type)
Treatment decisions will be based on “institutional knowledge”

13. When should an ECV not be used?
When breakpoints have been published
As a strong predictor of clinical response to therapy
Rather as only an indicator of possibly acquired resistance mechanisms which could affect response to treatment

17. CLSI website data available
Cryptococcus neoformans and fluconazole
Fluconazole
Lab 1
Lab 2
Lab 3
Lab 4
Lab 5
Lab 6
Total
≤0.125 4
0.25 9 1 2 12
0.5 31 7 40 60 28 30 3
127
190 96
376
176
106
111 5 39 19
456 8 27 26 16 11 89 6 20 32 10 64
>64
507
238
246 21 69 56
1137

18. Sample data set

19. Do ECVs identify non-wild type isolates?
Number of isolates
MIC in µg/ml
1,380 isolates

20. Do ECVs identify non-wild type isolates?
FKS Mutation
Number of isolates
MIC in µg/ml

21. Do ECVs identify non-wild type isolates?
TR34
Number of isolates
MIC in µg/ml
Jacques Meis, personal communication

22. Obstacles exist…not all data is useable
MIC Value
Lab 1
Lab 2
Lab 3
Lab 4
Composite
0.0005 1
0.001
0.002
0.004
0.008 2
0.016 12
0.03 13 14
0.06 3 7
0.125 10 9 23
0.25 6 20 39
0.5 8 22 4
Total 19 41 36
35 
131

23. What else can we do?

24. Are ECVs going to be useful?
Yes.
We now have a pretty clear definition of what is phenotypic wild type
Clear definition of what is not phenotypic wild type
Dosage and duration can be based on whether an isolate looks like what we would consider “normal”

26. Suggested comment for discussion and for the report
Provided wording…
Isolate
Antifungal Agent
MIC
ECV
Suggested comment for discussion and for the report
Cryptococcus neoformans
fluconazole
32 g/mL
8 g/mL
There are currently no BPs for C. neoformans and drug fluconazole. The fluconazole MIC is above the WT MIC which suggests that this isolate may have an acquired mechanism of resistance and should be considered NWT.
The clinical implication of finding a NWT MIC is currently unknown. If the agent in question is being used for treatment, the patient should undergo clinical review, and in consultation with an infectious disease physician/pharmacist, the decision should be made to (i) continue the agent at the current dose, (ii) increase the dose of the agent, or (iii) switch to an alternative agent.

27. Outreach Review article on Establishment of ECVs for antifungals
Talks at major meetings
ICAAC, ASM
Microbe
ISHAM

28. Extra thoughts…
ECVs will only be established for species and antifungal combinations for which there is thought to be clinical efficacy
For example, no ECVs for Cryptococcus and echincandins
ECVs can be established for any species as long as there are enough isolates to test

29. Summary
The Antifungal Subcommittee has begun developing ECVs for specific fungus/antifungal combinations
We believe that ECVs will be clinically useful
ECVs will rely on “institutional knowledge” of antifungal PK/PD

30. Thank you!