Definitions

Thing What thing means
Sensitive Susceptible (THIS IS A JOKE DON’T EMAIL ME)
Susceptible Sensitive; ”high likelihood of therapeutic success using a standard dosing regimen of the agent”
Intermediate
Susceptible, increased exposure
Sensitive at higher doses
Sensitive, use high dose
etc “high likelihood of therapeutic success because exposure to the agent is increased by adjusting the dosing regimen or by its concentration at the site of infection”
Resistant Non-susceptible; “likelihood of therapeutic failure even when there is increased exposure”
MIC Minimum inhibitory concentration: Bacteriostasis value. Concentration at which visible growth of the pathogen is inhibited @24h
MBC Minimum bactericidal concentration: Bacteriocidality value. Concentration at which 3Log10 (i.e. 99.9%) of pathogens have been killed at 24h.
MIC90 or MIC50 MIC at which 90% (or 50%) of isolates will have had inhibited growth in a sample set of organisms.
ECOFF Epidemiological cutoff (NB: CLSI call this an ECV, or “Epidemiological Cutoff Value”) “the MIC above which bacterial isolates have phenotypically detectable acquired resistance”.
Species-specific, i.e. there is no CoNS ECOFF.
Clinical breakpoint S and R breakpoints that have been determined to be associated with therapeutic success (or failure) when this agent is used for this pathogen.

How to determine resistance & susceptibility

  1. Get N samples of your bug, wildtype, and incubate them with various concentrations of the drug you want to test against.

  2. Determine the concentration at which 50% & 90% of your samples have inhibited growth. These are your MIC50 & MIC90 for your population (NB: the higher N is the more accurate your results are). Bear in mind, the MIC90 just tells you about growth inhibition if your sample in-vitro, NOT how the drug will perform in the real world.

  3. Get a load of samples with acquired resistance mechanisms, and repeat the experiment.

  4. Plot your data on a ‘MIC distribution’ table (blue = wildtype distribution):

    Screenshot 2024-11-03 at 22.31.24.png

    Or graph:

    Screenshot 2024-11-03 at 22.45.36.png

  5. Determine the MIC that correlates with the start of the resistant population, i.e. no bugs with a resistance mechanism appear below this value. This is your ECOFF. Below the ECOFF is the wildtype population. In the graph above the wildtype population is in blue, the resistant population in red.

  6. Determine clinical breakpoints for a species using:

A note on breakpoints

Fantastic show.

Here we have the S breakpoint at 0.064, and the R breakpoint at 4. Anything between is classed as ‘Susceptible, increased exposure’ (formerly ‘intermediate’)

Here we have the S breakpoint at 0.064, and the R breakpoint at 4. Anything between is classed as ‘Susceptible, increased exposure’ (formerly ‘intermediate’)

The Rationalisation for this Episode

Item/link or DoI Authors Notes
EUCAST documents:
-Definitions of S, I & R
-Antimicrobial wildtype distributions of microorganisms
-Clinical Breakpoints EUCAST
How to: ECOFFs—the why, the how, and the don’ts of EUCAST epidemiological cutoff values.
10.1016/j.cmi.2022.02.024 Kahlmeter G, Turnidge J.
Article covering ECOFFs specifically.
Breakpoints talks breakpoints - podcast mini series Breakpoints Podcast mini-series of podcasts involving CLSI officials covering breakpoint setting
The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance. Pathogens. 2021 Feb 4;10(2):165.
10.3390/pathogens10020165 Kowalska-Krochmal B, Dudek-Wicher R. Intro to MICs and their interpretation