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AST definitions and breakpoints

In this video Gunnar Kahlmeter discusses AST definitions and breakpoints
Hello, everyone. I’m Gunnar Kahlmeter. I’m a clinical bacteriologist. I’ve spent a large part of my life with antimicrobial susceptibility testing and breakpoints. And, today, we’re going to talk about definitions and breakpoints.
Breakpoints distinguish between treatable and non-treatable organisms. Since the reference method is MIC by broth microdilution, the breakpoint is always a concentration at which a therapeutic success can be expected. The breakpoint will distinguish between treatable and non-treatable organism, as I said, and it will do that by categorising each organism as either susceptible, susceptible at increased exposure, the I, or resistant, the R, for an agent. A susceptibility test report may look something like this. In this case, Staphylococcus aureus is the infecting organism. So here is a very typical example. These are the MIC distribution– this is the MIC distribution of Streptococcus pneumoniae.
And you can see that the committee has decided to categorise all organisms with MICs of 0.06 and below as S, organisms between 0.12 and 2 as susceptible at increased exposure, and organisms at 4 and above as resistant, meaning that, whatever you do, you’re not going to successfully treat those organisms with, in this case, benzylpenicillin. Breakpoints are expressed as S less than or equal to a certain concentration in milligrammes per litre or R more than a certain concentration again in milligrammes per litre. Anything in between those two values is categorised as I, susceptible, increased exposure. And, of course, surrogate methods, methods which may measure activity in millimetres or some other measurement, will have corresponding breakpoints in that particular measurement.
To determine these breakpoints, the committee needs some tools. And these are some of the tools, the more important tools, that are needed. We need to know from the very beginning, which species are relevant for us. And we need to have MIC distributions and preferably ECOFFs of these relevant species. We need to know, are we going to treat urinary tract infections only or are we going to treat orthopaedic infections, pulmonary infections, because that will affect how we discuss and determine the breakpoints. We also need to know, is this an oral treatment only? Or is it only IV? Or is it maybe just topical?
We need to know something about the dose and the dosing intervals to be able to calculate a variety of indices in pharmacokinetics and pharmacodynamics. And also it’s important to know whether the maximum attainable concentration is the most important thing for the drug to be effective or whether it’s the time during which the concentration in the dosing interval is actually above the MIC. And then it’s good to have clinical evidence for effect. And, most of the time, we will be very happy to have good data to support that wild-type organisms, namely, organisms without resistance mechanisms, can be treated with the agent in question and that there is actually good evidence for that.
And, at times, we’re lucky, and we can find evidence that some non-wild-type organisms can be treated successfully with increased exposure or even standard exposure, as in ciprofloxacin. That will actually be able to treat some organisms with let’s say one mutation against fluoroquinolones. This is the EUCAST breakpoint table or a small section of it just as an example. And you can see down the columns that there are MIC breakpoints, S less than or equal to, R more than. In the left-hand column, there is an array of different beta-lactam antibiotics. And then you can see the zone diameter breakpoints that will correspond to those MIC breakpoints.
And, by going into the table, a clinical lab can say, well, you know, I have an MIC of 8 for ampicillin. And that renders my E. coli susceptible. So I will report it as S. Or I have a zone diameter of 14, or let’s say 18. And that again will render it S. So the table is the fundament for the clinical laboratory who wants to report on their susceptibility tests.

Antibiotic susceptibility testing is extremely important for determining which antimicrobials are most likely to be effective against different microorganisms. In this video, Professor Gunnar Kahlmeter gives us an insight into AST definitions and breakpoints.

Breakpoints are used to distinguish between treatable and non-treatable micro-organisms. A breakpoint is a concentration at which a therapeutic success can be expected. These allow for micro-organisms to be categorised into the following groups:

  • S for susceptible

  • I for susceptible at increased exposure

  • R for resistant

Below is an example of a susceptibility report for Staphylococcus aureus: Methicillin R Ceftaroline S Ciprofloxacin I Vancomycin S

MIC distribution (mg/L) data is used to determine ranges for S, I and R. As breakpoints are expressed as: MIC: S ≤ X mg/L and R > Y mg/L, MIC values between X and Y are categorised as I.

To determine the breakpoints, there are few things that we need to know, such as:

  • Which species are relevant

  • MIC distributions

  • Which infections are relevant

  • Mode of administration – IV, oral or topical along with dosing and dosing intervals

  • Pharmacokinetics and pharmacodynamics of agent

  • Clinical evidence for effect including data for wildtype and non-wildtype (often resistant) organisms along with how efficacy is related to different MIC values

EUCAST has breakpoint tables which include MIC breakpoints. These are used as reference ranges which determine how to report AST of particular microorganisms which can be found here.

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Introduction to Practical Microbiology

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