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EUCAST: Update on current guidelines plus UK specific advice v 9.0

Mandy Wootton

What’s new in EUCAST

Links to Expert rules & resistance docs added High dose therapy markers Taxomomic name changes Addition of BPs for new agents Revised BPs S. pneumoniae & H. influenzae – new flowcharts Redefinition of the Intermediate category Area of Technical Uncertainty (ATU) category added

Expert rules and Resistance mechanism docs

High dose therapy markers

Taxonomic name changes

Enterobacter aerogenes to Klebsiella aerogenes

– It has a native ampC ß-lactamase (like Enterobacterspp. but unlike Klebsiella spp.

– Treat as Enterobacter for susceptibility patterns

– Treat as Enterobacter for ESBL detection

Clostridium difficile to Clostridioides difficile

Proprionibacterium acnes to Cutibacterium acnes

Breakpoints for new agents

Meropenem-vaborbactam– MIC BPs only for Enterobacterales and Pseudomonas spp.

– Vaborbactam fixed conc 8mg/L

– Disc criteria in preparation

– MEV: activity against KPC producing Enterobacterales

– Complicated UTI

Breakpoints for new agents

Eravacycline– MIC BPs only for E. coli (only), S. aureus (only), Enterococci and

viridans streptococci

– Disc criteria in preparation

– Intra-abdominable infections

New agents: being worked on in 2019

Aztreonam/avibactam - active against Enterobacteriales with MBLs

Cefiderocol - active against ESBL, MBL, KPC, OXA-23 producers, Ab, Steno, Burk

Cefepime-tazobactam - ESBL producers

Delafloxacin - new FQ for skin infections

Imipenem-Relebactam - active against KPC producers and carb R PAER

Lefamulin - active against SPN, HI, MC for respiratory infections

Iclaprim - active against Gram positives in SSTI

Revised breakpoints

Carbapenems

BPs established in 2008

Changed in – Enterobacterales, – Pseudomonas, – Acinetobacter, – S. pneumoniae, – H. influenzae, – G+ and G- anaerobes.

PKPD

1

8

1/228/16

Enterobacterales

S. pneumoniae

Addition of a new AMP disc breakpoint

S. pneumoniae

Updated flowchart

H. influenzae

Addition of a flowchart

Better detection of BL Res

Reduces no of cephinasetests performed

Redefinition of the Intermediate category

OLD definitions

Clinically Susceptible (S)a micro-organism is defined as susceptible by a level of antimicrobial activity associated with a high likelihood of therapeutic success

Clinically Intermediate (I)a micro-organism is defined as intermediate by a level of antimicrobial activity associated with indeterminate therapeutic effect

Clinically Resistant (R) a micro-organism is defined as resistant by a level of antimicrobial activity associated with a high likelihood of therapeutic failure.

Redefinition of the Intermediate category

Redefinition of the Intermediate category

Dosing and mode of administration are in the EUCAST breakpoint table

Redefinition of the Intermediate category

All clinical breakpoints are related to the achievable level ofexposure* of the microorganism

Redefinition of the Intermediate category

Definition of Intermediate

Redefinition of the Intermediate category

Definition of Intermediate encompasses both…

Redefinition of the Intermediate category

Uncertainty and Exposure

Redefinition of the Intermediate category

Uncertainty and Exposure

Redefinition of the Intermediate category

NEW Definitions

Redefinition of the Intermediate category

NEW Definitions

Redefinition of the Intermediate category

NEW Definitions

Redefinition of the Intermediate category

Definition of OLD Intermediate

Redefinition of the Intermediate categoryProblems & Inconstsencies Some BPs needed revising

The treatment of infections with Pseudomonas spp require most often increased exposure – therefore wild type Pseudomonas should have been categorized ”Susceptible, increased exposure” for all antimicrobials except possibly carbapenems. The committee decided that more time is needed to explain that carbapenems should not because of this be preferred over other available antimicrobials.

The treatment of Enterobacterales with aminopenicillins and cefuroxime require increased exposure and should have been categorized ”Susceptible, increased exposure”. A general consultation on these issues is needed before a final decision so for 2019 wild type organisms will be reported ”Susceptible” with a note to use ”increased exposure”.

Redefinition of the Intermediate category

When S, increased exposure is the result AND HE symbol present, laboratories should consider adding information about the need for high exposure.

This is particularly important with

Pseudomonas and piperacillin-tazobactam, ceftazidime, cefepime, imipenem, aztreonam, fluroquinolones, aminoglycosides.

Enterobacterales and aminopenicillins without or with inhibitor and cefuroxime.

Redefinition of the Intermediate category

ReportingWe can report ”Susceptible (S)” and ”Resistant (R)” but can no longer be reported ”intermediate” to an agent and should instead be reported ”Susceptible, increased exposure (I)”.

EUCAST suggests one of the following wordings are included in reports:

An organism is categorised as Susceptible, increased exposure (abbreviated “I”) when there is a high likelihood of therapeutic success because exposure to the agent can be increased at the site of infection by adjusting the dosing regimen, mode of administration or because the concentration is naturally high at the site of infection (see http://www.eucast.org/clinical_breakpoints/).

This isolate is Susceptible to the agent provided higher exposure of the microorganism can be achieved (dose, frequency, mode of administration).

Area of Technical Uncertainty (ATU)

OLD and NEW definitions

There are situations where the test is known to be poorly reproducible, even when performed appropriately (i.e. with good consumables, QC etc).

Removed from NEW definition of I

Examples of where a warning against uncertain and poorly reproducible results is warranted:

Amoxicillin-clavulanic acid vs. Enterobacterales.– WT distribution of most Enterobacterales end at 8 mg/L. – PK/PD indicates a breakpoint of maximum 8 mg/L and then only if high

exposure is achieved (except for in UTI-32mg/L). – Unfortunately, when determining MICs or disk diffusion test results,

there is poor reproducibility in the critical area 16 mg/L.

Piperacillin-tazobactam vs. Enterobacterales.– WT distribution of most Enterobacterales end at 8 mg/L. – PK/PD indicates a breakpoint of 8/16 mg/L with the highest possible

exposure for organisms in the I-category. – Unfortunately, when determining MICs or disk diffusion test results,

there is poor reproducibility in the critical area 16mg/L.

Area of Technical Uncertainty (ATU)

Area of Technical Uncertainty (ATU)

Area of Technical Uncertainty (ATU)

Area of Technical Uncertainty (ATU)

Area of Technical Uncertainty (ATU)

Area of Technical Uncertainty (ATU)

Area of Technical Uncertainty (ATU)

Enterobacterales 4 agents

Pseudomonas spp 2 agents

Staphylococcus spp 4 agents

H. influenzae 8 agents

Other species 0 agents

Area of Technical Uncertainty (ATU)

For laboratory action:

The warning affects the laboratory, not the clinician, and the laboratory needs a strategy to (1) ascertain the correctness or (2) to report the uncertainty of the result.

Area of Technical Uncertainty (ATU)

For laboratory action: Repeat the test – this is only if there is reason to suspect a technical error. Perform an alternative test (perform an MIC, a PCR, a test to determine

the resistance mechanism) – this is relevant when the alternative test is considered conclusive (PCR to detect a vanA or vanB gene in enterococci, a beta-lactamase test in H. influenzae).

Report results in the ATU as “uncertain” – this can be achieved by leaving a blank with a comment or by developing the LIS to deliver an asterix(instead of an S, I or R) which points to a comment explaining the uncertainty.

Report results in the ATU as “R”. If there are several good alternatives in the AST report this may be the easiest and safest option.

Take the opportunity to discuss the results with the clinician

Area of Technical Uncertainty (ATU)

ATU - the appropriate action may vary with circumstances:

IF few antibiotics available to the clinician, THEN try to achieve

trustworthy categorisation.

IF in a blood culture, THEN try to achieve trustworthy categorisation.

IF can be solved with an alternative method without delay, THEN try to achieve trustworthy categorisation.

IF many alternative antibiotics available, THEN report R (with or without a comment).

IF the result must be reported, THEN include a comment to discuss uncertainty.

Any Questions?

N. gonorrhoeae

EUCAST disc method not available

Reference method: Agar dilution Study with Colindale, European GC & EDL

Comparing agars for agar dilution

Comparing agars for gradient strips

Develop a disc method if possible in time

Interim measures: MIC using gradient strips, use manufacturers media choice

Continue with BSAC disc method

Update of BSAC ”UK Specific Advice” in 2018

EtestBioMerieux

MIC Test Strip

Liofilchem

GC agar base + 1%

IsoVitalex

GC agar base + 1%

IsoVitalex

MH + 1% IsoVitalex +

1% haemoglobin

MH Chocolate

agar

Combination discs for ESBL detection

Combination discs usually contain 30ug of cephalosporin Some ceph 10ug discs on market

EUCAST: 10ug CAZ, 10ug CPD, 5ug CTX Do 30ug and 10ug discs detect ESBLs?

Conclusion: 30ug and 10ug Ceph discs detect ESBLs in combination discs.