Issues relevant to the UK which are not covered by EUCAST

The BSAC AST Standing Committee recognise that there are areas of current UK susceptibility testing laboratory practice, which are perceived as not covered by the EUCAST disc diffusion method, breakpoints and guidelines. The following information has been added to give clarification of EUCAST guidelines and extra advice for UK laboratories.

EUCAST began harmonising the European clinical breakpoints over 10 years ago using an evidence based approach to setting breakpoints for many commonly used agents. They continue to review existing breakpoints using new pharmacokinetic/pharmacodynamics data or clinical therapeutic efficacy evidence and set clinical breakpoints for new agents, publishing updates every year. The EUCAST disc method was developed in 2009, evaluating the accuracy of the susceptibility test for each organism/agent combination. The method continues to be updated to improve accuracy of existing tests and to include more antimicrobial agents and bacterial species.

The areas where UK laboratory practice and EUCAST methods, guidelines and breakpoints do not align are discussed in detail below. Please click on a banner to read the relevant information.

Nitrofurantoin or mecillinam clinical breakpoints for Enterobacterales are limited to E. coli (nitrofurantoin) or E. coli, Citrobacter spp., Klebsiella spp., Raoultella spp., Enterobacter spp. and P. mirabilis (mecillinam)

There are currently EUCAST clinical breakpoints for nitrofurantoin and mecillinam, however these breakpoints can only be used to interpret tests performed on E. coli (nitrofurantoin) or E. coli, Citrobacter species, Klebsiella species, Raoultella species, Enterobacter species and P. mirabilis (mecillinam) from uncomplicated UTI.

Some UK laboratories extrapolate the nitrofurantoin and mecillinam clinical breakpoints to interpret all Enterobacterales, however, this is not recommended.

EUCAST have recently reviewed these breakpoints and have expanded the mecillinam breakpoints to include Citrobacter spp., Raoultella spp., and Enterobacter spp.. In previous years, the clinical breakpoint was for interpretation of E. coli, Klebsiella spp. and P. mirabilis only. The change followed a BSAC/EUCAST collaborative study which investigated whether the current breakpoints could distinguish between isolates with and without resistance mechanisms in species other than those listed. After reviewing current clinical evidence EUCAST decided that the breakpoints could also be used for Citrobacter spp., Enterobacter spp. and Raoultella spp.

After a similar review, the nitrofurantoin clinical breakpoints could not be extended to include any other Enterobacterales species.

Nitrofurantoin susceptibility in Enterobacterales varies, with E. coli particularly susceptible and Proteeae (e.g. Proteus, Morganella and Providencia spp.), some Klebsiella species and Pseudomonas species carrying intrinsic resistance. Infections with Enterobacterales other than E. coli or staphylococci other than S. saprophyticus are commonly associated with upper urinary tract or complicated infections. EUCAST clinical breakpoints are based upon pharmacokinetic data, microbiological data and clinical experience. Most nitrofurantoin and mecillinam clinical data are derived from acute UTI studies, mostly comprising of E. coli (Hüttner et al., 2015). For these reasons, EUCAST considers Enterobacterales other than E. coli, P. aeruginosa, Acinetobacter species, staphylococci other than S. saprophyticus, streptococci other than group B, H. influenzae, Moraxella catarrhalis, Neisseria species and anaerobes as poor targets for nitrofurantoin or inappropriate for nitrofurantoin therapy. For mecillinam, P. aeruginosa, Acinetobacter species, Staphylococcus species, Enterococcus species, streptococci, H. influenzae, M. catarrhalis, Neisseria species and anaerobes were considered poor targets or inappropriate for mecillinam therapy.

BSAC CURRENTLY RECOMMENDS: DO NOT REPORT nitrofurantoin or mecillinam results for those species without breakpoints.

No EUCAST disc diffusion method for Neisseria species

There is currently NO EUCAST disc diffusion method for susceptibility testing Neisseria species. MIC determination is recommended using EUCAST clinical breakpoints. It is important for UK laboratories to continue susceptibility testing N. gonorrhoeae as resistance to azithromycin and ceftriaxone is increasing in this country.

For N. gonorrhoeae, disc diffusion methodology has been extensively tested in Europe and the UK and found to be problematic; with the main issues being poor growth and lack of correlation of zone diameters to MIC. Therefore MIC determination is recommended to establish susceptibility. Most laboratories use gradient strips to determine MICs; using the manufacturers recommended media.

BSAC, in collaboration with the Specialist Antimicrobial Chemotherapy Unit (SACU) Public Health Wales and the Antimicrobial Resistance in Sexually Transmitted Infections (AMRSTI), Public Health England (PHE) have evaluated different commercial media and are planning to evaluate gradient strip manufacturers for determining MICs in N. gonorrhoeae.

Six commercial agar plates have been evaluated and although most performed well, some showed lower agreement with MICs performed by the reference method. The full study details can found here: BSAC GC media evaluation.

For N. meningitidis, there is considerable uncertainty as to the validity of a disc diffusion method plus clinical significance of reported resistance. BSAC is collaborating with SACU and Meningococcal Reference Unit (MRU) to evaluate a disc diffusion method for use in susceptibility testing on N. meningitidis. Results will be published in 2021.

BSAC CURRENTLY RECOMMENDS: Perform MIC testing for all clinically relevant N. gonorrhoeae and N. meningitidis as per gradient strip manufacturers’ instructions and EUCAST clinical breakpoints.

BSAC RECOMMENDS: Two control organisms to be tested for N. gonorrhoeae: N. gonorrhoeae ATCC 49226 (fully susceptible) plus N. gonorrhoeae WHO X (Ceftriaxone & Azithromycin R; click here for reference) if required.

No EUCAST disc diffusion method for Anaerobic bacteria

EUCAST currently have NO disc diffusion test for anaerobic bacteria. MIC determination is recommended using EUCAST clinical breakpoints. Most laboratories will perform gradient strips to determine MICs, using manufacturer’s instructions (including media recommendation). EUCAST have been working with laboratories throughout Europe, including the Anaerobe Reference Unit (ARU) in the UK, to form a sub-committee to develop a disc diffusion method. Work has progressed well and a proposal is being evaluated by the EUCAST steering committee in winter 2020. Until disc diffusion methods and criteria are published by EUCAST, BSAC is recommending the following advice:

BSAC CURRENTLY RECOMMENDS: Perform MIC testing for all clinically relevant anaerobic bacterial species as per gradient strip manufacturer’s instructions and using EUCAST clinical breakpoints. The anaerobe specific recommended media and inoculum preparation broths for gradient strips is not always readily available in the UK. Please check with your usual manufacturer.

Most appropriate method for Enterobacteriales or Pseudomonas species against colistin

No current disc method is adequate to determine susceptibility/resistance to colistin in Enterobacterales or Pseudomonas species. Please see link for advice on colistin susceptibility testing in Gram-negative organisms.

BSAC CURRENTLY RECOMMENDS: Please read our Colistin Guidance

Rapid Antimicrobial Susceptibility Testing (RAST) in Blood Cultures

EUCAST have recently developed a new rapid disc diffusion method and breakpoints for susceptibility testing directly from positive blood cultures. Positive blood cultures are one of the most important specimens in the diagnostic microbiology laboratory. Current practice in the UK is either an in-house disc diffusion test on the positive blood culture (results at 24h post positivity) or a EUCAST disc diffusion test on the isolate (48h post positivity). Whereas the latter method is a standardised and as such results proved reliable, the former are not standardised and can often have poorer reproducibility. There is an obvious clinical need for more rapid results for positive blood cultures.

The RAST method is a standardised disc diffusion method for certain bacteria and antimicrobial agents. The method uses specialised breakpoint criteria for reading after 4, 6 and 8h incubation The method was extensively evaluated in 55 European laboratories alongside the standardised EUCAST disc diffusion method. Categorical agreement was high with error rates at acceptable levels.

Please find details of the method here and results of the method evaluation here.

We would like to hear from you if your laboratory is using or plans to use the RAST method, please contact Mandy Wootton.

No EUCAST disc diffusion criteria or MIC breakpoints for temocillin

There are currently no EUCAST disc diffusion or MIC breakpoints for temocillin; however, the EUCAST steering committee has been reviewing data and it is likely that breakpoints for a limited number of Enterobacterales species will be published soon. Read more…

BSAC/EUCAST do not have any recommendation as yet but some laboratories have been testing and interpreting using BSAC methods/breakpoints. However, this is not ideal when the majority of disc diffusion testing is performed by the EUCAST method. A few laboratories have been testing with the EUCAST disc diffusion method then interpreting using the breakpoint and zone diameter criteria suggested in a 2013 paper: Vanstone et. al, ‘’ Temocillin disc diffusion susceptibility testing by EUCAST methodology’’ J. Antimicrob Chemother (2013) 68 (11): 2688-2689. Here ≥20mm and ≥12mm correspond to ≤8mg/L and ≤32mg/L MIC breakpoints. This is the criteria used by some automated instruments. BSAC/EUCAST will not endorse these criteria until more data and discussions have taken place.

No EUCAST clinical breakpoints for trimethoprim against H. influenzae or M. catarrhalis

There are no EUCAST zone diameter criteria or MIC breakpoints for trimethoprim against H. influenzae or M. catarrhalis. For other species (e.g. Enterobacterales & S. aureus) the trimethoprim MIC breakpoints and disc criteria are for non-complicated UTI only.

It is considered that trimethoprim is not the optimal choice in these clinical scenarios, especially as monotherapy; there is no clinical evidence of efficacy. Other therapeutic options should be considered for which disc criteria and MIC breakpoints exist, as per co-trimoxazole.

No disc diffusion criteria for S. aureus against vancomycin/teicoplanin

The disc diffusion method (BSAC or EUCAST) does not accurately identify glycopeptide resistance in Staphylococci. Guidance from the EUCAST is to perform an MIC by broth microdilution, due to variability seen in gradient strips. Results with gradient strip methods may be 0.5-1 two-fold dilution steps higher than the results obtained by broth microdilution. The variability of gradient strip MICs are currently being reviewed by BSAC/EUCAST.

BSAC CURRENTLY RECOMMENDS: Perform an MIC test by broth microdilution preferably or await outcome of review

No disc diffusion criteria for S. pneumoniae against cephalosporins

The preferred algorithm for susceptibility testing of cephalosporins in S. pneumoniae is to perform an MIC method following the ß-lactam screen test using an oxacillin (1ug) disc. The flow chart at the bottom of the S. pneumoniae EUCAST breakpoint table should be used.

Other useful EUCAST guidance documents include:

  • For situations where there is no clinical breakpoint
  • On the implementation and use of the 2020 revised aminoglycoside breakpoints
  • ATU – the Area of Technical Uncertainty – Guidance

Further information can be found on the EUCAST guidance webpage.

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