Concepts and needs for expert rules and intrepretive reading of the antibiogram The EUCAST perspective

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Concepts and needs for expert rules and
intrepretive reading of the antibiogram The
EUCAST perspective

• Derek Brown
• Health Protection Agency
• Addenbrookes Hospital, Cambridge

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What is an expert rule?

• Description of action to be taken, based on
  current evidence, in response to specific
  antimicrobial susceptibility test results

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What is interpretive reading?

• Inference of resistance mechanisms from
  susceptibility test results and interpretation of
  clinical susceptibility on the basis of the
  resistance mechanism
• This is one type of expert rule

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Types of expert rules

• Intrinsic resistance
• Exceptional phenotypes (mainly resistance)
• Interpretive reading

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Intrinsic resistance

• Inherent (not acquired) resistance which is a
  characteristic of all or almost all
  representatives of the species.
• Antimicrobial susceptibility testing unnecessary
  but may be done as part of panels of test agents.
  
• Susceptible results should be viewed with
  caution
• errors in identification or susceptibility
  testing
• If susceptibility is confirmed the drug should be
  used with caution

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Intrinsic resistance examples

• Specific Gram-positive or Gram-negative agents
• Enterobacteriaceae and glycopeptides
• Enterococci and fusidic acid
• Klebsiella sp. and ampicillin
• Proteus mirabilis and nitrofurantoin or colistin
• Serratia marcescens and colistin

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Exceptional phenotypes (usually resistance)

• Resistance in a species where resistance has not
  been seen or is rare.
• Resistant results should be viewed with caution
• errors in identification or susceptibility
  testing
• If resistance is confirmed send the isolate to a
  reference laboratory for independent confirmation
• Exceptional resistance phenotypes may change with
  time
• There may also be regional or national differences

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Exceptional phenotype examples

• S. pyogenes resistant to penicillin
• S. aureus resistant to vancomycin
• E. faecalis resistant to ampicillin
• Enterobacteriaceae resistant to carbapenems
• Anaerobes resistant to metronidazole
• E. faecium susceptible to ampicillin

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Interpretive reading

• Test susceptibility
• Infer resistance mechanism
• Interpret clinical susceptibility on the basis of
  the resistance mechanism

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Interpretive reading examples

• may be simple e.g. ..IF S. aureus is resistant
  to oxacillin or cefoxitin
• Resistance mechanism PBP2 mediated by mecA
• THEN report resistant to all ß-lactams
• or more complicated e.g.IF Enterobacteriaceae
  intermediate to tobramycin, resistant to
  gentamicin and susceptible to amikacin
• Resistance mechanism ANT(2) enzyme - may be low
  expression and isolates may have decreased
  susceptibility to tobramycin.
• THEN report resistant to tobramycin

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Actions indicated by expert rules

• Recommendations on reporting
• Inference of susceptibility
• Editing of results from S to I or R, from I to R,
  but NEVER I or R to S
• Suppression of results
• Addition of comments
• Advice on further tests
• Advice on referral of isolates

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Requirements for use of expert rules in clinical
laboratories

• Identify the organism fully
• May need to test an extended range of appropriate
  antibiotics
• Access to a set of expert rules

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An expert system for susceptibility testing?
Human experts are rare and are not available in
most laboratories..
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Expert systems for susceptibility testing are
computer based programs for application of expert
rules

• Stand alone programs
• Laboratory information systems
• Programs linked to susceptibility testing devices
  and rules applied automatically to susceptibility
  results

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EUCAST expert rules

• Written description of current expert rules
• Comprehensive collection of rules brought
  together by an expert subcommittee
• May be applied manually or incorporated into
  automated systems

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Development of EUCAST expert rules

• First draft prepared by expert subcommittee
• Consultation with EUCAST national breakpoint
  committees
• Second draft for open consultation via EUCAST
  public website, EUCAST national breakpoint
  committees, EUCAST national representatives,
  industry networks and experts
• Version 1 published April 2008
• Will need to be updated regularly and validated
  for EUCAST breakpoints

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Expert rules should be evidence based

• Should be based on current evidence
• Evidence should be published
• Quality of evidence should be assessed
• Exceptions should be noted

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Grading of evidence base for EUCAST Expert rules

• A There is clinical evidence that reporting the
  test result as susceptible leads to clinical
  failures.
• B Evidence is weak and based only on a few case
  reports or on experimental models. It is presumed
  that reporting the test result as susceptible may
  lead to clinical failures.
• C There is currently no clinical evidence, but
  microbiological data suggest that clinical use of
  the agent should be discouraged.

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Presentation of EUCAST expert rules Intrinsic
resistances
Rule no. Organism Ampicillin Amoxicillin-clavulanate Ticarcillin Piperacillin Cefazolin Cefoxitin
1.1 Citrobacter koseri R R R
1.2 Citrobacter freundii R R R R
1.3 Enterobacter cloacae R R R R
1.4 Enterobacter aerogenes R R R R
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Presentation of EUCAST expert rules Exceptional
phenotypes
Rule no. Organism Exceptional phenotype
6.1 Staphylococcus aureus Resistant to vancomycin, linezolid, quinupristin/dalfopristin, daptomycin, tigecycline.
6.2 Coagulase-negative staphylococci Resistant to vancomycin, linezolid, quinupristin/dalfopristin, daptomycin, tigecycline.
6.3 JK coryneform organisms Resistant to vancomycin, teicoplanin, linezolid, quinupristin/dalfopristin, daptomycin, tigecycline.
6.4 Streptococcus pneumoniae Resistant to imipenem, meropenem, vancomycin, teicoplanin, linezolid, quinupristin/dalfopristin, daptomycin, tigecycline, rifampicin.
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Presentation of EUCAST expert rules
Interpretive reading rules for specific groups
of organisms
Rule no. Organism Agent Rule Exceptions Scientific basis Evidence grade References
8.1 Staphylococcus spp. Isoxazolyl-penicillins If resistant to isoxazolyl-penicillins (as determined with oxacillin or cefoxitin, or by detection of mecA-gene or PBP2a) report as resistant to all ß-lactams Developmental anti-MRSA cephalosporins, e.g. ceftobiprole and ceftaroline Production of PBP2a (encoded by mecA) leads to cross resistance to ß-lactams except ceftobiprole and ceftaroline A Chambers HF et al., 1990. Page MG et al., 2006.
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Expert rules

• EUCAST expert rules are an up-to-date and
  comprehensive collection of accumulated knowledge
  of intrinsic resistances, exceptional phenotypes
  and interpretive reading
• It is intended that the rules will be applied to
  routine antimicrobial susceptibility tests and
  will make a significant contribution to the
  quality of reported results