JIRA ID: 

Release used for analysis: 2019-07-31

Approvals 

 Content Issue Summary

Summary of Issue

The descendants of 409793007 |Antimicrobial resistant bacteria (organism)| (n= 84) are concepts that represent special cases of bacterial resistance that are of interest to public health organizations including WHO and CDC.  Issues with this group of concepts include a lack of terming rules (and subsequent term inconsistency), the existing concept hierarchy is not pharmacologically sound (it is not currently based on the SCT substance hierarchy, and classification (subsumption) based on organism expression of resistance factors (e.g. Extended Spectrum Beta Lactamase - EBSL) is inconsistent.  The project as envisaged would be a very subtle re-organization of the hierarchy to more correctly classify the antimicrobials by antimicrobial class,  make the terms consistent, edit relevant style guidance, and remove ISA relationships that assume the presence of a resistance factor confers clinical (laboratory) resistance.

Related content projects and requests

 Analysis of Issue 

Inconsistent terms

The pattern for terms includes one or more of the following descriptors: extent of resistance or mechanism of resistance + name of drug or drug class + resistant + name of organism (which may be as general as "bacteria" or as specific as bacteria of a genetic strain).  All FSNs include the name of an organism, while all other descriptor types are optional.  For most terms, the order or presentation is as stated.  However, within the descriptors, multiple terming patterns exist:

• extent of resistance

  • "multidrug" resistant...

  • multi drug-resistant...

  • multiple drug resistant...

  • multiple antimicrobial drug... 

  • non-multiple drug resistant...

  • extensively resistant...

  • pan antimicrobial drug resistant...

• Mechanism of resistance (n.b. in at least 2 cases the mechanism of resistance is implied in the name of the organism)

  • Vancomycin resistant enterococcus vanA strain

  • Vancomycin resistant vanB2 and vanB3 Enterococcus

  • Enterococcus faecium genotype van A

  • Extended spectrum beta-lactamase and carbapenemase producing...

  • Carbapenemase-producing...

• drug or drug class

  • Methicillin resistant...

  • Tetracycline-resistant...

  • Beta lactam resistant...

Content is neither pharmacologically sound nor complete

Antibacterial resistance content in SCT is included primarily to support public health reporting of specific bacteria resistant to pharmaceutical agents "of special concern."  Special concern is generated by public health interest in infectious disease categories such as tuberculosis, hospital acquired infections, food-borne illness, and sexually transmitted diseases.  Special concern also exists when the resistance is related to antibacterials are considered to be critically important (Critically Important Antimicrobials for Human Medicine, 6th Revision, WHO).  Content inclusion is request driven and has changed over time.

It is not reasonable to assert that this content supports routine reporting of individual culture and susceptibility reporting as isolates are tested against multiple agents at one time.  Results for individual agents tested for a single organism may be susceptible (S), intermediate (I) or resistant (R).  Requirements for this purpose would include hundreds of individual bacteria tested against several dozen antimicrobials and each result would be one of three result categories (S,I,R).  The resulting concept list would number in the thousands.

• Not all drug classes and certainly not all drugs are represented

  • This is true if we simply wanted to include classes that WHO considers critical

  • As this content is almost entirely request driven, no action is required at this time

• Organism concepts that refer to individual drugs are not consistently subtypes of resistance concepts that refer to more a more general class

  • 710891006 |Methicillin resistant Staphylococcus (organism)| is not a descendant of 710877000 |Beta lactam resistant bacteria (organism)|

  • 409807008 |Penicillin resistant Streptococcus pneumoniae (organism)| is not a descendant of 710877000 |Beta lactam resistant bacteria (organism)|

• Drug names that represent both a drug class and an individual drug are not adequately specified "penicillin" resistant might refer to either:
  
  

  • penicillin antibacterial(s) (the class)

  • benzyl penicillin G

Classification of concepts referring to resistance mechanism or factor is inconsistent

In SCT, antimicrobial resistance concepts may state the existence of resistance and include the mechanism of resistance (e.g., 710333000 |Vancomycin resistant enterococcus vanA strain (organism)|) OR may refer only to the presence of a resistance mechanism without stating that the organism has been shown to be resistant a particular drug (e.g., 734350003 | Carbapenemase-producing bacteria (organism) |).  In the former case, where resistance to a drug or drug class is part of the concept FSN, it seems reasonable to include these concepts as descendants of 409793007 |Antimicrobial resistant bacteria (organism)|.  In the latter case, current editorial policy specifies that it is incorrect to assume that the presence of a resistance factor (whether via gene testing or by confirming the expression of the genetic factor) automatically confers clinical resistance.

• There are a number of instances where current editorial policy is not followed.  In these two cases, the subtyping assumes that the presence of (or expression of) a resistance factor confers resistance.  Editorial policy states that the presence of the resistance factor is just that and may or may not confer (clinical or laboratory) resistance:

  • 762987008 |Extended spectrum beta-lactamase and carbapenemase producing bacteria (organism)| → is a subtype of →

    • 707497007 |Carbapenem resistant bacteria (organism)| → is a subtype of →

      • 409793007 |Antimicrobial resistant bacteria (organism)|

  • 409799006 |Extended spectrum beta-lactamase producing bacteria (organism)| → is a subtype of -> 

    • 714789002 |Extensively antimicrobial drug resistant bacteria (organism)| is a subtype of →

      • 409793007 |Antimicrobial resistant bacteria (organism)|

• There are instances where the pharmacological import of the resistance factor is incorrectly classified:
  
  

  • Carbapenemase is an extended spectrum beta-lactamase

    • 734350003 | Carbapenemase-producing bacteria (organism) | → is a subtype of →
      
      

      • 409822003 |Domain Bacteria (organism)|

    • → it should ALSO be a subtype of →

      • 409799006 |Extended spectrum beta-lactamase producing bacteria (organism)|
        
        

• Existing content is incomplete:

  • not all general mechanisms are present

  • MANY specific subtypes are not present

    • there are dozens of subtypes of beta-lactamase

      • only penicillinase, extended spectrum beta-lactamase and carbapenemase examples exist

• this content is challenging to maintain

  • one resistance mechanism may be present in or produced by many different bacteria

  • relationships between the resistance factors and the various antibacterials and classes to which they would confer some measure of resistance is complex

Epidemiological resistance concepts

Concern for widespread antimicrobial resistance and the protection of therapeutic drug classes has lead to creation of three concept classes: "multidrug-resistant" (MDR), "extensively drug-resistant" (XDR) and "pandrug-resistant" (PDR) bacteria.  The definitions (included as SCT descriptions) were created by a group of international experts and published by the European Society of Clinical Microbiology and Infectious Disease (Clinical Microbiology and Infection, 2012; 18: 268-281).  The concepts themselves are used in public health reporting systems.  It is not clear that they are correctly classified in SCT.   The authors of the cited reference suggest that correct assignment of individual isolates to these categories is based on evolving CLSI breakpoints, the list of available antimicrobial drugs, and the variation in the list of antimicrobials tested by individual labs.  They do not comment on the logical relationships between them.

Specific challenges for positioning these in the SCT hierarchy (and attempts to automate classification of clinical isolates) include:

• Evolution in CLSI standard interpretations and the list of available antimicrobial agents

• The drug classes are referred to (in the text definitions) as "epidemiologically significant" which has no precise definition

• "One agent in 3 or more classes" (MDR) is not distinct from "all but 2 or fewer classes" (XDR) or "all classes" (PDR)

Strict interpretation of the definitions of PDR and XDR produce a logical distinction between them, but both would seem to be subtypes of MDR (Figure 2).

•  

  • 713351000 | MDR | - resistant to three or more epidemiologically significant drug classes

    • 714789002 | XDR | - resistant to all but two or fewer drug classes

    • 714792003 | PDR | - resistant to at least one agent in all drug classes.

Figure 1. Epidemiological categories - MDR, XDR, and PDR are currently arranged according to this subtype hierarchy.

Figure 1. Epidemiological categories - MDR, XDR, and PDR are currently arranged according to this subtype hierarchy.
Open

Figure 2. Epidemiological categories - Strict interpretation of the definitions produce this set of relationships as there is no maximum antimicrobial count included in the definition of MDR.

Figure 2. Epidemiological categories - Strict interpretation of the definitions produce this set of relationships as there is no maximum antimicrobial count included in the definition of MDR.
Open

Incorrect subtyping and inconsistent naming of resistant bacteria strains

• 707768008 |Enterococcus faecium genotype vanA (organism)| → is not a logical subtype of →

  • 710333000 |Vancomycin resistant enterococcus vanA strain (organism)| 

    • even though Enterococcus faecium is a descendant of the genus Enterococcus

    • "vanA strain" refers to a specific alteration in the (normal) pathway bacteria synthesize peptidoglycan, the pathway is encoded in the genome of the bacteria

• The word "strain" is ambiguous

  • In clinical microbiology it is a single isolate from a single (tissue) source

  • In bacterial taxonomy "strain" is almost equivalent to subspecies 

  • strains are (usually) considered to be intraspecies variants 

    • based on SNOMED's organism logic 710333000 |Vancomycin resistant enterococcus vanA strain (organism)| is a a supertype for all of the species "strains"

    • genetic diagnostic testing could make this a clinical diagnosis

Additional issues identified  

Possible content additions

The list of drugs and drug classes in SCT is small compared to the list of available agents and classes considered to be important by the World Health Organization (WHO).  At this time, large-scale additions are not being considered, but editorial staff should be aware of their presence.   Specific drug class additions can or should be made (as supertypes) when an agent from an unrepresented class is presented for addition.

WHO "critically Important" drug classes not represented:

WHO "critically important" drug subclasses not represented:

WHO "highly important" drug classes not represented:

WHO "highly important" drug subclasses not represented:

WHO "important" drug classes not represented:

(For glycopeptides and macrolides, representative antibacterial substances are represented but the class is not.  For cephalosporins the class is represented but there are no representative durgs.  For tetracyclines, a single ambiguous concept exists that could either represent the class or the antimicrobial substance tetracycline).

Solution 

Terming rules

Basic pattern

Multiple drug pattern

Resistant strains

Mechanism(s) of resistance

For the purpose of these examples, the factors confer resistance (enzymes, alterations of cell walls, etc.) will be called "gene products."  

Phenotype is specified:

Genotype is specified:

Drug class hierarchy

Antimicrobial substance and its correct antimicrobial class or subclass present

Antimicrobial substance present in SCT, class or WHO critical subclass absent from SCT

Antimicrobial WHO critical class or subclass present, representative antimicrobial subclass absent

Concepts that incorporate resistance factor

Correct subtype hierarchy

Epidemiological resistance

Magiorakis et al (Clinical Microbiology and Infection, 2012; 18: 268-281) defined Multidrug resistant (MDR), Extensively resistant (XDR), and Pandrug resistant (PDR).  MDR is defined as an organism resistant to at least ONE antimicrobial from 3 or more "antimicrobial categories" (pharmacological "antimicrobial classes").  The paper does not clearly define category.  Beta-lactam is certainly a class for this definition  (would be one of 3).  It's not clear whether resistance to "penicillins + cephalosporins + carbapenems" (beta-lactam subclasses) only would define an organism as MDR.  An XDR bacteria is one resistant to at least one drug in all but 2 or fewer antimicrobial classes.  Pandrug resistance (PDR) is defined as resistance to all antimicrobials in all classes.

Correct subtype hierarchy

Resistant strains

Correct subtype hierarchy

 Construction

Correction of terms

Resistance to Substance

• 409793007 |Antimicrobial resistant bacteria (organism)| → edit FSN → 

  • Antimicrobial-resistant bacteria (organism)

• 277502005 |Tetracycline-resistant Neisseria gonorrhoeae| → is correct

• 406576009 |Vancomycin intermediate/resistant Staphylococcus aureus (organism)| → retire concept as ambiguous → may be a

  • 406962002 |Vancomycin-intermediate Staphylococcus aureus (organism)|

  • 404680007 |Vancomycin-resistant Staphylococcus aureus (organism)|

Resistance to Substance class

• 710877000 |Beta lactam resistant bacteria| → edit FSN→

  • Beta-lactam antibiotic-resistant bacteria (organism)

• 409807008 |Penicillin resistant Streptococcus pneumoniae (organism)| → retire concept as ambiguous → may be a →

  • Penicillin antibiotic-resistant Streptococcus pneumoniae (organism)

  • Benzylpenicillin-resistant Streptococcus pneumoniae (organism)

Multiple drugs

• 713351000 | Multiple antimicrobial resistant bacteria (organism)| → edit FSN →

  • Multidrug-resistant bacteria?

  • Multiple antimicrobial-class-resistant bacteria?

• 446157004 | Multidrug resistant Acinetobacter (organism)| → edit FSN ->

  • Multidrug-resistant Acinetobacter (organism)

• 715353004 |Multiple drug-resistant Acinetobacter baumannii (organism)| → edit FSN →
  
  

  • Multidrug-resistant Acinetobacter baumannii (organism)

• 707330008 |Multidrug resistant Achromobacter xylosoxidans (organism)| → edit FSN →
  
  

  • Multidrug-resistant Achromobacter xylosoxidans (organism)

• 707293009 |Multidrug resistant Morganella morganii (organism)| → edit FSN →
  
  

  • Multidrug-resistant Morganella morganii (organism)|

• 710332005 |Multidrug resistant Pseudomonas aeruginosa (organism)| → edit FSN →
  
  

  • Multidrug-resistant Pseudomonas aeruginosa (organism)|

• 715206000 |Multiple drug-resistant Citrobacter freundii (organism)| → edit FSN →

  • Multidrug-resistant Citrobacter freundii (organism)

• 714316001 |Multiple drug-resistant Enterobacter asburiae (organism)| → edit FSN →
  
  

  • Multidrug-resistant Enterobacter asburiae (organism)

• 714317005 |Multiple drug-resistant Enterobacter cloacae (organism)| → edit FSN →
  
  

  • Multidrug-resistant Enterobacter cloacae (organism)|

• 713925008 |Multiple drug-resistant Escherichia coli (organism)| → edit FSN →
  
  

  • Multidrug-resistant Escherechia coli (organism)

• 715308001 |Multiple drug-resistant Klebsiella aerogenes (organism)|  → edit FSN →
  
  

  • Muiltidrug-resistant Klebsiella aerogenes (organism)

• 714315002 |Multiple drug-resistant Klebsiella pneumoniae (organism)|  → edit FSN →
  
  

  • Multidrug-resistant Klebsiella aerogenes (organism)

• 713926009 |Multiple drug-resistant Klebsiella pneumoniae subsp. ozaenae (organism)|  → edit FSN →
  
  

  • Multidrug-resistant Klebsiella pneumoniae subsp. ozaenae (organism)

• 714314003 |Multiple drug-resistant Proteus mirabilis (organism)| → edit FSN →
  
  

  • Multidrug-resistant Proteus mirabilis (organism)

• 715354005 |Multiple drug-resistant Serratia marcescens (organism)| → edit FSN →
  
  

  • Multidrug-resistant Serratia marcenscens (organism)

• 716530009 |Non-multiple drug resistant methicillin resistant Staphylococcus aureus (organism)| → edit FSN→
  
  

  • Non-multidrug-resistant methicillin-resistant Staphylococcus aureus (organism)|

Drug Class Hierarchy

• Organize beta-lactam class-resistance under 710877000 |Beta lactam resistant bacteria (organism)|

  • Create penicillin class-resistant bacteria concept → subtypes

    • Penicillin class-resistant Streptococcus pneumoniae concept (created above)

      • Benzylpenicillin-resistant Streptococcus pneumoiae concept (created above)

    • 710891006 |Methicillin resistant Staphylococcus (organism)|→ edit FSN→ Methicillin-resistant Staphylococcus (organism)
      
      

      • 115329001 |Methicillin resistant Staphylococcus aureus (organism)|→ edit FSN→ Methicillin-resistant Staphylococcus aureus (organism)

        • Non-multiple drug resistant methicillin resistant Staphylococus aureus (organism)| → edit FSN→ see concept in previous section.

      • 13923001 | Methicillin resistant Staphylococcus epidermidis (organism)|→ edit FSN→ Methicillin-resistant Staphylococcus epidermidis (organism)

      • 443457000 |Methicillin resistant Staphylococcus intermedius (organism)| → edit FSN→ Methicillin-resistant Staphylococcus intermedius (organism)

      • 443474000 |Methicillin resistant Staphylococcus pseudintermedius (organism)|→ edit FSN→ Methicillin-resistant Staphylococcus peudintermedius (organism

      • 722384007 |Methicillin resistant Staphylococcus, coagulase negative (organism)|→ edit FSN→ Methicillin-resistant Staphylococcus, coagulase negative (organism)

• Add class concepts if specific substance 

  • Create Macrolide class resistant bacteria → (supertype of) →

    • 726493005 |Clarithromycin resistant bacteria (organism)|
      
      

      • 726496002 |Clarithromycin resistant Helicobacter pylori (organism)|→ edit FSN→ Clarithromycin-resistant Helicobacter pylorii (organism)

  • Create Glycopeptide class-resistant bacteria (supertype of) →

    • 404679009 |Glycopeptide resistant Staphylococcus aureus (organism)|→ edit FSN→ 

      • Glycopeptide antibiotic-resistant Staphylococcus aureus (organism)

    • 404680007 |Vancomycin resistant Staphylococcus aureus|→ edit FSN→ 

      • Vancomycin resistant Staphylococcus aureus (organism)

    • 113727004 |Vancomycin resistant enterococcus|→ edit FSN→ Vancomycin-resistant enterococcus (organism)

      • 712663006 |Vancomycin resistant Enterococcus faecalis|→ edit FSN→ 

        • Vancomycin-resistant Enterococcus faecalis (organism)

      • 712665004 |Vancomycin resistant Enterococcus faecium|→ edit FSN→ 

        • Vancomycin-resistant Enterococcus faecalis (organism)

      • 782959008 |Vancomycin resistant Enterococcus raffinosus| → edit FSN→ 

        • Vancomycin-resistant Enterococcus raffinosus (organism)

      • 710333000 |Vancomycin resistant enterococcus vanA strain|→ edit FSN→ 

        • Vancomycin-resistant enterococcus vanA genotype

      • 710334006 |Vancomycin resistant enterococcus vanB strain|→ edit FSN→ 

        • Vancomycin-resistant enterococcus vanB genotype

      • 707767003 |Vancomycin resistant vanB2 and vanB3 Enterococcus| → edit FSN→ 

        • Vancomycin-resistant vanB2 and vanB3 enterococcus (organism)

  • Create Glycopeptide antibiotic-intermediate bacteria (supertype of) →

    • 783025003 |Vancomycin intermediate Enterococcus (organism)|→ edit FSN→ 

      • Vancomycin-intermediate Enterococcus (organism)

    • 712664000 |Vancomycin intermediate Enterococcus faecalis (organism)|→ edit FSN→ 

      • Vancomycin-intermediate Enterococcus faecalis(organism)

    • 712666003 |Vancomycin intermediate Enterococcus faecium (organism)|→ edit FSN→ 

      • Vancomycin-intermediate Enterococcus faecium (organism)

    • 782960003 |Vancomycin intermediate Enterococcus mundtii (organism)|→ edit FSN→ 

      • Vancomycin-intermediate Enterococcus mundtii (organism)

    • 406605001 |Glycopeptide intermediate Staphylococcus aureus (organism)|→ edit FSN→ 

      • Glycopeptide antibiotic-intermediate Staphylococus aureus (organism)

      • 406962002 |Vancomycin intermediate Staphylococcus aureus (organism)|→ edit FSN→ 

        • Vancomycin-intermediate Staphylococcus aureus (organism)

Resistance factors

• Remove is a relationships between resistance factor concepts and resistance supertypes

  • 409799006 |Extended spectrum beta-lactamase producing bacteria| → remove is a →

    • 714789002 |Extensively antimicrobial drug resistant bacteria (organism)|

Epidemiological resistance 

• Edit subtype hierarchy according to Figure 2 above

  • 714792003 |Pan antimicrobial drug resistant bacteria (organism)| → is a (subtype) of
    
    

    • 713351000 |Multiple antimicrobial drug resistant bacteria (organism)|

  • 714789002 |Extensively antimicrobial drug resistant bacteria (organism)| → is a (subtype) of
    
    

    • 713351000 |Multiple antimicrobial drug resistant bacteria (organism)|

Resistant strains

• Edit terms

•  

  • 710333000 |Vancomycin resistant enterococcus vanA strain (organism)| → 
    
    

    • Vancomycin-resistant enterococcus vanA genotype

  • 710333000 |Vancomycin resistant enterococcus vanB strain (organism)| →
    
    

    • Vancomycin-resistant enterococcus vanB genotype

•  

  • 707768008 |Enterococcus faecium genotype vanA (organism)| →
    
    

    • Vancomycin-resistant Enterococcus faecium vanA genotype (orgnism)

  • 707769000 |Enterococcus faecium genotype vanB (organism)| →
    
    

    • Vancomycin-resistant Enterococcus faecium vanB genotype (organism)

• Correct subtypes

  • 707767003 |Vancomycin resistant vanB2 and vanB3 Enterococcus (organism)| → is a (subtype) of
    
    

    • 710333000 |Vancomycin-resistant enterococcus vanB strain (organism)| 

6. Transition phase 

7. Glossary of Terms