Antimicrobial Resistance

Resistance is the complete or partial loss of response of an organism to a certain antimicrobial agent, and is particularly problematic for Gram negative bacteria which have developed a wide spectrum of resistance to many antibiotic classes. Resistance is classified into:

Broadly, resistance may occur by:

  • Enzymatic inactivation of antimicrobial
  • Change to antimicrobial binding site
  • ↓ Antimicrobial uptake
  • Altered metabolic pathway that obviates antimicrobial action

Mechanisms of Resistance

Inducible β-lactamase

Group of Gram-negative organisms which:

  • Rapidly develop resistance to β-lactam antibiotics
    • Due to inducible β-lactamase
      Chromosomal-mediated cephalosporinase enzyme that is strongly selected for in the presence of β-lactam antibiotics.
    • May be inhibited by tazobactam, and so piperacillin/tazobactam may be effective
    • General require treatment with a carbapenem
  • Should be treated with non-β-lactam agents, even if they initially appear sensitive
  • Include the ESCHAPPM (or ESCAPPM) organisms:
    • Enterobacter spp.
    • Serratia spp.
    • Citrobacter
    • Hafnia spp.
    • Acinetobacter and Aeromonas spp.
    • Proteus spp.
      Excluding P. mirabilis
    • Providencia spp.
    • Morganella morgani

Extended Spectrum β-lactamase

Describes organisms that develop a β-lactamase that also produces resistance to other antibiotic classes. The ESBL:

  • Provides (variable) resistance to:
    • Third-generation cephalosporins
      e.g. Ceftriaxone.
    • Fluoroquinolones
    • Aminoglycosides
  • Producing organisms include:
    • Enterobacteriae:
      • E. Coli
      • Klebsiella spp.
      • Enterobacter spp.
      • Serratia spp.
      • Proteus spp.
    • Citrobacter spp.
  • Can spread by plasmid transmission
    Bacteria share chromosomal coding for the β-lactamase between organisms, resulting in rapid ↑ resistance in a colony.

Carbapenemases

Carbapenems are typically reserved for treating ESBL and AmpC producing organisms, and so carbapenemase-producing organisms are particularly problematic. Carbapenemases are divided into three groups by their Ambler class:

Although many organisms may produce carbapenemases, carbapenemase-producing Enterobacteriaceae (CPE) are of significantly concern due to the native resistance of Enterobacteriaceae to many other classes of antibiotics.

  • Class A
    Most common form, which include:
    • Klebsiella Pneumoniae Carbapenemase (KPC)
    • Imipenem-hydrolysing beta-lactamase
  • Class B
    • Often found on plasmid vectors
      Allows transmission of resistance between organisms.
    • Significant genetic variability limits testing accuracy
    • Include:
      • Metallo-beta-lactamase (NDM-1)
      • Imipenem-resistant Pseudomonas
      • Verona integron-encoded metallo-lactamase
  • Class D
    • Oxacillin-hydrolysing carbapenemase

Treatment:

  • Often difficult due to complex resistance patterns
  • Microbiology and infectious disease involvement recommended
  • Prevention of transmission is critical:
    • Regular surveillance
    • Epidemiological assessment of detected cases
    • Contact precautions for all suspected or confirmed cases
  • Possible antibiotics (often in combination) include:
    • Carbapenems
    • Polymyxins (colistin)
    • Aminoglycosides
    • Fosfomycin
    • Tigecycline

Treatment of Multidrug Resistant Organisms

  • Determine colonisation vs. infection
  • Source control
  • Early specialist ID advice

Specific therapy:

  • Pharmacological
    • Antimicrobial therapy
      • ↑ Dose to overcome MIC
      • Novel (or very old) antibiotics
        • Ceftaroline
        • Ceftobiprole
        • Colistin
        • Fosfomycin
        • Tigecycline
        • Aztreonam/Avibactam
          For metallo-carbapenemases.
      • Combination therapy
        Interaction of two antibiotics may overcome intrinsic resistance. Options include:
        • Add colistin
        • Add gentamicin
        • Use two drugs from the same class
  • Procedural
    • Source control
  • Physical

References

  1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
  2. Smith HZ, Kendall B. Carbapenem Resistant Enterobacteriaceae. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Oct 1].