Antimicrobial

• Antimicrobial resistance mechanism


  • Inactivation (usually enzymatic) of the antibiotic agent by hydrolysis or modification
  • Alteration (or loss) of the antibiotic target through either genetic mutation or post-translational modification
  • Reduced intracellular accumulation of antibiotic either through restricted uptake/reduced permeability or increased efflux
• Beta-lactamases


  • Structural change of beta-lactam ring by opening it, can't fit the active site
  • Examples: Carbapenemases, Extended spectrum beta lactamases, New-delhi metallo-beta-lactamase (NDM-1)
• Beta-lactamase inhibitors


  Used in combination with beta-lactams to reduce resistance, examples: Clavulanic acid, Sulbactam, Tazobactam, Avibactam, Vaborbactam
• Aminoglycoside modifying enzymes


  • Add new functional groups like Acetyltransferases (AAC), Phosphotransferases (ANT), Nucleotidyltrasferases (APH) to change hydrophobicity and steric hinderance, altering interaction with target
• MRSA


  • Gene (mecA) produces a second penicillin binding protein that maintains cell wall synthesis whilst antibiotic is intact to the first/native binding protein
• Vancomycin resistance in Enterococci

  • Produces cell wall precursors (D-ala-D-ala to D-ala-D-Lac) that have low affinity for vancomycin, loss of 1 hydrogen bond makes it unstable
• Colistin resistance


  • Mobilized colistin resistance (mcr1) gene synthesizes phosphatidylethanolamine transferase, which catalyses transfer of a phosphoethanolamine residue to the lipid A on cell membrane, decreasing affinity for colistin
• Macrolide, Lincosamide, Streptogramin resistance

  • Erythromycin ribosome methylase methylates 16s rRNA, altering drug binding site
• Reduced intracellular accumulation of antibiotics

  • Reduction or alteration of outer membrane porins
  • Increased efflux via tetracycline pumps or multidrug resistance efflux pumps (MDR) which span across cytoplasmic membrane, periplasm and outer membrane
• Risk and rate of antibiotic resistance is controlled by exposure, it can be reduced by prudent prescribing and judicious use
• Antimicrobial Stewardship


  Coordinated interventions to improve and measure the appropriate use of antimicrobial agents by promoting the selection of optimal antimicrobial drug regimen, duration of therapy and route of administration
• Aims of Antimicrobial Stewardship

  • Improve antimicrobial prescribing
  • Improve clinical outcomes for patients
  • Minimise toxicity and adverse events
  • Reduce the costs associated with inappropriate prescribing
  • Reduce the selective pressure on bacterial populations
  • Reduce resistance levels, or, at the very least, decelerate the development of antibiotic-resistant bacterial strains
• Antimicrobial Stewardship Team


  • Infectious diseases physician
  • Clinical pharmacist with infectious diseases specialization
  • Medical microbiologist
  • Infection control specialist
  • Hospital epidemiologist
  • Information technology specialist
• Strongly recommended Antimicrobial Stewardship interventions

  • Preauthorisation and/or prospective audit and feedback
  • Interventions to reduce use of antibiotics associated with a high risk of Clostridiodes difficle infection
  • Implementation of pharmacokinetic monitoring and adjustment programmes for aminoglycosides in hospitals
  • Greater use of oral antibiotics
  • Implementation of guidelines to reduce therapy to the shortest effective duration
• The 6 R's when advising on self-limiting conditions

  • Reassurance
  • Reasons
  • Relief options
  • Realistic times
  • Reinforcement
  • Rescue information
• Basic principles of AMR action planning

  • Improve awareness and understanding of antimicrobial resistance
  • Strengthen surveillance and research
  • Reduce the incidence of infection
  • Optimize the use of antimicrobial medicines
  • Ensure sustainable investment in countering antimicrobial resistance
• Tackling Antimicrobial Resistance 2019-2024 plan sets targets to halve healthcare associated Gram-negative bloodstream infections, reduce specific drug-resistant infections by 10% by 2025, reduce UK antimicrobial use in humans by 15% by 2024, and reduce UK antibiotic use in food-producing animals by 25% between 2016 and 2020
• How to prolong the therapeutic life of current antimicrobials

  • Maintain heterogeneity of antibiotics through drug cycling and drug mixing (personalized medicine requires better diagnostics)
  • Ensure adequate serum drug concentrations
  • Repurposing of withdrawn and underused antibiotics
  • Combination therapy