Mechanisms of Antimicrobial resistance

• Antibiotics interfere with bacterial cell wall synthesis (e.g., beta-lactams & glycopeptides), disrupt membrane structure (e.g., polymyxins, daptomycin), inhibit protein synthesis (e.g., macrolides, tetracyclines), interfere with nucleic acid synthesis (e.g., fluoroquinolones, rifampicin), and inhibit metabolic pathways (e.g., trimethoprim-sulfamethoxazole)
• Factors contributing to antibiotic resistance include antimicrobial use, availability of antimicrobials over the counter, unnecessary use of antimicrobials, patient non-compliance, sub-therapeutic dosing, low penetration to body sites, inadequate infection control procedures, overcrowding in healthcare and children facilities, and increased travel
• Bacteria can become resistant to antibiotics through mechanisms like natural selection, mutations, inherent resistance, and the transfer of resistance genes
• Genetic exchange processes in bacteria include transformation, conjugation, transduction, and transposition, facilitating the rapid dissemination of antibiotic resistance genes among different bacterial species
• Mechanisms of antibiotic resistance in bacteria:

  • Inactivation of agent before reaching target
  • Agent prevented from reaching target due to permeability changes or drug efflux
  • Target altered so it no longer recognizes the antimicrobial
  • Bacterium acquires an alternative metabolic pathway bypassing the site of action
  • Can have multiple mechanisms in one bacterium
• Inactivating enzymes:

  • Bacteria produce enzymes like beta-lactamases that destroy or alter antibiotics
  • Aminoglycoside-modifying enzymes add chemical groups to antibiotics, altering their structure and interfering with transport
• Beta-lactamases:

  • Produced by many bacteria
  • e.g., Most staphylococci can produce beta-lactamase that destroys penicillin
  • Extended spectrum beta-lactamases (ESBLs) produced by some Gram-negatives, mainly Enterobacterales, destroy many beta-lactam antibiotics
• Permeability changes:

  • If permeability is impaired, the agent cannot penetrate as well
  • Changes in outer membrane porins or cell membrane transport proteins can make it harder for some antibiotics to gain entry
• Drug efflux:

  • Active transport of the drug from the cell
  • It can pump the drug back out, preventing it from accumulating or reaching its target
• Target modification:

  • Antimicrobial agent does not bind as well due to a modification at the binding site of the target
  • Altered penicillin binding protein (PBP2a) in MRSA has lower affinity for penicillin
• Metabolic bypass:

  • Bacteria can activate new metabolic pathways for production of essential components, bypassing the action of antibiotics
• Problems caused by antimicrobial resistance:

  • More limited antimicrobial choice leading to some infections being untreatable
  • Time lost with inappropriate treatment results in patient morbidity and mortality
  • Increased hospital stay and costs
  • Increased antibiotic use leads to more resistance
  • More toxic, less effective, and expensive drugs may be required
• Key prevention strategies:

  • Vaccination
  • Good catheter care
  • Antimicrobial stewardship
  • Rapid diagnosis of antimicrobial resistance and infection
  • Infection prevention & control