Principles of Antimicrobial Therapy

Principles of Antimicrobial Therapy

Principles of Antimicrobial Therapy

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Antimicrobial Arsenal - Class & Action Central

  • Cell Wall Synthesis Inhibitors:
    • Beta-lactams (Penicillins, Cephalosporins, Carbapenems): Inhibit transpeptidases (Penicillin-Binding Proteins, PBPs).
    • Vancomycin: Binds D-Ala-D-Ala terminus; blocks transglycosylation & transpeptidation.
  • Protein Synthesis Inhibitors: (📌 "Buy AT 30, CCELL at 50")
    • 30S Subunit: Aminoglycosides (cause mRNA misreading), Tetracyclines (block tRNA attachment).
    • 50S Subunit: Macrolides, Clindamycin, Linezolid (block peptide chain translocation/initiation complex formation). Chloramphenicol (inhibits peptidyl transferase).
  • Nucleic Acid Synthesis/Function Inhibitors:
    • Fluoroquinolones: Inhibit DNA gyrase (topoisomerase II) & topoisomerase IV.
    • Rifampin: Inhibits DNA-dependent RNA polymerase.
    • Sulfonamides & Trimethoprim: Sequentially inhibit folate synthesis.
  • Cell Membrane Integrity Disruptors:
    • Polymyxins (e.g., Colistin): Disrupt Gram-negative bacterial outer membrane.
    • Daptomycin: Depolarizes Gram-positive bacterial cell membrane.

4 Ways Antibiotics Affect Bacterial Cells

⭐ Beta-lactams exhibit time-dependent killing (Time > MIC is critical), while Aminoglycosides show concentration-dependent killing (Peak/MIC ratio) and a post-antibiotic effect (PAE).

Drug Dynamics - PK/PD & Dosing Dance

  • PK/PD Indices & Dosing: Core goal is to optimize exposure to achieve bacterial kill & prevent resistance.
    • Cmax/MIC (Concentration-dependent):
      • Drugs: Aminoglycosides, Fluoroquinolones, Daptomycin.
      • Goal: Peak conc. (Cmax) 8-10x MIC.
      • Dosing: Large doses, less frequent intervals.
    • T > MIC (Time-dependent):
      • Drugs: Beta-lactams, Clindamycin, Linezolid.
      • Goal: Drug conc. above MIC for 40-70% of dosing interval.
      • Dosing: Frequent smaller doses or continuous/prolonged infusion.
    • AUC/MIC (Exposure-dependent):
      • Drugs: Vancomycin (target AUC/MIC > 400), Azithromycin, Fluoroquinolones, Tetracyclines.
      • Goal: Optimize total drug exposure over 24h.
  • Post-Antibiotic Effect (PAE): Persistent bacterial suppression after drug levels fall below MIC (e.g., Aminoglycosides, Fluoroquinolones).
  • Dosing Adjustments: Crucial in renal impairment (e.g., Beta-lactams, Vancomycin) & hepatic dysfunction (e.g., Macrolides, Metronidazole).

⭐ For Vancomycin, trough concentrations (15-20 mg/L for severe infections like MRSA pneumonia/endocarditis; 10-15 mg/L for less severe infections) are often used as a practical surrogate for achieving the target AUC/MIC > 400.

PK/PD indices: T>MIC, Cmax/MIC, AUC/MIC relationships

Resistance Rampage - Bugs Fight Back!

Mechanisms of antibiotic resistance

  • Primary Mechanisms of Resistance:

    • Altered Target Site: Modification of drug binding site. e.g., PBPs (mecA in MRSA → Methicillin resistance), Ribosomes (rRNA methylation by erm genes → Macrolide resistance).
    • Enzymatic Inactivation: Bacterial enzymes destroy/modify antibiotic. e.g., β-lactamases (ESBLs, AmpC, KPC, NDM-1), Aminoglycoside-modifying enzymes.
    • Decreased Permeability/Increased Efflux:
      • Reduced drug entry: Porin loss (e.g., Pseudomonas vs Carbapenems).
      • Active drug removal: Efflux pumps (e.g., Tetracyclines, Fluoroquinolones). 📌 MDRugs Pumped Out!
  • Acquisition & Spread:

    • Intrinsic Resistance: Natural to the organism.
    • Acquired Resistance:
      • Mutations: Spontaneous changes in bacterial DNA.
      • Horizontal Gene Transfer (HGT): Sharing resistance genes.

⭐ Carbapenemases like NDM-1 (New Delhi Metallo-β-lactamase) confer broad β-lactam resistance, including carbapenems, limiting therapeutic options significantly.

Therapy Tactics - Smart Drug Choices

  • Selection Factors: Host (allergy, organ function), Drug (PK/PD, spectrum, cost), Site, Local Antibiogram.
  • Combination Therapy Uses:
    • Synergy (e.g., endocarditis: β-lactam + aminoglycoside).
    • Polymicrobial infections.
    • Prevent resistance (e.g., TB, HIV).
    • Empirical for severe sepsis/neutropenic fever.
  • Antimicrobial Prophylaxis:
    • Surgical: Give <60 min pre-incision. Re-dose if surgery >2 drug half-lives or major blood loss.
    • Medical: Specific high-risk groups (e.g., PCP in HIV, rheumatic fever recurrence).
  • PK/PD Insights: Time-dependent (e.g., β-lactams: $T > MIC$) vs. Concentration-dependent (e.g., Aminoglycosides: $C_{max}/MIC$).

⭐ Surgical site infection (SSI) prophylaxis: Cefazolin is a common choice. For high MRSA risk, consider adding Vancomycin. Prophylaxis is typically discontinued within 24h post-operatively for most procedures.

Core elements of antibiotic stewardship diagram

High‑Yield Points - ⚡ Biggest Takeaways

  • Bactericidal drugs (e.g., Beta-lactams) kill bacteria; Bacteriostatic (e.g., Macrolides) inhibit growth.
  • Time-dependent killing (e.g., Beta-lactams) needs levels above MIC; Concentration-dependent (e.g., Aminoglycosides) needs high peaks.
  • Post-Antibiotic Effect (PAE) allows extended dosing intervals for drugs like Aminoglycosides.
  • Major resistance mechanisms: Enzymatic inactivation (β-lactamases), target modification (MRSA), efflux pumps.
  • Empirical therapy guides initial choice; de-escalate based on culture and sensitivity.
  • Combination therapy for synergy, broad-spectrum cover, or preventing resistance.

Practice Questions: Principles of Antimicrobial Therapy

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Which antibiotic acts by inhibiting protein synthesis?

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Flashcards: Principles of Antimicrobial Therapy

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_____ prophylaxis for Mycobacterium avium complex should be started with CD4+ counts < 50

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_____ prophylaxis for Mycobacterium avium complex should be started with CD4+ counts < 50

Azithromycin

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