Principles of Antimicrobial Therapy

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.

⭐ 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.

Resistance Rampage - Bugs Fight Back!

• 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.

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.