Harvey's Garden

Combination antibiotic use

2 min read

  • Rationale for Combination Therapy
    • Synergism: The combined effect of two drugs is greater than the sum of their individual effects (1 + 1 > 2).
    • Broad-spectrum Empiric Coverage: Used in critically ill patients (e.g., sepsis, neutropenic fever) before the causative organism is identified. Covers gram-positive, gram-negative, and anaerobic possibilities.
    • Prevention of Resistance: Primarily used in treatment (Tx) of infections that rapidly develop resistance to monotherapy.
      • Classic examples: RIPE therapy for Tuberculosis (Rifampin, Isoniazid, Pyrazinamide, Ethambutol) and multi-drug regimens for H. pylori and HIV.
  • Mechanisms of Antibiotic Synergy
    • Sequential Blockade of a Metabolic Pathway
      • Two drugs inhibit different steps in the same critical pathway.
      • Classic Example: Trimethoprim-Sulfamethoxazole (TMP-SMX).
        • Sulfamethoxazole inhibits dihydropteroate synthase.
        • Trimethoprim inhibits dihydrofolate reductase.
        • Together, they block sequential steps in bacterial folate synthesis.
    • Blockade of Drug Inactivation
      • One drug protects the other from enzymatic degradation.
      • Classic Example: β-lactam + β-lactamase inhibitor.
        • Amoxicillin + Clavulanic Acid
        • Piperacillin + Tazobactam
        • Ampicillin + Sulbactam
        • The inhibitor (e.g., Clavulanate) irreversibly binds to and inactivates the bacterial β-lactamase enzyme, allowing the β-lactam antibiotic to work.
    • Enhanced Drug Uptake
      • One drug damages the bacterial cell wall, increasing the penetration/uptake of a second drug.
      • Classic Example: Penicillins + Aminoglycosides.
        • A cell wall synthesis inhibitor (e.g., Penicillin G, Ampicillin) damages the peptidoglycan wall.
        • This allows the Aminoglycoside (e.g., Gentamicin, Streptomycin) to enter the cell and reach its target (30S ribosomal subunit) more effectively.
        • Key use: Serious gram-positive infections like Enterococcal endocarditis.
  • Antagonism
    • The combined effect of two drugs is less than the effect of the more efficacious drug alone.
    • This can occur when a bacteriostatic drug is combined with a bactericidal drug.
    • Classic Example: Tetracycline + Penicillin.
      • Penicillin is bactericidal and requires bacterial cells to be actively dividing and synthesizing their cell wall.
      • Tetracycline is bacteriostatic; it inhibits protein synthesis, thereby halting cell division.
      • By stopping bacterial growth, the tetracycline prevents the penicillin from working effectively.

Examples

  • Sepsis / Hospital-Acquired Pneumonia:
    • Vancomycin + Piperacillin-Tazobactam: Broadest empiric coverage (MRSA + Pseudomonas + anaerobes).
  • Inpatient Community-Acquired Pneumonia:
    • Ceftriaxone + Azithromycin: Covers typicals (S. pneumo) + atypicals (Mycoplasma, Legionella).
  • Intra-abdominal Infections (e.g., diverticulitis):
    • Ceftriaxone + Metronidazole: Covers enteric gram-negatives (E. coli) + anaerobes (Bacteroides).
  • Enterococcal Endocarditis:
    • Ampicillin + Gentamicin: Classic synergy; cell wall inhibitor enhances aminoglycoside entry.
  • Tuberculosis:
    • RIPE therapy: Prevents resistance.
  • H. pylori Infection:
    • Amoxicillin + Clarithromycin + PPI: Prevents resistance.

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