What are the principles of antibiotic selection and dosing in antibiotics stewardship, considering pharmacokinetics and pharmacodynamics?

Principles of Antibiotic Selection and Dosing in Antibiotic Stewardship

Understanding pharmacokinetics and pharmacodynamics is essential for optimal antibiotic selection and dosing to maximize therapeutic efficacy while minimizing resistance development and adverse effects. 1

Pharmacokinetic and Pharmacodynamic Principles

Time-Dependent vs. Concentration-Dependent Antibiotics

• Time-dependent antibiotics (e.g., beta-lactams):

  • Efficacy depends on time above MIC (minimum inhibitory concentration)
  • Require more frequent dosing or prolonged/continuous infusions
  • Higher peak concentrations are not beneficial 2
  • Example: For beta-lactams, higher-frequency dosing, prolonged infusions, and continuous infusions should be utilized to maximize time above MIC 2

• Concentration-dependent antibiotics (e.g., aminoglycosides, fluoroquinolones):

  • Efficacy correlates with peak concentration relative to MIC
  • Should be administered once daily or with minimal daily doses
  • Higher peak concentrations improve efficacy 2, 3
  • Example: Aminoglycosides should be administered in a once-daily manner to achieve high peak plasma concentrations 2

Loading Doses

• Critical for hydrophilic antibiotics (beta-lactams, aminoglycosides, glycopeptides)
• Essential in critically ill patients to overcome "third spacing phenomenon"
• Ensures optimal exposure at infection site from treatment initiation
• Missing loading doses results in underexposure that may be critical for patient outcomes 2, 4

Antibiotic Selection Framework

AWaRe Classification System

The WHO categorizes antibiotics into three groups to guide selection 2, 1:

1. Access (green): First-line options with lower resistance potential

   • Should be widely available in all healthcare facilities
   • Generally narrow-spectrum with favorable risk-benefit profiles

2. Watch (orange): Higher resistance potential

   • Targets for monitoring and stewardship
   • Often associated with more adverse events and toxicities
   • Generally broader-spectrum agents

3. Reserve (red): Last-resort options

   • Only for confirmed or suspected multidrug-resistant infections
   • Major targets for stewardship programs

First and Second Choice Selection

• First-choice antibiotics: Usually narrow-spectrum agents with favorable risk-benefit ratios and low resistance levels
• Second-choice antibiotics: Generally broader-spectrum agents with higher resistance rates or less favorable risk-benefit profiles 2

Dose Optimization Strategies

1. Patient-specific factors to consider:

   • Age (pediatric, adult, geriatric)
   • Weight
   • Renal function
   • Hepatic function
   • Site of infection 2, 3

2. Infection-specific considerations:

   • Pathogen (known or suspected)
   • Local resistance patterns
   • Tissue penetration requirements 2, 3

3. Special dosing strategies:

   • Prolonged beta-lactam infusions for critically ill patients
   • Higher doses of fluoroquinolones for specific pathogens
   • Loading doses for hydrophilic antibiotics 2

Streamlining and De-escalation

1. Empiric to targeted therapy transition:

   • Begin with appropriate broad-spectrum coverage based on local resistance patterns
   • Obtain cultures before starting antibiotics when possible
   • Review microbiological results to narrow therapy
   • Switch to the narrowest effective spectrum once pathogen is identified 2, 1

2. Duration optimization:

   • Use the shortest effective duration based on infection type and patient response
   • Avoid unnecessarily prolonged therapy that increases resistance risk
   • Consider syndrome-specific duration recommendations 2, 1

Common Pitfalls and How to Avoid Them

1. Underdosing in critically ill patients:

   • Account for altered volume of distribution in sepsis, trauma, edema
   • Consider enhanced renal clearance in burns, hyperdynamic conditions
   • Use loading doses for hydrophilic antibiotics 4

2. Failure to adjust for organ dysfunction:

   • Reduce doses appropriately in renal impairment
   • Consider drug levels when available (e.g., vancomycin, aminoglycosides) 3, 4

3. Inappropriate broad-spectrum use:

   • Reserve broad-spectrum therapy for critically ill patients or those with risk factors for resistant organisms
   • De-escalate therapy promptly when culture results are available 1, 5

4. Neglecting local resistance patterns:

   • Develop and utilize facility-specific antibiograms
   • Consider unit-specific patterns (e.g., ICU vs. general ward) 2, 1

Implementation in Antibiotic Stewardship Programs

1. Develop local guidelines for common infections based on:

   • Local resistance patterns
   • Patient populations
   • Available antibiotics 2, 1

2. Measure antibiotic consumption with regular benchmarking and feedback to prescribers 2

3. Implement dose optimization protocols based on PK/PD principles:

   • Extended/continuous infusions for beta-lactams
   • Once-daily dosing for aminoglycosides
   • Loading doses for critically ill patients 2

4. Provide education on PK/PD principles to all prescribers 2, 1

5. Utilize rapid diagnostics when available to guide therapy decisions 2

By applying these pharmacokinetic and pharmacodynamic principles to antibiotic selection and dosing, clinicians can optimize therapeutic outcomes while minimizing the development of resistance, ultimately improving patient morbidity and mortality.