Bacteremia
Offending agent: Methicillin-resistant Staph. aureus (MRSA)
Drug of Choice: Vancomycin
Physicochemical Properties: - pKa: 7.75 (basic drug; partially ionized at physiological pH) - logP: -3.1 (highly hydrophilic; very limited lipid solubility)
Tissue Distribution Rationale: Vancomycin’s very low logP (-3.1) and basic pKa (7.75) result in predominantly hydrophilic distribution with limited tissue penetration. Its large molecular size and hydrophilic nature restrict it mainly to extracellular fluid, making it ideal for bloodstream infections where high systemic concentrations are achieved.
PK/PD Target: AUC/MIC ≥ 400-600 (higher for resistant organisms)
Key PK Parameters for Bacteremia: - Volume of Distribution: 0.4-0.9 L/kg (good systemic penetration) - Protein Binding: ~90% (free fraction = 0.1) - Renal Clearance: ~80% unchanged in urine
This interactive module demonstrates multiple dosing pharmacokinetics using patient-specific parameters.
Patient Generator
- Age: - years
- Sex: -
- Height: - cm
- Weight: - kg
- Creatinine: - mg/dL
Fast (IV Bolus)
PK Parameters
1.0
0.9
0.65 L/kg
0.85
Dosing
1250 mg
750 mg
12 hrs
10 days
Loading interactive chart…
20 mg/L
5 mg/L
| Subject | Drug Name | Age | Sex | Ht (cm) | Wt (kg) | BMI | IBW (kg) | Adj IBW (kg) | Creatinine (mg/dL) | CrCl (mL/min) | Loading Dose (mg) | Dose (mg) | Interval (hrs) | Duration (days) | Clearance (L/h) | Volume (L) | Fraction Unbound | Vss,u (L) | Bioavailability | Half-life (h) | Css,avg | AUC0-24h | Cmax | AUC/Efficacy | Cmax/Efficacy | Time>Efficacy (%) |
|---|
MRSA Bacteremia Pharmacokinetics of Vancomycin
Systemic Circulation Target: For bacteremia caused by MRSA, the primary site of infection is the bloodstream itself. This makes vancomycin an ideal choice as it achieves excellent systemic exposure with minimal tissue penetration requirements.
Volume of Distribution for Bacteremia: Vancomycin has a relatively small Vd (0.4-0.9 L/kg) which means it stays primarily in the vascular space and extracellular fluid - exactly where it’s needed for bloodstream infections.
AUC/MIC Target for MRSA Bacteremia: The target AUC₀₋₂₄/MIC ≥ 400-600 ensures adequate exposure throughout the dosing interval. Higher targets (≥600) may be needed for more resistant organisms or severe infections.
Protein Binding Considerations: Vancomycin is ~90% protein bound, meaning only 10% is pharmacologically active. However, for bacteremia, the high protein binding actually helps maintain therapeutic concentrations in plasma.
Renal Clearance Monitoring: With 80% renal elimination, creatinine clearance directly impacts vancomycin dosing. Dose adjustments are critical in renal impairment to prevent accumulation and nephrotoxicity.
Trough vs. AUC Monitoring: While trough levels (15-20 mg/L) were historically used, AUC-guided dosing is now preferred for optimizing efficacy while minimizing nephrotoxicity risk.
MRSA-Specific Considerations: - MIC Breakpoint: MRSA susceptibility defined as MIC ≤ 2 mg/L - Heteroresistance: Some MRSA strains show subpopulations with higher MICs - Biofilm Formation: MRSA in bacteremia may form biofilms requiring higher exposures - Source Control: Removal of infected devices critical for treatment success
Dosing Strategy for MRSA Bacteremia: - Loading Dose: 25-30 mg/kg to rapidly achieve target concentrations - Maintenance: 15-20 mg/kg q8-12h based on renal function - Monitoring: Target AUC₀₋₂₄ = 400-600 mg⋅h/L - Duration: Minimum 2 weeks, longer for complicated infections
Blood Sampling Strategy
In this simulation, blood samples are collected every 1 hour to provide a detailed view of how pharmacokinetic data is collected in clinical practice. This sampling frequency allows us to:
- Capture both peak and trough concentrations
- Observe the full absorption and elimination phases
- Reduce the burden on patients compared to more frequent sampling
- Provide sufficient data points for pharmacokinetic analysis
Simplified Pharmacokinetic Model
This simulation uses a simplified one-compartment model with first-order absorption that focuses on the minimum essential parameters needed to generate a multiple dosing pharmacokinetic plot:
Essential PK Parameters: - Clearance (CL): Automatically calculated from patient’s creatinine clearance using Cockcroft-Gault equation - Volume of Distribution (Vd): Drug-specific volume per kg multiplied by patient weight - Bioavailability (F): Fraction of dose reaching systemic circulation
Patient-Specific Factors: - Creatinine Clearance: Calculated using Cockcroft-Gault: CrCl = [(140 - age) × weight × (0.85 if female)] / (72 × serum creatinine) - Weight-Based Dosing: Volume of distribution scales directly with patient weight
Dosing Parameters: - Dose: Amount of drug administered per dose - Dosing Interval: Time between doses - Treatment Duration: Total length of treatment
This approach incorporates key patient-specific factors (age, sex, weight, creatinine) while maintaining the core functionality needed to understand multiple dosing pharmacokinetics and the clinical application of the Cockcroft-Gault equation.
Test your understanding by calculating the following parameters for the current patient:
1. Creatinine Clearance (mL/min):
2. Adjusted Body Weight (kg):
3. Volume of Distribution of Unbound Drug (L):
4. Time to Steady State - tss (hours):
5. Average Steady-State Concentration - Css,avg (mg/L):
Hint: For bases: unionized % = 100/(1 + 10^(pH-pKa))
7. Distribution: Why is vancomycin primarily restricted to extracellular fluid?
8. PK/PD Target: What is the optimal AUC/MIC target for vancomycin against MRSA?