Endocarditis
Offending agent: Vancomycin-resistant Enterococcus faecium (VRE)
Drug of Choice: Daptomycin
Physicochemical Properties: - pKa: 2.8 (acidic drug; predominantly ionized at physiological pH) - logP: -0.1 (moderately hydrophilic with some lipophilic character)
Tissue Distribution Rationale: Daptomycin’s moderate logP (-0.1) and acidic pKa (2.8) provide balanced hydrophilic/lipophilic properties enabling good tissue penetration. Its calcium-dependent mechanism requires adequate tissue calcium concentrations, and its moderate lipophilicity allows penetration into cardiac tissues affected in endocarditis.
PK/PD Target: AUC/MIC ≥ 666, Cmin ≥ 24.3 mg/L (high dose for endocarditis)
Key PK Parameters for Endocarditis: - Volume of Distribution: 0.1 L/kg (poor tissue penetration) - Protein Binding: ~8% (high free fraction = 0.92) - Cardiac Tissue: Limited penetration, requires high systemic exposure - Dosing: 8-10 mg/kg/day for complex endocarditis
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
0.08
0.1 L/kg
0.5
Dosing
700 mg
700 mg
24 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 (%) |
|---|
Endocarditis-Specific Pharmacokinetic Concepts
Cardiac Tissue Penetration Challenges: Endocarditis involves infected cardiac valves with poor vascularization and biofilm formation. Daptomycin has limited tissue penetration (Vd = 0.1 L/kg) but high systemic exposure compensates.
High-Dose Strategy for VRE Endocarditis: Target AUC₀₋₂₄/MIC ≥ 666 and Cmin ≥ 24.3 mg/L requires aggressive dosing (8-10 mg/kg/day). Higher doses may be needed for complex cases (up to 12 mg/kg/day).
Calcium-Dependent Activity: Daptomycin requires physiologic calcium concentrations for antimicrobial activity. Serum calcium should be monitored and maintained >8.5 mg/dL.
Protein Binding Considerations: Low protein binding (~8%) means 92% is active, contributing to excellent antimicrobial effect despite poor tissue penetration.
Unique Monitoring Requirements: - CPK levels: Monitor for myopathy (dose-related toxicity) - Pulmonary function: Rare but serious eosinophilic pneumonia - Renal function: Potential nephrotoxicity with high doses
Extended Treatment Duration: Endocarditis requires 4-6 weeks of therapy. Some cases may need surgical intervention combined with antimicrobial therapy for optimal outcomes.
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: Use Henderson-Hasselbalch equation. For acids: ionized % = 100 × 10^(pH-pKa)/(1 + 10^(pH-pKa))
7. Cardiac Penetration: Why does daptomycin require high systemic exposure (8-10 mg/kg/day) for endocarditis treatment?
8. Mechanism Dependency: What unique feature of daptomycin’s mechanism affects its tissue distribution?