Meningitis
Offending Agent: Penicillin-resistant Strep. pneumonia (PRSP)
Drug of Choice: Vancomycin + ceftriaxone (or cefotaxime)
Physicochemical Properties of Vancomycin: - 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 large molecular size result in poor CNS penetration under normal conditions. However, during meningeal inflammation, increased blood-brain barrier permeability allows therapeutic CSF concentrations. The combination with ceftriaxone (better CNS penetration) provides broader coverage and improved CNS drug delivery.
PK/PD Target: AUC/MIC ≥ 400 (vancomycin) + %T>MIC ≥ 50% (ceftriaxone)
Key PK Parameters for Meningitis: - Volume of Distribution: 0.1-0.15 L/kg (poor CNS penetration for vancomycin) - CSF Penetration: Vancomycin CSF/plasma ratio ≈ 0.05-0.2 (inflamed meninges) - Protein Binding: Vancomycin ~90%, Ceftriaxone ~95% - CNS Dosing: Higher doses needed due to blood-brain barrier
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
1000 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 (%) |
|---|
Meningitis-Specific Pharmacokinetic Concepts
Blood-Brain Barrier Challenges: The CNS is a pharmacokinetic sanctuary site due to tight junctions in brain capillaries. Most antibiotics, including vancomycin, have poor CNS penetration with CSF/plasma ratios of only 0.05-0.2 even in inflamed meninges.
Combination Therapy Rationale: Vancomycin + ceftriaxone combination provides: - Vancomycin: covers MRSA and resistant enterococci (though poor CNS penetration) - Ceftriaxone: excellent CNS penetration (CSF/plasma ≈ 0.1-0.3) and covers resistant S. pneumoniae
Volume of Distribution for CNS Infections: The restrictive Vd (0.1-0.15 L/kg) for vancomycin means most drug remains in plasma, requiring higher doses to achieve therapeutic CSF concentrations.
AUC-Guided Dosing in Meningitis: Target AUC₀₋₂₄/MIC ≥ 400 requires aggressive dosing due to poor penetration. Some cases may need intrathecal administration for resistant organisms.
CSF Sampling Considerations: CSF drug concentrations are often monitored in severe cases. Timing of lumbar puncture relative to dosing affects interpretation of results.
Duration and Monitoring: CNS infections require prolonged therapy (14-21 days) with careful monitoring for neurotoxicity and nephrotoxicity from high-dose regimens.
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 bases: ionized % = 100 × 1/(1 + 10^(pH-pKa))
7. CNS Penetration: Why does vancomycin achieve therapeutic CSF concentrations in meningitis despite poor blood-brain barrier penetration?
8. Combination Therapy: What is the primary pharmacokinetic rationale for combining vancomycin with ceftriaxone in meningitis?