Pneumonia
Offending Agent: ampC+ Pseudomonas aeruginosa
Drug of Choice: Cefepime
Physicochemical Properties: - pKa: 2.5 (acidic drug; predominantly ionized at physiological pH) - logP: -1.0 (hydrophilic; limited lipid solubility)
Tissue Distribution Rationale: Cefepime’s low logP (-1.0) and ionized state at physiological pH (pKa 2.5) limit passive membrane diffusion but enable good hydrophilic tissue penetration. Its excellent lung penetration (ELF/plasma ratio 0.6-1.0) makes it ideal for pneumonia treatment, particularly against resistant Pseudomonas aeruginosa.
PK/PD Target: %T>MIC ≥ 70% (or %T>4×MIC ≥ 50% for Pseudomonas)
Key PK Parameters for Pneumonia: - Volume of Distribution: 0.2-0.3 L/kg (excellent lung penetration) - Protein Binding: ~20% (free fraction = 0.8) - Renal Clearance: ~85% unchanged in urine - Lung Penetration: ELF/plasma ratio ≈ 0.6-1.0
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
0.8
0.25 L/kg
0.85
Dosing
1000 mg
1000 mg
8 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 (%) |
|---|
Pneumonia-Specific Pharmacokinetic Concepts
Lung Tissue Penetration: Cefepime achieves excellent penetration into lung tissue and epithelial lining fluid (ELF). The ELF/plasma ratio is approximately 0.6-1.0, making it highly effective for pneumonia treatment.
Volume of Distribution for Pneumonia: Cefepime has a small Vd (0.2-0.3 L/kg) but this is ideal for lung infections as it maintains high plasma concentrations that effectively penetrate into pulmonary tissues.
%T>MIC Target for Pseudomonas Pneumonia: The target %T>MIC ≥ 70% ensures the free drug concentration remains above the MIC for sufficient time during each dosing interval. For resistant Pseudomonas, %T>4×MIC ≥ 50% may be more appropriate.
Protein Binding Considerations: Cefepime is only ~20% protein bound, meaning 80% is pharmacologically active. This high free fraction contributes to excellent tissue penetration.
β-lactam Dosing Strategy: More frequent dosing (every 8 hours) maximizes time above MIC. Extended or continuous infusions can further optimize %T>MIC for critical infections.
Renal Dose Adjustment: With 85% renal elimination, dose adjustment is critical in renal impairment to maintain efficacy while preventing accumulation.
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. Tissue Penetration: Given cefepime’s logP (-1.0), explain why it achieves good lung penetration despite low lipophilicity:
8. PK/PD Target: For Pseudomonas pneumonia, what %T>MIC target should be achieved for optimal cefepime efficacy?