Urinary Tract Infection
Offending Agent: Fluoroquinolone-resistant, ESBL+ uropathogenic E. coli (UPEC)
Drug of Choice: Ertapenem
Physicochemical Properties: - pKa: 2.8 (acidic drug; predominantly ionized at physiological pH) - logP: -0.5 (moderately hydrophilic with some lipophilic character)
Tissue Distribution Rationale: Ertapenem’s moderate logP (-0.5) and acidic pKa (2.8) provide balanced hydrophilic/lipophilic properties enabling good tissue penetration. Its renal excretion and moderate lipophilicity allow effective urinary tract concentrations while maintaining good tissue penetration for complicated UTIs.
PK/PD Target: %T>MIC ≥ 40% (β-lactam for UTI)
Key PK Parameters for UTI: - Volume of Distribution: 0.1-0.2 L/kg (excellent urinary concentration) - Protein Binding: ~95% (free fraction = 0.05) - Renal Clearance: ~90% unchanged in urine - Urine Concentrations: 10-100× higher than plasma levels
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
0.05
0.15 L/kg
0.9
Dosing
1000 mg
1000 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 (%) |
|---|
UTI-Specific Pharmacokinetic Concepts
Exceptional Urinary Concentration: Ertapenem achieves urinary concentrations 10-100× higher than plasma levels due to active renal secretion and concentration mechanisms. This makes relatively modest plasma levels highly effective for UTI treatment.
Volume of Distribution for UTI: The small Vd (0.1-0.2 L/kg) means most drug remains in plasma and is rapidly excreted unchanged in urine, exactly where it’s needed for urinary tract infections.
%T>MIC Target for UTI: Lower target %T>MIC ≥ 40% is sufficient for UTI due to the extraordinarily high urinary concentrations achieved. This is much more forgiving than systemic infections.
Protein Binding Considerations: Despite 95% protein binding, the massive urinary concentrations mean adequate free drug levels are achieved in the urinary tract for antimicrobial effect.
ESBL Coverage Strategy: Ertapenem provides excellent coverage against ESBL-producing E. coli, including those resistant to fluoroquinolones. The carbapenem backbone is stable against ESBL enzymes.
Monitoring and Duration: UTI typically requires shorter duration (5-7 days) compared to other sites. Urine culture and susceptibility testing guide duration and confirm eradication.
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. Urinary Concentrations: Why does ertapenem achieve excellent urinary tract penetration for UTI treatment?
8. ESBL Coverage: What makes ertapenem particularly effective against ESBL+ E. coli in UTIs?