Osteomyelitis

Offending Agent: Methicillin-susceptible Staph. aureus (MSSA)

Drug of Choice: Cefazolin

Physicochemical Properties: - pKa: 2.1 (acidic drug; predominantly ionized at physiological pH) - logP: -1.2 (hydrophilic; limited lipid solubility)

Tissue Distribution Rationale: Cefazolin’s low logP (-1.2) and acidic pKa (2.1) result in predominantly hydrophilic distribution. Despite limited lipophilicity, it achieves good bone tissue concentrations due to its excellent tissue penetration via extracellular fluid and its affinity for bone tissue, making it effective for osteomyelitis treatment.

PK/PD Target: %T>MIC ≥ 70% (bone penetration critical)

Key PK Parameters for Osteomyelitis: - Volume of Distribution: 0.15-0.25 L/kg (moderate bone penetration) - Protein Binding: ~85% (free fraction = 0.15) - Bone Penetration: Bone/plasma ratio ≈ 0.1-0.2 - Duration: 4-6 weeks minimum for adequate bone sterilization

This interactive module demonstrates multiple dosing pharmacokinetics using patient-specific parameters.

Patient Generator

• Age: - years
• Sex: -
• Height: - cm
• Weight: - kg
• Creatinine: - mg/dL

Drug Name:

Formulation: Slow (Extended Release) Medium (Standard Oral) Fast (IV Bolus) Fast (IV Bolus)

PK Parameters

Bioavailability (F): 1.0

Fraction Unbound: 0.15

Volume of Distribution (L/kg): 0.2 L/kg

Fraction Renally Cleared: 0.9

Dosing

Loading Dose (mg): 1500 mg

Dose (mg): 1500 mg

Dosing Interval (hrs): 8 hrs

Treatment Duration (days): 10 days

Plot

Loading interactive chart…

Reference Lines

Toxicity Threshold (mg/L): 20 mg/L

Efficacy Threshold (mg/L): 5 mg/L

Data

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 (%)

Education

Osteomyelitis-Specific Pharmacokinetic Concepts

Bone Tissue Penetration: Cefazolin achieves moderate bone penetration with bone/plasma ratios of 0.1-0.2. While not ideal, the high systemic concentrations and favorable PK/PD profile make it effective for MSSA osteomyelitis.

Volume of Distribution for Bone Infections: The moderate Vd (0.15-0.25 L/kg) reflects cefazolin’s distribution into bone and soft tissues while maintaining adequate plasma concentrations for sustained antimicrobial effect.

%T>MIC Target for Osteomyelitis: Target %T>MIC ≥ 70% ensures sustained antimicrobial activity throughout the dosing interval. The high MIC breakpoint challenges require aggressive dosing strategies.

Protein Binding Impact: Cefazolin is ~85% protein bound, but the high total concentrations achieved still provide adequate free drug levels in bone tissue.

Prolonged Treatment Requirements: Osteomyelitis requires 4-6 weeks minimum due to: - Poor vascularization of infected bone - Biofilm formation by Staphylococcus species
- Need for complete bone sterilization - Prevention of chronic infection development

Surgical Considerations: Many cases require surgical debridement combined with antimicrobial therapy. Drug penetration into devitalized tissue is minimal, making surgical intervention critical.

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.

Quiz

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):

6. Cefazolin PK/PD: Based on cefazolin’s pKa (2.1) and physiological pH (7.4), what percentage of the drug is ionized?

Hint: Use Henderson-Hasselbalch equation. For acids: ionized % = 100 × 10^(pH-pKa)/(1 + 10^(pH-pKa))

7. Bone Penetration: How does cefazolin achieve therapeutic bone concentrations despite limited lipophilicity (logP -1.2)? Select your answer… Hydrophilic distribution via extracellular fluid and bone tissue affinity Active transport mechanisms into bone Actually has high lipophilicity despite negative logP Local bone metabolism concentrates the drug

8. Treatment Duration: Why does osteomyelitis typically require 4-6 weeks of antibiotic therapy? Select your answer… Extended duration needed for adequate bone sterilization and biofilm penetration Prevents development of antibiotic resistance Poor oral absorption requires longer treatment Lower doses require longer duration to avoid toxicity

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