Antibiotic Dosing in Obesity

INTRODUCTION

The WHO recognizes obesity as a global health problem. As of 2005, 400 million people worldwide were obese with 1.6 billion overweight. Epidemiologic studies have linked obesity to a number of comorbidities including hypertension, coronary artery disease, stroke, type 2 diabetes mellitus, osteoarthritis, depression, and several forms of cancer. Although obese patients are encountered frequently in practice, very little data exist concerning drug dosing and obesity. In fact, many researchers exclude obese patients during clinical trials. Most of the data describing the pharmacokinetics and pharmacodynamics of the majority of drugs come from case reports and small case series.

DEFINING BODY COMPOSITION

There are several different means to measure and classify body composition.

Direct quantification
- Underwater weighing, skinfold measurement, and bioelectric impedance
- Most accurate
- Difficult and impractical
Indirect measures
- Body mass index (BMI)
  - Calculated as weight in kilograms divided by square of the height in meters
  - The WHO classification
    - underweight as BMI <18.5 kg/m2
    - normal weight 18.5 to 24.99 kg/m2
    - overweight as 25 to 29.99 kg/m2
    - obese class I as 30 to 34.99 kg/m2
    - obese class II as 35 to 39.99 kg/m2
    - obese class III or morbid obesity as >40 kg/m².
- Percentage of ideal body weight (IBW) as a function of height
  - For a man, IBW equals 50 kg plus 2.3 kg for every inch above 5 feet
  - For a woman, IBW equals 45.5 kg plus 2.3 kg for every inch above 5 feet
  - Classification
    - Underweight <80% of IBW
    - Normal weight is 80% to 124% of IBW
    - Obesity is 125% to 190% of IBW
    - Morbid obesity is >190% of IBW

EFFECTS OF OBESITY ON PHARMACOKINETICS

When compared to the bacterial minimum inhibitory concentration (MIC), three pharmacodynamic principals predict therapeutic response: peak concentration (C_max), area under the concentration-time curve/24 hours (AUC), and time above MIC (T>MIC). However, these parameters fail to capture the complete picture due to many unknowns such as bound versus free drug, blood versus tissue levels, and interstitial versus intracellular concentrations (please see Table 55-1). In the absence of a more substantial model, most of pharmacokinetics is simplified to two parameters: volume of distribution (Vd) and drug clearance (Cl). Volume of distribution plays an important role in loading and maintenance doses, while drug clearance more affects the frequency of administration.

Volume of distribution
- Affected by many factors including body composition, regional blood flow, drug lipophilicity, and plasma protein binding
- Maximum blood flow into adipose tissue is <5% of cardiac output.
- Hydrophilic drugs should not be significantly affected by increased body weight.
- For a list of hydrophilic versus lipophilic drugs, see Table 55-2.
- Drugs bound to albumin are also not likely to be significantly affected by obesity.
- However, antibiotics bound to α₁-acid glycoprotein may have changes in volume of distribution.
- For hydrophilic drugs, IBW tends to be a better measure.
- For lipophilic drugs, measurements that include added mass (total body-weight [TBW] or adjusted body weight [ABW]) for obesity may be a better descriptor.
- For lipophilic drugs given at a flat dose such as fluoroquinolones, macrolides, linezolid, sulfonamides, and fluconazole, it is not unreasonable to consider higher doses to attain more appropriate levels (please see Table 55-3).
Drug clearance
- Accomplished primarily by the liver and kidney
- Metabolism of drugs primarily performed by the liver
  - Phase I consists of oxidation, reduction, and hydrolysis.
  - Phase II consists of glucuronidation and sulfation.
  - Both of which can increase in obesity
- Elimination occurs primarily by the kidneys.
  - Most antibiotics are renally eliminated.
  - Clearance involving the kidney occurs through a variety of mechanisms: glomerular filtration, tubular secretion, and tubular reabsorption.
  - One report states that obesity may result in a state of glomerular hyperfiltration, similar to the early stages of diabetic nephropathy.
  - Another study using [125I]Na iothalamate CL showed a higher GFR in obese females than normal-weight controls, although the results were not significant.