In this episode, I’ll discuss beta-lactam antibiotic dosing concerns in obese adult patients.
The volume of distribution (Vd) is generally increased in obesity as a result of extra fat tissue and accompanying lean muscle. An exception is with hydrophyllic medications such as cephalosporins. In this case, the volume of distribution would not be correctly estimated using actual body weight, and an adjusted body weight may be more accurate.
Clearance (Cl) can be increased as well in obesity. Total body clearance of a medication results from eliminating organs, and the mass of the liver and kidneys are increased in obesity.
What is often overlooked is the fact that these changes in clearance and volume of distribution can also change the half-life of a medication. We all remember that half-life equals 0.693 divided by the elimination rate constant. But the elimination rate constant is derived from dividing the clearance by the volume of distribution. If these parameters do not increase equally in obesity then the half-life of the medication will change up or down accordingly.
The lack of therapeutic drug monitoring makes dosing beta-lactam antibiotics in obesity especially challenging.
Penicillins
Of the beta-lactam antibiotics, piperacillin-tazobactam appears to have the most data examining the effects of obesity on pharmacokinetic and pharmacodynamic parameters. Pharmacodynamic target attainment (PTA) with intermittent infusions of piperacillin-tazobactam is predicted to be less than ideal for obese patients. Prolonged infusion strategies seem to increase the chances of attaining pharmacodynamic targets. This may be especially true in critically ill patients who may have drastically changing kidney function and plasma levels. Although there is no data to suggest it, some experts suggest applying the principle of extended infusion in obese patients to other penicillins besides piperacillin-tazobactam.
Cephalosporins
Studies that show inadequate tissue penetration and subtherapeutic levels in obese patients of cephalosporins are mostly related to single doses given for surgical prophylaxis. Theoretical data for some of the newer cephalosporins ceftaroline, ceftolozone, and ceftazidime/avibactam suggest that changes in Vd and Cl from obesity are not likely to affect clinical outcomes.
However small studies of ceftazidime and cefepime in obese critically ill and noncritically ill patients suggest that if the MIC is near the resistance breakpoint, the required target pharmacodynamic parameters may not be obtained due to subtherapeutic concentrations, elevated Vd, and increased Cl.
Carbapenems
Ertapenem at the standard dose is likely adequate for the treatment of moderate to severe diabetic foot infections and complicated intraabdominal infections. In one study, obesity was not identified as a risk factor for treatment failure and cure rates were similar between obese and nonobese groups.
Meropenem Vd and Cl is increased by obesity in both critically ill and noncritically ill patients, however, these differences do not seem to affect the change of attaining adequate pharmacodynamic targets. Rather than normal body weight, factors such as prolonged infusion, increasing age, and Clcr less than 100 mL/min appear to be the factors associated with achieving pharmacodynamic targets for meropenem in obese critically ill patients.
Without drug level monitoring, clinical response is all that can be used to determine the effectiveness of antibiotics in obese patients. Based on the limited data available, if I encountered an obese patient on a cephalosporin that was not having an adequate clinical response, I would consider switching the antibiotic to an extended infusion of piperacillin-tazobactam or carbapenem if appropriate for the infection being treated.
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