Chapter 3

### DRUG OVERVIEW

As a class, beta-lactam antibiotics are a mainstay of therapy and are recommended for nearly all infection types in clinical practice guidelines1, 2, 3, 4, 5, and 6, often as first-line agents. Overall, they are a broad class of antibiotics and consist of penicillins, cephalosporins, monobactams, and carbapenems. Beta-lactams exhibit bactericidal activity by binding to penicillin-binding proteins and, ultimately, inhibiting cell wall synthesis. Since the discovery of penicillin, it has been known that prolonging the infusion duration (originally done as a continuous infusion) or more frequent dosing resulted in improved outcomes7 and 8; however, the utilization of prolonged or continuous infusion has remained a matter of debate and much research has been undertaken to understand and justify these dosing strategies.

### THERAPEUTIC CONCENTRATIONS

With increasing antimicrobial resistance and limited novel antimicrobials on the horizon, a resurgence of interest in optimizing currently available treatment options has occurred. The potency of an antimicrobial is measured as the lowest concentration that inhibits visible bacterial growth, also known as the minimum inhibitory concentration (MIC). While in vitro potency is relatively straightforward, in vivo potency is much more complex and is described using pharmacodynamics. The pharmacodynamic parameter for beta-lactams that best correlates with efficacy is the percentage of the dosing interval that free drug concentration remains above the MIC (fT>MIC)9. Thus, the optimization of beta-lactam therapy relies on the duration of exposure (i.e., time-dependent) to maximize fT>MIC (Figure 3-1).

###### FIGURE 3-1

Beta-lactam in vivo efficacy is best predicted by the percentage of the dosing interval that free drug concentrations remains above the MIC (fT>MIC).

Three factors affect the clinical outcome of the patient: the patient, the bug, and the drug. Of these factors, the drug is the only one that is easily modified, and the various methods to achieve maximal fT>MIC include administering doses more frequently, administering higher doses, or changing the infusion duration. Dose escalation strategies add little additional benefit in optimizing the drug exposures and are not cost effective when the overall drug cost is often doubled. However, decreasing the dosing interval or increasing the length of infusion can have a considerable impact on fT>MIC (Figure 3-2). When designing dosing regimens to optimize beta-lactam therapy, it is important to consider what fT>MIC are required to maximize antibacterial activity, and these targets vary by class of beta-lactam. In general, maximal efficacy, often denoted as a 2-log decrease in bacterial density, requires a fT>MIC of 40 percent for carbapenems, 50 percent for penicillins, and 50–70 percent for cephalosporins; whereas, the fT>MIC for stasis (i.e., no bacterial killing or growth) is 20 percent for carbapenems, 30 percent for penicillins, and 40 percent for cephalosporins.10, 11...

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