Therapeutic drug monitoring of β-lactam antibiotics

Abstract

Therapeutic drug monitoring (TDM) of antimicrobials is most commonly performed for compounds with narrow therapeutic-toxic windows, like glycopeptides and aminoglycosides. While β-lactam (BL) antibiotics are generally considered to have low toxicity, growing evidence indicates that TDM of BLs is necessary to ensure therapeutic efficacy. BLs are frequently used to treat severe infections in intensive care unit (ICU) patients, where significant pharmacokinetic and pharmacodynamic variability can lead to unpredictable BL concentrations. Despite the increasing amount of literature supporting the relevance of TDM for BLs, its implementation in routine clinical care remains sparse. This presentation will review the current state-of-the-art of TDM for BL, address the challenges associated with BL measurements, and propose potential solutions to address these issues.

A first challenge is the instability of BLs in biological fluids during the pre-analytical phase. For example, meropenem and piperacillin are stable for only 4 hours at room temperature or 6 hours at 4° C. As a result, strict pre-analytical conditions are required, which adds complexity, especially since only a few laboratories perform these measurements. This necessitates sending samples to analyzing labs using non-standard transport methods.

Another challenge is that BLs are primarily administered to critically ill patients, where rapid measurements with short turnaround times are crucial for timely dose adjustments, ultimately leading to better treatment outcomes. However, unlike for the glycopeptides and aminoglycosides, no such straightforward and fast methods are currently available. BLs in plasma are typically measured using in-house developed multi-analyte LC-MS methods.

Furthermore, most labs measure total BL concentrations in plasma rather than unbound (free) concentrations, as the latter require more complex and challenging procedures. However, it is the unbound drug that reaches the site of infection and exerts the pharmacological activity. Measuring free concentrations is particularly important for compounds that are highly-protein bound, such as flucloxacillin and ceftriaxone, where small changes in protein levels can lead to significant changes in free drug concentrations. If the ratio of free versus total concentration remains constant within a patient, total concentrations can serve as surrogate markers. However, this is generally not the case for ICU patients, where substantial variability in protein binding is observed.

In addition to the total versus free debate, it is assumed that tissue concentrations at the site of infection determine the antibiotic efficacy. However, for most infections, obtaining tissue samples at the target site is challenging, and when available, the analytical procedures for measurement of these matrices are far from straightforward. The measurement of BL in abdominal fluid, cerebrospinal fluid and exhaled breath has been described in the literature.

In conclusion, to fully realize the potential of TDM in optimizing BL antimicrobial therapy, accurate, fast, and reliable measurements of (free) concentrations are needed.