Update on Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Critically Ill Patients—A Narrative Review

Abstract

Beta-lactam antibiotics remain one of the most preferred groups of antibiotics in critical care due to their excellent safety profiles and their activity against a wide spectrum of pathogens. The cornerstone of appropriate therapy with beta-lactams is to achieve an adequate plasmatic concentration of a given antibiotic, which is derived primarily from the minimum inhibitory concentration (MIC) of the specific pathogen. In a critically ill patient, the plasmatic levels of drugs could be affected by many significant changes in the patient’s physiology, such as hypoalbuminemia, endothelial dysfunction with the leakage of intravascular fluid into interstitial space and acute kidney injury. Predicting antibiotic concentration from models based on non-critically ill populations may be misleading. Therapeutic drug monitoring (TDM) has been shown to be effective in achieving adequate concentrations of many drugs, including beta-lactam antibiotics. Reliable methods, such as high-performance liquid chromatography, provide the accurate testing of a wide range of beta-lactam antibiotics. Long turnaround times remain the main drawback limiting their widespread use, although progress has been made recently in the implementation of different novel methods of antibiotic testing. However, whether the TDM approach can effectively improve clinically relevant patient outcomes must be proved in future clinical trials.

Beta‐lactam antibiotic concentrations in critically ill patients with standard and adjusted dosages: A prospective observational study

“…The literature on beta-lactam concentrations and toxicity is heterogeneous, without clearly defined thresholds associated with toxicity but upper limits has been suggested as $35 mg/L for cephalosporins, 130 mg/L for piperacillin/tazobactam and 44 mg/L for meropenem. 25,26 A few patients in our study reached concentrations toward those levels but did not surpass to any larger extent. These patients were given standard or high dosage despite low eGFR and no CRRT, suggesting that increased dosage may be excessive when eGFR is low.…”

Translational PK/PD for the Development of Novel Antibiotics—A Drug Developer’s Perspective

“…These examples highlight that efficacy is influenced by the full concentration-time profile and that translating from nonclinical efficacious exposure to a clinically efficacious dose by achieving a summary PK value bears some risks. Indeed, while for beta-lactamsfT > MICfT > MIC, the nonclinical exposure target has been defined as 50-70% fT > MIC in critically ill patients, a higher exposure of 100% fT > MIC is linked with improved outcomes [104][105][106].…”

Development and Validation of a Capillary Zone Electrophoresis–Tandem Mass Spectrometry Method for Simultaneous Quantification of Eight β-Lactam Antibiotics and Two β-Lactamase Inhibitors in Plasma Samples

“…A good example, is critically ill patients in particular, who are very often affected by receiving insufficient ATB treatment under such regimens [ 4 ]. Special patient groups, including critically ill, obese, or older individuals, typically exhibit an altered volume of distribution, protein binding, clearance, and other pathophysiological changes, making the prediction of antibiotic concentrations challenging [ 5 ]. Additionally, new information indicates a possible correlation between the clinical outcomes of critically ill patients and the serum concentrations of β-lactam ATBs [ 6 ].…”