The Current Status and Future Perspectives of Beta-Lactam Therapeutic Drug Monitoring in Critically Ill Patients

Abstract

Beta-lactams (BL) are the first line agents for the antibiotic management of critically ill patients with sepsis or septic shock. BL are hydrophilic antibiotics particularly subject to unpredictable concentrations in the context of critical illness because of pharmacokinetic (PK) and pharmacodynamics (PD) alterations. Thus, during the last decade, the literature focusing on the interest of BL therapeutic drug monitoring (TDM) in the intensive care unit (ICU) setting has been exponential. Moreover, recent guidelines strongly encourage to optimize BL therapy using a PK/PD approach with TDM. Unfortunately, several barriers exist regarding TDM access and interpretation. Consequently, adherence to routine TDM in ICU remains quite low. Lastly, recent clinical studies failed to demonstrate any improvement in mortality with the use of TDM in ICU patients. This review will first aim at explaining the value and complexity of the TDM process when translating it to critically ill patient bedside management, interpretating the results of clinical studies and discussion of the points which need to be addressed before conducting further TDM studies on clinical outcomes. In a second time, this review will focus on the future aspects of TDM integrating toxicodynamics, model informed precision dosing (MIPD) and “at risk” ICU populations that deserve further investigations to demonstrate positive clinical outcomes.

The Subcutaneous Administration of Beta-Lactams: A Case Report and Literary Review—To Do Small Things in a Great Way

“…Unfortunately, in this particular case, we did not achieve microbiological isolation, which precluded us from conducting a precise assessment of the T/MIC. Nevertheless, when considering one of the worst-case scenarios, 16 mg/L, corresponding to the ECOFF of Pseudomonas aeruginosa, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), as a surrogate MIC value [22,23], we observed that, in the initial measurement, piperacillin blood concentrations exceeded the presumed MIC for the suspected bacterium but fell slightly below the PD target of four times the MIC (64 mg/L) specified for beta-lactams [24,25]. However, 7 days and 10 days from the initiation of antibiotic treatment, piperacillin blood concentrations were substantially superior to the PD target, by four times compared to the MIC.…”

Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting

“…In fact, our study revealed overestimation and mediocre performance of the respective model in the investigated critically ill patients (A/B1/B2: MPE 24.9/18.6/22.8%; MAPE 43.5/34.6/36.9%). Thus, it can only be speculated whether model selection had a relevant influence on the study results, also because the trial included several β-lactams, whereas our study included only PIP [ 22 , 47 , 48 ]. However, both studies combined highlight the key role of externally evaluating PopPK models prior to clinical implementation.…”

“…However, the unbound fraction may vary in critically ill patients, and possible skewing of the results can therefore not be excluded [ 27 , 32 , 51 ]. Sixth, our study exemplarily followed a recommended PIP c target of 64 mg/L, but for β-lactams “the optimal PK/PD target remains debated” according to Novy et al [ 47 ]. A range of 32–96 mg/L was considered acceptable.…”

Real-Time Monitoring of Antibiotics in the Critically Ill Using Biosensors

“…In response to the difficulty in accurately dosing antibiotics, therapeutic drug monitoring (TDM) has become the standard of care for many antibiotics, including vancomycin, aminoglycosides, and linezolid and increasingly being considered for beta lactam antibiotics [2]. With this approach, knowledge of a drug's plasma concentration is used to inform future drug dosing.…”