Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR)

Abstract

Background: Beta-lactam antibiotics (βLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients.

Methods: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations.

Results: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding βLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of βLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement.

Conclusions: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering βLA in critically ill patients.

Keywords: Beta-lactam antibiotics; Continuous infusion; Dosage; Pharmacodynamics; Pharmacokinetics; Therapeutic drug monitoring.

Fig. 1

Simulated plasma concentrations obtained for a 12 g piperacillin daily dose delivered as intermittent administrations (IA, right) or continuous infusion without (CI, left) or with a loading dose (Bolus+CI, middle). The continuous infusion preceded by a loading dose is the regimen that achieves the greatest % fT ≥ MIC. The trough concentration before the next injection falls below the MIC in the discontinuous administration regimen, while the concentration may remain below the MIC for several hours after the beginning of the infusion in the case of continuous administration without a loading dose.

Fig. 2

Care protocol suggested by the experts (expert opinion, strong agreement). *Taking into account the stability of the administered beta-lactam after its reconstitution, i.e., using several syringes continuously infused IV per day