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)

Guilhaumou, Romain; Benaboud, Sihem; Bennis, Youssef; Dahyot-Fizelier, Claire; Dailly, Eric; Gandia, Peggy; Goutelle, Sylvain; Lefeuvre, Sandrine; Mongardon, Nicolas; Roger, Claire; Scala-Bertola, Julien; Lemaitre, Florian; Garnier, Marc

doi:10.1186/s13054-019-2378-9

Critical Care

Table 2 Target trough total (Cmin) or free (fCmin) plasma concentration following intermittent administration and target total (Css) or free (fCss) steady-state plasma concentration following continuous administration for the main beta-lactam antibiotics

From: 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)

	Free fraction (%)	Recommended target concentrations^#		MIC threshold^£ [130]	Ref.
	Free fraction (%)	Documented infection	Non-documented infection	MIC threshold^£ [130]	Ref.
Amoxicillin	≈ 80%	fCmin or fCss ≥ 4× MIC Cmin or Css < 80 mg/L	Cmin 40–80^*mg/L^§ Css 40–80 mg/L	8 mg/L (ECOFF E. coli)	[131]
Cefazolin	≈ 15–20%	fCmin or fCss ≥ 4× MIC Cmin or Css < 80 mg/L	Cmin 40–80 mg/L^§ Css 40–80 mg/L	2 mg/L (ECOFF S. aureus)	[132]
Cefepime	80%	fCmin or fCss ≥ 4× MIC Cmin < 20 mg/L Css < 35 mg/L	Cmin 5–20 mg/L Css 5–35 mg/L	1 mg/L (Enterobacteriaceae)^§§	[21, 72, 73]
Cefotaxime	≈ 60–80%	fCmin or fCss ≥ 4× MIC Cmin or Css < 60 mg/L	Cmin 25–60 mg/L Css 25–60 mg/L	4 mg/L (ECOFF S. aureus)	[133]
Ceftazidime	≈ 90%	fCmin or fCss ≥ 4× MIC Cmin or Css < 80 mg/L	Cmin 35–80 mg/L^§ Css 35–80 mg/L	8 mg/L (ECOFF P. aeruginosa)	[77]
Ceftriaxone	≈ 10%	fCmin ≥ 4× MIC Cmin < 100 mg/L	Cmin 20–100 mg/L	0.5 mg/L (ECOFF E. cloacae)	[129]
Cloxacillin	≈ 10%	fCmin or fCss ≥ 4× MIC Cmin ou Css < 50 mg/L	Cmin 20–50 mg/L^§ Css 20–50 mg/L	0.5 mg/L (ECOFF S. aureus)	[131]
Ertapenem	≈ 10%	fCmin ou fCss ≥ 4× MIC Cmin < 10 mg/L	Cmin 5–10 mg/L	0.125 mg/L (H. influenzae)^§§§	[117, 134]
Imipenem	≈ 80%	fCmin ≥ 4× MIC Cmin < 5 mg/L	Cmin 2.5–5 mg/L	0.5 mg/L (ECOFF E. coli)	[135]
Meropenem	≈ 100%	fCmin ou fCss ≥ 4× MIC Cmin ou Css < 16 mg/L	Cmin 8–16 mg/L^§ Css 8–16 mg/L	2 mg/L (ECOFF P. aeruginosa)	[136]
Piperacillin	≈ 80%	fCmin ou fCss ≥ 4× MIC Css < 160 mg/L	Css 80–160 mg/L	16 mg/L (ECOFF P. aeruginosa)	[75]

£The Minimum Inhibitory Concentration (MIC) threshold was chosen by considering the treatment with beta-lactam antibiotics either (i) during the empirical phase or (ii) in the case of no microbiological documentation, when the beta-lactam antibiotic administered is the object of a clinical bet to cover a maximum of the bacterial species usually identified in the considered infection
#The highest values of the targets should be considered for infections of tissues in which beta-lactam diffusion is reduced (endocarditis, infection of prosthetic material, mediastinitis, etc.)
*The target trough free plasma concentration of four to eight times the MIC is 32 to 64 mg/L considering a MIC threshold set at 8 mg/L (E. coli Epidemiological Cut-OFF (ECOFF) for amoxicillin). As the free fraction is about 80% of the total dose, the target trough total plasma concentration is estimated at 40 to 80 mg/L. The same calculation has been made for all the other beta-lactam antibiotics taking into account their binding to plasma proteins and the considered MIC threshold
§In this situation, the minimal target trough plasma concentration is difficult to achieve by intermittent administration, encouraging to prefer a continuous administration in order to reach this target
§§ The highest ECOFF value (8 mg/L for P. aeruginosa) was not considered to calculate the target plasma concentration, since this would have resulted in a concentration above the clinically defined toxic threshold. To be consistent with the maximal plasma concentrations that could be achieved without neurological toxic effect [21, 72, 73], the clinical breakpoint for Enterobacteriaceae (1 mg/L, which is the higher ECOFF value except for P. aeruginosa) was considered to estimate the target
§§§ The highest ECOFF value (1 mg/L for S. aureus) was not considered to calculate the target plasma concentration, since this would have resulted in a concentration not consistent with the plasma concentrations usually reported [117, 134]. To be consistent with the plasma concentrations usually reported in the literature, the clinical breakpoint for H. influenzae (0.125 mg/L, which is the higher ECOFF value except for S. aureus) was considered to estimate the target

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