Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

Abstract

Background: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1-4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.

Methods: This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MIC_ECOFF and ƒT > 4×MIC_ECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.

Results: A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MIC_ECOFF and 36.7% achieved 100%ƒT > 4×MIC_ECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m², and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MIC_ECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.

Conclusions: Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients.

Trial registration: Netherlands Trial Registry (EXPAT trial), NTR 5632 . Registered on 7 December 2015.

Keywords: Beta-lactam; Critically ill patients; Pharmacodynamics; Pharmacokinetics; Risk factors; Target attainment.

Fig. 1

Box (median, 25th and 75th percentiles) and whisker (10th and 90th percentiles) plots of unbound trough (ƒC_min) plasma concentrations observed in critically ill patients treated with beta-lactam antibiotics. The green areas indicate the target exposure (ƒC_min = 1–10×MIC_ECOFF), the blue areas indicate suboptimal exposure (ƒC_min <1×MIC_ECOFF), and the red areas indicate threshold for dose reduction (ƒC_min > 10×MIC_ECOFF). The numbers of trough samples (n) are presented per antibiotic. Outliers are removed using the ROUT method (Q = 0.5%). Filled circles are remaining outliers. *Amoxicillin and amoxicillin/clavulanic acid

Fig. 2

Target attainment in ICU patients for various beta-lactams and dosing regimens to reach the PDTs 100% ƒT > MIC (A1–F1) and 100% ƒT > 4×MIC (A2–F2) for a range of MICs. The numbers of patients (n) are presented per antibiotic and dose regimen. The dotted horizontal line indicates the intercept with the EUCAST epidemiological cut-off (ECOFF) breakpoints: amoxicillin 8 mg/L (Enterobacterales), cefotaxime 4 mg/L (Staphylococcus aureus), ceftazidime 8 mg/L (Pseudomonas aeruginosa), ceftriaxone 0.5 mg/L (Enterobacterales), cefuroxime 8 mg/L (Escherichia coli), and meropenem 2 mg/L (Pseudomonas aeruginosa)