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

• Published in: Critical care (London, England) Vol. 24; no. 1; pp. 1 - 12
• Main Authors: Abdulla, Alan, Dijkstra, Annemieke, Hunfeld, Nicole G. M, Endeman, Henrik, Bahmany, Soma, Ewoldt, Tim M. J, Muller, Anouk E, van Gelder, Teun, Gommers, Diederik, Koch, Birgit C. P
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 15-09-2020; BioMed Central; BMC
• Subjects: Antibiotics; Beta lactam antibiotics; Beta lactamases; Beta-lactam; Clinical outcomes; Critical care; Critically ill patients; Drug dosages; Epidemiology; Illnesses; Meropenem; Patients; Penicillin; Pharmacodynamics; Pharmacokinetics; Physiological aspects; Plasma; Risk factors; Sample size; Target attainment; Therapeutic drug monitoring
• ISSN: 1364-8535; 1364-8535; 1366-609X; 1466-609X
• DOI: 10.1186/s13054-020-03272-z

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 m
2
, 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.