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 > MICECOFF and ƒT > 4×MICECOFF) 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 > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. 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 > MICECOFF 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.

From Therapeutic Drug Monitoring to Model‐Informed Precision Dosing for Antibiotics

“…TDM is frequently not performed due to logistics, assay unavailability, and the assumption that there is no need for TDM of beta‐lactams, which generally display a wide therapeutic range and favorable safety profile. However, evidence is mounting that TDM of beta‐lactams can be useful also to maximize efficacy, especially in critically ill patients 85 who are prone to inadequate exposure of beta‐lactams. The importance of TDM in maximizing antimicrobial effectiveness and decreasing adverse events has been emphasized also for additional populations with altered PK, e.g., obese, elderly, pregnant, or burns patients, as well as patients with difficult‐to‐treat bone infections 76,86 …”

The Role of Subinhibitory Concentrations of Daptomycin and Tigecycline in Modulating Virulence in Staphylococcus aureus

“…MSSA (10E) also showed that most genes were unaffected upon exposure to sub-inhibitor concentrations of tigecycline. This is a particularly important observation, since a positive gene response to these antibiotics, even at low concentrations, may imply a worse clinical outcome [ 31 ]. It is probable that daptomycin and tigecycline treatment generate signals in diverse physiological pathways, which are recognized by multiple signal sensors that in turn activate multiple response regulators including the genes measured in this study [ 32 ].…”

A guide to therapeutic drug monitoring of β‐lactam antibiotics

“…More recently, a study of 147 ICU patients receiving one of many various β-lactams reported only 63.3% of patients achieved 100% fT>MIC; higher glomerular filtration was an identified risk of non-attainment. 37 Finally, to exemplify a similar concern in pediatrics, 95% of 82 critically ill children receiving a β-lactam did not achieve time above 4-6× MIC for at least 40% of their dosing interval; revised dosing regimens based on initial TDM resulted in target attainment for all patients, and microbiological response was observed in all with confirmed infections. 17 A common theme among many of these studies was that the MIC of the infecting organism was not available; therefore, most studies applied the epidemiological cut-off (ECOFF) or the susceptibility breakpoint of the presumed/identified pathogen.…”