An evaluation of risk factors to predict target concentration non-attainment in critically ill patients prior to empiric β-lactam therapy

Abstract

To determine whether target concentration non-attainment can be anticipated in critically ill patients prior to initiating empiric β-lactam antibiotic therapy based on readily available clinical factors. Retrospective review of consecutive patients treated with piperacillin or meropenem and who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015 was performed. Predefined subgroups were patients who received continuous renal replacement therapy (CRRT) and those who did not (non-CRRT). Potential risk factors were evaluated by correlation with β-lactam antibiotic trough concentrations (C) lower than or equal to targeted minimum inhibitory concentration (MIC). Only the first drug concentration after initiation of the antibiotic treatment was included to reflect empirical dose selection. A total of n = 249 patients (piperacillin, n = 169; meropenem, n = 80) were investigated. For non-CRRT patients (n = 210), multivariate analysis demonstrated the following: male gender (p = 0.006); younger age (p = 0.015); prescribed daily antibiotic dose less than 1.5 times the product information recommendations (p = 0.004); lack of positive microbiology (p = 0.006); lower overall illness severity (p = 0.005); and estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m (p < 0.001), to be associated with C ≤ MIC. No predictor variable was found to be significantly associated with C ≤ MIC for the CRRT cohort. Evaluating the risk of target concentration non-attainment using simple clinical factors is possible at the bedside for non-CRRT patients prior to empiric antibiotic initiation. Clinicians should be wary of selecting doses based on the product information especially when treating younger male patients with apparently 'normal' renal function.

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

“…Predictor variables in the multivariate analysis associated with increased odds for target non-attainment were male gender and eGFR ( Table 2). These associations in critically ill patients treated with beta-lactam antibiotics are in line with previous studies [25][26][27].…”

“…This means that patients with presumed "normal" or elevated renal function are at risk of target non-attainment and need to be identified early so that appropriate dose adjustment can be made. Moreover, Imani et al assessed the performance of eGFR as an independent predictor for target non-attainment using a ROC curve and found an eGFR threshold value of ≥ 71.5 mL/min/1.73 m 2 had a sensitivity and specificity of 77% and 65%, respectively [26]. As beta-lactam antibiotics are predominantly cleared by the kidney, high renal function (eGFR ≥ 130 mL/min), as observed in augmented renal clearance (ARC), contributes even more to suboptimal PK/PD target attainment.…”

“…We defined ICU length of stay (LOS) and 30-day survival from the start of therapy (enrollment) as our secondary endpoints. Factors likely to contribute to these two outcomes were analyzed for association based on clinical relevancy and previously described relationships [14,[24][25][26][27]. These included patient characteristics (age, gender, body mass index (BMI)), illness severity score (Sequential Organ Failure Assessment (SOFA) score at the start of target antibiotic), serum albumin, serum urea, sepsis, estimated glomerular filtration rate (eGFR ≥ 90 mL/min/1.73 m 2 ), and presence of continuous renal replacement therapy (CRRT).…”

“…To our knowledge, only a few other studies have attempted to quantify patient characteristics as potential predictors for beta-lactam antibiotics target attainment in critically ill patients [14,[24][25][26][27]. In some of these studies, limited numbers of patients and/or different beta-lactam antibiotics were investigated, while in only two of these studies, target attainment and relevant factors associated with clinical outcomes were investigated [24,27].…”

Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness—Experience and Recommendations from One Year in Routine Clinical Practice

“…To the best of our knowledge, this is one of the largest retrospective analyses of routine beta-lactam TDM in intensive care patients [27][28][29]. Many societies and authors recommend a daily TDM of beta-lactams in critically ill patients [16,25,28,30]. In this study, we examined for whom daily TDM is necessary, for whom a short infusion-dosing regimen is suitable, and which patients need other dosing strategies.…”