Risk factors for suboptimal target attainment of commonly used ß-lactam antibiotics in older adults: a prospective cohort study

OBJECTIVES: Age-related pathophysiological changes may impact the pharmacokinetics and pharmacodynamics (PK/PD) of ß-lactam antibiotics, potentially resulting in suboptimal concentrations in older adults. This study evaluated PK/PD target attainment with current intravenous amoxicillin-clavulanate and piperacillin-tazobactam dosing regimens in older adults, identified risk factors for target non-attainment, and assessed the prevalence of toxic concentrations. METHODS: This was a prospective, observational PK study in geriatric inpatients (≥75 years) who were treated intravenously with amoxicillin-clavulanate (1 g/0.2 g q6h as a 30-minute infusion) or piperacillin-tazobactam (4 g/0.5 g q6h as a 3-hour infusion). Trough blood samples were collected in steady-state conditions. Target attainment was evaluated against a 100%fT > MIC target. Risk factors for target non-attainment were identified by multivariable logistic regression analysis. Toxicity thresholds were defined as total Cmin concentrations of 80 mg/L for amoxicillin and 157.2 mg/L for piperacillin. RESULTS: Seventy-four patients (median age (IQR): 87 years (83-90)) were included. The PK/PD target was achieved in 15 of 35 and 33 of 39 patients for amoxicillin-clavulanate and piperacillin-tazobactam, respectively. Multivariable logistic regression analysis revealed an effect of comorbidity burden, assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), and estimated glomerular filtration rate that explained 23.8% of target non-attainment (P < 0.05). Receiver operator characteristic curves identified an eGFR of 67 mL/min/1.73m2 as a threshold associated with an increased risk of target non-attainment. Toxicity thresholds were never exceeded in this study. CONCLUSIONS: Health status and renal function, rather than chronological age, play a significant role in target non-attainment among older adults. Further research is required to delineate predictors for interpatient variability in PK and develop evidence-based dosing strategies. TRIAL REGISTRATION: Registration in ClinicalTrials.govTrial registration number: NCT04436991Registration date: 16/06/2020.