Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients

Background: The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk fac-tors for failure to achieve target concentrations.Patients and methods: Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of >= 1 and >= 2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT >= 1MIC, 50%fT >= 2MIC).Results: There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) pa-tients met the target of 50%fT >= 2MIC and 95 (95%) patients met the target of 50%fT >= 1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median un-bound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flu-cloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P= 0.002]. Younger age and higher creatinine clearance were associated with lower plasma concen-trations.Conclusions: Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.(c) 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.