Therapeutic drug monitoring of high-dosage intravenous flucloxacillin and mortality in patients with Staphylococcus aureus bacteremia: a retrospective cohort study using inverse probability weighting.

PURPOSE: Despite the increasing use of TDM, data on its effect on relevant patient outcomes for anti-staphylococcal penicillins (ASPs) remain scarce. METHODS: We performed a retrospective study using data from two Dutch cohorts of patients with Staphylococcus aureus bacteremia (SAB). Patients with MSSA bacteremia who started with the equivalent of flucloxacillin 12 g/24 h within seven days after the first positive blood culture were included. We compared the effects of a TDM-based dosing strategy versus a fixed-dosage strategy during high-dosage flucloxacillin therapy. Primary outcome was 90-day all-cause mortality. Secondary outcomes included incidence of antibiotic-associated adverse events and antibiotic consumption. We fitted a marginal structural model using inverse probability weighting to adjust for confounding (i.e. age, Charlson Comorbidity Index, persistent bacteremia, dominant focus of infection and ICU admission), time-dependent bias and exposure-confounder feedback. RESULTS: We included 285 patients of whom 132 were treated with a TDM-based dosing strategy and 153 with a fixed-dosage strategy. TDM-based dosing was on average associated with a 2.30 gram (95% CI 1.90-2.71) lower daily flucloxacillin dosage than a fixed-dosage regimen. In the TDM group 90-day all-cause mortality was 27% and in the fixed-dosage group 39%. In adjusted analyses, TDM-based dosing was not significantly associated with reduced mortality (HR 0.69, 0.46-1.05) nor with AKI (HR 1.41, 0.89-2.23), DILI (HR 1.79, 0.42-7.68) or hypokalemia (HR 0.90, 0.54-1.48). CONCLUSION: TDM in patients with SAB treated with high-dosage ASPs is associated with lower antibiotic consumption without a statistically significant difference in mortality. We found no evidence of a decrease in antibiotic-associated adverse events.