Tissue and Serum Concentrations of Time-Dependent Antibiotics in Infected Diabetic Foot Ulcers by Bolus or Continuous Administration: The Randomised DFIATIM Trial

Abstract

Aims

The clinical effectiveness of antibiotic (ATB) therapy in patients with infected diabetic foot ulcers (iDFUs) depends on achieving sufficient ATB concentrations in both serum and peripheral tissues. This study evaluated the availability and bactericidal activity of the time-dependent ATBs—ceftazidime (CTZ) and amoxicillin/clavulanate (AMC) in serum and peripheral tissues by comparing bolus versus continuous administration.

Methods

Sixty patients with iDFUs were randomised into four subgroups according to ATB and administration method: CTZ bolus (CTZ_bolus), CTZ continuous infusion (CTZ_continuous), AMC bolus (AMC_bolus), and AMC continuous infusion (AMC_continuous). Once steady-state concentrations were reached, microdialysis was used to assess ATB levels in tissue adjacent to the ulcer. Serum and tissue samples were collected over a 6-h period. Bactericidal activity was assessed by peak concentrations (Cmax), area under the curve (AUC), and the proportion of time free drug concentrations remained above the minimum inhibitory concentration (fT > MIC). Target thresholds were fT > MIC ≥ 60% for CTZ and ≥ 50% for AMC.

Results

All patients achieved serum fT > MIC targets for CTZ and AMC in 100% of AMC_bolus and 89% of AMC_continuous. In tissue, target attainment was 60% (CTZ_bolus), 73% (CTZ_continuous), 79% (AMC_bolus), and 83% (AMC_continuous). Bolus administration led to rapid serum peaks (5 min) and delayed tissue peaks (30–60 min), with subsequent declines. Continuous infusion produced gradual concentration increases over time.

Conclusions

While all patients achieved serum fT > MIC targets for CTZ and AMC (100% for AMC_bolus and 89% for AMC_continuous), target attainment in tissue was substantially lower. These findings suggest that although serum pharmacodynamic targets are reliably achieved, tissue exposure remains suboptimal.