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.