In vivo efficacy of humanised intermittent versus continuous ceftazidime in combination with tobramycin in an experimental model of pseudomonal pneumonia

In this study, we compared the efficacy of ceftazidime (CAZ) intermittent versus continuous infusion with or without tobramycin (TOB) for the treatment of pneumonia caused by Pseudomonas aeruginosa in rabbits. Treatments were humanised and mimicked intermittent CAZ (iCAZ) (2 g three times daily), continuous CAZ (cCAZ) (4 g once daily (qd)) and TOB (10 mg/kg qd). Minimum inhibitory concentrations (MICs) were 1 mg/L and 4 mg/L for TOB and CAZ, respectively. Bacterial efficacy in lungs was as follows: control, 9 ± 0.6 colony-forming units (CFU)/g; TOB monotherapy, 8 ± 0.5 CFU/g; iCAZ monotherapy, 7.8 ± 1.4 CFU/g; cCAZ monotherapy, 8 ± 0.4 CFU/g (P = 0.005); and iCAZ + TOB, 8 ± 0.5 CFU/g; cCAZ + TOB, 7.2 ± 0.3 CFU/g (P < 0.05). Bacterial efficacy in the spleen was as follows (% sterile): control, 4 ± 1.6 CFU/g (0%); TOB monotherapy, 1.7 ± 1.2 CFU/g (60%); iCAZ monotherapy, 3.5 ± 0.5 CFU/g (17%); cCAZ monotherapy, 1.5 ± 0.6 CFU/g (75%) (P = 0.02); and iCAZ + TOB, 2.1 ± 0.6 CFU/g (50%); cCAZ + TOB, 1.2 ± 0.3 CFU/g (82%) (P < 0.05). The time the drug concentration was above the MIC (T > MIC) was 62% and 99% for iCAZ and cCAZ, respectively. We conclude that CAZ is more effective when administered continuously, especially for the sterilisation of septicaemia. A synergistic therapeutic effect of the association CAZ + TOB was observed in vivo, which can be explained by the longer T > MIC of cCAZ. These findings suggest that continuous treatment with 4 g CAZ could be appropriate in patients with P. aeruginosa infections.