Intravenous amoxicillin-sulbactam against Escherichia coli: optimizing the dose, component ratio and infusion time using a human pharmacodynamic model.

Amoxicillin-sulbactam (AMX-SUL) is an aminopenicillin/beta-lactamase inhibitor combination currently available in 29 countries which may be a suitable option for treating intra-abdominal infections. The aim of this study was to identify the optimal dose and ratio between components of this formulation through an ex-vivo human pharmacodynamic model against Escherichia coli. Four volunteers were randomized to receive alternatively a single dose of AM-SUL infused either over 30 min or 3h in the following ratios (g/g): 1/0.5; 1/1, 2/0.5 and 0/2. Time-kill studies were performed with the 0-, 0.5-, 2-, 4-, 6- and 8-h post-dosing sera against E. coli ATCC 25922 (AMX MIC, 2 mu g/mL; AMX-SUL MIC, 2 mu g/mL) and E. coli ATCC 35218 (AMX MIC, 1024 mu g/mL; AMX-SUL MIC, 4-8 mu g/mL). AMX-SUL 1g/0.5g infused over 30 min was only active at 0.5 h after dose, being inferior to both AMX-SUL 1g/1g and AMX-SUL 2g/0.5g against E. coli ATCC 25922, for which the 2h post-dose serum proved active. When tested against E. coli ATCC 35218, AMX-SUL 1g/0.5g and AMX-SUL 2g/0.5g were active only at 0.5h post-dose, whereas AMX-SUL 1g/1g showed bactericidal activity 0.5h post-dose and was able to inhibit bacterial growth 2h post-dose. When infused over 3h, the antimicrobial activity of AMX-SUL was better than the 30-min infusion. Moreover, AMX-SUL 1g/1g was able to inhibit, and kill to some extent, the E. coli ATCC 25922 strain at 4h post-dose (i.e. 67% and 50% of a 6- and 8-h dosing interval, respectively). The present study suggests that 1g/1g is the best formulation for AMX-SUL against E. coli. The infusion over 3h optimizes its pharmacodynamic profile, as well as that of the 1g/0.5g combination. These findings encourage the performance of clinical trials to assess the efficacy of this combination, given as an extended infusion, in the treatment of community-acquired intra-abdominal infections.