Pharmacodynamic studies of amoxicillin against Streptococcus pneumoniae: comparison of a new pharmacokinetically enhanced formulation (2000 mg twice daily) with standard dosage regimens

Objectives: To compare the pharmacodynamic effects of a pharmacokinetically enhanced formulation of amoxicillin 2000 mg twice daily, with amoxicillin 875 mg twice daily, 875 mg three times daily and 500 mg three times daily against Streptococcus pneumoniae with different susceptibility to amoxicillin in an in vitro kinetic model. Methods: Strains of S. pneumoniae with amoxicillin MICs of 1, 2, 4 and 8 mg/L at an initial inoculum of approximately 10(5) cfu/mL were exposed to amoxicillin in an in vitro kinetic model simulating the human serum concentration-time profile of the pharmacokinetically enhanced formulation twice daily (C-max 17 mg/L after 1.5 h). All isolates were also exposed to amoxicillin with concentration-time profiles correlating to the human dosage of 875 mg twice daily (C-max 15 mg/L after 1 h), 875 mg three times daily and 500 mg (C-max 8 mg/L after 1 h) three times daily with simulated half-life of 1 h. Repeated samples were taken regularly during 24 h and viable counts were carried out. Results: Overall, the pharmacokinetically enhanced formulation was more effective at reducing bacterial counts than any of the other formulations evaluated. Eradication was achieved with the enhanced formulation for strains with a MIC of less than or equal to2 mg/L, however, regrowth occurred with the other dosing regimens. In the experiments with the strain with a MIC of 4 mg/L, the enhanced formulation kept the bacterial counts less than or equal to10(2) cfu/mL for at least 14 out of 24 h tested. In contrast, none of the other formulations reduced the bacterial counts down to less than or equal to10(2) cfu/mL at any point. None of the regimens was able to eradicate the strain with an MIC of 8 mg/L, even though an initial substantial kill was noted with the enhanced formulation after both doses. The least effective dosage regimen for all strains was 875 mg twice daily