Pulsatile delivery of amoxicillin against Streptococcus pneumoniae.

Abstract

Beta-Lactam antimicrobials are dosed intermittently or continuously based on their short half-lives and concentration-independent activity. Based on the relationship between antimicrobial killing and bacterial growth cycle, the pharmacodynamics of a unique pulsatile strategy was investigated. In vitro pharmacodynamic models with initial inocula of 6 log(10) cfu/mL were utilized to simulate amoxicillin regimens against two Streptococcus pneumoniae isolates: 16891 (MIC = 4 mg/L) and ATCC 49150 (MIC = 0.016 mg/L). Time-kill profiles of pulsatile dosing of amoxicillin (total daily dose fractionated equally and given at 0, 2, 4 and 6 h for each 24 h cycle) were compared with regimens of every 8 h and every 12 h with the same 24 h drug exposure. Each regimen targeted cumulative peak concentrations of 30, 15 and 5 mg/L for each 24 h cycle. A t(1/2) of 1 h was simulated for all experiments. Bacterial density was quantified over 96 h. Against 16891, every 8 h and every 12 h regimens exhibited minimal bacterial kill at all dosing levels. In contrast, pulsatile dosing at 30 mg/L/24 h resulted in an initial modest approximately 1 log(10) cfu/mL kill with regrowth to growth control levels at 24 h but was immediately followed by a rapid approximately 2 log(10) cfu/mL kill by 32 h. This pattern of kill and regrowth repeated at the same magnitude for each 24 h cycle for the 96 h study duration. Against the susceptible strain (ATCC 49150), both pulse and traditional dosing of amoxicillin resulted in rapid and significant kill to our detection limits for the entire study duration. A pattern of kill and regrowth was only observed at the lowest dose (0.05 mg/L) against ATCC 49150. At therapeutic levels, all regimens rapidly achieved undetectable limits against this strain for the study duration. No significant alterations in post-exposure MICs were noted. Overall bacterial density reduction was similar between the regimens for the susceptible isolate and greater with pulsatile regimens against the less susceptible strain. Pulsatile dosing, which involves administration of the total daily dose over the first 6 h of the day, may represent a unique and alternative strategy for dosing beta-lactam antimicrobials.