IngentaConnect Pulsatile delivery of amoxicillin against Streptococcus pneumonia...

Abstract:

Objective: 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.

Methods: In vitro pharmacodynamic models with initial inocula of 6 log<inf>10</inf> 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<inf>1/2</inf> of 1 h was simulated for all experiments. Bacterial density was quantified over 96 h.

Results: 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 sim

1 log<inf>10</inf> cfu/mL kill with regrowth to growth control levels at 24 h but was immediately followed by a rapid sim

2 log<inf>10</inf> 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.

Conclusion: 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.

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Pulsatile delivery of amoxicillin against Streptococcus pneumoniae