JAC Advance Access originally published online on October 14, 2004
Journal of Antimicrobial Chemotherapy 2004 54(6):1067-1071; doi:10.1093/jac/dkh452
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JAC vol.54 no.6 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved
Pulsatile delivery of amoxicillin against Streptococcus pneumoniae
1 Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences and 2 School of Medicine, Wayne State University, Detroit, MI, USA
* Correspondence address. Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA. Tel: +1-313-577-4376; Fax: +1-313-577-8915; Email: m.rybak{at}wayne.edu
Objective: ß-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 log10 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 t1/2 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 
1 log10 cfu/mL kill with regrowth to growth control levels at 24 h but was immediately followed by a rapid 2 log10 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 ß-lactam antimicrobials.
Keywords: pharmacodynamics , intermediate resistance , controlled drug release , in vitro models
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