Cha Raymond, Rybak Michael J
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences and School of Medicine, Wayne State University, Detroit, MI 48201, USA.
J Antimicrob Chemother. 2004 Dec;54(6):1067-71. doi: 10.1093/jac/dkh452. Epub 2004 Oct 14.
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.
β-内酰胺类抗菌药物因其半衰期短和浓度依赖性活性，给药方式为间歇给药或持续给药。基于抗菌药物杀菌作用与细菌生长周期之间的关系，对一种独特的脉冲给药策略的药效学进行了研究。
采用初始接种量为6 log(10) cfu/mL的体外药效学模型，模拟阿莫西林对两种肺炎链球菌分离株的给药方案：16891（MIC = 4 mg/L）和ATCC 49150（MIC = 0.016 mg/L）。将阿莫西林脉冲给药（每24小时周期的总日剂量平均分为4份，分别在0、2、4和6小时给药）的时间杀菌曲线与每8小时和每12小时给药且24小时药物暴露量相同的给药方案进行比较。每个给药方案在每24小时周期内的累积峰值浓度目标分别为30、15和5 mg/L。所有实验模拟药物半衰期（t(1/2)）为1小时。在96小时内对细菌密度进行定量分析。
对于16891分离株，每8小时和每12小时给药方案在所有给药水平下杀菌作用均极小。相比之下，24小时内30 mg/L的脉冲给药方案最初能使细菌数量适度减少约1 log(10) cfu/mL，但在24小时时细菌数量又恢复到生长对照水平，不过随后在32小时时细菌数量又迅速减少约2 log(10) cfu/mL。在96小时的研究期间，每24小时周期内这种杀菌和再生长的模式以相同幅度重复出现。对于敏感菌株（ATCC 49150），阿莫西林的脉冲给药和传统给药方案在整个研究期间均能迅速且显著地杀菌至检测限以下。仅在针对ATCC 49150的最低剂量（0.05 mg/L）时观察到杀菌和再生长模式。在治疗水平下，所有给药方案在研究期间均能迅速使该菌株的细菌数量降至检测限以下。暴露后最低抑菌浓度（MIC）未观察到显著变化。对于敏感分离株，各给药方案总体细菌密度降低情况相似；而对于较不敏感菌株，脉冲给药方案的杀菌效果更好。
脉冲给药是指在一天的前6小时内给予总日剂量，这可能是一种独特的β-内酰胺类抗菌药物给药替代策略。
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