Ibrahim Khalid H, Gunderson Brent W, Hermsen Elizabeth D, Hovde Laurie B, Rotschafer John C
Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 7-170 Weaver-Densford Hall, 308 Harvard St. SE, Minneapolis, MN 55455, USA.
Antimicrob Agents Chemother. 2004 Nov;48(11):4195-9. doi: 10.1128/AAC.48.11.4195-4199.2004.
Pulse dosing is a novel approach to dosing that produces escalating antibiotic levels early in the dosing interval followed by a prolonged dose-free period. Antibiotic is frontloaded by means of four sequential bolus injections, after which antibiotic levels are allowed to diminish until the next dose. This study compares standard thrice-daily dosing and pulse dosing of metronidazole against Bacteroides spp. in an in vitro model. Two American Type Culture Collection Bacteroides fragilis isolates (metronidazole MIC for each organism = 1 mg/liter) were exposed to metronidazole for 48 or 96 h. Human pharmacokinetics were simulated for an oral 500-mg dose given every 8 h (maximum concentration of drug [C(max)] = 12 mg/liter; half-life = 8 h; area under the curve [AUC] = 294 mg . h/liter) and for pulse dosing. Pulses, each producing an increase in metronidazole concentration of 9 mg/liter, were administered at times 0, 2, 4, and 6 h of each 24-h cycle, with a targeted half-life of 8 h (AUC = 347 mg . h/liter). A metronidazole-resistant B. fragilis strain (metronidazole MIC = 32 mg/liter) was exposed to both dosing regimens and, additionally, to a regimen of 1,500 mg administered once daily (C(max) = 36 mg/liter; AUC = 364 mg . h/liter). Furthermore, regimens against one B. fragilis isolate and one B. thetaiotaomicron isolate corresponding to one-fourth and one-eighth of the thrice-daily and pulse dosing regimens, mimicking peak metronidazole concentrations achieved in abscesses, were simulated in 48-h experiments (metronidazole MIC = 1 mg/liter). Time-kill curves were generated for each experiment and analyzed for bactericidal activity, defined as a bacterial burden reduction >/= 3 log(10) CFU/ml. The results of paired (Wilcoxon matched-pair signed-rank test) and nonpaired (Mann-Whitney test) statistical analyses conducted on time to 3 log(10) kill data and area under the kill curve data from each of the thrice-daily dosing experiments versus each of the pulse dosing experiments were considered not significant for a given isolate-dosing regimen combination. The thrice-daily dosing, pulse dosing, and once-daily dosing regimens all exhibited bactericidal activity. Metronidazole administered in standard or pulse dosing fashion was highly active against both susceptible and resistant strains of Bacteroides spp.
脉冲给药是一种新型给药方法，在给药间隔早期可使抗生素水平逐步升高，随后是较长的无药期。抗生素通过四次连续推注进行前期加载，之后让抗生素水平下降直至下一次给药。本研究在体外模型中比较了甲硝唑针对拟杆菌属的标准每日三次给药和脉冲给药。将两株美国典型培养物保藏中心脆弱拟杆菌分离株（每种菌株的甲硝唑最低抑菌浓度[MIC]=1毫克/升）暴露于甲硝唑48或96小时。模拟了口服500毫克剂量每8小时给药一次（药物最大浓度[C(max)]=12毫克/升；半衰期=8小时；曲线下面积[AUC]=294毫克·小时/升）以及脉冲给药的人体药代动力学情况。在每个24小时周期的0、2、4和6小时给予脉冲剂量，每次使甲硝唑浓度增加9毫克/升，目标半衰期为8小时（AUC=347毫克·小时/升）。一株耐甲硝唑的脆弱拟杆菌菌株（甲硝唑MIC=32毫克/升）暴露于两种给药方案，另外还暴露于每日一次给予1500毫克的方案（C(max)=36毫克/升；AUC=364毫克·小时/升）。此外，在48小时实验中模拟了针对一株脆弱拟杆菌分离株和一株多形拟杆菌分离株的给药方案，分别相当于每日三次给药方案和脉冲给药方案的四分之一和八分之一，模拟脓肿中达到的甲硝唑峰值浓度（甲硝唑MIC=1毫克/升）。为每个实验绘制时间 - 杀菌曲线，并分析杀菌活性，杀菌活性定义为细菌载量降低≥3 log(10)CFU/毫升。对每个每日三次给药实验与每个脉冲给药实验的达到3 log(10)杀灭所需时间数据和杀菌曲线下面积数据进行配对（Wilcoxon配对符号秩检验）和非配对（Mann - Whitney检验）统计分析，结果表明对于给定的分离株 - 给药方案组合不具有显著性。每日三次给药、脉冲给药和每日一次给药方案均表现出杀菌活性。以标准或脉冲给药方式给予的甲硝唑对拟杆菌属的敏感和耐药菌株均具有高度活性。
