Tam Vincent H, Kabbara Samer, Vo Giao, Schilling Amy N, Coyle Elizabeth A
University of Houston College of Pharmacy, Houston, TX 77030, USA.
Antimicrob Agents Chemother. 2006 Aug;50(8):2626-31. doi: 10.1128/AAC.01165-05.
Aminoglycosides are often used to treat severe infections with gram-positive organisms. Previous studies have shown concentration-dependent killing by aminoglycosides of gram-negative bacteria, but limited data are available for gram-positive bacteria. We compared the in vitro pharmacodynamics of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. Five S. aureus strains were examined (ATCC 29213 and four clinical isolates). Time-kill studies (TKS) in duplicate (baseline inocula of 10(7) CFU/ml) were conducted to evaluate bacterial killing in relation to increasing gentamicin concentrations (0 to 16 times the MIC). Serial samples were obtained over 24 h to quantify bacterial burden. Similar TKS with P. aeruginosa ATCC 27853 were conducted, and the time courses of the all bacterial strains were mathematically modeled for quantitative comparison. A dose fractionation study (using identical daily doses of gentamicin) in an in vitro hollow-fiber infection model (HFIM) over 5 days was subsequently used for data validation for the two ATCC strains. Model fits to the data were satisfactory; r(2) values for the S. aureus and P. aeruginosa ATCC strains were 0.915 and 0.956, respectively. Gentamicin was found to have a partially concentration-dependent killing effect against S. aureus; concentrations beyond four to 8 times the MIC did not result in significantly faster bacterial killing. In contrast, a concentration-dependent profile was demonstrated in suppressing P. aeruginosa regrowth after initial decline in bacterial burden. In HFIM, thrice-daily gentamicin dosing appeared to be superior to once-daily dosing for S. aureus, but they were similar for P. aeruginosa. Different killing profiles of gentamicin were demonstrated against S. aureus and P. aeruginosa. These results may guide optimal dosing strategies of gentamicin in S. aureus infections and warrant further investigations.
氨基糖苷类药物常用于治疗革兰氏阳性菌引起的严重感染。以往研究表明氨基糖苷类药物对革兰氏阴性菌具有浓度依赖性杀菌作用，但针对革兰氏阳性菌的数据有限。我们比较了庆大霉素对金黄色葡萄球菌和铜绿假单胞菌的体外药效学。检测了5株金黄色葡萄球菌（ATCC 29213和4株临床分离株）。进行了一式两份的时间-杀菌研究（TKS）（初始接种量为10(7) CFU/ml），以评估与庆大霉素浓度增加（0至16倍MIC）相关的细菌杀灭情况。在24小时内获取系列样本以量化细菌载量。对铜绿假单胞菌ATCC 27853进行了类似的TKS，并对所有菌株的时间进程进行数学建模以进行定量比较。随后在体外中空纤维感染模型（HFIM）中进行了为期5天的剂量分割研究（使用相同的每日庆大霉素剂量），以对两种ATCC菌株的数据进行验证。数据的模型拟合良好；金黄色葡萄球菌和铜绿假单胞菌ATCC菌株的r(2)值分别为0.915和0.956。发现庆大霉素对金黄色葡萄球菌具有部分浓度依赖性杀菌作用；超过4至8倍MIC的浓度并未导致细菌杀灭明显加快。相比之下，在细菌载量初始下降后抑制铜绿假单胞菌再生长方面呈现出浓度依赖性特征。在HFIM中，对于金黄色葡萄球菌，每日三次给予庆大霉素似乎优于每日一次给药，但对于铜绿假单胞菌两者相似。庆大霉素对金黄色葡萄球菌和铜绿假单胞菌表现出不同的杀菌特征。这些结果可能指导庆大霉素在金黄色葡萄球菌感染中的最佳给药策略，值得进一步研究。
