Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Antimicrob Agents Chemother. 2013 Apr;57(4):1736-42. doi: 10.1128/AAC.02011-12. Epub 2013 Jan 28.
Although azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC(90) ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.
尽管阿奇霉素被广泛用于治疗呼吸道感染以及皮肤和皮肤相关感染，但阿奇霉素在细胞外空间液（即其治疗靶位之一）中的药代动力学尚未完全阐明。在这项研究中，在治疗第 1 天和第 3 天以及治疗结束后第 2 天和第 7 天，测定了肌肉和皮下脂肪组织细胞外空间、血浆和白细胞中的阿奇霉素浓度-时间曲线。在所有的隔室中，白细胞中的阿奇霉素浓度最高，证明了细胞内的积累。然而，在治疗期间和治疗后，两种软组织中的阿奇霉素浓度均明显低于血浆中的浓度。对选定病原体的 0 至 24 小时（AUC（0-24）/MIC（90）比值的浓度-时间曲线下面积的计算表明，在本研究中测量的阿奇霉素浓度在所有时间点均低于软组织和血浆中观察到的大多数时间点的抑制浓度。因此，可以推测阿奇霉素的临床疗效不仅依赖于升高的细胞内浓度，还可能依赖于其已知的多效性作用，包括免疫调节和对细菌毒力因子的影响。然而，在本研究中观察到的靶位长时间处于亚抑制浓度的阿奇霉素可能有利于细菌耐药性的出现，因此应引起关注。总之，这项研究为广泛使用的抗生素药物阿奇霉素的药代动力学特征提供了重要信息，并凸显了进一步研究其诱导细菌耐药性潜力的必要性。
