Frossard M, Joukhadar C, Erovic B M, Dittrich P, Mrass P E, Van Houte M, Burgmann H, Georgopoulos A, Müller M
Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, University of Vienna Medical School, Vienna, Austria.
Antimicrob Agents Chemother. 2000 Oct;44(10):2728-32. doi: 10.1128/AAC.44.10.2728-2732.2000.
Fosfomycin is a broad-spectrum antibiotic which is established as therapy for uncomplicated lower urinary tract infections. In addition, preliminary data indicate that fosfomycin has a potential role in the treatment of soft tissue infections. However, the use of fosfomycin has not been established for this condition, and it is unclear whether the level of fosfomycin penetration into human soft tissues is high enough to eradicate relevant pathogens. To better characterize the antibiotic potential of fosfomycin, we applied a combined in vivo pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For this purpose fosfomycin concentrations in vivo in the fluid of the interstitial space of human soft tissues were measured by microdialysis following intravenous infusion of 4 or 8 g of fosfomycin (n = 6). Subsequently, bacterial isolates with relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high degree of soft tissue penetration for fosfomycin, with ratios of the area under the concentration-time curve from 0 to 8 h for muscle (AUC(0-8(muscle)))/AUC(0-8(serum)) of 0.48+/-0.08 and 0.53+/-0.04 and ratios of AUC(0-8(adipose tissue))/AUC(0-8(serum)) of 0.74+/-0.12 and 0.71+/-0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with selected isolates of Staphylococcus aureus, Enterobacter cloacae, and Serratia marcescens for which MICs were 16 microg/ml, organisms were undetectable after a single dosing interval. Fosfomycin exhibits a strong ability to penetrate into the fluid of the interstitial space of soft tissues and reaches levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. We therefore conclude that fosfomycin might qualify as an alternative candidate for the therapy of soft tissue infections.
磷霉素是一种广谱抗生素，已被确立为治疗非复杂性下尿路感染的药物。此外，初步数据表明磷霉素在治疗软组织感染方面具有潜在作用。然而，磷霉素在这种情况下的应用尚未确立，并且尚不清楚磷霉素渗透到人体软组织中的水平是否足够高以根除相关病原体。为了更好地描述磷霉素的抗菌潜力，我们对人类志愿者应用了体内药代动力学 - 体外药效学联合模型。为此，在静脉输注4克或8克磷霉素（n = 6）后，通过微透析测量人体软组织间质液中的体内磷霉素浓度。随后，将与软组织感染相关的细菌分离株暴露于根据微透析获得的间质液体内药代动力学曲线得出的浓度下。我们的实验表明磷霉素具有高度的软组织渗透性，给药4克和8克后，肌肉的0至8小时浓度 - 时间曲线下面积比（AUC(0 - 8(muscle))/AUC(0 - 8(serum))）分别为0.48±0.08和0.53±0.04，脂肪组织的AUC(0 - 8(adipose tissue))/AUC(0 - 8(serum))比分别为0.74±0.12和0.71±0.11。在针对金黄色葡萄球菌、阴沟肠杆菌和粘质沙雷氏菌的选定分离株进行的相应体外模拟实验中，这些菌株的最低抑菌浓度（MIC）为16微克/毫升，在单个给药间隔后检测不到这些微生物。磷霉素表现出强大的渗透到软组织间质液中的能力，并达到足以在靶部位基本抑制相关细菌生长的水平。因此，我们得出结论，磷霉素可能有资格作为治疗软组织感染的替代候选药物。
