Distribution and antimicrobial activity of fosfomycin in the interstitial fluid of human soft tissues.

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.

Serum concentrations of squamous cell carcinoma antigen in patients with vulvar intraepithelial neoplasia and vulvar cancer.

Our aim was to evaluate whether serum concentrations of squamous cell carcinoma antigen (SCC-Ag) are an independent prognostic factor in patients with vulvar cancer. We measured SCC-Ag in pretreatment serum samples of 55 patients with squamous cell vulvar cancer, 30 patients with vulvar intraepithelial neoplasia (VIN) grade III and 50 healthy female controls. The results were compared with clinical data. Median serum concentrations of SCC-Ag in healthy female controls, patients with VIN III, and patients with invasive vulvar cancer were 0.5 (range 0.1 to 3.8) ng/mL, 0.5 (range 0 to 4.1) ng/mL and 1.6 (range 0.3 to 65) ng/mL, respectively (Mann-Whitney U test, p < 0.001). The 75% quantile of serum concentrations of SCC-Ag in patients with vulvar cancer was defined as cut-off level. Elevated pretreatment serum concentrations of SCC-Ag were significantly correlated with a shorter disease-free and overall survival (log-rank test, p=0.002; and p<0.001, respectively). A multivariate Cox regression model showed that serum concentrations of SCC-Ag are a prognostic factor of disease-free and overall survival independent of tumour stage (multivariate Cox regression model, p=0.03; and p=0.048, respectively). Pre-treatment serum concentrations of SCC-Ag were not correlated with tumour stage, histological grade and patients' age. In summary, our data indicate that serum concentrations of SCC-Ag may be an additional independent prognostic factor of disease-free and overall survival in patients with vulvar cancer.