[Importance of local antibiotics in the prophylaxis and treatment of fracture-associated infections]. / Stellenwert lokaler Antibiotika für die Prophylaxe und Therapie frakturassoziierter Infektionen.

BACKGROUND: Fracture-associated infections (FRI) are a severe complication that lead to higher morbidity and high costs for the healthcare system. An effective prophylaxis and treatment of FRI are therefore of great interest. OBJECTIVE: The aim of this review is to summarize the available evidence on the use of local antibiotics for the prophylaxis and treatment of FRI. MATERIAL AND METHODS: A thorough search and a narrative synthesis of the available literature were performed. Their depiction is supplemented by an illustrative presentation of a case report. RESULTS: A robust consensus definition of FRI has existed since 2018. The current use of local antibiotics for the prophylaxis and treatment of FRI in Germany is heterogeneous. There is no consensus on local antibiotic treatment of FRI. The available literature shows an advantage for the additive local antibiotic treatment of open fractures. In closed fractures there is a tendency towards an advantage especially in the presence of further risk factors (long duration of external fixation, higher degree of closed tissue damage, compartment syndrome). According to analogous data from the field of endoprosthetics, additive local antibiotic treatment could also be advantageous under closed soft tissue conditions. The evidence is insufficient to enable the recommendation for a specific antibiotic or a specific mode of application. Local and systemic adverse reactions are frequently discussed in the literature but their incidence is low. CONCLUSION: Overall, additive local antibiotic treatment is to be recommended for open fractures and in closed fractures in the presence of other risk factors. Local and systemic adverse reactions as well as the development of antibiotic resistance must be weighed up in individual cases.

The small-molecule protein ligand interface stabiliser E7820 induces differential cell line specific responses of integrin α2 expression.

BACKGROUND: The mechanism of small-molecule stabilised protein-protein interactions is of growing interest in the pharmacological discovery process. A plethora of different substances including the aromatic sulphonamide E7820 have been identified to act by such a mechanism. The process of E7820 induced CAPERα degradation and the resultant transcriptional down regulation of integrin α2 expression has previously been described for a variety of different cell lines and been made responsible for E7820's antiangiogenic activity. Currently the application of E7820 in the treatment of various malignancies including pancreas carcinoma and breast cancer is being investigated in pre-clinical and clinical trials. It has been shown, that integrin α2 deficiency has beneficial effects on bone homeostasis in mice. To transfer E7820 treatment to bone-related pathologies, as non-healing fractures, osteoporosis and bone cancer might therefore be beneficial. However, at present no data is available on the effect of E7820 on osseous cells or skeletal malignancies. METHODS: Pre-osteoblastic (MC3T3 and Saos-2) cells and endothelial (eEnd2 cells and HUVECs) cells, each of human and murine origin respectively, were investigated. Vitality assay with different concentrations of E7820 were performed. All consecutive experiments were done at a final concentration of 50 ng/ml E7820. The expression and production of integrin α2 and CAPERα were investigated by quantitative real-time PCR and western blotting. Expression of CAPERα splice forms was differentiated by semi-quantitiative reverse transcriptase PCR. RESULTS: Here we present the first data showing that E7820 can increase integrin α2 expression in the pre-osteoblast MC3T3 cell line whilst also reproducing canonical E7820 activity in HUVECs. We show that the aberrant activity of E7820 in MC3T3 cells is likely due to differential activity of CAPERα at the integrin α2 promoter, rather than due to differential CAPERα degradation or differential expression of CAPERα spliceforms. CONCLUSION: The results presented here indicate that E7820 may not be suitable to treat certain malignancies of musculoskeletal origin, due to the increase in integrin α2 expression it may induce. Further investigation of the differential functioning of CAPERα and the integrin α2 promoter in cells of various origin would however be necessary to more clearly differentiate between cell lines that will positively respond to E7820 from those that will not.