Study On Flufenamic Acid In Prevention And Treatment Of Drug-resistant Staphylococci Infections And Osteolysis

OBJECTIVEDrug-resistant Staphylococcus infections and osteoclast activation due to infections are major challenges faced by the orthopaedic doctors.It often leads to the formation of bacterial biofilms on implant surfaces and loosening of prostheses.In recent years,due to the prevalence of a large number of drug-resistant Staphylococci and the lack of available new antibiotics,people have paid a high cost in the treatment of various drugresistant bacteria infections.Flufenamic acid,a clinically used non-steroidal antiinflammatory drug,is often used by rheumatoid arthritis patients to relieve pain and inflammation.In this study,we focused on the reuse of flufenamic acid,explored its efficacy in preventing drug-resistant Staphylococcus infection,and further tested its potential to inhibit osteoclast differentiation.METHODS1.Constructing rabbit tibia staphylococcus infection and aseptic inflammation model.Observing the effects of staphylococcal concentration and virulence on bone mass and bone biological characteristics,and compare staphylococcal infection and aseptic inflammation on bone mass and bone biomechanics difference.2.Detecting the minimum effective bacteriostatic concentration and timebactericidal kinetic curve of flufenamic acid against drug-resistant Staphylococcus.Investigating the effect of flufenamic acid on the biofilm formation on the implant surface and observing the changes in the ultrastructure of bacteria.The mechanism of killing drug-resistant Staphylococcus by flufenamic acid was explored.A mouse skin and soft tissue infection model was constructed to investigate the antibacterial effect of flufenamic acid in animals.3.To detect the effects of flufenamic acid on the proliferation,differentiation and bone resorption of osteoclast precursor cells.To explore the mechanism of flufenamic acid inhibiting osteoclast differentiation.Constructing a mouse osteoporosis model and exploring the effect of flufenamic acid in preventing bone loss in animals.RESULTS1.In the model of staphylococcal infection and aseptic inflammation,the effect of staphylococcal infection on bone mass and bone biomechanical characteristics is greater than that of aseptic inflammation.And the greater the virulence of staphylococcus,the higher the density of staphylococcus infection,and the more obviously the bone mass and biomechanical characteristics of tibia decreased.2.In vitro,flufenamic acid can effectively inhibit the growth of resistant Staphylococcus.Even with continuous passage at sublethal concentrations,bacteria are less likely to develop resistance mutations.At the same time,flufenamic acid at antibacterial concentration has almost no proliferative toxicity to animal cells.In addition,flufenamic acid inhibits the expression of bacterial resistance genes,enhances the bactericidal activity of β-lactam antibiotics,and inhibits the synthesis of bacterial walls.For biofilm-associated infections,flufenamic acid also prevents the adhesion of bacteria on the surface of the implant.In vivo,flufenamic acid can alleviate skin and soft tissue infections caused by drug-resistant Staphylococci and reduce the bacterial load.3.In vitro,flufenamic acid inhibits the differentiation of osteoclast precursor cells and reduces their bone resorption.At the same time,it does not induce osteoclast apoptosis.In addition,flufenamic acid inhibits the expression of osteoclast-related genes,affects the signal transduction of the MAPK pathway and reduces the protein level of the transcription factor NFATc1.In vivo,flufenamic acid relieves bone density reduction caused by osteoclast activation and prevents osteoporosis.CONCLUSIONS1.Staphylococcal infection can cause more severe bone loss and changes in bone biomechanical properties compared to aseptic inflammation.When treating staphylococcal infections,especially high-concentration,high-pathogenic bacteria,care must be taken to prevent the occurrence of osteoporosis.2.Flufenamic acid effectively inhibits the infection of resistant staphylococci,enhances the bactericidal effect of β-lactam antibiotics,and further prevents biofilmrelated infections.It is a potential drug for the treatment of resistant staphylococcal infections.3.Flufenamic acid inhibits the differentiation and bone resorption of osteoclast precursor cells,reduces the expression of osteoclast differentiation-related genes,and prevents bone loss caused by osteoclast activation in the body.It is an effective treatment for osteoporosis drug.