Local Application Of Vancomycin In The Prophylaxis And Treatment Of Periprosthetic Joint Infection After Artificial Joint Replacement

Total joint arthroplasty(TJA)surgery is an effective therapeutic method for terminal joint diseases such as degenerative osteoarthropathy,which effectively relieve patients’ pain and rebuild joint function.Periprosthetic joint infection(PJI)is one of the most serious complications after TJA,which not only seriously damages the bone mass and joint function,but also brings heavy medical burden.The main reasons of recurrence and difficulty in controlling for clinical PJI are mature bacterial biofilm,which resisted to mechanical debridement,host immunity and antibiotics.One-stage and two-stage revision arthroplasty are the main treatment options for PJI,but the infection eradication rate remain unsatisfactory.The management of postoperative antibiotics is a key link during either one-stage or twostage revision,especially in the case of the increasing number of multidrug-resistant bacteria.The consensus of 2018 Philadelphia International Conference proposed that the minimum biofilm eradication concentration(MBEC)was several orders of magnitude(about 100 to 1000 times)above minimum inhibitory concentration(MIC),which could be a better indicator of anti-biofilm activity than MIC of planktonic bacteria.The concentrations of systemic antibiotic intravenously resulted in the synovial fluid could generally reach 2-3 times of MIC.However,increasing the duration,dosage,and concentration of systemic antibiotics may increase the incidence of drug adverse effects and lead to the formation of resistant bacterial strains.Therefore,to improve the concentration of antibiotics in surgical site tissues in order to treat infection and reduce the complications effectively,scholars promoted the adoption of unique strategies to improve the prognosis of PJI.Local application of antibiotics may be one of the effective ways to provide adequate MEBC presently.Topical high levels of antibiotics are critical for infection prophylactics after TJA or revision arthroplasty after PJI.Gram-positive bacteria such as staphylococcus is the major pathogenic bacteria of PJI.The proportion of methicillin-resistant staphylococcus increased year by year due to bacterial variation and antibiotic resistance.Vancomycin has a broad spectrum of antibacterial activities against Gram-positive bacteria,especially those of methicillinresistant staphylococcus,which is considered as the primary intravenous systemic antibiotics for the prevention and treatment of methicillin-resistant staphylococcus.In the past few years,some orthopedists had tried to apply vancomycin(powder or injection)locally in clinical TJA surgery or PJI revision arthroplasty to explore the effects in the prophylaxis and treatment of PJI and obtain some inspiring clinical results.Local vancomycin application has not been rarely reported to lead to aseptic incision complications,poor antimicrobial effects,changes of microbial spectrum and drug toxicity.Moreover,the data above were from retrospective studies,or even case reports and experience sharing.there was no standardized studies and evaluations of the effectiveness,dosage and safety of local vancomycin administration in perioperative period of PJI.Herein,this study established a total knee arthroplasty(TKA)rat models in order to mimic clinical TKA surgery,and the acute and chronic PJI rat models were established.Based on the above TKA rat model,the efficacy,dosage and safety of intra-articular use of vancomycin powder for infection prophylactics after TKA surgery.The safety and efficacy of local vancomycin application were evaluated respectively in the established acute and chronic PJI rat models compared with systemic vancomycin.This study evaluated the efficacy and safety of local use of vancomycin after artificial joint arthroplasty and PJI revision surgery from the perspective of improving vancomycin levels in surgical site,in order to provide theoretical and experimental basis for clinical formulation of antibiotic management plan in joint replacement or revision arthroplasty.Part Ⅰ Intra-articular vancomycin for the prophylaxis of periprosthetic joint infection caused by methicillin-resistant S.aureus after total knee arthroplasty in a rat model: the dosage,efficacy,and safetyObjective Although intra-articular vancomycin powder(VP)is sometimes applied before the closure of the incision to prevent periprosthetic joint infection(PJI)after joint replacement,the dosage,efficacy and safety remain controversial.This study aimed to explore the dosage,efficacy,and safety of intra-articular VP in the prophylaxis of infection after total knee arthroplasty(TKA)in a rat model.Methods Rats were divided into 5 groups after receiving TKA surgery: Control(without systemic or local antibiotics);SV(systemic vancomycin;88mg/kg,intraperitoneal injection,equal to 1g in a patient weighted 70 kg,30 min pre-surgery,single dosage);VP0.5,VP1.0 and VP2.0(intra-articular vancomycin powder;44 mg/kg,88 mg/kg,and 176 mg/kg,equal to 0.5 g,1.0 g and 2.0 g in a patient weighted 70 kg,respectively,before closure of the capsule intraoperative,single dosage).All animals were inoculated in the knee joint cavity with methicillin-resistant S.aureus(MRSA) before the closure of capsule.General status,serum biomarkers,inflammation of the surrounding tissue,radiology,microbiological assay and histopathological tests were assessed within 14 days post-operatively.Results No post-surgery deaths,incision complications and signs of obvious vancomycin toxicity were observed.Compared with the Control and SV groups,bacterial counts,knee-width,tissue inflammation,and osteolysis were reduced in the VP0.5,VP1.0 and VP2.0 groups,without notable bodyweight loss and incision complications.Among all the VP groups,VP1.0 and VP2.0 groups presented superior outcomes in the knee-width and tissue inflammation than the VP0.5 group.Microbial culture indicated that no MRSA survived in the knee of VP1.0 and VP2.0 groups,while bacteria growth was observed in VP0.5 group.No obvious changes in the structure and functional biomarkers of liver and kidney were observed in both SV and VP groups.Conclusion Intra-articular vancomycin powder at the single dosage from 88 mg/kg to 176 mg/kg(equal to 1.0 g ~ 2.0 g in a patient weighted 70 kg)may be more effective and safer than systemic vancomycin in preventing PJI induced by methicillin-resistant S.aureus in the rat TKA model.Part Ⅱ Local application of vancomycin in one-stage revision arthroplasty of acute prosthetic joint infection caused by methicillinresistant S.aureusObjective One-stage revision arthroplasty may be the best option for some acute periprosthetic joint infection(PJI)patients with clear diagnosis of pathogenic bacteria,but the antibacterial management is a key point,especially with the increasing number of multidrug-resistant bacteria.The PJI eradication rate caused by methicillin-resistant S.aureus(MRSA)is still not satisfactory by systemic vancomycin administration in one-stage revision arthroplasty,while long-term use may lead to drug resistance and systemic toxicity.This study aimed to explore the efficacy and safety of intra-articular use of vancomycin in the control of MRSA-PJI after one-stage revision surgery in a rat model.Methods PJI modeling by knee prosthesis implantation and MRSA inoculation,debridement and implant exchange were performed in Wistar rats on days 8 successively to mimic the one-stage revision arthroplasty of clinical PJI cases.Rats was divided into 4 groups after revision:(1)control group(CON;without systemic or local antibiotics);(2)systemic vancomycin group(SV;88mg/kg,equal to 1 g in a 70 kg patient,intraperitoneal injection,every 12 hours post-surgery,consecutive 14 days);(3)intra-articular vancomycin powder group(VP;176 mg/kg,equal to 2.0 g in a patient weighted 70 kg,intra-articular before closure of the capsule intraoperative,single dosage)and(4)intra-articular vancomycin injection group(IAV;44 mg/kg,equal to 0.5 g in a 70 kg patient,intra-articular injection,once a day post-surgery,consecutive 14 days).Detections were performed on days 14 after revision arthroplasty:(1)General status(body weight,body temperature,local temperature around the knee);(2)Serum biochemical markers and serum vancomycin levels;(3)Inflammatory gene expression in periprosthetic tissues;(4)Microbial counts;(5)X-ray and Micro-CT scanning;(6)Prosthesis SEM scanning and evaluation;(7)Histopathology of knee,liver and kidney.Results No post-surgery deaths,incision complications and signs of drug toxicity were observed.No significant difference in body weight and body temperature were observed in the four treatment groups throughout the experiment period.The rats of IAV and VP groups showed a better outcome in local skin temperature,bacterial counts,biofilm on the prosthesis,serum inflammatory marker,residual bone volume,and inflammatory reaction in the joint tissues than those with systemic vancomycin and control groups,while rats with IAV administration showed the best outcomes in antiinfection effects compared with VP group.Minimal changes of renal pathology were observed in systemic vancomycin groups,rather than local vancomycin groups,while no obvious changes were observed in the liver,as well as serum markers.Conclusion Local use of vancomycin is effective and safe after one-stage revision surgery in the acute PJI rat model caused by MRSA compared with systemic administration.Rats with IAV administration showed the best outcomes,without any drug toxicity and incision complications.Part Ⅲ Intra-articular versus systemic vancomycin for the treatment of chronic periprosthetic joint infection after debridement and cement spacer implantation in a rat modelObjective Two-stage revision is the gold standard for the treatment of chronic periprosthetic joint infections(PJI).Treatment outcomes for PJI induced by methicillinresistant S.aureus(MRSA)by using systemic vancomycin and antibacterial cement spacers during two-stage revision arthroplasty remain unsatisfactory.This study explored the efficacy and safety of intra-articular(IA)vancomycin injections for PJI controlling after debridement and cement spacer implantation in a rat model.Methods 1 g,2 g and 4 g vancomycin powder were added into 40 g acrylic bone cement respectively for making antibiotic bone cement in vitro experimental samples and performing the studies of in vitro mechanics,elution and antibacterial properties,in order to select the best vancomycin concentration in acrylic bone cement for animal experiment.Wistar rats underwent total knee arthroplasty surgery and MRSA inoculation in the knee cavity.Microbial culture and related identification were confirmed that the PJI model was successfully established on post-surgery days 14.Debridement and cement spacer implantation was performed successively in rats to mimic first-stage treatment procedure of the two-stage revision arthroplasty.Rats was then divided into 4 groups:(1)control(antibiotic-free cement spacer;without systemic or local antibiotics);(2)vancomycin-cement spacer(the above best vancomycin concentration in bone cement;without systemic or local antibiotics);(3)vancomycincement spacer(the above best vancomycin concentration in bone cement)and systemic vancomycin(88 mg/kg,equal to 1 g in a 70 kg patient,intraperitoneal injection,every 12 hours,consecutive 14 days);(4)vancomycin-cement spacer(the above best vancomycin concentration in bone cement)and intra-articular vancomycin injection(44 mg/kg,equal to 0.5 g in a 70 kg patient,intraperitoneal injection,once a day,consecutive 14 days).Vancomycin was administered intraperitoneally or intra-articular injection for 2 weeks to control the infection after debridement and spacer implantation.After 2 weeks of treatment,relevant tests were performed:(1)general status(body weight,body temperature,weight-bearing activities of affected limb);(2)Blood biochemical marker;(3)Inflammatory gene expression of periprosthetic tissues;(4)Microbiological analysis;(5)X-ray and Micro-CT scan of knee joint;(6)Scanning electron microscope of cement spacer;(7)Histopathology of knee bone,soft tissue,liver and kidney.Results The compressive strength of tested vancomycin cement was all above 70 MPa,and in vitro release and antibacterial effect increased with vancomycin concentration of cement.The cement spacer contained(10 wt%)vancomycin was selected and made for animal in vivo experiment.Rats receiving intra-articular vancomycin injection showed the best outcomes among the 4 treatment groups,with negative bacterial cultures,increased weight gain,increased capacity for weight-bearing activities,increased residual bone volume preservation,and reduced inflammatory reactions in the joint tissues,indicating MRSA eradication in the knee.The vancomycin-spacer or/and systemic vancomycin failed to eliminate the MRSA infections following a 2-week antibiotic course.Serum vancomycin levels did not reach nephrotoxic levels in any group.Mild renal histopathological changes,without changes in serum creatinine(Cr)and urea nitrogen(UN)levels,were observed in the systemic vancomycin group compared with the intra-articular vancomycin group,but no changes in hepatic structure or serum alanine aminotransferase(ALT)or aspartate aminotransferase(AST)levels were observed.No local complications were observed,such as sinus tract or nonhealing surgical incisions.Conclusion Intra-articular vancomycin injection was effective and safe for chronic PJI control following debridement and cement spacer implantation in a rat model during two-stage revision arthroplasty,better outcomes than systemic vancomycin administration,without any drug toxicity and incision complications.