Treatment Of Musculoskeletal Infections Research Articles

Bacteriophage therapy in musculoskeletal infections: from basic science to clinical application.

The treatment of musculoskeletal infections (MSIs), including periprosthetic joint infection (PJI) and fracture-related infection (FRI), is often complicated by biofilm-related challenges necessitating multiple revision surgeries and incurring substantial costs. The emergence of antimicrobial resistance (AMR) adds to the complexity of the problem, leading to increased morbidity and healthcare expenses. There is an urgent need for novel antibacterial strategies, with the World Health Organization endorsing non-traditional approaches like bacteriophage (phage) therapy. Phage therapy, involving the targeted application of lytic potent phages, shows promise in the treatment of MSIs. Although historical clinical trials and recent case studies present significant milestones in the evolution of phage therapy over the past century, challenges persist, including variability in study designs, administration protocols and phage selection. Efforts to enhance treatment efficacy consist of personalized phage therapy and combination with antibiotics. Future perspectives entail addressing regulatory barriers, standardizing treatment protocols, and conducting high-quality clinical trials to establish phage therapy's efficacy for the treatment of MSIs. Initiatives like the PHAGEFORCE study and the PHAGEinLYON Clinic programme aim to streamline phage therapy, facilitating personalized treatment approaches and systematic data collection to advance its clinical utility in these challenging infections.

Current developments and future perspectives of nanotechnology in orthopedic implants: an updated review.

Orthopedic implants are the most commonly used fracture fixation devices for facilitating the growth and development of incipient bone and treating bone diseases and defects. However, most orthopedic implants suffer from various drawbacks and complications, including bacterial adhesion, poor cell proliferation, and limited resistance to corrosion. One of the major drawbacks of currently available orthopedic implants is their inadequate osseointegration at the tissue-implant interface. This leads to loosening as a result of immunological rejection, wear debris formation, low mechanical fixation, and implant-related infections. Nanotechnology holds the promise to offer a wide range of innovative technologies for use in translational orthopedic research. Nanomaterials have great potential for use in orthopedic applications due to their exceptional tribological qualities, high resistance to wear and tear, ability to maintain drug release, capacity for osseointegration, and capability to regenerate tissue. Furthermore, nanostructured materials possess the ability to mimic the features and hierarchical structure of native bones. They facilitate cell proliferation, decrease the rate of infection, and prevent biofilm formation, among other diverse functions. The emergence of nanostructured polymers, metals, ceramics, and carbon materials has enabled novel approaches in orthopaedic research. This review provides a concise overview of nanotechnology-based biomaterials utilized in orthopedics, encompassing metallic and nonmetallic nanomaterials. A further overview is provided regarding the biomedical applications of nanotechnology-based biomaterials, including their application in orthopedics for drug delivery systems and bone tissue engineering to facilitate scaffold preparation, surface modification of implantable materials to improve their osteointegration properties, and treatment of musculoskeletal infections. Hence, this review article offers a contemporary overview of the current applications of nanotechnology in orthopedic implants and bone tissue engineering, as well as its prospective future applications.

Local Administration of Antibiotics in Orthopedics and Traumatology.

2022 marks the 50th anniversary of the development of the antibiotic loaded PMMA chain. The loading of bone cements with antibiotics was a major advance in the treatment of musculoskeletal infections and is still a proven standard today. The research and use of novel antibiotic carriers continues to be an important part of research in the context of musculoskeletal infections. The article provides an overview of the various local antibiotics available and their specifics. In addition, current adapted treatment concepts are discussed.

The potential of suspended chitosan nanoparticles as a surgical irrigation fluid.

In this study, we sought to synthesize chitosan nanoparticles (CS-NPs) and characterize their morphology, efficacy in inhibiting bacterial attachment, and efficacy in eradicating bacteria established on implantable hardware. CS-NPs possess desirable properties, including antibacterial properties in biofilm-mediated infections. CS-NPs were produced using ionic gelation and characterized via scanning electron microscope imaging. Staphylococcus aureus was incubated with CS-NPs at various concentrations and compared to a 1% povidone-iodine with 1% H2 O2 control in 24-well plates. Stainless steel bone screws were placed in six-well plates and inoculated with S. aureus. After 24 h, the screws were transferred to one of three solutions (saline, 40 mg/mL CS-NP, or 1% povidone-iodine with 1% H2 O2 ). Four screws from each group were vortexed in saline and plated. The remaining screw from each group was prepped and imaged to map the location of persistent bacteria. Synthesized CS-NPs had a mean diameter of 0.39 ± 0.13 μm and circularity of 0.87 ± 0.05. The percent inhibition of bacterial attachment was 73% at 20 mg/mL, 73% at 30 mg/mL, 75% at 40 mg/mL, 79% at 50 mg/mL, and 78% at 60 mg/mL. When compared to saline, the 40 mg/mL CS-NP solution reduced bacteria on the screws by 76%. No bacteria were retrieved from the 1% povidone-iodine with 1% H2 O2 group. This study demonstrated that CS-NP solution effectively inhibited S. aureus bacterial attachment and was more effective than saline in eradicating bacteria from orthopedic hardware, suggesting that CS-NPs have the potential for prevention and treatment of musculoskeletal infections as a component of an intraoperative surgical irrigation solution.

Evidence for Local Antibiotics in the Prevention of Infection in Orthopaedic Trauma.

Prevention of fracture-related infection (FRI) remains a substantial challenge in orthopaedic trauma care. There is evolving evidence to support the use of local antibiotics for both the prevention and treatment of musculoskeletal infection. Local antibiotics can achieve higher local tissue concentrations with a lower risk of systemic complications compared to intravenously administered antibiotics. These antibiotics may be administered in powder or liquid form without carrier, or if sustained release is desired, using a carrier. Polymethylmethacrylate (PMMA), ceramics, and hydrogels are examples of antibiotic carriers. Unlike PMMA, ceramics and hydrogels have the advantage of not requiring a second surgery for removal. The VANCO trial supported the use of powdered vancomycin in high-risk fracture cases for the reduction of Gram-positive infections; although, data is limited. Future studies will evaluate the use of aminoglycoside antibiotics to address Gram-negative infection prevention. While theoretical concerns exist with the use of local antibiotics, available studies suggest local antibiotics are safe with a low-risk of adverse effects.

Cefadroxil Use for Musculoskeletal Infections in an Academic Pediatric Hospital.

Forty-nine of 52 (94.2%) children with musculoskeletal infection (MSKI) were successfully treated with cefadroxil dosed at 30 mg/kg/day over a 10-year time period. Two failures were associated with poor medication adherence. Our study suggests that treatment of MSKI with cefadroxil offers acceptable outcomes. Confirmation through clinical trials is appropriate.

Outcome analysis of antibiotic-loaded poly methyl methacrylate (PMMA) beads in musculoskeletal infections

ObjectiveDespite the availability of an extensive array of antibiotics, musculoskeletal infections are not cured successfully. It is necessary to remove sequestra, infected necrotic tissue, and implants. This study was undertaken to assess the efficacy of poly methyl methacrylate (PMMA) beads and identify the variables that influence eradication and recurrence in the treatment of musculoskeletal infections. MethodsThis study was conducted on 82 patients with chronic osteomyelitis who were treated over a period of 6 years at our tertiary care hospital. We followed up with 71 patients for one year. Clinicoradiological data for the control of infection and bone healing were assessed at the final follow up visit. The correlation between antibiotic sensitivity/resistance and infection was evaluated for Gentamicin + Cefuroxime and Gentamicin + Vancomycin combinations. Chi-squared testing, using SPSS version 16.0, was used for statistical analysis, and a p-value < 0.05 was considered significant. ResultsFifty-three patients (65.4%) had an exogenous route of infection. Fifty-six patients (68.51%) presented with a discharging sinus on first presentation. In 42 patients (59%), the diagnosis was verified with a positive bacterial culture. In addition, we used antibiotic beads of Gentamicin + Cefuroxime in 74 patients (90%), while in 8 patients (10%), we used Gentamicin + Vancomycin, based on culture and sensitivity results. Recurrence was found in five cases of Gentamicin + Cefuroxime and two cases of Gentamicin + Vancomycin (p = 0.065). ConclusionAntibiotics containing PMMA beads are effective in the treatment of chronic osteomyelitis and in preventing the recurrence of infection. It is imperative to identify various factors responsible for the recurrence of infection. This may help clinicians predict the prognosis of the disease and minimise the risk of adverse outcomes.

The efficacy of 16S ribosomal DNA sequencing in the diagnosis of bacteria from blood, bone and synovial fluid samples of children with musculoskeletal infections.

BackgroundMusculoskeletal infections are among the most common bacterial infections in children leading to hospitalization, invasive procedures and prolonged antibiotic administration. Blood, synovial and sometimes tissue cultures are essential for the diagnosis and treatment of musculoskeletal infections; 16S ribosomal DNA (rDNA) sequencing is a novel diagnostic tool for the detection of bacteria.While the yield of 16S rDNA sequencing in synovial fluid was previously assessed, data regarding the efficacy of this method from blood samples or partially treated children with suspected musculoskeletal infections is lacking.In this study we assessed the yield of 16S rDNA sequencing in blood, bone and synovial samples of children with musculoskeletal infections.MethodsBlood, synovial and bone samples were collected from children with suspected musculoskeletal infections and analyzed for the presence of 16S rDNA, the results were then compared with the benchmark microbial cultures.ResultsDuring the study period, 41 children (18 boys and 23 girls) with suspected acute musculoskeletal infection were enrolled. A positive blood culture was found in 6/31 cases (19.4%) with methicillin-susceptible Staphylococcus aureus being the most commonly isolated bacterium. No significant 16S rDNA detection in blood samples was recorded.Synovial fluid culture was positive in 6/28 samples (21%), Kingella kingae being the most common pathogen. When using the 16S rDNA sequencing method, the rate of positive results in synovial fluid was higher with bacterial detection in 12/23 (52%) samples. The 16S rDNA sequencing method was also able to identify pathogens in samples taken from partially treated children where cultures were negative with 16S rDNA detection in 5/5 samples.ConclusionAlthough 16S rDNA sequencing may increase the yield of bacterial detection in synovial samples of patients with musculoskeletal infections, there is no benefit from applying this method on blood samples. The 16S rDNA sequencing method may be particularly beneficial when antibiotic treatment was started prior to synovial fluid sampling.Level of EvidenceLevel-II diagnostic study

Infection

Musculoskeletal infection is a clinical problem with significant direct healthcare costs. The prevalence of infection after closed, elective surgery is frequently estimated to be less than 2%, but in severe injuries, posttraumatic infection rates have been reported as 10% or greater. Although clinical infections are found outside the realm of medical devices, it is clear that the enormous increase of infections associated with the use of implants presents a major challenge worldwide. This review summarizes recent advances in the understanding, diagnosis, and treatment of musculoskeletal infections.

Papers Presented at the 2008 Meeting of the Musculoskeletal Infection Society: Editorial Comment

Surgical site infections after orthopaedic surgery are a source of considerable postoperative morbidity and mortality and are associated with increased rehospitalization and higher healthcare expenditures. Patients with surgical site infections may develop greater physical limitations that lead to reductions in health-related quality of life, particularly if they require reoperation and/or removal of an orthopaedic implant such as a joint prosthesis. While much of the science of infection prevention and treatment has yet to be explored, there has been substantial progress in improving methods for addressing surgical site infections. The 18th annual meeting of the Musculoskeletal Infection Society of North America was held in August 2008 at Lake Tahoe, California. In this issue, CORR features papers presented at the annual session. Three themes emerge from the series of papers—prevention, diagnosis, and treatment of musculoskeletal infection. Several papers focus on prevention by presenting risk factors associated with the development of surgical site infections, including modifiable risk factors. These modifiable risk factors, such as diabetes, can be improved by patients and physicians prior to orthopaedic surgery to decrease the risk of surgical site infection in the individual patient. The utility of specific preoperative preventive measures such as different types of barrier preparations were also discussed, as were the effect of the attachment of antibiotics to prostheses to reduce the risk of surgical site infection on the topography of titanium alloy surfaces. The increasing use of ingrowth prostheses that do not allow for antibiotic impregnated cement makes this an important issue for future basic science and translational research. Regarding the diagnosis of musculoskeletal infection, the utility of MRI to improve preoperative planning in patients with musculoskeletal infections was reviewed. More work in this area relating to the cost effectiveness of the approach is warranted. The majority of the papers presented at the annual session discussed the treatment of infection, with the focus on implant-related infection. Topics range from the basic science of local antibiotic delivery to the clinical experience of major limb amputations due to uncontrolled infection. Also addressed were important specific topics relating to the reasons for unexpected hospital readmission following discharge after treatment of musculoskeletal infection, and the increasing threat of antimicrobial resistance among organisms causing musculoskeletal infection. In this era of optimization of patient safety and infection prevention, addressing the problem of surgical site infections begins with careful patient selection and preoperative improvement in modifiable risk factors, proper surgical technique with meticulous environmental control, and heightened awareness for effective surveillance. Once diagnosed, successful treatment of musculoskeletal infection requires a team approach that employs evidence-based practices whenever possible. It is through dialogue—between orthopaedists, infectious disease specialists, and basic scientists—that we advance our understanding of musculoskeletal infection, its prevention, diagnosis, and treatment. We hope you enjoy and learn from the articles in the symposium as we did upon hearing them presented at the annual session in 2008. We invite you to join us for our 2009 annual meeting.

Local Antibiotic Delivery with OsteoSet??, DBX??, and Collagraft??

Biodegradable local antibiotic delivery systems have gained interest for prophylaxis and treatment of musculoskeletal infections. We studied the biodegradable materials Osteo- Set, DBX and Collagraft for local delivery of vancomycin and gentamicin in vitro. We determined the antimicrobial activity of vancomycin and gentamicin after mixing with each biodegradable material and determined the release of each antimicrobial from each material in an intermittent flow chamber. Antimicrobial activity was expressed as percent of antimicrobial loaded into each sample that was detected; antimicrobial release was expressed as concentration (microg/mL) after timed intervals of chamber flow, peak concentration, area under the curve and percent antimicrobial recovered. Activity of vancomycin after mixing with Osteo- Set, DBX and Collagraft was > 73%. Activity of gentamicin after mixing with DBX was 100%; after mixing with OsteoSet and Collagraft it was reduced to < 61%. AUC0-48hrs of vancomycin was 469, 426 and 432 microg x hr/mL, and the AUC0-48hrs of gentamicin was 368, 306 and 301 microg x hr/mL after release from OsteoSet, DBX, and Collagraft, respectively. Recovered percentages of vancomycin were 39%, 11% and 25%, and recovered percentages of gentamicin were 39%, 9% and 23% after release from OsteoSet, DBX, and Collagraft, respectively. OsteoSet, DBX and Collagraft may be suitable for local delivery of vancomycin and gentamicin.

Local Antibiotic Delivery Systems

Local Antibiotic Delivery Systems

Local Antibiotic Delivery Vehicles in the Treatment of Musculoskeletal Infection

The primary benefit achieved with local antibiotic delivery vehicles is the ability to obtain extremely high levels of local antibiotics without increasing systemic toxicity. Antibiotic-loaded bone cement represents the current standard as an antibiotic delivery vehicle in orthopaedic surgery. Biodegradable alternatives to antibiotic-loaded bone cement also are being used clinically and there are many new products in the active stages of development. These alternatives can be categorized as bone graft, bone graft substitutes or extenders, natural polymers (protein-based products), and synthetic polymers. Composite biomaterials that simultaneously provide the functions of variable antibiotic delivery patterns and also contribute to the process of bone regeneration represent the most ideal class of local antibiotic delivery vehicles. High concentrations of certain antibiotics have been shown to affect the process of normal bone regeneration adversely in a dose dependent response. Considerable investigation still is required to determine the proper use of locally administered antibiotics to negotiate the balance between eradicating infection without excessively inhibiting the processes of bone regeneration.

Antimicrobial release kinetics from polymethylmethacrylate in a novel continuous flow chamber.

Polymethylmethacrylate is used for local delivery of antimicrobials in the treatment of musculoskeletal infections. A novel continuous flow chamber system was designed to measure in vitro antimicrobial release. Three-millimeter beads containing amikacin, gentamicin, tobramycin, or vancomycin [concentration of 7.5% (weight per weight)] were placed individually in a continuous flow chamber with a total volume of 1 mL Kreb's Ringer buffer flowing at 1 mL/hour. Effluent was sampled hourly for 24 hours and then every 2 hours up to 48 hours; antimicrobial concentrations were measured in triplicate by bioassay. The mean peak concentrations were 40.9, 30.1, 30.0, and 19.1 microg/mL; the mean areas under the concentration time curves (Time 0 to infinity) were 263, 327, 110, and 180 hours x microg/mL of antibiotic; and the mean percentages of initial amount of antimicrobial released were 11.7%, 14.5%, 6.6%, and 10.9% for tobramycin, gentamicin, amikacin, and vancomycin, respectively. The results for each polymethylmethacrylate-antimicrobial agent combination were reproducible. In contrast to other in vitro elution systems, this novel system operates under the premise that there is dynamic flow surrounding polymethylmethacrylate in vivo and permits rapid in vitro comparison of the relative release of antimicrobial agents from polymethylmethacrylate.

The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets

Calcium sulfate was used as a biodegradable delivery system for the administration of antibiotics in musculoskeletal infection. New Zealand white rabbits were infected with Staphylococcus aureus, debrided, and randomized to one of four treatment groups: calcium sulfate pellets with 10% tobramycin sulfate, placebo calcium sulfate pellets and IM tobramycin, placebo calcium sulfate pellets, or debridement. Serum and wound exudate tobramycin concentrations and serum calcium levels were measured. Radiographs, cultures, and histology were analyzed for efficacy and treatment. Rabbits treated with 10% tobramycin sulfate pellets showed a significantly higher eradication of infection (11/13) than rabbits treated with debridement only (5/12), placebo pellets and IM tobramycin (5/14), or placebo pellets (3/13). In the group receiving 10% tobramycin sulfate pellets, serum tobramycin concentrations peaked 3 h post-operatively at 5.87 μg/ml and were non-detectable after day 1. In the group receiving placebo pellets and IM tobramycin, serum concentrations peaked at 7.82 μg/ml 1 h post-operatively, fell to 6.12 μg/ml on day 2, and averaged 4.18 μg/ml for the remainder of the treatment period. The wound exudate tobramycin concentrations in the animals treated with tobramycin sulfate pellets peaked at 11.9 mg/ml on day 1 and dropped to 2.5 μg/ml on day 7. There was no significant difference in the serum calcium levels in any of the treatment groups. Calcium sulfate containing tobramycin sulfate has potential utility as a biodegradable local antibiotic delivery system in the treatment of musculoskeletal infections.

Anti-infective therapy in orthopaedics

Successful treatment of musculoskeletal infection can be a challenge. It requires an understanding of clinical microbiology and anti-infective therapy, in addition to debridement and reconstructive surgery. In this article, the authors hope to provide practical guidelines for the prevention and appropriate diagnosis of orthopaedic infections. The essential elements of antibiotic selection, delivery, adverse effects, and drug interactions are outlined.

The history of the treatment of musculoskeletal infection

The documented history of the management of infections of the musculoskeletal system date back to ancient Egypt, and great strides have been made since, especially in the last two centuries. This chapter presents an overview of the important achievements in treating these conditions, as well as some of the challenges faced by the various physicians—from Hippocrates to Lister—who sought to cure them. Because of the constraints of chapter length and the excellent current literature available, no attempt will be made to deal with the past fifty years.

Elution characteristics of gentamicin-PMMA beads after implantation in humans.

Seventeen patients had gentamicin-PMMA beads implanted for treatment of orthopedic infections. The authors found that beads implanted in patients for 3 to 36 weeks were capable of eluting high levels of antibiotic after retrieval. Beads that were implanted in patients for less than 10 weeks eluted significantly higher antibiotic levels than beads were implanted for more than 14 weeks. This study supports the local use of these beads in the treatment of musculoskeletal infections.

Antimicrobial Therapy in Musculoskeletal Surgery

The treatment of musculoskeletal infections often involves a combined surgical and antibiotic approach. The antimicrobial therapy of these infections does not differ in basic principles from that of other infections. Because many different microorganisms can cause musculoskeletal infection, appropriate antimicrobial therapy depends on proper culturing, isolation, identification, and antibiotic susceptibility testing of the etiologic infectious agent. The need for long-term treatment makes the proper selection of antibiotic and monitoring of therapy imperative. The least toxic, least expensive, and most effective antibiotic should be selected.

Actions and Uses of Antimicrobial Agents in the Treatment of Musculoskeletal Infections

The antimicrobial therapy of musculoskeletal infections does not differ in basic principles from the therapy of any infection. However, the chronic nature of certain of these infections and the need for long-term treatment make essential the proper selection and monitoring of the antimicrobial agents. This can be done only by obtaining proper specimens for microbiologic identification and, in many cases, by in vitro susceptibility tests of the infecting organisms. Thus, the least toxic, effective antimicrobial agent can be selected and administered without inadequate therapy or toxic side effects.