Treatment Of Chronic Osteomyelitis Research Articles

Shock wave assisted intracellular delivery of antibiotics against bone infection with Staphylococcus aureus via P2X7 receptors

BackgroundTreatment of chronic osteomyelitis (bone infection) remains a clinical challenge; in particular, it requires enhanced delivery of antibiotic drugs for the treatment of intracellular Staphylococcus aureus (S. aureus), which prevents infection recurrence and resistance. Previous studies have found that noninvasive shock waves used to treat musculoskeletal diseases can alter cell permeability, however, it is unclear whether shock waves alter cell membrane permeability in chronic osteomyelitis. Furthermore, it remains unknown whether such changes in permeability promote the entry of antibiotics into osteoblasts to exert antibacterial effects. MethodsIn our study, trypan blue staining was used to determine the shock wave parameters that had no obvious damage to the osteoblast model; the effect of shocks waves on the cell membrane permeability of osteoblast model was detected by BODIPY®FL vancomycin; high performance liquid chromatography-mass spectrometry (HLPC-MS) was used to detect the effect of shock wave on the entry of antibiotics into the osteoblast model; plate colony counting method was used to detect the clearance effect of shock wave assisted antibiotics on S. aureus in the osteoblast model. To explore the mechanism, the effect of different pulses of shock waves on S. aureus was examined by plate colony counting method, besides, P2X7 receptor in osteoblast was detected by immunofluorescence and the extracellular ATP levels was detected. Furthermore, the effect of P2X7 receptor antagonists KN-62 or A740003 on the intracellular antibacterial activity of shock-assisted antibiotics was observed. Then, we used S. aureus to establish a rat model of chronic tibial osteomyelitis and investigated the efficacy and safety of shock-wave assisted antibiotics in the treatment of chronic osteomyelitis in rats. ResultsThe viability of the osteoblast models of intracellular S. aureus infection was not significantly affected by the application of up to 400 shock wave pulses at 0.21 mJ/mm2. Surprisingly, the delivery of BODIPY®FL vancomycin to osteoblast model cells was markedly enhanced by this shock wave treatment. Furthermore, the shock wave therapy increased the delivery of hydrophilic antibiotics (vancomycin and cefuroxime sodium), but not lipophilic antibiotics (rifampicin and levofloxacin), which improved the intracellular antibacterial effect. Afterwards, we discovered that shock wave treatment increased the extracellular concentration of ATP (the P2X7 receptor activator)， while KN-62 or A740003, a P2X7 receptor inhibitor, decreased intracellular antibacterial activity. We then found that 0.1 mL of 1 × 1011 CFU/mL ATCC25923 S. aureus was suitable for modeling chronic osteomyelitis in rats. Besides, the shock wave-assisted vancomycin treatment with the strongest antibacterial and osteogenic effects among the tested treatments was confirmed in vivo by imaging examination, microbiological cultures, and histopathology, with favorable safety. ConclusionsOur results suggest that shock waves can promote the entry of antibiotics into osteoblasts for antibacteria by changing the cell membrane permeability in a P2X7 receptor-dependent manner. Besides, considering antibacterial and osteogenic efficiency and a high degree of safety in rat osteomyelitis model, shock wave-assisted vancomycin treatment may thus represent a possible adjuvant therapy for chronic osteomyelitis.

Extracorporeal shock wave therapy: options in chronic osteomyelitis (literature review)

The use of extracorporeal shock wave therapy under experimental conditions has shown the effectiveness of the method in soft tissue and skeletal infections. In vitro, an energy-dependent effect of shock waves on reducing the viability of Staphylococcus aureus and other pathogenic flora was revealed. For the manifestation of the antibacterial activity of shock waves towards pathogenic bacteria of the typical flora in chronic osteomyelitis, at least 1,000 pulses were required, and for its almost complete eradication (99 %), 4,000 pulses were applied at an energy flux density of 0.59–0.96 mJ/mm2. Most authors confirm the isolated (without antibiotics) antibacterial effect of shock waves in vitro, although there are opposite opinions. It is known that pathogenic bacteria, including Staphylococcus aureus, form protective biofilms on infected soft, bone tissues, implants. Due to this, the emerging infection is difficult to treat for a number of reasons — the biofilm prevents the penetration of antibiotics and immune cells. In vitro studies have shown that shock waves destroy biofilms of pathogenic bacteria and create conditions for a joint bactericidal effect with antibiotics. In vivo observations under the conditions of modeling experimental osteomyelitis in animals have demonstrated bacteriologically that extracorporeal shock wave therapy, when used alone, does not have an antibacterial effect, however, a lower degree of osteomyelitis was detected morphologically. The authors stated the synergism of shock waves with antibiotics in the treatment of chronic osteomyelitis in animals, up to the bactericidal effect. Studies on the impact of shock waves on biofilms of pathogenic bacteria typical for soft tissue infections, chronic osteomyelitis, both in vivo and in vitro, showed that after the application of the method, the pathogenic flora becomes susceptible to antibiotic therapy. The currently widespread opinion about the contraindication of extracorporeal shock wave therapy in the presence of infection in the body, due to the risk of exacerbation of the inflammatory process, the likelihood of bacteremia, sepsis, and foci of secondary infection, has not been confirmed in the experimental studies in vivo. Many research have shown the absence of similar or other complications in animals after the use of shock waves. The analysis of the presented data indicates the need for further study of the mechanism of extracorporeal shock wave effect on chronic osteomyelitis, possible complications associated with the use of the method, as well as its approbation in the clinic.

Clinical outcomes and complications of S53P4 bioactive glass in chronic osteomyelitis and septic non-unions: a retrospective single-center study.

Dead space management following debridement surgery in chronic osteomyelitis or septic non-unions is one of the most crucial and discussed steps for the success of the surgical treatment of these conditions. In this retrospective clinical study, we described the efficacy and safety profile of surgical debridement and local application of S53P4 bioactive glass (S53P4 BAG) in the treatment of bone infections. A consecutive single-center series of 38 patients with chronic osteomyelitis (24) and septic non-unions (14), treated with bioactive glass S53P4 as dead space management following surgical debridement between May 2015 and November 2020, were identified and evaluated retrospectively. Infection eradication was reached in 22 out of 24 patients (91.7%) with chronic osteomyelitis. Eleven out of 14 patients (78.6%) with septic non-union achieved both fracture healing and infection healing in 9.1 ± 4.9 months. Three patients (7.9%) developed prolonged serous discharge with wound dehiscence but healed within 2 months with no further surgical intervention. Average patient follow-up time was 19.8 months ± 7.6 months. S53P4 bioactive glass is an effective and safe therapeutic option in the treatment of chronic osteomyelitis and septic non-unions because of its unique antibacterial properties, but also for its ability to generate a growth response in the remaining healthy bone at the bone-glass interface.

Dielectric and Magnetic Composites of Fe3O4@APNs for Superior Microwave Thermal Effect.

As for the deep tissue infections of chronic osteomyelitis, antibiotics are hard to deliver into the infected bone tissue, which makes it difficult to be cured completely in clinic. Microwave has strong penetration, and the medium can produce a good bactericidal effect through the microwave thermal effect (MTE). Here, a new microwave sensitizer (Fe3O4@APNs) was prepared and evaluated. Black phosphorus nanosheets modified with phytic acid dodecasodium (APNs) were fabricated by a liquid-phase exfoliation method that exhibited good water oxygen stability. A complex with Fe3O4 compound and APNs (Fe3O4@APNs) was formed by an ultrasonic mixing process, which showed excellent MTE (quickly increased to 53.5 °C in 5 min at 2.45 GHz, 10 W/cm2) via dielectric versus magnetic loss (reflect loss value of -5.94 dB at 2.45 GHz). The Fe3O4@APNs microwave sensitizer developed in this study has an outstanding in vitro antibacterial effect and might show promise for the treatment of chronic osteomyelitis enabled by local tissue heating via the MTE.

A Review of the Clinical Utilization of Oral Antibacterial Therapy in the Treatment of Bone Infections in Adults.

Chronic osteomyelitis in adults is managed with prolonged courses of intravenous antibiotics in conjunction with surgical debridement of necrotic bone. Over the past 40 years, there has been no paradigm shift in this approach, as randomized controlled trials of this standard of care compared to alternatives such as prolonged oral antibiotics are scarce. However, there have been many small trials, case reports, and review papers evaluating the effectiveness of oral treatment for chronic osteomyelitis. The oral route for infections requiring prolonged treatment is intuitively and practically more favorable due to several advantages, the most important of which is the avoidance of long-term IV antimicrobial therapy with its complications, inconvenience, and cost. In this paper, we review the literature evaluating oral antibiotic therapy in the management of chronic bone infections since 1975. The majority of osteomyelitis infections are caused by Staphylococcus aureus, hence we focus on its treatment using oral antibiotics; however, we also emphasize subpopulations of patients with diabetes, implanted hardware, and with less common bacterial organisms. The primary objective of this review is to promulgate clinical recommendations on the use of oral antibiotics in bone infections in the context of initial therapy, transition from intravenous therapy, and the role of chronic suppression. The secondary objective is to summarize current knowledge of the specific oral antimicrobial agents that are commonly utilized, together with a synopsis of the available literature pertaining to their pharmacokinetic/pharmacodynamic properties and duration of therapy in bone infection.

ANTIBIOTIC-TARGETED CEMENT RODS IN CHRONIC OSTEOMYELITIS: LONG-TERM OUTCOMES FROM A LEVEL ONE SOUTH AFRICAN TRAUMA CENTRE

Fracture related infection, in particular chronic osteomyelitis, requires complex management plans. Meta analyses and systematic reviews have not found a gold standard of treatment for this disease. In 2017 an alternative treatment protocol was undertaken in our institution; whereby staged surgery with the use of cheaply manufactured tailored antibiotic cement rods was used in the treatment of chronic osteomyelitis, secondary to traumatic long bone fractures. Short term outcomes for this protocol demonstrated a 75.7% microbiological resolution to a negative culture and a good clinical outcome of 84.2% overall was demonstrated in terms of sinus resolution, skin changes, pain and function. Our aim now was to assess the long term outcomes of this treatment strategy.A cross-sectional study of patients who had previously undergone the set treatment protocol was performed. Patient satisfaction, effects on activities of daily living, return to work and clinical improvement at 5 years following the intervention were assessed using a patient questionnaire and the validated AAOS lower limb score.The average AAOS lower limb score was 88 which was en par to other similar studies. 80% of patients had returned to some form of work. Ongoing mild pain was a persistent problem for 50% of the patients however 98% of the patients were overall satisfied with the treatment satisfaction at 5 years. Only 1 patient required further treatment. 8 patients could not be located for follow up.Chronic osteomyelitis remains a complex disease to treat. This treatment protocol demonstrates favourable microbiological, serological and clinical short term outcomes and favourable patient satisfaction and functional long term outcomes at 5 years. Our study highlights antibiotic targeted cement rods as a feasible treatment option in managing chronic osteomyelitis.

<i>In vivo</i> effectiveness of polymer hydrogels impregnated with an antibacterial drug in chronic osteomyelitis

Introduction Polymethyl methacrylate (PMMA) is a common depot system in the treatment of chronic osteomyelitis. However, a lot of its shortcomings do not allow us to consider it ideal.Purpose of the work was to study in vivo the effectiveness of a polymer hydrogel containing an antibiotic for chronic osteomyelitis of the tibia in a rabbit model and compare it with PMMA.Materials and methods The study was performed on the lower leg of 25 mature Chinchilla rabbits. A model of chronic osteomyelitis of the tibia was created. A methicillin-sensitive strain of Staphylococcus aureus (MSSA), highly active against cefazolin, was chosen as an infectious agent. Surgical debridement started 21 days after the clinical, laboratory, radiological and microbiological confirmation of the diagnosis, the technique for all animals was the same. The experimental group (n = 11) was treated by implantation of a polymer hydrogel, the comparison group (n = 11) with PMMA, and the control group (n = 3) had no implanted substance. In the postoperative period, monitoring of the local status, weight and body temperature of the animals, microbiological and radiological studies were carried out. Animals were taken out of the experiment by stages. Biopsies were sent for bacteriological and histomorphometric studies. Statistical comparison of the groups was performed using the Mann ‑ Whitney, Kruskell ‑ Wallis and Tukey criteria, descriptive statistics were used for the control group.Results In the experimental group, in all cases, postoperative wounds healed in a timely manner, the levels of WBC and CRP significantly (p = 0.040) decreased from 14 and 21 days, respectively. Microbiologically, the growth of microflora from the wound discharge and biopsy specimens was not detected; radiographic progression of chronic osteomyelitis was not observed; histomorphometry revealed a significant (p = 0.002) effective relief of the inflammatory process. In the comparison group, systemic antibiotic therapy was required from postoperative day 7. Levels of inflammatory markers decreased less effectively than in the experimental group. MSSA was verified from wound discharge and biopsy specimens at almost every follow-up time-point. X-rays and histomorphometry (p = 0.001), on average, detected exacerbation of osteomyelitis. In the control group, systemic therapy did not give positive dynamics.Discussion A comparative analysis showed that the hydrogel impregnated with an antibacterial agent, unlike PMMA, reliably arrests chronic osteomyelitis without auxiliary systemic antibiotic therapy and does not cause material-associated bone resorption. The clinical and laboratory picture is fully consistent with the data of microbiology, radiology and histomorphometry.Conclusion Hydrogel impregnated with an antibiotic reliably and effectively stops chronic osteomyelitis compared to PMMA.

In situ sprayed hydrogels containing resiquimod-loaded liposomes reduce chronic osteomyelitis recurrence by intracellular bacteria clearance.

At present, surgical debridement and systematic administration of antibiotics represent the mainstay of treatment for chronic osteomyelitis. However, it is now understood that Staphylococcus aureus (S. aureus) can survive within excessively polarized M2 macrophages and evade antibiotics, accounting for the high recurrence of chronic osteomyelitis. Effective treatments for intracellular infection have rarely been reported. Herein, we designed an in situ sprayed liposomes hydrogels spray with macrophage-targeted effects and the ability to reverse polarization and eradicate intracellular bacteria to reduce the recurrence of osteomyelitis. Resiquimod (R848)-loaded and phosphatidylserine (PS)-coating nanoliposomes were introduced into fibrinogen and thrombin to form the PSL-R848@Fibrin spray. Characterization and phagocytosis experiments were performed to confirm the successful preparation of the PSL-R848@Fibrin spray. Meanwhile, in vitro cell experiments validated its ability to eliminate intracellular S. aureus by reprogramming macrophages from the M2 to the M1 phenotype. Additionally, we established a chronic osteomyelitis rat model to simulate the treatment and recurrence process. Histological analysis demonstrated a significant increase in M1 macrophages and the elimination of intracellular bacteria. Imaging revealed a significant decrease in osteomyelitis recurrence. Overall, the liposome hydrogels could target macrophages to promote antibacterial properties against intracellular infection and reduce the recurrence of chronic osteomyelitis, providing the foothold for improving the outcomes of this patient population. STATEMENT OF SIGNIFICANCE: Chronic osteomyelitis remains a high recurrence although undergoing traditional treatment of debridement and antibiotics. S. aureus can survive within the excessively polarized M2 macrophages to evade the effects of antibiotics. However, few studies have sought to investigate effective intracellular bacteria eradication. Herein, we designed a macrophage-targeted R848-containing liposomes fibrin hydrogels spray (PSL-R848@Fibrin) that can reprogram polarization of macrophages and eradicate intracellular bacteria for osteomyelitis treatment. With great properties of rapid gelation, strong adhesion, high flexibility and fit-to-shape capacity, the facile-operated immunotherapeutic in-situ-spray fibrin hydrogels exhibited huge promise of reversing polarization and fighting intracellular infections. Importantly, we revealed a hitherto undocumented treatment strategy for reducing the recurrence of chronic osteomyelitis and potentially improving the prognosis of chronic osteomyelitis patients.

Muscle versus Fascia Free Tissue Transfer for Treatment of Chronic Osteomyelitis in the Comorbid Population.

In patients with chronic lower extremity (LE) wounds, chronic osteomyelitis confers additional complexity to achieving adequate treatment. Previous reviews demonstrate increased rates of osteomyelitis recurrence in patients who receive muscle flaps compared with fasciocutaneous flaps for LE limb salvage; however, these studies were not limited to atraumatic populations who receive exclusively free flaps. Thus, this study compared rates of recurrence in chronic osteomyelitis patients undergoing LE reconstruction with fasciocutaneous versus muscle free flaps. Patients undergoing free tissue transfer (FTT) between July 2011 and July 2021 were retrospectively reviewed. Patients were stratified into fasciocutaneous and muscle free flap groups. Primary outcomes included osteomyelitis recurrence, flap complications, limb salvage, and ambulatory status. Forty-eight patients with pathologic diagnosis of chronic osteomyelitis of the wound bed were identified, of which 58.3% received fasciocutaneous (n = 28) and 41.7% received muscle flaps (n = 20). The most common comorbidities included diabetes mellitus (n = 29, 60.4%), peripheral neuropathy (n = 27, 56.3%) and peripheral vascular disease (n = 24, 50.0%). Methicillin-resistant or methicillin -sensitive Staphylococcus aureus were the most common pathogen in 18.7% (n = 9) of procedures. The majority of patients underwent a median of three debridements followed by negative pressure wound therapy prior to receiving FTT. At a median follow-up of 16.6 months, the limb salvage and ambulatory rates were 79.2 (n = 38) and 83.3% (n = 40), respectively. The overall rate of microsurgical flap success was 93.8% (n = 45). Osteomyelitis recurred in 25% of patients (n = 12) at a median duration of 4.0 months. There were no significant differences in rates of osteomyelitis recurrence, flap complications, limb salvage, ambulation, and mortality. On multivariate analysis, flap composition remained a nonsignificant predictor of osteomyelitis recurrence (odds ratio: 0.975, p = 0.973). This study demonstrates that flap composition may not influence recurrence of osteomyelitis following free flap reconstruction of chronic LE wounds, suggesting that optimal flap selection should be based on wound characteristics and patient goals.

Rapid and effective treatment of chronic osteomyelitis by conductive network-like MoS2/CNTs through multiple reflection and scattering enhanced synergistic therapy

Staphylococcus aureus (S. aureus)-infected chronic osteomyelitis (COM) is one of the most devastating infectious diseases with a high recurrence rate, often leading to amputation and even death. It is incurable by all the current strategies involving the clinical use of radical debridement and systemic intravenous antibiotics. Here, we reported on a microwave (MW)-assisted therapy for COM by constructing a heterojunction formed by flake nanoflower-shaped molybdenum disulfide (MoS2) and tubular carbon nanotubes (CNTs). This composite could achieve a combination of MW thermal therapy (MTT) and MW dynamic therapy (MDT) to accurately and rapidly treat COM with deep tissue infection. In vitro and in vivo experiments showed that MoS2/CNTs were effective in non-invasively treating S. aureus-induced COM due to the heat and reactive oxygen species (ROS) produced under MW irradiation. The mechanism of heat and ROS generation was explained by MW network vector analysis, density of states (DOS), oxygen adsorption energy, differential charge and finite element (FEM) under MW irradiation. Since the Fermi layer was mainly contributed by the Mo-4d and C–2P orbitals, MoS2/CNTs could store a large amount of charge and easily release more electrons. In addition, charge accumulation and dissipation motion were strong on the surface of and inside MoS2/CNTs because of electromagnetic hot spots, resulting in the spilling out of a great deal of high-energy electrons. Due to the low oxygen adsorption energy of MoS2/CNTs-O2, these high-energy electrons combined further with the adsorbed oxygen to produce ROS.

A comparison of clinical and radiological outcomes between two different biodegradable local antibiotic carriers used in the single-stage surgical management of long bone osteomyelitis.

Dead-space management, following dead bone resection, is an important element of successful chronic osteomyelitis treatment. This study compared two different biodegradable antibiotic carriers used for dead-space management, and reviewed clinical and radiological outcomes. All cases underwent single-stage surgery and had a minimum one-year follow-up. A total of 179 patients received preformed calcium sulphate pellets containing 4% tobramycin (Group OT), and 180 patients had an injectable calcium sulphate/nanocrystalline hydroxyapatite ceramic containing gentamicin (Group CG). Outcome measures were infection recurrence, wound leakage, and subsequent fracture involving the treated segment. Bone-void filling was assessed radiologically at a minimum of six months post-surgery. The median follow-up was 4.6 years (interquartile range (IQR) 3.2 to 5.4; range 1.3 to 10.5) in Group OT compared to 4.9 years (IQR 2.1 to 6.0; range 1.0 to 8.3) in Group CG. The groups had similar defect sizes following excision (both mean 10.9 cm3 (1 to 30)). Infection recurrence was higher in Group OT (20/179 (11.2%) vs 8/180 (4.4%), p = 0.019) than Group CG, as was early wound leakage (33/179 (18.4%) vs 18/180 (10.0%), p = 0.024) and subsequent fracture (11/179 (6.1%) vs 1.7% (3/180), p = 0.032). Group OT cases had an odds ratio 2.9-times higher of developing any one of these complications, compared to Group CG (95% confidence interval 1.74 to 4.81, p < 0.001). The mean bone-void healing in Group CG was better than in Group OT, in those with ≥ six-month radiological follow-up (73.9% vs 40.0%, p < 0.001). Local antibiotic carrier choice affects outcome in chronic osteomyelitis surgery. A biphasic injectable carrier with a slower dissolution time was associated with better radiological and clinical outcomes compared to a preformed calcium sulphate pellet carrier.

Hydroxyapatite: An antibiotic recruiting moiety for local treatment and prevention of bone infections.

Treatment of chronic osteomyelitis by radical debridement and filling of the dead space with antibiotic containing calcium sulfate/hydroxyapatite (CaS/HA) bone substitute has shown excellent long-term outcomes. However, in extensive infections, sessile bacteria may remain in bone cells or soft tissues protected by biofilm leading to recurrences. The primary aim of this study was to evaluate if systemically administrated tetracycline (TET) could bind to pre-implanted HA particles and impart an antibacterial effect locally. In vitro studies indicated that the binding of TET to nano- and micro-sized HA particles was rapid and plateaued already at 1 h. Since protein passivation of HA after in-vivo implantation could affect HA-TET interaction, we investigated the effect of serum exposure on HA-TET binding in an antibacterial assay. Although, serum exposure reduced the zone of inhibition (ZOI) of Staphylococcus aureus, a significant ZOI could still be observed after pre-incubation of HA with serum. We could in addition show that zoledronic acid (ZA) competes for the same binding sites as TET and that exposure to high doses of ZA led to reduced TET-HA binding. In an in-vivo setting, we then confirmed that systemically administered TET seeks HA particles that were pre-implanted in muscle and subcutaneous pouches in rats and mice respectively, preventing HA particles from being colonized by S. aureus. Clinical Significance: This study describes a new drug delivery method that could prevent bacterial colonization of a HA biomaterial and reduce recurrences in bone infection.

Use of fibular graft in Masquelet technique in osteomyelitis of long bones-a novel modification in the technique

Background: Improper treatment of acute osteomyelitis mostly leads to chronic osteomyelitis. In the year 2000, Alain C. Masquelet described the Induced membrane technique for the first time. In this study, we aimed to determine the clinical efficiency of the Masquelet technique for bone loss due to osteomyelitis in the long bones. Methods: This study was conducted at our tertiary care centre Shri Vasantrao Naik medical college and hospital, Yavatmal between August 2016 and September 2020. Masquelet technique with some modification was performed in all cases. Results: In first stage, the defects were filled with antibiotic-loaded polymethyl methacrylate (PMMA) cement after radical debridement. In second stage after 6 to 8 weeks we used a combination of fibular strut graft with iliac cancellous graft. X-rays were taken before second stage and after 3 months, 6 months and 1 year to see for the union. The study included 10 patients, with 6 males and 4 females with mean age of 34 years (20 to 54). The mean duration of bone infection was 4 months (range: 3-5 months). All patients had an average follow-up period of 16 months (range, 12-24 months). Radiographic evidence of bone union was seen in 6 months (3 to 9 months) infection was not seen in any case. Conclusions: This modified Masquelet is an effective method for the treatment of chronic osteomyelitis of the long bones.

Mid-Term Results of Single-Stage Surgery for Patients with Chronic Osteomyelitis Using Antibiotic-Loaded Resorbable PerOssal® Beads.

This retrospective study reports on the treatment of chronic osteomyelitis with local debridement combined with PerOssal®. The diagnosis of chronic osteomyelitis was confirmed in all cases and classified according to the Cierny-Mader (C-M) classification. The primary outcome was the eradication of infection at a minimum of one year after surgery. A total of 93 patients (median age: 40 years) were included. The most represented sites were the femur (24, 25.8%) and tibia (52, 55.9%). Twenty-six patients (28.0%) had significant local or systemic comorbidities (C-M Class B hosts). According to anatomic type, 31 cases were type I, 13 type II, 21 type III and 28 type IV. Vancomycin was added to PerOssal® in most cases (80, 86.0%). In 24 (25.8%) cases, Vancomycin and Rifampicin were combined. In 32 (34.4%) cases, intraoperative cultures were negative. Staphylococcus aureus was isolated in 39 (63.9%) patients, and Gram-negative bacteria were isolated in 12 cases. The median follow-up was 21 months (range 12-84). A total of 21 (22.6%) patients developed an infection recurrence (IR) after a median follow-up of 11 months (range: 1-47). PerOssal® holds several practical advantages compared to other bone void fillers. Thus, due to its good biocompatibility and sufficient antibiotic release, it represents a viable adjuvant treatment in chronic osteomyelitis.

Efficacy and Safety of Antibiotic Impregnated Microporous Nanohydroxyapatite Beads for Chronic Osteomyelitis Treatment: A Multicenter, Open-Label, Prospective Cohort Study.

Chronic osteomyelitis is still a serious health problem that causes disabling conditions and has an impact on the quality of life. The objective of this study was to determine the clinical efficacy and safety of localized antibiotics delivery via impregnated microporous nanohydroxyapatite (nHA-ATB) beads for chronic osteomyelitis treatment. A total of 62 patients were enrolled in this study. After radical surgical debridement, the bone defect was filled with three types of antibiotics (vancomycin or gentamicin or fosfomycin) impregnated HA beads. The follow-up period was 48 weeks. It was found that the success rate was approximately 98% with a re-infection in only one patient. Quality of life of all patients after treatment improved significantly over time. Systemic exposure to vancomycin and gentamicin after beads implantation was limited and high local antibiotics concentrations were found in wound drainage fluid at 24, 48 and 72 h. Blood biochemistry measurements did not show any nephrotoxic or hepatotoxic effects. 20 adverse events were reported, but 90% of the events were resolved without having to remove the beads and the patients recovered. Satisfactory outcomes were observed in terms of success rate, quality of life and adverse effect. nHA-ATB beads impregnated by vancomycin or gentamicin or fosfomycin could potentially be employed as an alternative product of choice for localized antibiotics delivery in chronic osteomyelitis treatment.

Vancomycin-loaded silk fibroin microspheres in an injectable hydrogel for chronic osteomyelitis therapy.

Introduction: Chronic osteomyelitis remains a clinical challenge in orthopedics. Methods: In this study, silk fibroin microspheres (SFMPs) loaded with vancomycin are entrapped in an injectable silk hydrogel to form a vancomycin delivery system for treatment of chronic osteomyelitis. Results and Discussion: Vancomycin showed continuous release from the hydrogel for up to 25 days. The hydrogel shows strong antibacterial activity against both Escherichia coli and Staphylococcus aureus and a long antibacterial duration of 10 days without a decrease in the antibacterial effect. The injection of vancomycin-loaded silk fibroin microspheres entrapped in the hydrogel into the infected site of rat tibia reduced bone infection and improved bone regeneration compared with other treatment groups. Conclusion: Thus, the composite SF hydrogel features a sustained-release profile and good biocompatibility, making it promising for application in osteomyelitis treatment.

Systemic Antimicrobial Treatment of Chronic Osteomyelitis in Adults: A Narrative Review.

Chronic osteomyelitis in adults is a complex condition that requires prolonged and intensive antimicrobial therapy, but evidence on optimal selection and duration of antibiotics is limited. A review of PubMed and Ovid Embase databases was conducted to identify systematic reviews, meta-analyses, retrospective and randomised controlled trials (RCTs) on antibiotic treatment outcomes in adults with chronic osteomyelitis. Three main areas of interest were investigated: short-term versus long-term antibiotic therapy, oral versus parenteral antibiotic therapy, and combination antibiotic therapy with rifampicin versus without rifampicin. A total of 36 articles were identified and findings were synthesised using a narrative review approach. The available literature suffers from limitations, including a lack of high-quality studies, inconsistent definitions, and varying inclusion/exclusion criteria among studies. Most studies are open-labelled and lack blinding. Limited high-quality evidence exists that oral therapy is non-inferior to parenteral therapy and that shorter antibiotic duration might be appropriate in low-risk patients. Studies on the impact of rifampicin are inconclusive. Further well-designed studies are needed to provide more robust evidence in these areas.

Cost-effectiveness of a bone substitute delivering gentamicin in the treatment of chronic osteomyelitis of long bones: Protocol for the CONVICTION randomized multicenter study.

Chronic osteomyelitis is a serious osteoarticular infection that most often occurs in the long bones, responsible for significant morbidity with the risk of fracture and amputation. Despite advances in both antibiotics and surgical treatment, the probability of recurrence of infection remains at around 20%. Cerament-G (BONESUPPORT AB, Sweden) is a synthetic bone substitute that fills the bone void left by surgery, prevents infection and promotes bone regeneration within this space. Cerament-G also provides the local delivery of high doses of gentamicin over several weeks. Two prospective observational studies described a number of infectious recurrences of 4 and 5% after the use of Cerament-G. Although available in France, Cerament-G is currently not reimbursed and its high cost constitutes a barrier to its use. We hypothesize that the use of Cerament-G will lead to fewer costs to the collectivity while improving patient utility and, as an innovative strategy, will be superior to standard of care on recurrence of infection. The Conviction Study is a prospective, multicenter, randomized, single blind study conducted in 14 French Reference Centers for Complex Osteoarticular infections. The main objective is to evaluate the cost-effectiveness of using Cerament-G in the treatment of chronic long bone osteomyelitis by comparing this innovative strategy to standard of care. A cost-utility analysis from the collective perspective will be conducted over a 24-month time horizon after the initial surgery. The outcome for the main medico-economic evaluation will be Quality Adjusted Life Years (QALYs). The study is being conducted throughout the CRIOAc network in France, in referral centers for the management of complex infections which will facilitate patient recruitment. This study has several limitations: the investigators have to be trained to handle the device, and it was impossible to blind the surgeon. If the use of Cerament-G is demonstrated to be superior to leaving the dead space empty during surgery for patients with stage III chronic long bone osteomyelitis, its use will be recommended to improve the prognosis of such patients, and this device may eventually qualify for reimbursement through the French Health Insurance scheme. This protocol received authorization from the Ethics Committee CPP Sud Méditerranée V on April 27, 2021 (21.03.10.77652) and the French National Agency for Medicines and Health Products on May 6, 2021 (2020-A02299-30). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals.

Thermosensitive Nanotherapeutics for Localized Photothermal Ablation of MRSA-Infected Osteomyelitis Combined with Chemotherapy.

Chronic osteomyelitis is an inflammatory skeletal disease caused by a bacterial infection that affects the periosteum, bone, and bone marrow. Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent. The bacterial biofilm formed on the necrotic bone is a considerable challenge to treating MRSA-infected osteomyelitis. Here, we developed an all-in-one cationic thermosensitive nanotherapeutic (TLCA) for treating MRSA-infected osteomyelitis. The prepared TLCA particles were positively charged and <230 nm in size, which allowed them to diffuse effectively into the biofilm. The positive charges of the nanotherapeutic accurately targeted the biofilm, and it subsequently regulated the drug release under near-infrared (NIR) light irradiation, thereby efficiently exerting the synergistic effect of NIR light-driven photothermal sterilization and chemotherapy. More than 80% of the antibiotics were abruptly released at 50 °C, which dispersed the biofilm by up to 90%. When applied to MRSA-infected osteomyelitis, with a localized temperature of 50 °C induced by 808 nm laser irradiation, it not only eliminated the bacteria and controlled infection but also inhibited the bone tissue inflammatory response, significantly reducing TNF-α, IL-1β, and IL-6 levels. In conclusion, we constructed an all-in-one antimicrobial treatment modality that provides a new and effective strategy for the topical treatment of chronic osteomyelitis.

Diagnosis and treatment of chronic osteomyelitis based on nanomaterials.

Chronic osteomyelitis is a painful and serious disease caused by infected surgical prostheses or infected fractures. Traditional treatment includes surgical debridement followed by prolonged systemic antibiotics. However, excessive antibiotic use has been inducing rapid emergence of antibiotic-resistant bacteria worldwide. Additionally, it is difficult for antibiotics to penetrate internal sites of infection such as bone, thus limiting their efficacy. New approaches to treat chronic osteomyelitis remain a major challenge for orthopedic surgeons. Luckily, the development of nanotechnology has brought new antimicrobial options with high specificity to infection sites, offering a possible way to address these challenges. Substantial progress has been made in constructing antibacterial nanomaterials for treatment of chronic osteomyelitis. Here, we review some current strategies for treatment of chronic osteomyelitis and their underlying mechanisms.