[Infected nonunion: diagnostic and therapeutic work-up]. / Infizierte Pseudarthrose: diagnostischer und therapeutischer Ablauf.

BACKGROUND: Septic nonunion is one of the major complications in fracture healing. The challenge is to identify the infection as the cause of nonunion first and then to achieve healing of the infection and the bone. OBJECTIVE: Because of the more heterogeneous appearance of an infected nonunion, the prevalence of germ detection in surgical nonunion revision is often underestimated. MATERIAL AND METHODS: In a retrospective study between 2010 and 2017, 86 patients with radiologically confirmed femoral shaft nonunion without clinical evidence and unremarkable medical history of a florid infection as the cause of nonunion, who had undergone primary single-stage surgical nonunion revision were analyzed. At least four intraoperatively obtained samples were evaluated for microbiological diagnosis. A distinction was made between tissue samples with subsequent 48­h short-term incubation and tissue samples with 14-day long-term cultivation. The finding "germ detection" was made if at least two of the samples demonstrated bacterial growth. RESULTS: In 18 of 86 patients with a nonunion preoperatively judged to be aseptic, positive bacterial evidence was obtained after short-term incubation. After long-term cultivation, positive bacterial detection was possible in 38 of 86 patients with a femoral shaft nonunion initially classified as aseptic. Regarding potential risk factors, the two groups demonstrated no relevant differences. In 29 patients, 1 pathogen was isolated from the obtained samples, whereas in the remaining 9 patients, a mixed culture with an average of 2.9 ± 0.5 different bacteria was detected. Identification revealed mainly low-virulence bacteria, most commonly Staphylococcus epidermidis. CONCLUSION: If the preoperative diagnostics including clinical, laboratory and radiological examination as well as a careful anamnesis reveal indications of a possible infectious event, the surgical nonunion revision should be performed in two stages with specimen collection before definitive nonunion revision. For microbiological diagnosis, several representative tissue samples should independently be obtained from the nonunion site and incubated for 14 days. Only in the absence of evidence of septic nonunion is a single-stage procedure suggested.

Past and Future of Phage Therapy and Phage-Derived Proteins in Patients with Bone and Joint Infection.

Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being "GMP-like") targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally "phage therapy 2.0" has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial-academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance.

Bacteriophage therapy for bone and joint infections.

Antibiotic resistance represents a threat to human health. It has been suggested that by 2050, antibiotic-resistant infections could cause ten million deaths each year. In orthopaedics, many patients undergoing surgery suffer from complications resulting from implant-associated infection. In these circumstances secondary surgery is usually required and chronic and/or relapsing disease may ensue. The development of effective treatments for antibiotic-resistant infections is needed. Recent evidence shows that bacteriophage (phages; viruses that infect bacteria) therapy may represent a viable and successful solution. In this review, a brief description of bone and joint infection and the nature of bacteriophages is presented, as well as a summary of our current knowledge on the use of bacteriophages in the treatment of bacterial infections. We present contemporary published in vitro and in vivo data as well as data from clinical trials, as they relate to bone and joint infections. We discuss the potential use of bacteriophage therapy in orthopaedic infections. This area of research is beginning to reveal successful results, but mostly in nonorthopaedic fields. We believe that bacteriophage therapy has potential therapeutic value for implant-associated infections in orthopaedics. Cite this article: Bone Joint J 2021;103-B(2):234-244.

Lytic lesion of skull: a rare presentation of chronic granulomatous disease.

An 18-month-old boy presented with lytic lesion of skull and recurrent abscesses with Serratia marcescens The extensive work up revealed a gene mutation confirming the diagnosis of chronic granulomatous disease (CGD). This case scenario underscores the importance of exploring the possibility of immunodeficiency if there is a history of recurrent abscesses with atypical organism. The case also demonstrates that CGD can present as lytic lesion of skull.

Characteristics of Pyogenic Musculoskeletal Infections in Older Children and Adolescents.

The characteristics and clinical consequences of pyogenic bone and joint infections in older children and adolescents have received little attention. This study evaluated the presentation and complications of musculoskeletal infections involving the pelvis and extremities in children older than 10 years. Thirty patients 10 to 17 years old (mean, 12.7 years old) were treated for musculoskeletal infections. Mean time to diagnosis was 9.2 days. Prior to correct diagnosis, 83% were assessed by at least 1 outpatient provider. At the time of admission, 55% were weight bearing and 93% were afebrile. Twenty-eight percent had a multifocal infection. More than one-third had serious medical complications or orthopedic sequelae; compared with patients without complications, this group had a significantly higher admission C-reactive protein and longer hospital stay. Symptoms of musculoskeletal infection common among young children may be absent in adolescents. Axial imaging is recommended to identify adjacent or multifocal disease. The Kocher criteria are less sensitive for septic hip arthritis in the adolescent population. Prompt recognition and treatment are critical to avoid medical and musculoskeletal complications. [Orthopedics. 2020;43(4):e291-e298.].

Development and challenges in setting up an international bone infection registry.

INTRODUCTION: Osteomyelitis is an increasing burden on the society especially due to the emergence of multiple drug-resistant organisms. The lack of a central registry that prospectively collects data on patient risk factors, laboratory test results, treatment modalities, serological analysis results, and outcomes has hampered the research effort that could have improved and provided guidelines for treatments of bone infections. The current manuscript describes the lessons learned in setting up a multi-continent registry. MATERIALS AND METHODS: This multicenter, international registry was conducted to prospectively collect essential patient, clinical, and surgical data with a 1-year follow-up period. Patients 18 years or older with confirmed S. aureus long bone infection through fracture fixation or arthroplasty who consented to participate in the study were included. The outcomes using the Short Form 36 Health Survey Questionnaire (version 2), Parker Mobility Score, and Katz Index of Independence in Activities of Daily Living were assessed at baseline and at 1 month, 6 months, and 12 months. Serological samples were collected at follow-ups. RESULTS: Contract negotiation with a large number of study sites was difficult; obtaining ethics approvals were time-consuming but straightforward. The initial patient recruitment was slow, leading to a reduction of target patient number from 400 to 300 and extension of enrollment period. Finally, 292 eligible patients were recruited by 18 study sites (in 10 countries of 4 continents, Asia, North and South America, and Central Europe). Logistical and language barriers were overcome by employing courier service and local monitoring personnel. CONCLUSIONS: Multicenter registry is useful for collecting a large number of cases for analysis. A well-defined data collection practice is important for data quality but challenging to coordinate with the large number of study sites.

Musculoskeletal Infection in Pediatrics: Assessment of the 2018 International Consensus Meeting on Musculoskeletal Infection.

The Second International Consensus Meeting (ICM) on Musculoskeletal Infection was held in July 2018 in Philadelphia, Pennsylvania. This meeting involved contributions from an international multidisciplinary consortium of experts from orthopaedic surgery, infectious disease, pharmacology, rheumatology, microbiology, and others. Through strict delegate engagement in a comprehensive 13-step consensus process based on the Delphi technique, evidence-based consensus guidelines on musculoskeletal infection were developed. The 2018 ICM produced updates to recommendations from the inaugural ICM that was held in 2013, which primarily focused on periprosthetic infection of the hip and the knee, and added new guidelines with the expansion to encompass all subspecialties of orthopaedic surgery. The following proceedings from the pediatrics section are an overview of the ICM consensus recommendations on the prevention, diagnosis, and treatment of pediatric musculoskeletal infection.

Microwaves increase the effectiveness of systemic antibiotic treatment in acute bone infection: experimental study in a rat model.

BACKGROUND: Osteomyelitis is a challenge for orthopedic surgeons due to its protracted treatment process. Microwaves (MWs) can increase blood perfusion due to their thermal effect. Furthermore, MWs demonstrated significant bactericidal effects in vitro. In the present study, we assumed that the application of a 2450-MHz-frequency MW together with systemic antibiotic treatment would provide synergy for the treatment of acute osteomyelitis. METHODS: The medullary cavity of the right tibia was inoculated with 107 CFU of methicillin-sensitive Staphylococcus aureus (MSSA-ATCC 29213) in 40 rats, and the rats were randomly divided into four groups according to treatment: group I, saline (control); group II, saline + MW therapy; group III, systemic cefuroxime; and group IV, systemic cefuroxime + MW therapy. MWs were applied for 20 min per day to the infected limbs, and all rats were sacrificed on the 7th day. The severity of tibial osteomyelitis was assessed by quantitative culture analysis. RESULTS: Bacterial counts in groups III and IV were significantly reduced compared with those in the control (p = 0.001 and < 0.001, respectively). Furthermore, significant differences were detected between groups III and IV (p = 0.033). However, the difference between groups I and II was nonsignificant (p = 0.287). CONCLUSION: Our experimental model suggests that MW therapy provides a significant synergy for systemic antibiotic treatment. However, further clinical trials are required to safely use this treatment modality in patients.

Prevalencia de infecciones osteoarticulares por enterobacterias productoras de ß-lactamasas de espectro extendido / Prevalence of osteoarticular infections by Enterobacteria producing extended-spectrum ß-lactamases

Resumen: Introducción: Las infecciones por enterobacterias productoras de β-lactamasas de espectro extendido (BLEEs) ocasionan una gran carga a los sistemas de salud. Poco se conoce de las infecciones osteoarticulares, por lo que este trabajo estudió la prevalencia de estas infecciones en un hospital de tercer nivel. Material y métodos: Estudio de prevalencia en pacientes de un servicio de traumatología durante 2016, con criterios de infección proporcionados por el CDC de Atlanta, Georgia. Se utilizó el sistema VITEK® 2 AST-N272 (bioMérieux) para la identificación bacteriana a nivel de especie y para las pruebas de susceptibilidad antimicrobiana. Resultados: Se reportaron 7.85% (n = 86) con infecciones osteoarticulares; 22.09% (n = 19) fueron por enterobacterias BLEEs. Con un promedio de 77.1 días de hospitalización (DE 37.7) (46-200 días); el aislamiento del microorganismo se produjo 15 días posteriores al ingreso; 16 (84.2%) pacientes presentaron osteomielitis, tres (15.8%) tuvieron infección protésica de rodilla o cadera. El promedio de días de tratamiento fue de 60 días (21-129 días); 18 pacientes (94.7%) fueron dados de alta con resolución de su cuadro infeccioso; un paciente falleció con infección sobreagregada por neumonía debida a K. pneumoniae resistente a carbapenémicos. Discusión: La prevalencia de infecciones osteoarticulares por enterobacterias BLEEs no se pudo calcular con precisión, pero consideramos que se encuentra dentro de lo esperado, las medidas de control de infecciones requieren tener estándares más elevados y falta desarrollar programas de uso racional de antimicrobianos para controlar la aparición de estas patologías.

Abstract: Introduction: Infections of enterobacteria producing extended-spectrum ß-lactamases place a heavy burden on health systems. Little is known in osteoarticular infections, so this work studied the prevalence of these infections in a third-level hospital. Material and methods: Prevalence study in patients of a Traumatology Service during 2016, with infection criteria provided by the CDC in Atlanta, Georgia. The VITEK® 2 AST-N272 (bioMérieux) system was used for bacterial identification at the species level and for antimicrobial susceptibility tests. Results: 7.85% (n = 86) were reported with osteoarticular infections; 22.09% (n = 19) were by enterobacteria BLEEs. An average of 77.1 days of hospitalization (SD 37.7) (46-200 days); isolation of the microorganism occurred 15 days after entry. Sixteen (84.2%) patients had osteomyelitis, three (15.8%) had a prosthetic knee or hip infection. The average number of treatment days was 60 days (21-129 days). Eighteen patients (94.7%) were discharged with resolution of their infectious picture; one patient died with infection over aggregated pneumonia due to carbapenem-resistant K. pneumoniae. Discussion: The prevalence of osteoarticular infections by enterobacteria BLEEs could not be accurately calculated, but we consider it to be within what is expected, infection control measures require higher standards and there is a lack of development programs to use antimicrobials rationally to control the emergence of these pathologies.

Bone transport with a unilateral external fixator for femoral infected nonunion after intramedullary nailing fixation: A case control study.

This is a therapeutic study to evaluate the results of femoral infected nonunion using bone transport with an external fixator after debridement and irrigation. We retrospectively reviewed 15 patients with femoral infected nonunion after intramedullary nailing fixation of fractures from October 1999 to January 2010 in our institute. There were 7 males and 8 females with an average age of 32.5 years. First, the infection was eradicated completely, and the medullary canals were continuous irrigated for 2-3 weeks. After eradicating the infection tissues, the mean amount of bone defect was 8.7 cm (range, 4.0-16.0 cm). The unilateral consecutive distraction-compression osteosynthesis technique was applied after long-time medullary cavity-wound exclusion surgery. Enumeration data was described by frequency and measurement data by mean. Bone infections were controlled in all patients except 1 patient after the first debridement and irrigation. All patients have achieved bony union without recurrence of infection during the follow-up period, the mean external fixation index was 43.4 day/cm. According to the criteria recommended by Paley, the bone results were graded as excellent in 13 (86.7%) cases and good in 2 (13.3%) cases; the functional results were graded as excellent in 6 (40.0%) cases, good in 6 (40.0%) cases and fair in 3 (20.0%) cases. In management of femoral infectious nonunion which caused by intramedullary nailing fixation, the surgery of consecutive compression-distraction osteogenesis with unilateral external fixator achieves a highly effective treatment, and the method of debridement and irrigation is a compatible choice on the phase of infection-elimination.

Hand Infections in the Immunocompromised Patient: An Update.

Physicians are increasingly caring for immunocompromised individuals owing, in part, to the improved treatments and the increased life expectancy in these patients. Presentation of a patient with hand infection can vary greatly depending on the patient's underlying immune status. It is important to recognize and treat the infections quickly and effectively owing to the higher morbidity and mortality that may result from ineffective or delayed treatment in this patient population. The purpose of this article is to provide an outline of the most common and some of the more exotic organisms causing hand infections in patients with human immunodeficiency virus/acquired immunodeficiency syndrome, diabetes, and patients on immunosuppressive treatment. We discuss presentation, clinical picture, evidence-based approaches in treatment, and possible complications. It is important to inform surgeons of the atypical presentation of hand infections and systemic infections with hand manifestation in immunocompromised patients in order to shorten time to accurate diagnosis and effective treatment.

Mycobacterial Musculoskeletal Infections.

Although less common as causes of musculoskeletal infection than pyogenic bacteria, both Mycobacterium tuberculosis and nontuberculous mycobacteria can infect bones and joints. Although tuberculous arthritis and osteomyelitis have been recognized for millennia, infections caused by nontuberculous mycobacteria are being identified more often, likely because of a more susceptible host population and improvements in diagnostic capabilities. Despite advances in modern medicine, mycobacterial infections of the musculoskeletal system remain particularly challenging to diagnose and manage. This article discusses clinical manifestations of musculoskeletal infections caused by Mycobacterium tuberculosis and nontuberculous mycobacteria. Pathogenesis, unique risk factors, and diagnostic and therapeutic approaches are reviewed.

Combination drug chemotherapy and massive skeletal allograft in the management of hydatid disease of femur.

Hydatid disease of long bone is a rare presentation. Chemotherapy and surgery constitute the standard treatment of choice. Non-union of a pathological fracture of femur particularly due to hydatid disease has been known to be resistant to treatment. These resistant cases require combination drug chemotherapy and excision of the lesion. Reconstruction of a large skeletal defect following resection of the lesion poses a challenge to the orthopaedic surgeons. We discuss the staged treatment of hydatid disease of shaft of femur with resection and cement spacer application followed by reconstruction using massive skeletal allograft under cover of combination drug chemotherapy.

Treatment of infected non-unions of the femur and tibia in a French referral center for complex bone and joint infections: Outcomes of 55 patients after 2 to 11 years.

INTRODUCTION: An infected non-union is a major complication following bone fracture. While bone union can be obtained in 70% to 100% of cases, treatment of osteomyelitis is less predictable, with reported healing rates ranging from 40% to 100%. The primary aim of this study was to assess the success rate of treating infected non-unions of the tibia and femur by a team specializing in complex bone and joint infections. MATERIAL AND METHODS: This single-center retrospective study included all patients operated between 2002 and 2012 due to an infected non-union of the femur or tibia using standardized surgical methods. The procedure was typically done in two phases: excision of the infected site and stabilization, followed by bone reconstruction after a waiting period. Additional procedures (lavage and/or bone grafting) were performed in some cases. A minimum 6-week course of antibiotic therapy was given. The primary endpoint was successful medical and surgical treatment after a minimum 2 years' follow-up defined as healing of the infection (no local clinical signs of infection, ESR≤20mm and CRP≤10mg/L, no mortality attributed to the infection) and radiological and clinical bone union, with the lower limb spared. RESULTS: Fifty-five patients (39 men, 16 women) were included with an average age of 37±11 years. There were 40 tibial fractures and 15 femur fractures. A polymicrobial infection was present in 47% of cases. Repeat surgery was required in 56.4% of patients. At an average of 4±2 years from the first surgical procedure, the treatment was successful in 49 patients (89%): 36 tibia (90%) and 13 femur (87%). The mean time to union was 9±4 months. There were six failures: 3 amputations at 5, 6 and 16 months; 1 mechanical and infection-related failure; 2 failed union. CONCLUSION: This study found that 89% of patients with an infected tibial or femoral non-union treated by a team specialized in complex bone and joint infections using a standardized surgical protocol had bone union and healing of the infection in an average of 9 months. LEVEL OF EVIDENCE: IV, retrospective study.

Cutaneous Sinus Tract from Mandibular Second Molar with C-shaped Canal System and Improper Former Root Canal Treatment: A Case Report.

Here, we report the diagnosis and treatment of an extraoral cutaneous sinus tract originating in a mandibular second molar with a C-shaped root canal system. The patient was referred to our department by a dermatologist after a series of unsuccessful treatments, including antibiotics. Diffuse radiolucency on a preoperative radiograph revealed that earlier root canal treatment had been only partially successful. Consequently, we performed retreatment of the root canal comprising removal of the former restoration and gutta-percha, cleaning and shaping, and passive irrigation with sodium hypochlorite. The patient responded well, and the cutaneous lesion completely resolved uneventfully within 1 month postoperatively. Preoperative recognition and thorough knowledge of the root canal anatomy and conventional methods of obturation are necessary in performing successful endodontic treatment.

Local transplantation of bone marrow concentrated granulocytes precursors can cure without antibiotics infected nonunion of polytraumatic patients in absence of bone defect.

PURPOSE: Infected, long bone non-unions present a significant clinical challenge. New and alternative therapies are needed to address this problem. The purposes of this study were to compare the number of circulating granulocyte-macrophage colony-forming units (CFU-GM) in the peripheral blood of polytraumatic patients with infected tibial non-unions and in the peripheral blood of control patients with the hypothesis that their number was decreased in polytraumatic patients; and to treat their infection without antibiotics and with local transplantation of bone marrow concentrated granulocytes precursors. METHODS: Thirty (18 atrophic and 12 hyperthrophic ) infected tibial non-unions (without bone defect) that occurred after open fractures in polytraumatic patients were treated without antibiotics and with percutaneous injection of autologous bone marrow concentrate (BMC) containing granulocytes precursors (CFU-GM). CFU-GM progenitors were assessed in the bone marrow aspirate, peripheral blood, and fracture site of these patients. The number of these progenitors was compared with the CFU-GM progenitors of control patient samples (healthy donors matched for age and gender). Outcome measures were: timing of union, callus formation (radiographs and CT scan), and recurrence of clinical infection. RESULTS: As compared to control patients, the number of CFU GM derived colonies was lower at peripheral blood in patients with infected nonunions. The bone marrow graft injected in nonunions contained after concentration 42 621 ± 20 350 CFU-GM-derived colonies/cc. Healing and cure of infection was observed at six months for 25 patients and at one year follow up for 30 patients. At the median ten year follow-up (range: 5 to 15), only one patient had clinical recurrent infection after healing (between 6 months and last follow-up). CONCLUSION: The peripheral blood of these polytraumatic patients with infected nonunions had a remarkable decrease in CFU-GM-derived colonies as compared with normal controls. Local transplantation of concentrated CFU-GM-derived colonies aspirated from bone marrow allowed cure of infection and healing without antibiotics.

Oncological approach with antihelminthic chemotherapy and wide resection in the treatment of musculoskeletal hydatidosis. A review of 10 cases with mean follow-up of 64 months.

The objective of this retrospective study was to evaluate clinical outcomes, local recurrence and complication rates of antihelminthic chemotherapy and wide resection in patients with muscle or bone hydatidosis. The authors treated 10 patients (6 females, 4 males) between 2004 and 2012: 8 with muscle and 2 with bone hydatidosis. The mean age at surgery was 42.5 years (range, 11-66 years). All patients were treated with wide resection and pre- and postoperative chemotherapy with albendazole. The mean follow-up was 64 months (range, 28-120 months). All patients achieved satisfactory clinical outcomes. There were no local recurrences. Surgical complications were seen in 3 patients (30%) : one superficial infection, one deep infection, and one hematoma. Two (20%) required additional surgery. An aggressive oncological approach, consisting of antihelminthic chemotherapy and wide resection, can provide favorable clinical outcomes and prevent local recurrence in patients with musculoskeletal hydatidosis. Potential complications of aggressive surgery should be preferred to potential morbidity of local and systemic dissemination.

Dimorphic fungal osteoarticular infections.

The objective of this investigation was to review the clinical manifestations, management, and outcome of osteoarticular infections caused by dimorphic fungi. We exhaustively reviewed reports of bone and joint infections caused by dimorphic fungi published between 1970 and 2012. Underlying conditions, microbiological features, histological characteristics, clinical manifestations, antifungal therapy, and outcome were analyzed in 222 evaluable cases. Among 222 proven cases (median age 41 years [interquartile range (IQR) 26-57]), 73 % had no predisposing condition. Histopathology performed in 128 (57 %) cases and culture in 170 confirmed diagnosis in 63 % and 98 % of the cases, respectively. Diagnosis was obtained from an extra-osteoarticular site in 16 cases. The median diagnostic time was 175 days (IQR 60-365). Sporothrix schenckii was the most frequent pathogen (n = 84), followed by Coccidioides immitis (n = 47), Blastomyces dermatitidis (n = 44), Histoplasma capsulatum (n = 18), Paracoccidioides brasiliensis (n = 16), and Penicillium marneffei (n = 13). Arthritis occurred in 87 (58 %) cases and osteomyelitis in 64 (42 %), including 19 vertebral osteomyelitis. Dissemination was reported in 123 (55 %) cases. Systemic antifungal agents were used in 216 (97 %) patients and in combination with surgery in 129 (60 %). Following the Infectious Diseases Society of America (IDSA) guidelines, a successful initial medical strategy was observed in 97/116 (84 %) evaluable cases. The overall mortality was 6 %, and was highest for P. marneffei (38.5 %). This study demonstrates that dimorphic osteoarticular infections have distinctive clinical presentations, occur predominantly in apparently immunocompetent patients, develop often during disseminated disease, and may require surgical intervention.