Effect of achieving bone sterilisation on bone architecture and bone marrow, in an experimental rabbit model of osteomyelitis caused by carbapenemase-producing Enterobacterales.

OBJECTIVES: Natural history and treatment of bone infections caused by carbapenemase-producing Enterobacterales (CPE) are poorly defined. We evaluated the effect of treatment on the progression of subacute osteomyelitis in a rabbit model. METHODS: Two isolates were used: a KPC-producing Klebsiella pneumoniae and an Escherichia coli harbouring blaOXA-48 and blaCTX-M15 inserts, both susceptible to gentamicin, colistin, fosfomycin, and ceftazidime-avibactam. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 colony-forming units/mL. Antibiotics were started 14 d later, for 7 d, in 6 groups of 12 rabbits. Three days after treatment completion (D24), rabbits were euthanised and bones were cultured. Bone marrow and bone architecture macroscopic changes were evaluated through analysis of pictures by investigators unaware of the rabbit treatment group and microbiological outcome, using scales ranging from 0 (normal) to 3 (severe lesions) depending on modifications. RESULTS: Bone marrow modifications induced by local infection were similar between prematurely deceased animals and non-sterilised animals (P = 0.14) but differed significantly from animals that achieved bone sterilisation after treatment (P = 0.04). Conversely, when comparing bone deformity, rabbits who died early (n = 13) had similar bone architecture as those achieving bone sterilisation (P = 0.12), as opposed to those not sterilised after treatment (P = 0.04). After a multivariate logistic regression, bone marrow scale ≤2 was associated with bone sterilisation (P < 0.001), and bone architecture scale ≤2 was associated with bone sterilisation (adjusted odds ratio = 2.7; 95% confidence interval 1.14-6.37) and KPC infection (adjusted odds ratio = 5.1; 95% confidence interval 2.17-12.13). CONCLUSION: Effective antibacterial treatment reduces bone architecture distortion and bone marrow changes. These variables may be used as proxy for bone sterilisation.

Neurogenic heterotopic ossification in the upper limb.

Neurogenic heterotopic ossifications (NHOs) are periarticular ectopic ossifications that frequently develop after a central nervous system injury, most often a traumatic one. They limit range of motion and cause pain, interfering with limb positioning and function, whether active or passive. Highly described in the lower limbs, NHOs can also develop in the upper limb, with specific characteristics depending on their location. This article provides a summary of the diagnostic and therapeutic management of NHOs in the upper limb, based on the current literature.

Clinical assessment of upper limb hypertonia in central neurological diseases.

The clinical assessment of a hypertonic upper limb in central neurological diseases should be analytical, systematic (shoulder, elbow, extrinsic and intrinsic hand) and focused on the patient or caregiver's wishes and on the expected objectives (esthetic, hygienic, functional). Nerve blocks can help to separate mixed contractures, show the existence of antagonist muscles or find a starter muscle in dystonia patterns. The etiology (especially the evolving nature of the disease), general health condition (especially in older adults), associated deficits (cerebellar, sensory and cognitive; hemineglect) are considered together to arrive at a contract with patients and/or caregivers.

Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis.

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

Colistin-containing cement spacer for treatment of experimental carbapenemase-producing Klebsiella pneumoniae prosthetic joint infection.

Carbapenemase-producing Enterobacteriaceae (CPE) are emerging multidrug-resistant bacteria responsible for invasive infections, including prosthetic joint infections (PJIs). Local administration of colistin may provide bactericidal concentrations in situ. This study evaluated the efficacy of a colistin-impregnated cement spacer, alone and in combination with systemic antibiotics, in a rabbit model of CPE-PJI. Elution of 3 MIU of colistimethate sodium (CMS) in 40 g of poly(methyl methacrylate) cement was studied in vitro. In vivo, 5 × 108 CFU of KPC-producing Klebsiella pneumoniae (colistin and meropenem MICs of 1 mg/L and 4 mg/L, respectively) were injected close to a prosthetic knee. Surgical debridement and prosthesis removal were performed 7 days later, and rabbits were assigned to six treatment groups (11-13 rabbits each): drug-free spacer; colistin-loaded spacer; colistin intramuscular (i.m.); colistin i.m. + colistin spacer; colistin i.m. + meropenem subcutaneous (s.c.); and colistin i.m. + meropenem s.c. + colistin spacer. Systemic treatment was administered at doses targeting pharmacokinetics in humans, and rabbits were euthanised 7 days later to evaluate bacterial counts in infected bones. In vitro, CMS elution was low (<0.1% at 24 h) but reached a local concentration of ≥20 mg/L (>20 × MIC). In vivo, combinations of local and systemic colistin, with or without meropenem, were the only regimens superior to the control group (P ≤ 0.05) in terms of viable bacterial counts and the proportion of rabbits with sterile bone, with no emergence of colistin-resistant strains. Colistin-loaded cement spacer in combination with systemic antibiotics were the most effective regimens in this CPE-PJI model.

Resection of neurogenic heterotopic ossification (NHO) of the hip.

Neurogenic heterotopic ossification of the hip is secondary to neurologic lesions such as cranial trauma, stroke, medullary injury or cerebral anoxia. We shall not deal here with the other etiologies of heterotopic ossification. There are numerous locations within the hip, depending on etiology and relations with adjacent neurovascular structures are sometimes close. Preoperative work-up should include contrast-enhanced CT; scintigraphy is non-contributive. Indications for surgery are decided in a multidisciplinary team meeting, with a contract laying out expected functional gain. It is this contract that determines the extent of resection, without seeking complete resection, which would incur an increased risk of complications. The surgical approach and resection strategy depend on lesion location and any resulting neurovascular compression. The most common complications are infection and postoperative hematoma. No adjuvant treatments have demonstrated efficacy against recurrence.

Postoperative infections after excision of neurogenic heterotopic ossifications at the hip: Risk factors and causative organisms.

BACKGROUND: Neurogenic heterotopic ossification (NHO) is usually treated by surgical excision. Postoperative infection (POI) is a possible complication, whose epidemiology, causative organisms, and risk factors are poorly known. We therefore conducted a case-control study to (1) identify the risk factors for POI after surgical excision of NHO at the hip, (2) determine the frequency of POI, (3) and identify the causative organisms. HYPOTHESIS: Risk factors for POI after NHO excision at the hip can be identified. MATERIAL AND METHODS: In this retrospective case-control study, the BANKHO database for patients with NHO at our centre was used to identify risk factors by comparing patients with and without POI after NHO excision at the hip. To this end, odds ratios (ORs) with their 95% confidence intervals (95%CIs) were computed for each main criterion. Postoperative follow-up was at least 6 months. RESULTS: Between 1993 and 2013, 411 hip NHO excisions were performed. Among them, 42 (10%) were followed by POI. The American Society of Anesthesiologists (ASA) score was I in 2/42 (5%) patients with vs. 74/369 (20%) patients without POI, II in 30/42 (71%) patients with vs. 258/369 (70%) patients without POI, and III in 10/42 (24%) patients with vs. 37/369 (10%) patients without POI (P<0.01). Mean age was 31±11 years (range, 17-79years) in the group with POI and 39±14 years (range, 15-77years) in the group without POI (P<0.01). The NHO was related to spinal cord injury in 26/42 (62%) patients with POI compared to 92/369 (25%) patients without POI (P<0.01). ORs indicated a significant risk increase in patients with an ASA score of III (2.84; 95%CI, 1.28-6.31), age younger than 30 years (1.85; 95%CI, 1.03-3.32), and spinal cord injury as the cause of NHO (4.89; 95%CI, 2.67-8.98). The predominant organisms were staphylococci (skin flora) in the patients with spinal cord injury and bacteria commonly found in intensive care units in the other patients. DISCUSSION: A higher ASA score, younger age, and spinal cord injury as the cause of NHO at the hip are risk factors for POI. The proportion of patients with POI after hip NHO excision was 10%, in accordance with previous reports. POI was more common among patients with spinal cord injury (22% vs. 5% in the other patients). Neither changes in prophylactic antibiotic therapy regimens nor the institution of a detailed skin preparation protocol affected the frequency of POI. Skin pH alterations may deserve to be investigated with the goal of diminishing the risk of POI, most notably in spinal cord injury patients. LEVEL OF EVIDENCE: III, case-control study.

Critical analysis of experimental models of periprosthetic joint infection.

INTRODUCTION: Because the extreme diversity of clinical situations makes formal clinical trials difficult to carry out, animal models of periprosthetic infection in orthopaedics are needed to understand the aetiology and pathology of these infections, and to test new treatment methods. These experimental models must reproduce the features of the infections encountered in clinical practice. One of the model variables is the method of inoculation: local (intra-articular), intravenous or intra-arterial. Another is the timing of the inoculation: intra-operative or postoperative. Together, these options simulate the different contamination methods: direct, by proximity or blood-borne. However, the chosen inoculation route can also affect the infection rate and severity in the various models, and in some cases do not accurately reproduce the postoperative infections encountered clinically. HYPOTHESIS: The direct inoculation method is the most effective for inducing a local infection on a foreign body in a joint, and the least iatrogenic. METHODS: A critical analysis of published studies was carried out to evaluate each model against three endpoints, according to the type of inoculation. The primary endpoint was the infection rate, which should be as close as possible to 100%. The secondary endpoints were the mortality rate and rate of spontaneous healing, both of which should be as low as possible. Twenty-one articles were reviewed. RESULTS: Intra-articular and intra-medullary inoculations had induction rates between 70 and 100%; intra-arterial inoculations had an induction rate of 100%, while intravenous inoculation had a rate of 47 to 77%. The mortality rates were lower with the intra-articular and intramedullary inoculations (5 to 23%) than for the intra-arterial inoculations (37%) and intravenous inoculations (28 to 56%). The spontaneous healing rate was 0 to 30% for intra-articular and intramedullary inoculations, 30 to 53% for intravenous inoculations and 0% for intra-arterial inoculations. CONCLUSION: Direct inoculation methods are most effective at reproducing chronic periprosthetic joints infections, without putting the animal's life at risk or allowing for spontaneous healing. The simulation of blood-borne infections is more random.

Beliefs relating to recurrence of heterotopic ossification following excision in patients with spinal cord injury: a review.

STUDY DESIGN: Review of the literature. OBJECTIVES: It is widely believed that the timing of surgery and the size of the initial Neurological Heterotopic Ossification (NHO) affect the recurrence risk of NHO after SCI. A large number of studies were published in the 80s and the 90s, mostly of poor quality despite the fact that they were carried out by experienced surgical teams. The aim of this study was to suggest recommendations relating to the timing of excision of heterotopic ossification after SCI following the analysis of a recent review of the literature. SETTING: France. METHODS: A systematic literature search was performed in the PubMed Embase from January 2002 until June 2014 using the MESH headings 'spinal cord injury', 'paraplegia', 'heterotopic ossification' and 'surgery'. Results were compared with results from epidemiological studies based on the BANKHO database (patients who underwent surgery for troublesome HO after central neurological system (CNS) lesions in our center (357 patients, 539 surgeries)). RESULTS: Few studies were found in the literature, results were sometimes contradictory and practices heterogeneous. Results from the BANKHO database showed that troublesome recurrence of NHO was not associated with 'early' surgery (before 6 months), and no association was found between recurrence and the size of the NHO around the joint (Brooker status). CONCLUSION: We suggest that surgical excision of the NHO should be carried out when it begins to be troublesome, as soon as comorbid factors are under control and the HO is sufficiently constituted for excision.

Anterior hip dislocation in children with neurological disorders. A retrospective study of ten operated hips.

INTRODUCTION: Patients with neurological disorders often exhibit dislocation or subluxation of the hip. Anterior dislocation is rare, little known, and often associated with deformities. Its surgical treatment has rarely been studied. HYPOTHESIS: Hip surgery (with open reduction, femoral and pelvic osteotomy, and adapted tenotomies) could provide a centered hip that is supple and painless. MATERIALS AND METHODS: Ten hips (seven dislocated, three subluxated) in six patients with a mean age of 8.3 years were operated between 1995 and 2009 and revised with a mean follow-up of 6.5 years. The deformities comprised four cases of abduction, extension, and external rotation and six cases of adduction, extension, and external rotation. Four patients had lost the ability to walk or maintain the sitting position. Intraoperative findings were an increased neck-shaft angle, anterosuperior acetabular dysplasia, and in only one case increased femoral anteversion. In all cases of dislocation, open reduction was necessary, and all hips underwent pelvic and femoral osteotomy. RESULTS: At the longest follow-up, hips were centered on X-rays. Five patients could walk or sit as they had done before and hips were supple, with no deformities. DISCUSSION: The study of deformities and intraoperative findings is mandatory for surgical management, whose mid-term results are encouraging. Femoral anteversion does not seem to be excessive, but the increase of femoral valgus is constant, as is anterosuperior acetabular dysplasia. We propose a decision tree for the management of these patients. DESIGN OF STUDY: Retrospective. LEVEL OF SCIENTIFIC EVIDENCE: IV.