Temocillin: a new candidate antibiotic for local antimicrobial delivery in orthopaedic surgery?

OBJECTIVES: To assess the performance of the Gram-negative-specific antibiotic temocillin in polymethylmethacrylate bone cement pre-loaded with gentamicin, as a strategy for local antibiotic delivery. METHODS: Temocillin was added at varying concentrations to commercial gentamicin-loaded bone cement. The elution of the antibiotic from cement samples over a 2 week period was quantified by LC-MS. The eluted temocillin was purified by fast protein liquid chromatography and the MICs for a number of antibiotic-resistant Escherichia coli were determined. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. RESULTS: LC-MS data showed temocillin eluted to clinically significant concentrations within 1 h in this laboratory system and the eluted temocillin retained antimicrobial activity against all organisms tested. Impact strength analysis showed no significant difference between cement samples with or without temocillin. CONCLUSIONS: Temocillin can be added to bone cement and retains its antimicrobial activity after elution. The addition of up to 10% temocillin did not affect the impact strength of the cement. The results show that temocillin is a promising candidate for use in antibiotic-loaded bone cement.

Systemic antibiotics are not required for successful two-stage revision hip arthroplasty.

The duration of systemic antibiotic treatment following first-stage revision surgery for periprosthetic joint infection (PJI) after total hip arthroplasty (THA) is contentious. Our philosophy is to perform an aggressive debridement, and to use a high local concentration of targeted antibiotics in cement beads and systemic prophylactic antibiotics alone. The aim of this study was to assess the success of this philosophy in the management of PJI of the hip using our two-stage protocol. The study involved a retrospective review of our prospectively collected database from which we identified all patients who underwent an intended two-stage revision for PJI of the hip. All patients had a diagnosis of PJI according to the major criteria of the Musculoskeletal Infection Society (MSIS) 2013, a minimum five-year follow-up, and were assessed using the MSIS working group outcome-reporting tool. The outcomes were grouped into 'successful' or 'unsuccessful'. A total of 299 two-stage revision THAs in 289 patients met the inclusion criteria, of whom 258 (86%) proceeded to second-stage surgery. Their mean age was 68.1 years (28 to 92). The median follow-up was 10.7 years (interquartile range (IQR) 6.3 to 15.0). A 91% success rate was seen in those patients who underwent reimplantation, decreasing to 86% when including those who did not proceed to reimplantation. The median duration of postoperative systemic antibiotics following the first stage was five days (IQR 5 to 9). There was no significant difference in outcome between those patients who were treated with antibiotics for ≤ 48 hours (p = 0.961) or ≤ five days (p = 0.376) compared with those who were treated with longer courses. Greater success rates were seen for Gram-positive PJIs (87%) than for Gram-negative (84%) and mixed-Gram PJIs (72%; p = 0.098). Aggressive surgical debridement with a high local concentration of targeted antibiotics at the time of first-stage revision surgery for PJI of the hip, without prolonged systemic antibiotics, provides a high rate of success, responsible antibiotic stewardship, and reduced hospital costs.

Iliopsoas tendonitis caused by overhang of a collared femoral prosthesis.

Pain after total hip arthroplasty can be due to a variety of causes, one of the less common being iliopsoas tendonitis. We report an unusual case of iliopsoas tendonitis caused by overhang of the femoral calcar by a collared femoral prosthesis resulting in impingement on the iliopsoas tendon. An ultrasound-guided corticosteroid and local anesthetic diagnostic injection to the site of impingement confirmed the diagnosis with temporary symptom relief. Revision of the femoral stem to a collarless prosthesis resulted in immediate and complete resolution of symptoms.

Review of total hip arthroplasty in patients younger than 30 years: mid- to long-term results.

BACKGROUND: Data on the outcome of THA in patients under the age of 30 years is sparse. There is a perceived reluctance to offer surgery to young patients on the basis of potential early failure of the implant. The aim of this study was to review clinical and radiological outcomes of THA in patients under the age of 30 years in a high-volume specialist arthroplasty unit. METHODS: A retrospective review of patients between 1989 and 2009 was undertaken. 95 patients (118 THAs) were identified but 17 patients were excluded for lack of clinical records or for follow-up under 5 years. Clinical records were reviewed for demographics, underlying pathology, details of operation and failures. Radiographs were reviewed for evidence of loosening and wear of the components. Functional assessment was carried out using the modified Hip disability and Osteoarthritis Outcome Score, Oxford Hip Score and EQ-5D-5L. RESULTS: Mean age was 25 (16-30) years and 65% patients were females. The most common underlying pathologies were development dysplasia of the hip (29%) and juvenile rheumatoid arthritis (25%). Mean follow-up was 12.6 (5-24) years, during which 19 patients (25%) were revised. The majority of the revisions were for aseptic loosening of the acetabular component. CONCLUSIONS: Surgeons are cautious when considering THA in very young patients despite the significant documented improvement in function and quality of life after THA. This study reports on the mid- to long-term results of THA which will be valuable when advising young patients on the prospects of revision surgery at the time of primary THA.

The antimicrobial activity and biocompatibility of a controlled gentamicin-releasing single-layer sol-gel coating on hydroxyapatite-coated titanium.

AIMS: The aim of this study was to develop a single-layer hybrid organic-inorganic sol-gel coating that is capable of a controlled antibiotic release for cementless hydroxyapatite (HA)-coated titanium orthopaedic prostheses. METHODS: Coatings containing gentamicin at a concentration of 1.25% weight/volume (wt/vol), similar to that found in commercially available antibiotic-loaded bone cement, were prepared and tested in the laboratory for: kinetics of antibiotic release; activity against planktonic and biofilm bacterial cultures; biocompatibility with cultured mammalian cells; and physical bonding to the material (n = 3 in all tests). The sol-gel coatings and controls were then tested in vivo in a small animal healing model (four materials tested; n = 6 per material), and applied to the surface of commercially pure HA-coated titanium rods. RESULTS: The coating released gentamicin at > 10 × minimum inhibitory concentration (MIC) for sensitive staphylococcal strains within one hour thereby potentially giving effective prophylaxis for arthroplasty surgery, and showed > 99% elution of the antibiotic within the coating after 48 hours. There was total eradication of both planktonic bacteria and established bacterial biofilms of a panel of clinically relevant staphylococci. Mesenchymal stem cells adhered to the coated surfaces and differentiated towards osteoblasts, depositing calcium and expressing the bone marker protein, osteopontin. In the in vivo small animal bone healing model, the antibiotic sol-gel coated titanium (Ti)/HA rod led to osseointegration equivalent to that of the conventional HA-coated surface. CONCLUSION: In this study we report a new sol-gel technology that can release gentamicin from a bioceramic-coated cementless arthroplasty material. In vitro, local gentamicin levels are in excess of what can be achieved by antibiotic-loaded bone cement. In vivo, bone healing in an animal model is not impaired. This, thus, represents a biomaterial modification that may have the potential to protect at-risk patients from implant-related deep infection. Cite this article: Bone Joint J 2021;103-B(3):522-529.

Infection and failure rates following total hip arthroplasty for septic arthritis: a case-controlled study.

INTRODUCTION: Total hip arthroplasty (THA) is performed as a 2-stage or single stage procedure in patients with a history of septic arthritis of the native hip joint. The decision is based on whether the infection is active or quiescent in the joint. The aim of this study was to compare the outcomes of total hip arthroplasty for septic arthritis of the native hip to a control series of patients treated for primary osteoarthritis of the hip with standard THA. METHODS: Between March 2000 and March 2013, 18 cases of septic arthritis of the hip treated with THA were retrospectively identified. During the same time period, 18 control cases of THA for degenerative osteoarthritis were identified. Cases and controls were comparable in age, gender, body mass index, type of anaesthesia and American Society of Anesthesiologists score. RESULTS: 11 and 7 cases received 2-stage and single stage total hip arthroplasty respectively for septic arthritis. There was a mean interval of 4 months between 1st and 2nd-stage operations. Cases and controls were followed up for a mean of 70 and 72 months respectively. There was no reinfection or implant failure in the cases, and comparable functional outcomes between cases and controls. CONCLUSIONS: Two-stage and single-stage THA for active and quiescent native hip infection respectively, achieved similar outcomes to THA for primary osteoarthritis in controls.

"Combined Diagnostic Tool" APPlication to a Retrospective Series of Patients Undergoing Total Joint Revision Surgery.

Background: Differentiating between septic and aseptic joint prosthesis may be challenging, since no single test is able to confirm or rule out infection. The choice and interpretation of the panel of tests performed in any case often relies on empirical evaluation and poorly validated scores. The "Combined Diagnostic Tool (CDT)" App, a smartphone application for iOS, was developed to allow to automatically calculate the probability of having a of periprosthetic joint infection, on the basis of the relative sensitivity and specificity of the positive and negative diagnostic tests performed in any given patient. Objective: The aim of the present study was to apply the CDT software to investigate the ability of the tests routinely performed in three high-volume European centers to diagnose a periprosthetic infection. Methods: This three-center retrospective study included 120 consecutive patients undergoing total hip or knee revision, and included 65 infected patients (Group A) and 55 patients without infection (Group B). The following parameters were evaluated: number and type of positive and negative diagnostic tests performed pre-, intra- and post-operatively and resultant probability calculated by the CDT App of having a peri-prosthetic joint infection, based on pre-, intra- and post-operative combined tests. Results: Serological tests were the most common performed, with an average 2.7 tests per patient for Group A and 2.2 for Group B, followed by joint aspiration (0.9 and 0.8 tests per patient, respectively) and imaging techniques (0.5 and 0.2 test per patient). Mean CDT App calculated probability of having an infection based on pre-operative tests was 79.4% for patients in Group A and 35.7 in Group B. Twenty-nine patients in Group A had > 10% chance of not having an infection, and 29 of Group B had > 10% chance of having an infection. Conclusion: This is the first retrospective study focused on investigating the number and type of tests commonly performed prior to joint revision surgery and aimed at evaluating their combined ability to diagnose a peri-prosthetic infection. CDT App allowed us to demonstrate that, on average, the routine combination of commonly used tests is unable to diagnose pre-operatively a peri-prosthetic infection with a probability higher than 90%.

Precision of periprosthetic bone mineral density measurements using Hologic Windows versus DOS-based analysis software.

Dual energy X-ray absorptiometry (DXA) is a precise tool for measuring bone mineral density (BMD) around total joint prostheses. The Hologic "metal-removal hip" analysis package (Hologic Inc., Waltham, MA) is a Microsoft DOS-based analysis platform that has undergone a change in the operating platform to a Microsoft Windows-based system that has also incorporated changes to DXA image manipulation on-screen. We evaluated the impact of these changes on instrument precision by analysis of sequential DXA scans taken on the same day using the Hologic QDR-4500A fan beam densitometer (Hologic Inc.) in 29 subjects after total hip arthroplasty. The coefficient of variation percentage (CV%) for the net pelvic region was 3.04 for Windows versus 2.36 for DOS (p>0.05). The CV% for the net femoral region was 1.75 for Windows versus 1.51 for DOS (p>0.05). Absolute BMD values for the net pelvic and net femoral regions were similar (Bland-Altman, Windows minus DOS; pelvic region mean=-1.0%; femoral region mean=1.3%; p>0.05 for both comparisons). Our results suggest that scans analyzed using each platform may be used interchangeably without the need for a calibration correction.

One-stage or two-stage revision surgery for prosthetic hip joint infection--the INFORM trial: a study protocol for a randomised controlled trial.

BACKGROUND: Periprosthetic joint infection (PJI) affects approximately 1% of patients following total hip replacement (THR) and often results in severe physical and emotional suffering. Current surgical treatment options are debridement, antibiotics and implant retention; revision THR; excision of the joint and amputation. Revision surgery can be done as either a one-stage or two-stage operation. Both types of surgery are well-established practice in the NHS and result in similar rates of re-infection, but little is known about the impact of these treatments from the patient's perspective. The main aim of this randomised controlled trial is to determine whether there is a difference in patient-reported outcome measures 18 months after randomisation for one-stage or two-stage revision surgery. METHODS/DESIGN: INFORM (INFection ORthopaedic Management) is an open, two-arm, multi-centre, randomised, superiority trial. We aim to randomise 148 patients with eligible PJI of the hip from approximately seven secondary care NHS orthopaedic units from across England and Wales. Patients will be randomised via a web-based system to receive either a one-stage revision or a two-stage revision THR. Blinding is not possible due to the nature of the intervention. All patients will be followed up for 18 months. The primary outcome is the WOMAC Index, which assesses hip pain, function and stiffness, collected by questionnaire at 18 months. Secondary outcomes include the following: cost-effectiveness, complications, re-infection rates, objective hip function assessment and quality of life. A nested qualitative study will explore patients' and surgeons' experiences, including their views about trial participation and randomisation. DISCUSSION: INFORM is the first ever randomised trial to compare two widely accepted surgical interventions for the treatment of PJI: one-stage and two-stage revision THR. The results of the trial will benefit patients in the future as the main focus is on patient-reported outcomes: pain, function and wellbeing in the long term. Patients state that these outcomes are more important than those that are clinically derived (such as re-infection) and have been commonly used in previous non-randomised studies. Results from the INFORM trial will also benefit clinicians and NHS managers by enabling the comparison of these key interventions in terms of patients' complication rates, health and social resource use and their overall cost-effectiveness. TRIAL REGISTRATION: Current controlled trials ISRCTN10956306 (registered on 29 January 2015); UKCRN ID 18159.

Polyethylene wear rate and osteolysis: critical threshold versus continuous dose-response relationship.

We studied the relationship between polyethylene wear and osteolysis in 230 subjects after cemented Charnley total hip arthroplasty in order to examine the validity of the wear rate threshold concept. Polyethylene wear measured using image analysis (EBRA) software was compared in 115 subjects with osteolysis versus 115 control subjects that were individually matched for age, sex, and follow up period. Subjects with osteolysis had almost twice the mean annual wear rate versus the controls. The incidence of osteolysis increased in a linear manner with each quintile increase in wear rate throughout the range 0.01-0.54 mm/year. The odds-ratio for osteolysis approximately doubled with each quintile increase in wear rate above the middle quintile (wear rate 0.08-0.11 mm/year), and decreased at a similar rate with each quintile decrease in wear rate below the middle quintile. Our data suggests that the association of osteolysis with polyethylene wear rate represents a continuous dose-response relationship and does not support the concept of a discrete critical wear rate threshold above which the risk of osteolysis is disproportionately increased.

Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial.

In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar (P = 0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.

Re-infection outcomes following one- and two-stage surgical revision of infected hip prosthesis in unselected patients: protocol for a systematic review and an individual participant data meta-analysis.

BACKGROUND: Several aggregate published reviews have compared the effectiveness of one- and two-stage surgical revision to prevent re-infection following prosthetic hip infection and have reported inconsistent results. In addition, there were several features of these previous reviews which limited the validity of the findings. In the absence of a well-designed clinical trial, we propose the Global Infection Orthopaedic Management (INFORM) collaboration, a worldwide collaborative systematic review and meta-analysis of individual participant data (IPD) to address the existing uncertainties. METHODS: Cohort studies (prospective or retrospective) and randomised controlled trials conducted in unselected patients with infection treated exclusively by one- or two-stage revision and reporting re-infection outcomes within 2 years of revision will be retrieved by searching the following databases: MEDLINE, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and the WHO International Clinical Trials Registry Platform. Reference lists of relevant studies will be manually scanned and there will be email contact with investigators of grey literature and conference abstracts. Investigators will be invited to join the Global INFORM collaboration and share their individual level data. The primary outcome of the analyses will be incidence of re-infection within 2 years of commencement of revision surgery. Primary analyses will be conducted comparing the one-stage to the two-stage surgical revision. IPD analyses will be based on Cox proportional hazard (PH) models estimated for each study separately. Study-specific log hazard ratios will be combined using random-effects meta-analysis with fixed-effects meta-analysis in subsidiary analyses. Hazard ratios for re-infection according to different individual level characteristics such as sex, age groups, body mass index and comorbidities will also be assessed. DISCUSSION: The analyses will enable a consistent approach to the definition of re-infection outcomes, more detailed analyses under a broader range of circumstances and exploration of potential sources of heterogeneity and produce much more valid and precise estimates of re-infection outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015: CRD42015016664.

Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplasty.

UNLABELLED: Genetic factors may influence implant failure caused by osteolysis after THA. In an association study of 481 subjects after THA, we found that carriage of the TNF-238A allele was associated with an increased incidence of osteolysis versus noncarriage (odds ratio, 1.7) and was independent of other risk factors. Genetic and environmental factors influence implant survival after THA. INTRODUCTION: Tumor necrosis factor (TNF) is thought to play a role in osteolysis, the major cause of implant failure after total hip arthroplasty (THA). Natural sequence variations at -238 and -308 in the TNF gene promoter are associated with differences in susceptibility to several TNF-mediated diseases. We tested whether these polymorphisms are associated with osteolysis after THA. MATERIALS AND METHODS: A total of 481 whites (214 with failed versus 267 with intact implants) were recruited 11.7 +/- 4 years after cemented THA. Genomic DNA was extracted from peripheral blood and genotyped for the -238 and -308 polymorphisms using the Taqman 5' nuclease method. Healthy controls (n = 500) from the background population were also genotyped to establish the local prevalence of these alleles. RESULTS: The carriage of -238A was 8.8% in the background population and 10.9% in the THA controls (p > 0.05). Carriage of -238A in the osteolysis group was 17.3% (odds ratio, 1.7; 95% CI, 1.0-2.9). Carriage was highest (20.5%) in patients with more widespread osteolysis (OR, 2.1; 1.2-3.8). The association of -238A with osteolysis was independent of other risk factors for osteolysis (logistic regression analysis: OR, 1.8; 1.0-3.2). Carriage of -308A was not associated with osteolysis. CONCLUSION: Genetic, as well as environmental factors, influence implant failure after THA. Whether the TNF-238 polymorphism causes a biological change that predisposes to loosening or is in linkage disequilibrium with such a locus is not yet known.

Biochemical markers of bone turnover and development of heterotopic ossification after total hip arthroplasty.

We studied biochemical markers of bone turnover markers in 20 men and women over 26 weeks after total hip arthroplasty (THA) in order to characterize the changes in bone metabolism associated with developing heterotopic ossification (HO). Transient increases in biochemical markers of both osteoclast and osteoblast activity occurred after surgery. Subjects developing HO (n=9) had greater rises in the osteoclast marker C-telopeptide of type-I collagen (CTX-I; ANOVA P=0.004), and the osteoblast markers N-terminal propeptide of type-I procollagen (PINP; ANOVA P=0.01) and osteocalcin (OC; ANOVA P=0.02) than those who did not develop HO. A rise of >42% in CTX-I at one week after surgery had a sensitivity of 89% and a specificity of 82% for predicting HO development at week 26 (P<0.05). Rises of >57% in PINP and >13% in OC at week 6 had sensitivities of 89% and 56%, and specificities of 82% and 91%, respectively for development of HO. Transient increases in osteoblast and osteoclast activity occur after THA. These changes are greater in patients developing HO than in those who do not develop HO. The potential applications of these markers are as a non-invasive, radiation-free tool for investigating the pathogenesis of HO, and as an early surrogate outcome marker for HO development in clinical trials of novel prophylaxis regimes for its prevention.

Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty.

The aims of this study were to determine whether subjects with aseptic loosening after total hip arthroplasty (THA) have regional differences in periprosthetic bone mineral density (BMD) and systemic biochemical markers of bone turnover compared to subjects with successful implants.Proximal femoral and pelvic BMD were measured by dual energy X-ray absorptiometry and bone turnover markers were assayed in 49 subjects 12.6+/-4.3 (mean+/-SD) years after cemented THA. Femoral BMD was lower in Gruen zones 2, 5, 6, and 7 in subjects with a loose femoral implant (n=17) compared to those (n=32) with fixed femoral implants (P<0.05 all comparisons). This BMD difference was greatest (-31%, P=0.02) in the proximal and medial region of the femur. Subjects with femoral loosening had higher levels of the bone resorption marker N-telopeptides of type-I collagen (P=0.02) than those with a fixed femoral implant. No differences in pelvic BMD or bone turnover markers were found between subjects with loose (n=18) versus fixed (n=31) pelvic implants. This study suggests that failure of femoral components after cemented THA is associated with region-specific decreases in BMD and an increase in urinary excretion of N-telopeptide cross-links of type-I collagen. These surrogate outcome markers may be of value in monitoring response to antiresorptive therapies used to treat periprosthetic osteolysis, although the diagnosis of aseptic loosening remains clinical and radiological.