Local Application Of Antibiotics Research Articles

Bumblefoot in a pigeon (Columba livia): A clinical case report

Avian bumblefoot or ulcerative pododermatitis is a term used to denote inflammatory, infectious or degenerative conditions of the avian foot and can cause mild swelling and redness to ulceration of the planter surfaces of feet and toes. This report documents the clinical case of a rescued Rock Pigeon (Columba livia) which was diagnosed with bumblefoot based on the clinical observations. The Rock Pigeon was successfully treated and eventually released using a therapeutic treatment protocol involving systemic antibiotic administration, local antibiotic application, bandaging of the affected portion with supportive therapy. This case report describes the successful therapeutic management of ulcerative pododermatitis or bumblefoot in a Pigeon.

The prospects of antimicrobial coated medical implants.

The implants are increasingly being a part of modern medicine in various surgical procedures for functional or cosmetic purposes. The progressive use of implants is associated with increased infectious complications and prevention of such infections always remains precedence in the clinical settings. The preventive approaches include the systemic administration of antimicrobial agents before and after the surgical procedures as well as the local application of antibiotics. The relevant literature and existing clinical practices have highlighted the role of antimicrobial coating approaches in the prevention of implants associated infections, although the applications of these strategies are not yet standardized, and the clinical efficacy is not much clear. The adequate data from the randomized control trials is challenging because of the unavailability of a large sample size although it is compulsory in this context to assess the clinical efficacy of preemptive practices. This review compares the efficacy of preventive approaches and the prospects of antimicrobial-coated implants in preventing implant-related infections.

Early application of topical antibiotic powder in open-fracture wounds: A strategy to prevent biofilm formation and infections.

Despite meticulous surgical care and systemic antibiotics, open fracture wounds have high rates of infection leading to increased morbidity. To reduce infection rates, orthopaedic surgeons may administer local antibiotics using various carriers that may be ineffective due to poor antibiotic release from carriers, subsequent surgery to remove nondegradable carriers, and mismatch between release kinetics and material degradation. Biofilms form rapidly as bacteria that are within the wound multiply quickly and transform from the antibiotic-susceptible planktonic phenotype to the antibiotic-tolerant biofilm phenotype. This tolerance to antibiotics can occur within hours. Currently, local antibiotics are placed in the wounds using a carrier such as polymethylmethacrylate beads; however, this occurs after surgical debridement that can be hours to even a day after initial injury allowing bacteria enough time to form a biofilm that makes the antibiotic containing polymethylmethacrylate beads less effective. In contrast, emerging practices in elective surgical procedures, such as spine fusion, place antibiotic powder (e.g. vancomycin) in the wound at the time of closure. This has been shown to be extremely effective, presumably because of the very small-time period between potential contamination and local antibiotic application. There is evidence that suggests that the ineffectiveness of local antibiotic use in open fractures is primarily due to the delay in application of local antibiotics from the time of injury and propose a concept of topical antibiotic powder application in the prehospital or emergency department setting.

Local antibiotics in primary hip and knee arthroplasty: a systematic review and meta-analysis.

Infection is a truly devastating complication of total joint arthroplasty, causing most patients to undergo a revision surgery, and to bear significant psychological and financial burden. The purpose of this study is to systematically evaluate the literature to determine the efficacy and complication profile of local antibiotic application in primary total joint arthroplasty. All studies of primary total joint arthroplasty which assessed local antibiotics in any form other than antibiotic-impregnated cement as an intervention were included. Studies that reported at least one outcome related to infection and were available in full text in English were eligible for inclusion. Studies which included both primary and revision cases but did not report the stratified data for each type of surgery and studies on fracture populations were excluded. A total of 9 studies involving 3,714 cases were included. The pooled deep infection rate was 1.6% in the intervention groups and 3.5% in the control groups. Meta-analysis revealed a RR of 0.53 (95%CI: 0.35-0.79, p = 0.002) with no heterogeneity (I2 = 0%) for infection in the intervention groups. Meta-analysis revealed a non-significant reduction in superficial infection rates in the intervention groups; however, there was a significant increase in aseptic wound complications in the intervention groups. Local antibiotic application results in a moderate reduction in deep infection rates in primary total joint arthroplasty, with no significant impact on superficial infection rates. However, local antibiotic application may be associated with a moderate increase in aseptic wound complications.

Nonsurgical Treatment of Peri-Implantitis: Case Series

Peri-implantitis is one of the most important biological complication of dental implants. It has inflammatory nature, proved association with plaque accumulation in peri-implant tissues, and can be progressive on background of several factors, like comorbidity factors and bad habits. The prophylaxis and different methods of treatment were discussed during last 30 years, and surgical and nonsurgical techniques have their foes, benefits, and disadvantages. In this article, we describe the case series of various nonsurgical treatments of peri-implantitis with the use of protocols based on the application of local antibiotics (doxycycline, lincomycin, and erythromycin), mechanical and chemical debridement of dental implant surface, and mini-invasive regenerative technique with injections of bovine collagen. All these three cases demonstrated good results with the maintenance of bone level and absence of clinical signs of inflammation for at least a year according to the X-ray imaging (bone defect volume) and clinic assessments (probing depth, bleeding or suppuration, mucosa color, and pain presence).

Current Insights in the Application of Bone Grafts for Local Antibiotic Delivery in Bone Reconstruction Surgery.

Introduction: Bone implant related infection is still one of the biggest challenges in bone and joint surgery. Antibiotic impregnated bone grafts seem to be promising in both treatment and prevention of these infections. However, great variance in methodology predominates this field of research. This paper gives an overview of the published literature.Methods: The PRISMA-flowchart was used as protocol for article selection. Medline was searched and articles were selected in accordance with predetermined exclusion criteria.Results: Forty-eight articles were included in the synthesis. Topics including bone graft type, manipulations of the graft, elution profile, bacterial inhibition, osteotoxicity, incorporation, special impregnation methods, clinical use and storage were investigated.Therapeutically, high initial levels seem appropriate for biofilm eradication. A single stage procedure in the treatment of bone implant related infection seems feasible. Prophylactically, the literature indicates a reduction of postoperative infections when using antibiotic impregnated bone grafts.Conclusion: Bone grafts are a suitable carrier for local antibiotic application both therapeutically and prophylactically.

Risk assessment of antibiotic resistance development by antibiotic-loaded bone cements: is it a clinical concern?

Because of the risk of bacterial biofilm infections, prophylactic use of antibiotics in orthopaedic procedures involving the implantation of large prosthesis systems is considered mandatory.A strategy based on the rationale that local antibiotics released from bone cement or other carriers establish a second antibacterial frontline in and around the prosthesis is considered complementary to the administration of systemic antibiotics.Although less common as a consequence of the initially very high drug concentrations of local antibiotics in the tissues, a selection process of previous high resistance bacteria may occur, leading to antibiotic resistance.The use of antibiotic combinations in bone cement is generally accepted to improve antibiotic efficacy and minimizes the treatment failure risk due to antibiotic resistance. This is important in septic revisions and/or in patients at particularly high risk of infection.On an individual basis, the benefit of a lower infection probability with combined systemic and local antibiotic application should outweigh the risk of the selection of more resistant bacteria. Each prevented infection means that a complex and extended antibiotic therapy with risk of resistance development over time has been avoided.On an epidemiological level there is no clinical evidence that the routine use of bone cement impregnated with appropriate bactericidal antibiotics promotes the widespread development of antibiotic resistance and thereby puts the successful treatment of a prosthetic joint infection at higher risk.Cite this article: EFORT Open Rev 2019;4:576-584. DOI: 10.1302/2058-5241.4.180104

The effect of stereotactic intracavity injection of antibiotics on systemic antibiotics therapy in patients with brain abscess

Objective To investigate the feasibility of intracavity administration of high-dose antibiotics to shorten the course of systemic antibiotic therapy. Methods A total of 107 patients with bacterial brain abscesses (155 abscesses) who were treated with stereotactic aspiration and intracavity injection of high-dose antibiotic combined with systemic antibiotic therapy(intracavitary treatment group) at Department of Neurosurgery, Chinese PLA General Hospital Sixth Medical Center from January 2005 to June 2018 were enrolled in this study. From January 1995 to December 2004, 51 patients with bacterial brain abscesses who were admitted to Department of Neurosurgery, Chinese PLA General Hospital Sixth Medical Center were treated with traditional stereotactic surgery (traditional treatment group). Clinical characteristics, treatment and prognosis in the 2 groups were compared. Results During the follow-up period (mean: 26.2±12.5 months, range: 6-72 months), all the abscesses of the intracavitary treatment group subsided with no recurrence. No adverse effects related to topical use of antibiotics occurred. At the end of follow-up, 78 patients had good outcomes, 21 had mild neurological deficits, 3 had moderate deficits, 1 was in vegetative state, and 4 died of accidents not related to brain abscesses. The course of systemic antibiotic application in the intracavitary treatment group was shorter than that in the traditional treatment group (21.5±2.3 d vs. 36.3±5.2 d, t=25.765, P 0.05). Conclusions Our preliminary results indicated that the local application of antibiotics in brain abscess cavity could reduce the length of time of systemic antibiotic therapy. This treatment could reduce the abscess recurrence rate compared to traditional treatment. Key words: Brain abscess; Stereotactic aspiration; Antibiotics; Route of medication

Status quo and difficulties in standardized treatment of infected nonunion of tibia

In recent years, infection and infected nonunion after surgical treatment of tibial fracture have gradually increased, which has brought tremendous psychological and economic burdens to patients. At present, awareness and attention in the field of traumatic bone infections is insufficient, and many experienced orthopedic surgeons lack the basic knowledge and formal training on management of traumatic bone infections. Tibial intramedullary nail infection and infectious bone defect nonunion are difficult to treat and have a high recurrence rate. This article reviews the special principles of bacterial biofilm formation, surface competition, Klemm three factors and bone infection typing in the treatment of bone infection, the reamed debridement of tibial intramedullary nail fixation infection, the application of local antibiotics and the comparison between bone transport and inducing membrane techniques in the treatment of infectious nonunion. This article aims to provide some help for orthopedic surgeons in the systematic treatment of tibial infection. Key words: Osteomyelitis; Tibial fractures; Fracture fixation, intramedullary; Infected nonunion

Fibrin glue as a local drug-delivery system for bacteriophage PA5

Fibrin glue has been used clinically for decades in a wide variety of surgical specialties and is now being investigated as a medium for local, prolonged drug delivery. Effective local delivery of antibacterial substances is important perioperatively in patients with implanted medical devices or postoperatively for deep wounds. However, prolonged local application of antibiotics is often not possible or simply inadequate. Biofilm formation and antibiotic resistance are also major obstacles to antibacterial therapy. In this paper we test the biocompatibility of bacteriophages incorporated within fibrin glue, track the release of bacteriophages from fibrin scaffolds, and measure the antibacterial activity of released bacteriophages. Fibrin glue polymerized in the presence of the PA5 bacteriophage released high titers of bacteriophages during 11 days of incubation in liquid medium. Released PA5 bacteriophages were effective in killing Pseudomonas aeruginosa PA01. Overall, our results show that fibrin glue can be used for sustained delivery of bacteriophages and this strategy holds promise for many antibacterial applications.

In vitro study of new combinations for local antibiotic therapy with calcium sulphate - Near constant release of ceftriaxone offers new treatment options.

Introduction: Local application of antibiotics provides high concentrations at the site of interest, with minimal systemic toxicity. Carrier materials might help manage dead space. Calcium sulphate (CaSO4) has a dissolution time that only slightly exceeds the usually recommended duration of systemic antibiotic treatments. This in vitro study evaluates compatibility, release kinetics and antibacterial activity of new combinations of antibiotics with CaSO4 as carrier material.Methods: CaSO4 pellets added with 8% w/w antibiotic powder were exposed once in phosphate-buffered saline (PBS) solution and once in bovine plasma, in an elution experiment run over 6 weeks at 37 °C. Antibiotic elution was examined at various time points. Concentration was measured by liquid chromatography with tandem mass spectrometry. Antimicrobial activity was checked with an agar diffusion test.Results: Piperacillin-tazobactam, ceftazidime, cefepime, and meropenem showed fast reduction of concentration and activity. Flucloxacillin and cefuroxime remained present in relevant concentrations for 4 weeks. Ciprofloxacin, levofloxacin and clindamycin lasted for 6 weeks, but also at cell toxic concentrations. Ceftriaxone showed a near-constant release with only a small reduction of concentration from 130 to 75 mg/l. Elution profiles from PBS and plasma were comparable.Conclusion: CaSO4 provides new possibilities in the local treatment of bone and joint infections. Ceftriaxone appears to be of particular interest in combination with CaSO4. Release persists at clinically promising concentrations, and appears to have a depot-like slow release from CaSO4, with only a small reduction in activity and concentration over 6 weeks. To the best of our knowledge, such a particular persistent release never was described before, for any antibiotic in combination with a carrier material for local application.

The effect of local antibiotic prophylaxis when treating open limb fractures: A systematic review and meta-analysis.

ObjectivesAs well as debridement and irrigation, soft-tissue coverage, and osseous stabilization, systemic antibiotic prophylaxis is considered the benchmark in the management of open fractures and considerably reduces the risk of subsequent fracture-related infections (FRI). The direct application of antibiotics in the surgical field (local antibiotics) has been used for decades as additional prophylaxis in open fractures, although definitive evidence confirming a beneficial effect is scarce. The purpose of the present study was to review the clinical evidence regarding the effect of prophylactic application of local antibiotics in open limb fractures.MethodsA comprehensive literature search was performed in PubMed, Web of Science, and Embase. Cohort studies investigating the effect of additional local antibiotic prophylaxis compared with systemic prophylaxis alone in the management of open fractures were included and the data were pooled in a meta-analysis.ResultsIn total, eight studies which included 2738 patients were eligible for quantitative synthesis. The effect of antibiotic-loaded poly(methyl methacrylate) beads was investigated by six of these studies, and two studies evaluated the effect of local antibiotics applied without a carrier. Meta-analysis showed a significantly lower infection rate when local antibiotics were applied (4.6%; 91/1986) than in the control group receiving standard systemic prophylaxis alone (16.5%; 124/752) (p < 0.001) (odds ratio 0.30; 95% confidence interval 0.22 to 0.40).ConclusionThis meta-analysis suggests a risk reduction in FRI of 11.9% if additional local antibiotics are given prophylactically for open limb fractures. However, due to limited quality, heterogeneity, and considerable risk of bias, the pooling of data from primary studies has to be interpreted with caution.Cite this article: M. Morgenstern, A. Vallejo, M. A. McNally, T. F. Moriarty, J. Y. Ferguson, S. Nijs, WJ. Metsemakers. Bone Joint Res 2018;7:447–456. The effect of local antibiotic prophylaxis when treating open limb fractures: A systematic review and meta-analysis. DOI: 10.1302/2046-3758.77.BJR-2018-0043.R1

Antimicrobial hydrogels: promising materials for medical application.

The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Local application of antibiotics might be a solution. In local application, materials need to act as the drug delivery system. The drug delivery system should be biodegradable and prolonged antibacterial effect should be provided to satisfy clinical demand. Hydrogel is a promising material for local antibacterial application. Hydrogel refers to a kind of biomaterial synthesized by a water-soluble natural polymer or a synthesized polymer, which turns into gel according to the change in different signals such as temperature, ionic strength, pH, ultraviolet exposure etc. Because of its high hydrophilicity, unique three-dimensional network, fine biocompatibility and cell adhesion, hydrogel is one of the suitable biomaterials for drug delivery in antimicrobial areas. In this review, studies from the past 5 years were reviewed, and several types of antimicrobial hydrogels according to different ingredients, different preparations, different antimicrobial mechanisms, different antimicrobial agents they contained and different applications, were summarized. The hydrogels loaded with metal nanoparticles as a potential method to solve antibiotic resistance were highlighted. Finally, future prospects of development and application of antimicrobial hydrogels are suggested.

Local Antibiotic Delivery Systems: Current and Future Applications for Diabetic Foot Infections.

Foot infections are common among diabetic patients with peripheral neuropathy and/or peripheral arterial disease, and it can be the pivotal event leading to a minor or major amputation of the lower extremity. Treatment of diabetic foot infections, especially deep-seated ones, remains challenging, in part because impaired blood perfusion and the presence of biofilms can impair the effectiveness of systemic antibiotics. The local application of antibiotics is an emerging field in the treatment of diabetic foot infections, with demonstrable advantages. These include delivery of high concentrations of antibiotics in the affected area, limited systemic absorption, and thus negligible side effects. Biodegradable vehicles, such as calcium sulfate beads, are the prototypical system, providing a good elution profile and the ability to be impregnated with a variety of antibiotics. These have largely superseded the nonbiodegradable vehicles, but the strongest evidence available is for calcium bead implantation for osteomyelitis management. Natural polymers, such as collagen sponge, are an emerging class of delivery systems, although thus far, data on diabetic foot infections are limited. There is recent interest in the novel antimicrobial peptide pexiganan in the form of cream, which is active against most of the microorganisms isolated in diabetic foot infections. These are promising developments, but randomized trials are required to ascertain the efficacy of these systems and to define the indications for their use. Currently, the role of topical antibiotic agents in treating diabetic foot infections is limited and outside of routine practice.

A huge absence of skin on the trunk: aplasia cutis congenita

A 2590 g female infant was born at 39 weeks' gestation to a 34-year-old gravida 4 para 4 mother via cesarean section. Upon delivery she was noted to have an absence of skin on the huge part of the trunk. Lesion was unilateral, gelatinous and covered by a thin membrane. The pregnancy history was unremarkable, the mother denied having taken any drugs and there was no family history of congenital anomalies or consanguinity. The physical examination of the infant was otherwise unremarkable. Conservative treatment was recommended by dermatologist with gentle cleansing and application of local antibiotics. Ultrasonographic evaluation of abdomen and kranium, echocardiographic evaluation and detailed genetic assessment were normal. The patient was discharged home on full oral feedings on day 6 and recommended follow up at the outpatient dermatology clinic. Definition of aplasia cutis congenita (ACC) is, complete or partial absence or scarcity of skin at birth. ACC can occur anywhere in the body but majority of cases occur on the scalp. In most cases ACC is an isolated skin defect but some cases might be seen with congenital malformations involving the cardiovascular, gastrointestinal and central nervous systems. ACC is a rare condition with an incidence of 1/10,000 to 3/10,000 births and the exact mechanism is still unknown. Several factors like genetics, teratogens, intrauterin infections can lead to this condition. Most cases occur sporadically but rare familial cases have been reported. Physicians should remember the possible co-occurrence of other congenital anomalies in these infants.

Role of Antibiotics as Intracanal Medicament-A Literature Review

Antibiotics are an extremely valuable addition to the armamentarium available to health practitioners for management of bacterial infections. Due to the potential risk of adverse systemic effects of systemic applications and ineffectiveness of systemic antibiotics in the necrotic pulpless tooth and the periradicular tissues, local application of antibiotics will be more effective since it is directly acting against the microorganism in the infected root canal. This paper reviews the applications of antibiotics and antibiotics containing medicaments in endodontics.

The levels of vancomycin in the blood and the wound after the local treatment of bone and soft-tissue infection with antibiotic-loaded calcium sulphate as carrier material.

Calcium sulphate (CaSO4) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO4 as an adjunct to the routine therapy of bone and joint infections. A total of 680 post-operative blood and 233 wound fluid samples were available for analysis from 94 implantations performed in 87 patients for various infective indications. Up to 6 g of vancomycin were used. Non-compartmental pharmacokinetic analysis was performed on the data from 37 patients treated for an infection of the hip. The overall systemic exposure remained within a safe range, even in patients with post-operative renal failure, none requiring removal of the pellets. Local concentrations were approximately ten times higher than with polymethylmethacrylate (PMMA) as a carrier, but remained below reported cell toxicity thresholds. Decreasing concentrations in wound fluid were observed over several weeks, but remained above the common minimum inhibitory concentrations for Staphylococcus up to three months post-operatively. This study provides the first pharmacokinetic description of the local application of vancomycin with CaSO4 as a carrier, documenting slow release, systemic safety and a release profile far more interesting than from PMMA. In particular, considering in vitro data, concentrations of vancomycin active against staphylococcal biofilm were seen for several weeks. Cite this article: Bone Joint J 2017;99-B:1537-44.

Local antibiotic therapy

The treatment of superficial wound infections with local antibiotics is considered to be problematic as it is accompanied by an increased risk of resistance development and ineffectiveness in deeper regions. On the contrary, the local application of antibiotics is useful in arthroplasty and necessary if implants are utilized. The reason for this is the prevention of a rapid biofilm formation on foreign implants and aresulting infection may remain undiscovered until it becomes chronic. Apart from exogenous material, necrotic tissue (e. g. bone sequestra) provides suitable retreat areas for pathogens in the body. Because of the characteristics of bone and joint infections and an exceptional infection recurrence rate, acombined approach is required. Systemic antibiotic prophylaxis is able to reduce the number of pathogens acquired by perioperative contamination or hematogenic spread from another focus of infection; however, systemically applied antibiotics often fail to form an effective colonization barrier around the implant because their ability to penetrate the bone is relatively low. On the other hand, the high concentration of locally released antibiotics leads to an effective protection of the implant from bacteria in situ. Thus, for the treatment of implant-associated infections, systemic and local application of anti-infective agents is areliable adjuvant measure that improves the therapeutic success. Polymethylmethacrylate (PMMA) bone cement is the most commonly used local drug carrier. Based on clinical and microbiological results, microbiologists and infectious disease experts together with the surgeon and pharmacist determine which anti-infective agents are indicated for systemic and local, PMMA cement-related application. Because there is no evident concept for the local application, unlike the recommendation for systemic use of anti-infective agents, this review article describes which aspects should be taken into account.

A study on microbiology culture of acute appendicectomy specimen and its correlation with wound infection

Background: Appendicitis is a common condition which frequently requires emergency surgery and has postoperative wound infection has been reported in few cases which can be influenced by many factors, the most important being surgical skill and technique and the criteria used to define the infection. Bacteria play an important role in appendicitis and the local application of antibiotics or antiseptics can reduce the incidence of wound infection. In this study, we analyse the microbiology culture of acute appendicectomy specimen and its correlation with wound infection.Methods: This is a randomised control test study which was carried out 56 patients with appendicitis. The swab was taken from appendix lumen after appendicectomy and wound infection was sent to laboratory to carry out histology findings and infective organisms respectively. All patients were followed postoperatively for wound infection.Results: Bacteria was isolated from 60% swabs taken from appendix lumen in which gram-negative bacilli isolated as commonest bacteria among which perforated appendicitis shows 66.7% isolation of bacteria. Wound infection among patients underwent appendicectomy was 21%. Gram-negative bacilli were isolated from almost all swabs (100%) taken from wound infection.Conclusions: From this study and results, it shows gram negative bacilli was the commonest organisms isolated from the swabs taken from both appendix lumen and wound infection.

Antibiotic stability over six weeks in aqueous solution at body temperature with and without heat treatment that mimics the curing of bone cement

ObjectivesThermal stability is a key property in determining the suitability of an antibiotic agent for local application in the treatment of orthopaedic infections. Despite the fact that long-term therapy is a stated goal of novel local delivery carriers, data describing thermal stability over a long period are scarce, and studies that avoid interference from specific carrier materials are absent from the orthopaedic literature.MethodsIn this study, a total of 38 frequently used antibiotic agents were maintained at 37°C in saline solution, and degradation and antibacterial activity assessed over six weeks. The impact of an initial supplementary heat exposure mimicking exothermically curing bone cement was also tested as this material is commonly used as a local delivery vehicle. Antibiotic degradation was assessed by liquid chromatography coupled to mass spectrometry, or by immunoassays, as appropriate. Antibacterial activity over time was determined by the Kirby-Bauer disk diffusion assay.ResultsThe heat exposure mimicking curing bone cement had minimal effect on stability for most antibiotics, except for gentamicin which experienced approximately 25% degradation as measured by immunoassay. Beta-lactam antibiotics were found to degrade quite rapidly at 37°C regardless of whether there was an initial heat exposure. Excellent long-term stability was observed for aminoglycosides, glycopeptides, tetracyclines and quinolones under both conditions.ConclusionsThis study provides a valuable dataset for orthopaedic surgeons considering local application of antibiotics, and for material scientists looking to develop next-generation controlled or extended-release antibiotic carriers.Cite this article: E. Samara, T. F. Moriarty, L. A. Decosterd, R. G. Richards, E. Gautier, P. Wahl. Antibiotic stability over six weeks in aqueous solution at body temperature with and without heat treatment that mimics the curing of bone cement. Bone Joint J 2017;6:296–306. DOI: 10.1302/2046-3758.65.BJR-2017-0276.R1.