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

Fracture-related infections (FRIs) are among the most common complications following fracture fixation, and they have a huge economic and functional impact on patients. Because consensus guidelines with respect to prevention, diagnosis, and treatment of this major complication are scarce, delegates from different countries gathered in Philadelphia in July 2018 as part of the Second International Consensus Meeting (ICM) on Musculoskeletal Infection. This paper summarizes the discussion and recommendations from that consensus meeting, using the Delphi technique, with a focus on FRIs. A standardized definition that was based on diagnostic criteria was endorsed, which will hopefully improve reporting and research on FRIs in the future. Furthermore, this paper provides a grade of evidence (strong, moderate, limited, or consensus) for strategies and practices that prevent and treat infection. The grade of evidence is based on the quality of evidence as utilized by the American Academy of Orthopaedic Surgeons. The guidelines presented herein focus not only on the appropriate use of antibiotics, but also on practices for the timing of fracture fixation, soft-tissue coverage, and bone defect and hardware management. We hope that this summary as well as the full document by the International Consensus Group are utilized by those who are charged with musculoskeletal care internationally to optimize their management strategies for the prevention and treatment of FRIs.

Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT.

BACKGROUND: Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes. OBJECTIVE: To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection. DESIGN: Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%. SETTING: Twenty-six NHS hospitals. PARTICIPANTS: Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively). INTERVENTIONS: Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm. MAIN OUTCOME MEASURE: The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data. RESULTS: Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial. LIMITATIONS: The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded. CONCLUSIONS: PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy. FUTURE WORK: Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN91566927. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 38. See the NIHR Journals Library website for further project information.

Treatment of bone and joint infection usually requires a long course of antibiotics. Doctors usually give these by injection through a vein (intravenously) for the first 4­6 weeks, rather than by mouth (orally). Although intravenous (IV) administration is more expensive and less convenient for patients, most doctors believe that it is more effective. However, there is little evidence to support this. The OVIVA (Oral Versus IntraVenous Antibiotics) trial set out to challenge this assumption. A total of 1054 patients from 26 UK hospitals were randomly allocated to receive the first 6 weeks of antibiotic therapy either intravenously or orally. Irrespective of the route of administration, the choice of antibiotic was left to an infection specialist so as to ensure that the most appropriate antibiotics were given. Patients were followed up for 1 year. Thirty-nine participants were lost to follow-up. Among the remaining 1015 participants, treatment failure occurred in 14.6% of those treated intravenously and 13.2% of those treated with PO antibiotics. This difference could easily have occurred by chance. Even if it was not by chance, the difference does not suggest that PO therapy is associated with worse outcomes than IV therapy and is too small to conclude that PO therapy is better than IV therapy. Participants in the IV group stayed in hospital longer and 10% of them had complications related to the IV line used for administering the antibiotics. In addition, their treatment was, overall, more expensive. We conclude that PO antibiotic therapy has no disadvantages for the early management of bone and joint infection. It is also cheaper and associated with fewer complications.

Cost-effectiveness of oral versus intravenous antibiotics (OVIVA) in patients with bone and joint infection: evidence from a non-inferiority trial.

Background: Bone and joint infections are becoming increasingly common and are usually treated with surgery and a course of intravenous antibiotics. However, there is no evidence to support the superiority of intravenous therapy and there is a growing body of literature showing that oral therapy is effective in treating these infections.Given this lack of evidence the clinical trial 'Oral Versus Intravenous Antibiotics' (OVIVA) was designed to assess the clinical and cost-effectiveness of intravenous versus oral antibiotics for the treatment of bone and joint infections, using a non-inferiority design. Clinical results from the trial indicate that oral antibiotics are non-inferior to intravenous antibiotics. The aim of this paper is to evaluate the cost-effectiveness of intravenous compared to oral antibiotics for treating bone and joint infections, using data from OVIVA. Methods: A cost-utility analysis was carried out, the main economic outcome measure was the quality adjusted life-year, measured using the EQ-5D-3L questionnaire, combined with costs to estimate cost-effectiveness over 12-months follow-up. Results: Results show that costs were significantly lower in the oral arm compared to the intravenous arm, a difference of £2,740 (95% confidence interval £1,488 to £3,992). Results of four sensitivity analyses were consistent with the base-case results. QALYs were marginally higher in the oral arm, however this difference was not statistically significant; -0.007 (95% confidence interval -0.045 to 0.031). Conclusions: Treating patients with bone and joint infections for the first six weeks of therapy with oral antibiotics is both less costly and does not result in detectable differences in quality of life compared to treatment with intravenous antibiotics. Adopting a practice of treating bone and joint infections with oral antibiotics early in the course of therapy could potentially save the UK National Health Service over £17 million annually.

Costs and renumeration of osteomyelitis treatment involving free flaps: implications of return to theatre.

Aim: This study aimed to define the costs of surgical management of chronic osteomyelitis where free tissue transfer was required in addition to debridement of bone, particularly the increased costs incurred by a return to theatre. We hypothesised that there would be a significantly greater cost when patients required re-exploration for vascular compromise. Method: We retrospectively analysed the costs of a consecutive series of sixty patient episodes treated at the Bone Infection Unit in Oxford from 2012 to 2015. Treatment involved excision of osteomyelitis with free tissue transfer for immediate soft tissue cover. We compared the costs of uncomplicated cases with those who returned to theatre and determined the profit / loss for the hospital from renumeration through the UK National Health Service Tariff Structure. Results: Hospital income according to UK HRG tariff was compared to the actual cost of treatment and these 60 cases were significantly underfunded overall (P < 0.005). In just 1 case, the cost to the hospital was completely covered by tariff. Six patients (10%) returned to theatre for urgent flap re-exploration with five flaps salvaged and one failed, requiring another free flap reconstruction (1.7%). These six patient episodes had a significantly higher mean cost compared to the uncomplicated cases. The average financial loss to the hospital for patients who did return to theatre was £19401 (range £8103 to £48380) and in those who did not was £9600 (range - £600 to £23717). The case requiring further free tissue transfer cost a total of £74158, £48380 more than the hospital was paid: the most extreme discrepancy. The overall loss for this group of 60 patients was £610 090. Conclusions: Surgery for chronic osteomyelitis is multidisciplinary, complex and therefore expensive with a significant risk of complications. However, this study demonstrates that the hospital currently makes a financial loss on almost all patients but especially if flap complications occur. This study has implications for the long term viability of specialist units treating this important disease.

The cost of infection in severe open tibial fractures treated with a free flap.

PURPOSE: Open tibial fractures needing soft tissue cover are challenging injuries. Infection risk is high, making treatment difficult and expensive. Delayed skin closure has been shown to increase the infection rate in several studies. We aimed at calculating the direct and indirect cost of treatment, and to determine the effect of delayed skin closure on this cost. METHODS: We reviewed all records of patients treated with a free flap in our institution for an open tibial fracture from 2002 to 2013. We calculated direct costs based on length of stay (LOS) and orthopaedic and plastic surgical procedures performed, including medications and intensive care. We analysed indirect cost in terms of absenteeism and unemployment benefits. The primary goal was to establish the extra cost incurred by an infection. RESULTS: We analysed 46 injuries in 45 patients. Infection increased the LOS from 41 to 74 days and increased the cost of treatment from € 49,817 in uninfected fractures to € 81,155 for infected fractures. Employed patients spent 430 days more on unemployment benefits, than a matched cohort in the background population. Achieving skin cover within seven days of injury decreased the infection rate from 60 to 27 %. CONCLUSIONS: Severe open tibial fractures covered with free flaps, cause over a year of absenteeism. Infection increases direct cost of treatment over 60 % and roughly doubles LOS. Early soft-tissue cover and correct antibiotics have been shown to improve outcomes-underscoring the need for rapid referral to centres with an ortho-plastic set-up to handle such injuries.

Development and validation of procedures for assessment of competency of non-pharmacists in extemporaneous dispensing.

OBJECTIVES: To develop and validate procedures that may be suitable for assessment of competency of two groups of non-pharmacist staff (pharmacy students and trainee support staff) in extemporaneous dispensing. This is important given the prospect of remote supervision of community pharmacies in the UK. METHODS: Analytical methods were validated according to International Conference on Harmonisation specifications and procedures were optimized to allow efficient drug extraction. This permitted straightforward determination of drug content in extemporaneously prepared lidocaine hydrochloride mouthwashes and norfloxacin creams and suspensions prepared by 10 participants recruited to represent the two groups of non-pharmacist staff. KEY FINDINGS: All 10 participants had completed the extemporaneous dispensing of all three products within 90 min. Extraction and analysis took approximately 15 min for each lidocaine hydrochloride mouthwash and 30 min for each diluted norfloxacin cream and norfloxacin suspension. The mean drug concentrations in lidocaine hydrochloride mouthwashes and diluted norfloxacin creams were within what are generally accepted as being pharmaceutically acceptable limits for drug content (100 +/- 5%) for both groups of participants. There was no significant difference in the mean drug concentration of norfloxacin suspensions prepared by the participant groups. However, it was notable that only one participant prepared a suspension containing a norfloxacin concentration that was within pharmaceutically acceptable limits (101.51%). CONCLUSIONS: A laboratory possessing suitable equipment and appropriately trained staff could cope readily with the large number of products prepared, for example, by a cohort of pre-registration students. Consequently, the validated procedures developed here could usefully be incorporated into the pre-registration examination for pharmacy students and a final qualifying examination for dispensers and pharmacy technicians. We believe that this is essential if the public and the profession are to have confidence in extemporaneous dispensing carried out in the absence of a pharmacist.