Evaluating the feasibility of medium-chain oleochemical synthesis using microbial chain elongation.

Chain elongating bacteria are a unique guild of strictly anaerobic bacteria that have garnered interest for sustainable chemical manufacturing from carbon-rich wet and gaseous waste streams. They produce C6-C8 medium-chain fatty acids, which are valuable platform chemicals that can be used directly, or derivatized to service a wide range of chemical industries. However, the application of chain elongating bacteria for synthesizing products beyond C6-C8 medium-chain fatty acids has not been evaluated. In this study, we assess the feasibility of expanding the product spectrum of chain elongating bacteria to C9-C12 fatty acids, along with the synthesis of C6 fatty alcohols, dicarboxylic acids, diols, and methyl ketones. We propose several metabolic engineering strategies to accomplish these conversions in chain elongating bacteria and utilize constraint-based metabolic modelling to predict pathway stoichiometries, assess thermodynamic feasibility, and estimate ATP and product yields. We also evaluate how producing alternative products impacts the growth rate of chain elongating bacteria via resource allocation modelling, revealing a trade-off between product chain length and class versus cell growth rate. Together, these results highlight the potential for using chain elongating bacteria as a platform for diverse oleochemical biomanufacturing and offer a starting point for guiding future metabolic engineering efforts aimed at expanding their product range. ONE-SENTENCE SUMMARY: In this work, the authors use constraint-based metabolic modelling and enzyme cost minimization to assess the feasibility of using metabolic engineering to expand the product spectrum of anaerobic chain elongating bacteria.

Local Antimicrobial Therapy with Combined Aminoglycoside and Vancomycin Compared to Aminoglycoside Monotherapy in the Surgical Management of Osteomyelitis and Fracture-Related Infection.

We investigated the effect of combination aminoglycoside and vancomycin local antibiotic treatment compared to aminoglycoside alone in the surgical management of bone infection. Data including patient demographics, type of surgery, microbiological characteristics, BACH score, duration of antibiotic treatment and clinical outcomes were collected. Failure of therapy was a composite of recurrence of infection, continued or new antimicrobial therapy, or reoperation with suspected or confirmed infection at one year after index surgery. A total of 266 patients met the inclusion criteria. 252 patients reached the final follow-up and were included in the final analysis. 113 patients had treatment with aminoglycoside alone and 139 patients had combination aminoglycoside and vancomycin. There was no difference in the failure rate between groups; 10/113 (8.8%) in the aminoglycoside alone and 12/139 (8.6%) in the combination group, p = 0.934. Multivariate analysis showed that there was no added benefit of combination therapy (OR 1.54: 95% CI 0.59-4.04, p = 0.38). BACH score and low BMI were associated with increased risk of failure (BACH OR 3.49: 95% CI 1.13-10.76, p = 0.03; Low BMI OR 0.91: 95% CI 0.84-0.99, p = 0.037). The form of the carrier material (pellets or injectable paste) had no effect on failure rate (p = 0.163). The presence of aminoglycoside resistance had no effect on failure rate (OR 0.39: 95% CI 0.05-3.01, p = 0.37). Clinical outcome was not improved by the addition of vancomycin to aminoglycoside alone as local therapy for the management of bone infection.

Landfill intermediate cover soil microbiomes and their potential for mitigating greenhouse gas emissions revealed through metagenomics.

Landfills are a major source of anthropogenic methane emissions and have been found to produce nitrous oxide, an even more potent greenhouse gas than methane. Intermediate cover soil (ICS) plays a key role in reducing methane emissions but may also result in nitrous oxide production. To assess the potential for microbial methane oxidation and nitrous oxide production, long sequencing reads were generated from ICS microbiome DNA and reads were functionally annotated for 24 samples across ICS at a large landfill in New York. Further, incubation experiments were performed to assess methane consumption and nitrous oxide production with varying amounts of ammonia supplemented. Methane was readily consumed by microbes in the composite ICS and all incubations with methane produced small amounts of nitrous oxide even when ammonia was not supplemented. Incubations without methane produced significantly less nitrous oxide than those incubated with methane. In incubations with methane added, the observed specific rate of methane consumption was 0.776 +/- 0.055 µg CH4 g dry weight (DW) soil-1 h-1 and the specific rate of nitrous oxide production was 3.64 × 10-5 +/- 1.30 × 10-5 µg N2O g DW soil-1 h-1. The methanotrophs Methylobacter and an unclassified genus within the family Methlyococcaceae were present in the original ICS samples and the incubation samples, and their abundance increased during incubations with methane. Genes encoding particulate methane monooxygenase/ ammonia monooxygenase (pMMO) were much more abundant than genes encoding soluble methane monooxygenase (sMMO) across the landfill ICS. Genes encoding proteins that convert hydroxylamine to nitrous oxide were not highly abundant in the ICS or incubation metagenomes. In total, these results suggest that although ammonia oxidation via methanotrophs may result in low levels of nitrous oxide production, ICS microbial communities have the potential to greatly reduce the overall global warming potential of landfill emissions.

Mid- to long-term results of single-stage surgery for patients with chronic osteomyelitis using a bioabsorbable gentamicin-loaded ceramic carrier.

AIMS: Excision of chronic osteomyelitic bone creates a dead space which must be managed to avoid early recurrence of infection. Systemic antibiotics cannot penetrate this space in high concentrations, so local treatment has become an attractive adjunct to surgery. The aim of this study was to present the mid- to long-term results of local treatment with gentamicin in a bioabsorbable ceramic carrier. METHODS: A prospective series of 100 patients with Cierny-Mader Types III and IV chronic ostemyelitis, affecting 105 bones, were treated with a single-stage procedure including debridement, deep tissue sampling, local and systemic antibiotics, stabilization, and immediate skin closure. Chronic osteomyelitis was confirmed using strict diagnostic criteria. The mean follow-up was 6.05 years (4.2 to 8.4). RESULTS: At final follow-up, six patients (six bones) had recurrent infection; thus 94% were infection-free. Three infections recurred in the first year, two in the second year, and one 4.5 years postoperatively. Recurrence was not significantly related to the physiological class of the patient (1/20 Class A (5%) vs 5/80 Class B (6.25%); p = 0.833), nor was it significantly related to the aetiology of the infection, the organisms which were cultured or the presence of nonunion before surgery (1/10 with nonunion (10%) vs 5/90 without nonunion (5.6%); p = 0.570). Organisms with intermediate or high-grade resistance to gentamicin were significantly more likely in polymicrobial infections (9/21; 42.8%) compared with monobacterial osteomyelitis (7/79 (8.9%); p < 0.001). However, recurrence was not significantly more frequent when a resistant organism was present (1/16 for resistant cases (6.25%) vs 5/84 in those with a microbiologically sensitive infection (5.95%); p = 0.958). CONCLUSION: We found that a single-stage protocol, including the use of a high-delivery local antibiotic ceramic carrier, was effective over a period of several years. The method can be used in a wide range of patients, including those with significant comorbidities and an infected nonunion.Cite this article: Bone Joint J 2022;104-B(9):1095-1100.

Systematic review of risk prediction studies in bone and joint infection: are modifiable prognostic factors useful in predicting recurrence?

Background: Classification systems for orthopaedic infection include patient health status, but there is no consensus about which comorbidities affect prognosis. Modifiable factors including substance use, glycaemic control, malnutrition and obesity may predict post-operative recovery from infection. Aim: This systematic review aimed (1) to critically appraise clinical prediction models for individual prognosis following surgical treatment for orthopaedic infection where an implant is not retained; (2) to understand the usefulness of modifiable prognostic factors for predicting treatment success. Methods: EMBASE and MEDLINE databases were searched for clinical prediction and prognostic studies in adults with orthopaedic infections. Infection recurrence or re-infection after at least 6 months was the primary outcome. The estimated odds ratios for the primary outcome in participants with modifiable prognostic factors were extracted and the direction of the effect reported. Results: Thirty-five retrospective prognostic cohort studies of 92 693 patients were included, of which two reported clinical prediction models. No studies were at low risk of bias, and no externally validated prediction models were identified. Most focused on prosthetic joint infection. A positive association was reported between body mass index and infection recurrence in 19 of 22 studies, similarly in 8 of 14 studies reporting smoking history and 3 of 4 studies reporting alcohol intake. Glycaemic control and malnutrition were rarely considered. Conclusion: Modifiable aspects of patient health appear to predict outcomes after surgery for orthopaedic infection. There is a need to understand which factors may have a causal effect. Development and validation of clinical prediction models that include participant health status will facilitate treatment decisions for orthopaedic infections.

Lower Success Rate of Débridement and Implant Retention in Late Acute versus Early Acute Periprosthetic Joint Infection Caused by Staphylococcus spp. Results from a Matched Cohort Study.

BACKGROUND: Surgical débridement, antibiotics and implant retention (DAIR) is currently recommended by international guidelines for both early acute (postsurgical) and late acute (hematogenous) periprosthetic joint infections (PJIs). However, due to a different pathogenesis of infection, a different treatment strategy may be needed. QUESTIONS/PURPOSES: (1) Compared with early acute PJIs, are late acute PJIs associated with a higher risk of DAIR failure? (2) When stratified by microorganism, is the higher risk of failure in late acute PJI associated with Staphylocococcus aureus infection? (3) When analyzing patients with S. aureus infection, what factors are independently associated with DAIR failure? METHODS: In this multicenter observational study, early acute and late acute PJIs treated with DAIR were retrospectively evaluated and matched according to treating center, year of diagnosis, and infection-causing microorganism. If multiple matches were available, the early acute PJI diagnosed closest to the late acute PJI was selected. A total of 132 pairs were included. Treatment success was defined as a retained implant during follow-up without the need for antibiotic suppressive therapy. RESULTS: Late acute PJIs had a lower treatment success (46% [60 of 132]) compared with early acute PJIs (76% [100 of 132]), OR 3.9 [95% CI 2.3 to 6.6]; p < 0.001), but the lower treatment success of late acute PJIs was only observed when caused by Staphylococcus spp (S. aureus: 34% versus 75%; p < 0.001; coagulase-negative staphylococci: 46% versus 88%; p = 0.013, respectively). On multivariable analysis, late acute PJI was the only independent factor associated with an unsuccessful DAIR when caused by S. aureus (OR 4.52 [95% CI 1.79 to 11.41]; p < 0.001). CONCLUSIONS: Although DAIR seems to be a successful therapeutic strategy in the management of early acute PJI, its use in late acute PJI should be reconsidered when caused by Staphylococcus spp. Our results advocate the importance of isolating the causative microorganism before surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

Short or Long Antibiotic Regimes in Orthopaedics (SOLARIO): a randomised controlled open-label non-inferiority trial of duration of systemic antibiotics in adults with orthopaedic infection treated operatively with local antibiotic therapy.

BACKGROUND: Orthopaedic infections, such as osteomyelitis, diabetic foot infection and prosthetic joint infection, are most commonly treated by a combination of surgical debridement and a prolonged course of systemic antibiotics, usually for at least 4-6 weeks. Use of local antibiotics, implanted directly into the site of infection at the time of surgery, may improve antibiotic delivery and allow us to shorten the duration of systemic antibiotic therapy, thereby limiting the frequency of side effects, cost and selection pressure for antimicrobial resistance. METHODS: SOLARIO is a multicentre open-label randomised controlled non-inferiority trial comparing short and long systemic antibiotic therapy alongside local antibiotic therapy. Adult patients with orthopaedic infection, who have given informed consent, will be eligible to participate in the study provided that no micro-organisms identified from deep tissue samples are resistant to locally implanted antibiotics. Participants will be randomised in a 1:1 ratio to receive either a short course (≤ 7 days) or currently recommended long course (≥ 4 weeks) of systemic antibiotics. The primary outcome will be treatment failure by 12 months after surgery, as ascertained by an independent Endpoint Committee blinded to treatment allocation. An absolute non-inferiority margin of 10% will be used for both per-protocol and intention-to-treat populations. Secondary outcomes will include probable and definite treatment failure, serious adverse events, treatment side effects, quality of life scores and cost analysis. DISCUSSION: This study aims to assess a treatment strategy that may enable the reduction of systemic antibiotic use for patients with orthopaedic infection. If this strategy is non-inferior, this will be to the advantage of patients and contribute to antimicrobial stewardship. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03806166. Registered on 11 November 2019.

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.

Management of Post-Traumatic Osteomyelitis in the Lower Limb: Current State of the Art.

Osteomyelitis (OM) of the lower limb represents a large unmet global healthcare burden. It often arises from a contiguous focus of infection and is a recognized complication of open fractures or their surgical treatment, arthroplasty, and diabetic foot ulcers. Historically, this debilitating condition is associated with high rates of recurrence and secondary amputation. However, excellent long-term outcomes are now achieved by adopting a multidisciplinary approach with meticulous surgical debridement, skeletal and soft tissue reconstruction, and tailored antimicrobial treatment. This review focuses on the modern evidence-based management of post-traumatic OM in the lower limb from a reconstructive plastic surgery perspective, highlighting the latest developments and areas of controversy.

The microbiology of chronic osteomyelitis: Changes over ten years.

AIM: This study quantified changes in the microbiology of osteomyelitis over a ten year period from a single centre within the UK with regard to infection with multi-drug resistant (MDR) bacteria and susceptibility of antimicrobial regimens. METHOD: Patients with chronic osteomyelitis undergoing definitive surgery from 2013-2017 were inluded (n = 223). Microbiology was compared to patients in a cohort from 2001-2004, using the same diagnostic criteria, and same deep tissue sampling technique (n = 157). Clinical features associated with MDR bacterial infection were analysed using logistic regression. RESULTS: Both cohorts had similar baseline characteristics. Despite a similar proportion of Staphylococcus aureus in both cohorts, the rate of methicillin resistant Staphylococcus aureus (MRSA) infection was lower in 2013-2017 compared to 2001-2004 (11.4% vs 30.8% of Staphylococcus aureus, p = 0.007). However, the proportion of MDR infections was similar in both cohorts (15.2% versus 17.2%). Metalwork was associated with MDR infection (unadjusted OR 5.0; 95% CI: 1.15 to 22.0). There was no change in resistance to glycopeptide / meropenem combination treatment (2.2% vs 2.5%, p > 0.9). CONCLUSIONS: In this centre, rates of MRSA osteomyelitis have fallen by two thirds, over the past 10 years, in line with the reducing rate of MRSA bacteraemia nationally. A history of metalwork may predict MDR infection. A glycopeptide with an anti-pseudomonal carbapenem remains the post-operative empiric systemic regimen of choice. Resistance patterns support the use of a glycopeptide with an aminoglycoside in local antibiotic therapy.

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.

Reducing Implant Infection in Orthopaedics (RIIiO): a pilot study for a randomised controlled trial comparing the influence of forced air versus resistive fabric warming technologies on postoperative infection rates following orthopaedic implant surgery in adults.

BACKGROUND: Approximately 70,000 to 75,000 proximal femoral fracture repairs take place in the UK each year. Hemiarthroplasty is the preferred treatment for adults aged over 60 years. Postoperative infection affects up to 3% of patients and is the single most common reason for early return to theatre. Ultraclean ventilation was introduced to help mitigate the risk of infection, but it may also contribute to inadvertent perioperative hypothermia, which itself is a risk for postoperative infection. To counter this, active intraoperative warming is used for all procedures that take 30 min or more. Forced air warming (FAW) and resistive fabric warming (RFW) are the two principal techniques used for this purpose; they are equally effective in prevention of inadvertent perioperative hypothermia, but it is not known which is associated with the lowest infection rates. Deep surgical site infection doubles operative costs, triples investigation costs and quadruples ward costs. The Reducing Implant Infection in Orthopaedics (RIIiO) study seeks to compare infection rates with FAW versus RFW after hemiarthroplasty for hip fracture. A cost-neutral intervention capable of reducing postoperative infection rates would likely lead to a change in practice, yield significant savings for the health economy, reduce overall exposure to antibiotics and improve outcomes following hip fracture in the elderly. The findings may be transferable to other orthopaedic implant procedures and to non-orthopaedic surgical specialties. METHODS: RIIiO is a parallel group, open label study randomising hip fracture patients over 60 years of age who are undergoing hemiarthroplasty to RFW or FAW. Participants are followed up for 3 months. Definitive deep surgical site infection within 90 days of surgery, the primary endpoint, is determined by a blinded endpoint committee. DISCUSSION: Hemiarthroplasty carries a risk of deep surgical site infection of approximately 3%. In order to provide 90% power to demonstrate an absolute risk reduction of 1%, using a 5% significance level, a full trial would need to recruit approximately 8630 participants. A pilot study is being conducted in the first instance to demonstrate that recruitment and data management strategies are appropriate and robust before embarking on a large multi-centre trial. TRIAL REGISTRATION: ISRCTN, ISRCTN74612906 . Registered on 27 February 2017.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. 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. 22, No. 59. See the NIHR Journals Library website for further project information.

Sonication versus Tissue Sampling for Diagnosis of Prosthetic Joint and Other Orthopedic Device-Related Infections.

Current guidelines recommend collection of multiple tissue samples for diagnosis of prosthetic joint infections (PJI). Sonication of explanted devices has been proposed as a potentially simpler alternative; however, reported microbiological yield varies. We evaluated sonication for diagnosis of PJI and other orthopedic device-related infections (DRI) at the Oxford Bone Infection Unit between October 2012 and August 2016. We compared the performance of paired tissue and sonication cultures against a "gold standard" of published clinical and composite clinical and microbiological definitions of infection. We analyzed explanted devices and a median of five tissue specimens from 505 procedures. Among clinically infected cases the sensitivity of tissue and sonication culture was 69% (95% confidence interval, 63 to 75) and 57% (50 to 63), respectively (P < 0.0001). Tissue culture was more sensitive than sonication for both PJI and other DRI, irrespective of the infection definition used. Tissue culture yield was higher for all subgroups except less virulent infections, among which tissue and sonication culture yield were similar. The combined sensitivity of tissue and sonication culture was 76% (70 to 81) and increased with the number of tissue specimens obtained. Tissue culture specificity was 97% (94 to 99), compared with 94% (90 to 97) for sonication (P = 0.052) and 93% (89 to 96) for the two methods combined. Tissue culture is more sensitive and may be more specific than sonication for diagnosis of orthopedic DRI in our setting. Variable methodology and case mix may explain reported differences between centers in the relative yield of tissue and sonication culture. Culture yield was highest for both methods combined.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.

Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial.

BACKGROUND: Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Current standard of care in most UK centres includes a prolonged course (4-6 weeks) of intravenous antibiotics supported, if available, by an outpatient parenteral antibiotic therapy service. Intravenous therapy carries with it substantial risks and inconvenience to patients, and the antibiotic-related costs are approximately ten times that of oral therapy. Despite this, there is no evidence to suggest that oral therapy results in inferior outcomes. We hypothesise that, by selecting oral agents with high bioavailability, good tissue penetration and activity against the known or likely pathogens, key outcomes in patients managed primarily with oral therapy are non-inferior to those in patients treated by intravenous therapy. METHODS: The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (>18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05). DISCUSSION: If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services. TRIAL REGISTRATION: ISRCTN91566927 - 14/02/2013.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and serious infection, with an associated mortality of ~25%. Once in the blood, S. aureus can disseminate to infect almost any organ, but bones, joints and heart valves are most frequently affected. Despite the infection's severity, the evidence guiding optimal antibiotic therapy is weak: fewer than 1,500 patients have been included in 16 randomised controlled trials investigating S. aureus bacteraemia treatment. It is uncertain which antibiotics are most effective, their route of administration and duration, and whether antibiotic combinations are better than single agents. We hypothesise that adjunctive rifampicin, given in combination with a standard first-line antibiotic, will enhance killing of S. aureus early in the treatment course, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Our aim is to determine whether adjunctive rifampicin reduces all-cause mortality within 14 days and bacteriological failure or death within 12 weeks from randomisation. METHODS: We will perform a parallel group, randomised (1:1), blinded, placebo-controlled trial in NHS hospitals across the UK. Adults (≥ 18 years) with S. aureus (meticillin-susceptible or resistant) grown from at least one blood culture who have received ≤ 96 h of active antibiotic therapy for the current infection and do not have contraindications to the use of rifampicin will be eligible for inclusion. Participants will be randomised to adjunctive rifampicin (600-900 mg/day; orally or intravenously) or placebo for the first 14 days of therapy in combination with standard single-agent antibiotic therapy. The co-primary outcome measures will be all-cause mortality up to 14 days from randomisation and bacteriological failure/death (all-cause) up to 12 weeks from randomisation. 940 patients will be recruited, providing >80% power to detect 45% and 30% reductions in the two co-primary endpoints of death by 14 days and bacteriological failure/death by 12 weeks respectively. DISCUSSION: This pragmatic trial addresses the long-standing hypothesis that adjunctive rifampicin improves outcome from S. aureus bacteraemia through enhanced early bacterial killing. If proven correct, it will provide a paradigm through which further improvements in outcome from S. aureus bacteraemia can be explored.

Serial measurement of the C-reactive protein is a poor predictor of treatment outcome in prosthetic joint infection.

OBJECTIVES: Prosthetic joint infection is usually treated using surgery and antibiotics. The response to the treatment regimen is often evaluated using serial monitoring of plasma C-reactive protein (CRP) concentrations. In order to examine how useful this monitoring is, we calculated the sensitivity and specificity of CRP concentrations for predicting treatment failure. PATIENTS AND METHODS: We examined 3732 CRP measurements from 260 patients who were treated by either two-stage revision or debridement and retention. We tested the association between CRP concentration and outcome using logistic regression models, and assessed sensitivity and specificity by using receiver operator curves. RESULTS: The areas under receiver operator curves for CRP concentrations predicting outcome ranged from 0.55 to 0.65. CONCLUSIONS: CRP concentrations did not accurately predict treatment failure. Serial monitoring may not be of benefit.

Sensitivity and specificity of an index for the diagnosis of TB meningitis in patients in an urban teaching hospital in Malawi.

Tuberculous (TB) meningitis is difficult to diagnose and has a high mortality rate, particularly when presentation is delayed. A diagnostic index developed in Vietnam, an area of low-HIV seroprevalence, has been proposed as a means to differentiate TB meningitis from acute bacterial meningitis using clinical and laboratory features. We applied this index over a 4-month period to adults presenting with meningitis to an urban teaching hospital in Malawi, where HIV seroprevalence is 70% among medical inpatients. Eighty-five consecutive eligible patients were studied. Nine had TB meningitis, 64 bacterial meningitis and 12 cryptococcal meningitis. The sensitivity of the diagnostic index for predicting TB meningitis was 78%, with a specificity of 43%, too low to be used in the diagnosis of TB meningitis in this setting. This finding is likely to be generalizable to other southern African countries with similarly high-HIV seroprevalences.