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AIM: This study investigated the compliance with a guideline-based antibiotic regimen on the outcome of patients surgically treated for a fracture-related infection (FRI). METHOD: In this international multicenter observational study, patients were included when diagnosed with an FRI between 2015 and 2019. FRI was defined according to the FRI consensus definition. All patients were followed for at least one year. The chosen antibiotic regimens were compared to the published guidelines from the FRI Consensus Group and correlated to outcome. Treatment success was defined as the eradication of infection with limb preservation. RESULTS: A total of 433 patients (mean age 49.7 ± 16.1 years) with FRIs of mostly the tibia (50.6%) and femur (21.7%) were included. Full compliance of the antibiotic regime to the published guidelines was observed in 107 (24.7%) cases. Non-compliance was mostly due to deviations from the recommended dosing, followed by the administration of an alternative antibiotic than the one recommended or an incorrect use or non-use of rifampin. Non-compliance was not associated with a worse outcome: treatment failure was 12.1% in compliant versus 13.2% in non-compliant cases (p = 0.87). CONCLUSIONS: We report good outcomes in the treatment of FRI and demonstrated that minor deviations from the FRI guideline are not associated with poorer outcomes. ispartof: JOURNAL OF INFECTION vol:86 issue:3 pages:227-232 ispartof: location:England status: published

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., Journal of Bone and Joint Infection, 6 (7)

Aims This study presents patient-reported quality of life (QoL) over the first year following surgical debridement of long bone osteomyelitis. It assesses the bone involvement, antimicrobial options, coverage of soft tissues, and host status (BACH) classification as a prognostic tool and its ability to stratify cases into ‘uncomplicated’ or ‘complex’. Methods Patients with long-bone osteomyelitis were identified prospectively between June 2010 and October 2015. All patients underwent surgical debridement in a single-staged procedure at a specialist bone infection unit. Self-reported QoL was assessed prospectively using the three-level EuroQol five-dimension questionnaire (EQ-5D-3L) index score and visual analogue scale (EQ-VAS) at five postoperative time-points (baseline, 14 days, 42 days, 120 days, and 365 days). BACH classification was applied retrospectively by two clinicians blinded to outcome. Results In total, 71 patients with long-bone osteomyelitis were included. There was significant improvement from time of surgery to one year postoperatively in mean EQ-VAS (58.2 to 78.9; p < 0.001) and mean EQ-5D-3L index scores (0.284 to 0.740; p < 0.001). At one year following surgery, BACH ‘uncomplicated’ osteomyelitis was associated with better QoL compared to BACH ‘complex’ osteomyelitis (mean EQ-5D-3L 0.900 vs 0.685; p = 0.020; mean EQ-VAS 87.1 vs 73.6; p = 0.043). Patients with uncomplicated bone involvement (BACH type B1, cavitary) reported higher QoL at all time-points when compared to complex bone involvement (B2, segmental or B3, osteomyelitis involving a joint). Patients with good antimicrobial options (Ax or A1) gave higher outcome scores compared to patients with multidrug-resistant isolates (A2). The need for microvascular tissue transfer (C1 and C2) did not impact significantly on QoL. Patients without major comorbidities (uncomplicated, H1) reported higher QoL compared to those with significant disease (complex, H2). Conclusion Uncomplicated osteomyelitis, as defined by BACH, gave higher self-reported QoL when compared to complex cases. The bone involvement, antimicrobial options, and host status variables were able to stratify patients in terms of QoL. These data can be used to offer prognostic information to patients who are undergoing treatment for long bone osteomyelitis. Cite this article: Bone Joint J 2020;102-B(11):1587–1596.

Diagnosis of orthopedic device-related infection is challenging, and causative pathogens may be difficult to culture. Metagenomic sequencing can diagnose infections without culture, but attempts to detect antimicrobial resistance (AMR) determinants using metagenomic data have been less successful. Human DNA depletion may maximize the amount of microbial DNA sequence data available for analysis. Human DNA depletion by saponin was tested in 115 sonication fluid samples generated following revision arthroplasty surgery, comprising 67 where pathogens were detected by culture and 48 culture-negative samples. Metagenomic sequencing was performed on the Oxford Nanopore Technologies GridION platform. Filtering thresholds for detection of true species versus contamination or taxonomic misclassification were determined. Mobile and chromosomal genetic AMR determinants were identified in Staphylococcus aureus-positive samples. Of 114 samples generating sequence data, species-level positive percent agreement between metagenomic sequencing and culture was 50/65 (77%; 95% confidence interval [CI], 65 to 86%) and negative percent agreement was 103/114 (90%; 95% CI, 83 to 95%). Saponin treatment reduced the proportion of human bases sequenced in comparison to 5-μm filtration from a median (interquartile range [IQR]) of 98.1% (87.0% to 99.9%) to 11.9% (0.4% to 67.0%), improving reference genome coverage at a 10-fold depth from 18.7% (0.30% to 85.7%) to 84.3% (12.9% to 93.8%). Metagenomic sequencing predicted 13/15 (87%) resistant and 74/74 (100%) susceptible phenotypes where sufficient data were available for analysis. Metagenomic nanopore sequencing coupled with human DNA depletion has the potential to detect AMR in addition to species detection in orthopedic device-related infection. Further work is required to develop pathogen-agnostic human DNA depletion methods, improving AMR determinant detection and allowing its application to other infection types.

Objectives The aim of this study was to assess the clinical application of, and optimize the variables used in, the BACH classification of long-bone osteomyelitis. Methods A total of 30 clinicians from a variety of specialities classified 20 anonymized cases of long-bone osteomyelitis using BACH. Cases were derived from patients who presented to specialist centres in the United Kingdom between October 2016 and April 2017. Accuracy and Fleiss’ kappa (Fκ) were calculated for each variable. Bone involvement (B-variable) was assessed further by nine clinicians who classified ten additional cases of long bone osteomyelitis using a 3D clinical imaging package. Thresholds for defining multidrug-resistant (MDR) isolates were optimized using results from a further analysis of 253 long bone osteomyelitis cases. Results The B-variable had a classification accuracy of 77.0%, which improved to 95.7% when using a 3D clinical imaging package (p < 0.01). The A-variable demonstrated difficulty in the accuracy of classification for increasingly resistant isolates (A1 (non-resistant), 94.4%; A2 (MDR), 46.7%; A3 (extensively or pan-drug-resistant), 10.0%). Further analysis demonstrated that isolates with four or more resistant test results or less than 80% sensitive susceptibility test results had a 98.1% (95% confidence interval (CI) 96.6 to 99.6) and 98.8% (95% CI 98.1 to 100.0) correlation with MDR status, respectively. The coverage of the soft tissues (C-variable) and the host status (H-variable) both had a substantial agreement between users and a classification accuracy of 92.5% and 91.2%, respectively. Conclusions The BACH classification system can be applied accurately by users with a variety of clinical backgrounds. Accuracy of B-classification was improved using 3D imaging. The use of the A-variable has been optimized based on susceptibility testing results. Cite this article: A. J. Hotchen, M. Dudareva, J. Y. Ferguson, P. Sendi, M. A. McNally. The BACH classification of long bone osteomyelitis. Bone Joint Res 2019;8:459–468. DOI: 10.1302/2046-3758.810.BJR-2019-0050.R1

Fracture-related infection (FRI) is common and often diagnosed late.Accurate diagnosis is the beginning of effective treatment.Diagnosis can be difficult, particularly when there are no outward signs of infection.The new FRI definition, together with clear protocols for nuclear imaging, microbiological culture and histological analysis, should allow much better study design and a clearer understanding of infected fractures.In recent years, there has been a new focus on defining FRI and avoiding non-specific, poorly targeted treatment. Previous studies on FRI have often failed to define infection precisely and so are of limited value. This review highlights the essential principles of making the diagnosis and how clinical signs, serum tests, imaging, microbiology, molecular biology and histology all contribute to the diagnostic pathway. Cite this article: EFORT Open Rev 2020;5:614-619. DOI: 10.1302/2058-5241.5.190072. ispartof: EFORT OPEN REVIEWS vol:5 issue:10 pages:614-619 ispartof: location:England status: published

Background The recent consensus definition for the diagnosis of fracture-related infection (FRI) includes the identification of indistinguishable microorganisms in at least 2 surgical deep-tissue specimens as a confirmatory criterion. However, this cut-off, and the total number of specimens from a patient with suspected FRI that should be sent for microbiological testing, have not been validated. We endeavored to estimate the accuracy of different numbers of specimens and diagnostic cut-offs for microbiological testing of deep-tissue specimens in patients undergoing surgical treatment for possible FRI. Methods A total of 513 surgical procedures in 385 patients with suspected FRI were included. A minimum of 2 surgical deep-tissue specimens were submitted for microbiological testing; 5 or more specimens were analyzed in 345 procedures (67%). FRI was defined by the presence of any confirmatory criteria other than microbiology. Resampling was utilized to model the sensitivity and specificity of diagnostic cut-offs for the number of surgical specimens yielding indistinguishable microorganisms and for the total number of specimens. The likelihood of detecting all clinically relevant microorganisms was also assessed. Results A diagnostic cut-off of at least 2 of 5 specimens with indistinguishable microorganisms identified by culture was 68% sensitive (95% confidence interval [CI], 62% to 74%) and 87% specific (95% CI, 81% to 94%) for the diagnosis of FRI. Two out of 3 specimens were 60% sensitive (95% CI, 55% to 66%) and 92% specific (95% CI, 88% to 96%). Submitting only 3 deep-tissue specimens risked missing clinically relevant microorganisms in at least 1 in 10 cases. Conclusions The present study was the first to validate microbiological criteria for the diagnosis of FRI, supporting the current confirmatory diagnostic criteria for FRI. Analysis of at least 5 deep-tissue specimens in patients with possible FRI is recommended. Level of evidence Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

This study presents patient-reported quality of life (QoL) over the first year following surgical debridement of long bone osteomyelitis. It assesses the bone involvement, antimicrobial options, coverage of soft tissues, and host status (BACH) classification as a prognostic tool and its ability to stratify cases into 'uncomplicated' or 'complex'.Patients with long-bone osteomyelitis were identified prospectively between June 2010 and October 2015. All patients underwent surgical debridement in a single-staged procedure at a specialist bone infection unit. Self-reported QoL was assessed prospectively using the three-level EuroQol five-dimension questionnaire (EQ-5D-3L) index score and visual analogue scale (EQ-VAS) at five postoperative time-points (baseline, 14 days, 42 days, 120 days, and 365 days). BACH classification was applied retrospectively by two clinicians blinded to outcome.In total, 71 patients with long-bone osteomyelitis were included. There was significant improvement from time of surgery to one year postoperatively in mean EQ-VAS (58.2 to 78.9; p0.001) and mean EQ-5D-3L index scores (0.284 to 0.740; p0.001). At one year following surgery, BACH 'uncomplicated' osteomyelitis was associated with better QoL compared to BACH 'complex' osteomyelitis (mean EQ-5D-3L 0.900 vs 0.685; p = 0.020; mean EQ-VAS 87.1 vs 73.6; p = 0.043). Patients with uncomplicated bone involvement (BACH type B1, cavitary) reported higher QoL at all time-points when compared to complex bone involvement (B2, segmental or B3, osteomyelitis involving a joint). Patients with good antimicrobial options (Ax or A1) gave higher outcome scores compared to patients with multidrug-resistant isolates (A2). The need for microvascular tissue transfer (C1 and C2) did not impact significantly on QoL. Patients without major comorbidities (uncomplicated, H1) reported higher QoL compared to those with significant disease (complex, H2).Uncomplicated osteomyelitis, as defined by BACH, gave higher self-reported QoL when compared to complex cases. The bone involvement, antimicrobial options, and host status variables were able to stratify patients in terms of QoL. These data can be used to offer prognostic information to patients who are undergoing treatment for long bone osteomyelitis. Cite this article

Aims The aim of this study was to evaluate the diagnostic value of preoperative serum CRP, white blood cell count (WBC), percentage of neutrophils (%N), and neutrophil to lymphocyte ratio (NLR) when using the fracture-related infection (FRI) consensus definition. Methods A cohort of 106 patients having surgery for suspected septic nonunion after failed fracture fixation were studied. Blood samples were collected preoperatively, and the concentration of serum CRP, WBC, and differential cell count were analyzed. The areas under the curve (AUCs) of diagnostic tests were compared using the z-test. Regression trees were constructed and internally cross-validated to derive a simple diagnostic decision tree. Results Using the FRI consensus definition, 46 patients (43%) were identified as infected. Sensitivity, specificity, and AUC of CRP were 67% (95% confidence interval (CI) 52% to 80%), 61% (95% CI 47% to 74%), and 0.64 (95% CI 0.54 to 0.74); of WBC count were 17% (95% CI 9% to 31%), 95% (95% CI 86% to 99%), and 0.57 (95% CI 0.50 to 0.62); of %N 13% (95% CI 6% to 26%), 87% (95% CI 76% to 93%), and 0.50 (95% CI 0.43 to 0.56); and of NLR 28% (95% CI 17% to 43%), 80% (95% CI 68% to 88%), and 0.54 (95% CI 0.46 to 0.63), respectively. A better performance of serum CRP was shown in comparison to the leucocyte count (p = 0.006), %N (p < 0.001), and NLR (p = 0.001). A statistically lower serum CRP level was shown in patients with an infection caused by a low virulence microorganism in comparison to high virulence bacteria (p = 0.008). We found that a simple decision tree approach using only low serum neutrophils (< 3.615 × 109/l) and low CRP (< 2.45 mg/l) may allow better identification of aseptic cases. Conclusion The evaluated serum inflammatory markers showed limited diagnostic value in the preoperative diagnosis of FRI when using the uniform FRI Consensus Definition. Therefore, they should remain as suggestive criteria in diagnosing FRI. Although CRP showed a higher performance in comparison to the other serum markers, it is insufficiently accurate to diagnose a septic nonunion, especially when caused by low virulence microorganisms. Cite this article: Bone Joint J 2020;102-B(7):904–911.

Background and Purpose: A case series review of chronic pelvic osteomyelitis treated with combined medical and surgical treatment by a multidisciplinary team.Methods: All patients treated with surgical excision of pelvic osteomyelitis at our tertiary referral centre between 2002 and 2014 were included. All received combined care from a clinical microbiologist, an orthopaedic surgeon and a plastic surgeon. The rate of recurrent infection, wound healing problems and post-operative mortality was determined in all. Treatment failure was defined as reoperation involving further bone debridement, a requirement for the use of long-term suppressive antibiotics or sinus recurrence.Results: Sixty-one adults (mean age 50.2 years, range 16.8-80.6) underwent surgery. According to the Cierny-Mader classification of osteomyelitis there were 19 type II, 35 type III and 7 type IV cases. The ischium was the most common site of infection. Osteomyelitis was usually the result of contiguous focus infection associated with decubitus ulcers, predominantly in patients with spinal or cerebral disorders. Most patients with positive microbiology had polymicrobial infection (52.5%). Thirty patients required soft tissue reconstruction with muscle or myocutaneous flaps.Twelve deaths occurred a mean of 2.8 years following surgery (range 7 days-7.4 years). Excluding these deaths the mean follow-up was 4.6 years (range 1.5-12.2 years). Recurrent infection occurred in seven (11.5%) a mean of 1.5 years post-operatively (92 days - 5.3 years). After further treatment 58 cases (95.1%) were infection free at final follow-up.Interpretation: Patients in this series have many comorbidities and risk factors for poor surgical outcome. Nevertheless, the multidisciplinary approach allows successful treatment in the majority of cases.

BackgroundOrthopaedic 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.MethodsSOLARIO 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.DiscussionThis 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 registrationClinicaltrials.gov,NCT03806166. Registered on 11 November 2019.

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.

It was with interest and alarm that we read the report by Vijakumar et al regarding antimicrobial susceptibility patterns of pathogens isolated from patients with chronic osteomyelitis.1 The authors reviewed 132 isolates from 100 patients managed in Davangere, Karnataka, South West India between January 2017-December 2019.

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.

We report our experience using a biodegradable calcium sulphate antibiotic carrier containing tobramycin in the surgical management of patients with chronic osteomyelitis. The patients were reviewed to determine the rate of recurrent infection, the filling of bony defects, and any problems with wound healing. A total of 193 patients (195 cases) with a mean age of 46.1 years (16.1 to 82.0) underwent surgery. According to the Cierny–Mader classification of osteomyelitis there were 12 type I, 1 type II, 144 type III and 38 type IV cases. The mean follow-up was 3.7 years (1.3 to 7.1) with recurrent infection occurring in 18 cases (9.2%) at a mean of 10.3 months post-operatively (1 to 25.0). After further treatment the infection resolved in 191 cases (97.9%). Prolonged wound ooze (longer than two weeks post-operatively) occurred in 30 cases (15.4%) in which there were no recurrent infection. Radiographic assessment at final follow-up showed no filling of the defect with bone in 67 (36.6%), partial filling in 108 (59.0%) and complete filling in eight (4.4%). A fracture occurred in nine (4.6%) of the treated osteomyelitic segments at a mean of 1.9 years (0.4 to 4.9) after operation.We conclude that Osteoset T is helpful in the management of patients with chronic osteomyelitis, but the filling of the defect in bone is variable. Prolonged wound ooze is usually self-limiting and not associated with recurrent infection.Cite this article: Bone Joint J 2014; 96-B:829–36

Vaccination against Plasmodium falciparum malaria could reduce the worldwide burden of this disease, and decrease its high mortality in children. Replication-defective recombinant adenovirus vectors carrying P. falciparum epitopes may be useful as part of a vaccine that raises cellular immunity to the pre-erythrocytic stage of malaria infection. However, existing immunity to the adenovirus vector results in antibody-mediated neutralization of the vaccine vector, and reduced vaccine immunogenicity. Our aim was to examine a population of children who are at risk from P. falciparum malaria for neutralizing immunity to replication-deficient recombinant chimpanzee adenovirus 63 vector (AdC63), compared to human adenovirus 5 vector (AdHu5). We measured 50% and 90% vector neutralization titers in 200 individual sera, taken from a cohort of children from Kenya, using a secreted alkaline phosphatase neutralization assay. We found that 23% of the children (aged 1-6 years) had high-titer neutralizing antibodies to AdHu5, and 4% had high-titer neutralizing antibodies to AdC63. Immunity to both vectors was age-dependent. Low-level neutralization of AdC63 was significantly less frequent than AdHu5 neutralization at the 90% neutralization level. We conclude that AdC63 may be a useful vector as part of a prime-boost malaria vaccine in children. (C) 2009 Elsevier Ltd. All rights reserved.