Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Thirty-day mortality following surgical management of hip fractures during the COVID-19 pandemic: findings from a prospective multi-centre UK study.

PURPOSE: Thirty-day mortality of patients with hip fracture is well researched and predictive; validated scoring tools have been developed (Nottingham Hip Fracture Score, NHFS). COVID-19 has significantly greater mortality in the elderly and comorbid patients which includes hip fracture patients. Non-operative treatment is not appropriate due to significantly higher mortality, and therefore, these patients are often exposed to COVID-19 in the peri-operative period. What is unclear is the effect of concomitant COVID-19 infection in these patients. METHODS: A multicentre prospective study across ten sites in the United Kingdom (responsible for 7% of hip fracture patients per annum in the UK). Demographic and background information were collected by independent chart review. Data on surgical factors included American Society of Anesthesiologists (ASA) score, time to theatre, Nottingham Hip fracture score (NHFS) and classification of fracture were also collected between 1st March 2020 and 30th April 2020 with a matched cohort from the same period in 2019. RESULTS: Actual and expected 30-day mortality was found to be significantly higher than expected for 2020 COVID-19 positive patients (RR 3.00 95% CI 1.57-5.75, p < 0.001), with 30 observed deaths compared against the 10 expected from NHFS risk stratification. CONCLUSION: COVID-19 infection appears to be an independent risk factor for increased mortality in hip fracture patients. Whilst non-operative management of these fractures is not suggested due to the documented increased risks and mortality, this study provides evidence to the emerging literature of the severity of COVID-19 infection in surgical patients and the potential impact of COVID-19 on elective surgical patients in the peri-operative period.

Correction to: Thirty-day mortality following surgical management of hip fractures during the COVID-19 pandemic: findings from a prospective multi-centre UK study.

The published online version contains mistake, as the Fig. 1 legend should read "Kaplan-Meier survival curve for 30-day survival for 2020 cohort COVID-19 positive vs COVID-19 negative" whilst the Fig. 2 legend should read "Kaplan-Meier survival curve for 30-day survival 2020 COVID-19 negative group vs 2019 cohort".

A comparative analysis of the patient characteristics and cost of managing intravenous drug users (IVDU) with soft tissue abscesses with non-IVDU.

BACKGROUND: Intravenous drug users (IVDU) often present to hospitals with complex co-morbidities, associated with prolonged in-patient admissions. The aim of this study was to compare a cohort of IVDU patients with soft tissue abscesses with non-IVDUs. We analysed the demographics, comorbidities, location of abscesses, multidisciplinary input and financial costs of managing both groups. METHODS: A retrospective cohort study was conducted between January 2010 and September 2013. Two age and sex matched cohorts were compared: IVDU and non-IVDU. RESULTS: We identified 44 IVDU patients and 54 non-IVDU patients. The IVDU had higher rates of smoking (89% p < 0.001) and unemployment (73% p < 0.05). The most common comorbidities in the IVDU cohort were hepatitis C (17%) and HIV (14%), whereas diabetes mellitus (15%) and hypertension (11%) were the most common in the non-IVDUs (p < 0.01). The most common location for an abscess in non-IVDU patients was the hand, whereas IVDU patients had abscesses in their groin. Groin injecting led to a referral to multiple specialties. The median length of stay for the IVDU patients was 4 days and for non-IVDU patients 1 day (p < 0.01). The average cost of managing IVDU patients in our unit was £1280: for non- IVDU the cost was £530 (p < 0.001). CONCLUSIONS: IVDU patients with soft tissue abscesses have higher rates of smoking, unemployment, infection with hepatitis C and HIV compared to a control group. We have suggested several recommendations to optimise the management of these patients including the implementation of an additional code to compensate for the complexity of their management.

Vancomycin therapeutics and monitoring: a contemporary approach.

Vancomycin remains a clinically useful antibiotic despite the advent of several alternative drugs. Optimising vancomycin therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacodynamic parameters in the case of vancomycin, an area under the concentration time curve/minimum inhibitory concentration ratio of ≥400. Vancomycin monitoring methods can be categorised into four categories: empiric trough concentrations; linear regression analysis (one-compartment model), population methods and Bayesian estimation procedures. Although the empiric trough concentrations and population methods are easy to use and require minimal resources, there are large differences in the published vancomycin model parameters. This demonstrates that there is great variance in pharmacokinetic parameters between the models and a single vancomycin model cannot be applied to all patient populations. The linear regression and Bayesian methods recommended more accurate dosage regimens; however, they require additional resources such as information technology and healthcare personnel with background training in pharmacokinetics. The Bayesian methods offered additional advantages such as calculation of doses based on a single-serum concentration and optimisation of the patient's previous pharmacokinetic data to determine subsequent dosage regimens. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy than the empiric trough concentrations and population methods. We recommend the use of these programs providing there is appropriate expertise available to make appropriate recommendations.

Use of Ceftriaxone and Benzylpenicillin in Outpatient Parenteral Antimicrobial Therapy: Spectrum vs Cost.

Background: The application of antimicrobial stewardship (AMS) principles may entail increased cost to allow for narrower-spectrum therapy. Prescribing benzylpenicillin (BP) and ceftriaxone (CRO) for outpatient parenteral antimicrobial therapy (OPAT) demonstrates the complex challenge of this principle. The aim of this study is to analyze the use of BP and CRO in our OPAT program, including indications and relative cost. Methods: We analyzed all adult patients in our OPAT program who received intravenous BP or CRO over 1 year. We identified a "crossover group" of patients who could have received either agent. Economic comparison was based on acquisition cost of the therapy (drug, infuser, and preparation costs). Results: Of 105 eligible patients, 54 (51%) and 51 (49%) received BP and CRO, respectively. Forty (38%) patients were suitable for either agent; of these, the majority (n = 31, 78%) were treated with BP. Economic analysis demonstrated that the average daily cost of BP therapy was $93.76/d (AUD) vs $1.23/d for CRO. Thus, across our OPAT programs, we had an additional average cost of $92.53/patient/d to use BP instead of CRO. Program-wide the annual additional cost of using BP and thus applying this AMS strategy was $68 386.12. Conclusions: BP is often selected over CRO by clinicians, where possible, as recommended by the Australian guidelines; however, BP is associated with higher daily acquisition costs. More broadly, a number of narrower-spectrum agents may involve significantly higher costs than comparators; as such, the $92.53/d to prevent CRO exposure can be considered when applying other antimicrobial-substitution AMS interventions in an acute health care setting.

Prolonged carriage of resistant E. coli by returned travellers: clonality, risk factors and bacterial characteristics.

The aim of this study was to delineate the potential risks and dynamics of the prolonged carriage of resistant E. coli in returned travellers. A sample of 274 previously collected E. coli resistant to ceftriaxone (CRO), ciprofloxacin, gentamicin and/or nalidixic acid recovered from 102 travellers was studied. Travellers were assessed pre-travel then longitudinally (maximum 6 months) with peri-rectal/rectal swabs. Clonality was determined by REP-PCR and the presence of O25b-ST131 was assessed. Comparison was made longitudinally for individuals and between identified co-travellers. The risk of prolonged carriage was lower for CRO than for ciprofloxacin or gentamicin resistance. Repeated isolation of the same phenotype at different time points occurred in 19% of initial CRO-resistant carriers compared with 50% of ciprofloxacin- or gentamicin-resistant carriers. The duration of carriage was also longer for the latter resistance phenotypes (75th quartile 8 vs 62 and 63 days respectively). In multivariate analysis, risks of prolonged carriage included antimicrobial use whilst travelling (3.3, 1.3-8.4) and phylogenetic group B2 (9.3, 3.4-25.6) and D (3.8, 1.6-8.8). Clonality amongst longitudinal isolates from the same participant was demonstrated in 92% of participants who were assessable and most marked amongst CRO-resistant isolates. ST-131 was surprisingly infrequent (3% of participants). Prolonged carriage of ciprofloxacin- and gentamicin-resistant isolates is more frequent and prolonged than CRO resistance after travel. Risks of prolonged carriage indicate a contribution of host and bacterial factors to this carriage. These require further elucidation. The strong clonality identified suggests that carriage of a "phenotype" was mediated by persistence of bacteria/plasmid combinations rather than persistence of the plasmid after horizontal transfer to other bacteria.

Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity.

The new Australian Therapeutic Guidelines: Antibiotic, version 14 have revised the recommendations for the use and monitoring of aminoglycosides. The guidelines have clear distinctions between empirical and directed therapy as well as revised recommendations about the monitoring of aminoglycosides. This has led many clinicians to review their current practice with regard to the use of aminoglycosides. This review summarizes why aminoglycosides are still a valid treatment option and discusses the rationale for current dosing regimens in Gram-negative infections. In particular it focuses on the various methods for monitoring aminoglycosides that are currently being used. The aminoglycoside monitoring methods can be categorized into three groups: linear regression analysis (one compartment model), population methods and Bayesian estimation procedures. Although the population methods are easy to use and require minimal resources they can recommend clinically inappropriate doses as they have constant pharmacokinetic parameters and are not valid in special population groups, that is, renal impairment. The linear regression and Bayesian methods recommend more accurate dosage regimens; however, they require additional resources, such as information technology and healthcare personnel with background training in pharmacokinetics. The Bayesian methods offer additional advantages, such as calculation of doses based on a single serum concentration and optimization of the patient's previous pharmacokinetic data, in order to determine subsequent dosage regimens. We recommend the Bayesian estimation procedures be used, wherever feasible. However, they require the expertise of healthcare practitioners with a good understanding of pharmacokinetic principles, such as clinical pharmacists/clinical pharmacologists, in order to make appropriate recommendations.

Optimising antimicrobial therapy through the use of Bayesian dosing programs.

The optimisation of antibiotic dosing therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacokinetic/pharmacodynamic parameters, maximising efficacy and minimising toxicity. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy compared to linear regression analysis and population methods. This article summarises various methods for dose optimisation of antibiotics with a focus on Bayesian programs.

Does a dedicated hip fracture unit improve clinical outcomes? A five-year case series.

INTRODUCTION: The aim of the study was to establish whether a dedicated hip fracture unit, geographically separate from the local major trauma centre, could improve clinical outcomes for patients sustaining proximal femoral fragility fractures. MATERIALS AND METHODS: This study was a retrospective case series, using data collected from Brighton and Sussex University Hospitals NHS Trust's submissions to the National Hip Fracture Database between 1 April 2011 and 16 September 2016. The outcomes measured were mortality, length of hospital stay, time from admission to surgical intervention and return to premorbid residence. Patients were compared before and after reconfiguration of services into a separate dedicated hip fracture unit geographically distinct from the major trauma centre. RESULTS: A total of 2117 patients (2178 injuries) were managed before the existence of the hip fracture unit, while 660 patients (673 injuries) were treated within the hip fracture unit. During the five-year study period, the 30-day mortality rate (pre-hip fracture unit 5.47% vs hip fracture unit 3.13%, P = 0.014), variance in the length of hospital stay (P < 0.001), mean time to surgical intervention (P = 0.044) and return to premorbid residence were significantly improved. An immediate 12-month comparison demonstrated significantly improved variance in length of hospital stay (P = 0.020) and return to premorbid residence (P = 0.015). DISCUSSION: The reconfiguration of services significantly reduced variance in length of stay, enabling accurate resource planning in future. Multiple incremental improvements in service provision, in addition to the hip fracture unit, may explain the lower mortality observed. CONCLUSION: While further research is required, replication of the hip fracture unit service model may potentially afford significant clinical and financial gains.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Topographical variation in glycosaminoglycan content in human articular cartilage.

The weight-bearing status of articular cartilage has been shown to affect its biochemical composition. We have investigated the topographical variation of sulphated glycosaminoglycan (GAG) relative to the DNA content of the chondrocyte in human distal femoral articular cartilage. Paired specimens of distal femoral articular cartilage, from weight-bearing and non-weight-bearing regions, were obtained from 13 patients undergoing above-knee amputation. After papain enzyme digestion, spectrophotometric GAG and fluorometric DNA assays assessed the biochemical composition of the samples. The results were analysed using a paired t-test. Although there were no significant differences in cell density between the regions, the weight-bearing areas showed a significantly higher concentration of GAG relative to DNA when compared with non-weight-bearing areas (p = 0.02). We conclude that chondrocytes are sensitive to their mechanical environment, and that local loading conditions influence the metabolism of the cells and hence the biochemical structure of the tissue.

Interobserver variation in the measurement of patellar height after total knee arthroplasty.

We assessed the reproducibility and accuracy of four ratios used to measure patellar height, namely the Blackburne-Peel, Caton-Deschamps, Insall-Salvati and modified Insall-Salvati, before and after total knee arthroplasty. The patellar height was measured, by means of the four ratios, on the pre- and post-operative lateral radiographs of 44 patients (45 knees) who had undergone total knee arthroplasty. Two independent observers measured the films sequentially, in identical conditions, totalling 720 measurements per observer. Statistical analysis, comparing both observers and ratios, was carried out using the intraclass correlation coefficient. Before operation there was greater interobserver variation using either the Insall-Salvati or modified Insall-Salvati ratios than when using the Caton-Deschamps or Blackburne-Peel methods. This was because of difficulty in identifying the insertion of the patellar tendon. Before operation, there was a minimal difference in reliability between these methods. After operation the interobserver difference was greatly reduced using both the Caton-Deschamps and Blackburne-Peel methods, which use the prosthetic joint line, compared with the Insall-Salvati and modified Insall-Salvati, which reference from the insertion of the patellar tendon. The theoretical advantage of using the Insall-Salvati and modified Insall-Salvati ratios in measuring true patellar height after total knee arthroplasty needs to be balanced against their significant interobserver variability and inferior reliability when compared with other ratios.

Trauma-related amputations in war and at a civilian major trauma centre-comparison of care, outcome and the challenges ahead.

The Afghanistan conflict has resulted in a large number of service personnel sustaining amputations. Whilst obvious differences exist between military and civilian trauma-related amputations both settings result in life changing injuries. Comparisons offer the potential of advancement and protection of the knowledge gained during the last 12 years. This paper compares the military and civilian trauma-related amputee cohorts' demographics, management and rehabilitation outcomes measures. The UK military Joint Theatre Trauma Registry and a civilian major trauma centre database of trauma-related amputees were analysed. 255 military and 24 civilian amputees were identified. A significant difference (p>0.05) was seen in median age (24, range 18-43, vs. 48, range 24-87 years), mean number of amputations per casualty (1.6±SD 0.678 vs. 1±SD 0.0), mean ISS (22±SD 12.8 vs. 14.7±SD 15.7) and gender (99% males vs. 78%). Rehabilitation outcome measures recorded included the Special Interest Group in Amputee Medicine score where the military group demonstrated significantly better scores (91% Grade E+ compared to 19%). Differences in patients underlying physiology and psychology, the military trauma system and a huge sustained investment in rehabilitation are all contributing factors for these differing outcomes. However the authors also believe that the use of a consultant-led MDT and central rehabilitation have benefited the military cohort in the acute rehabilitation stage and is reflected in the good short-term outcomes.

Systematic review of aspirin for thromboprophylaxis in modern elective total hip and knee arthroplasty.

AIMS: There is uncertainty regarding the optimal means of thromboprophylaxis following total hip and knee arthroplasty (THA, TKA). This systematic review presents the evidence for acetylsalicylic acid (aspirin) as a thromboprophylactic agent in THA and TKA and compares it with other chemoprophylactic agents. MATERIALS AND METHODS: A search of literature published between 2004 and 2014 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 13 studies were eligible for inclusion. RESULTS: Evidence from one good quality randomised controlled trial (RCT) showed no difference in rates of venous thrombo-embolism (VTE) in patients given aspirin or low molecular weight heparin (LMWH) following TKA. There was insufficient evidence from trials with moderate to severe risk of bias being present to suggest aspirin is more or less effective than LMWH, warfarin or dabigatran for the prevention of VTE in TKA or THA. Compared with aspirin, rates of asymptomatic deep vein thrombosis (DVT) in TKA may be reduced with rivaroxaban but insufficient evidence exists to demonstrate an effect on incidence of symptomatic DVT. Compared with aspirin there is evidence of more wound complications following THA and TKA with dabigatran and in TKA with rivaroxaban. Some studies highlighted concerns over bleeding complications and efficacy of aspirin. CONCLUSION: The results suggest aspirin may be considered a suitable alternative to other thromboprophylactic agents following THA and TKA. Further investigation is required to fully evaluate the safety and efficacy of aspirin. Cite this article: Bone Joint J 2016;98-B:1056-61.

Temporal variation in major trauma admissions.

INTRODUCTION: Trauma is a significant cause of morbidity and mortality in the UK. Since the inception of the trauma networks, little is known of the temporal pattern of trauma admissions. METHODS: Trauma Audit and Research Network data for 1 April 2011 to 31 March 2013 were collated from two large major trauma centres (MTCs) in the South East of England: Brighton and Sussex University Hospitals NHS Trust (BSUH) and St George's University Hospitals NHS Foundation Trust (SGU). The number of admissions and the injury severity score by time of admission, by weekdays versus weekend and by month/season were analysed. RESULTS: There were 1,223 admissions at BSUH and 1,241 at SGU. There was significant variation by time of admission; there were more admissions in the afternoons (BSUH p<0.001) and evenings (SGU p<0.001). There were proportionally more admissions at the weekends than on weekdays (BSUH p<0.001, SGU p=0.028). There was significant seasonal variation in admissions at BSUH (p<0.001) with more admissions in summer and autumn. No significant seasonal variation was observed at SGU (p=0.543). CONCLUSIONS: The temporal patterns observed were different for each MTC with important implications for resource planning of trauma care. This study identified differing needs for different MTCs and resource planning should be individualised to the network.

Factors affecting planned return to work after trauma: A prospective descriptive qualitative and quantitative study.

The use of patient reported outcome measures (PROMs) in trauma is limited. The aim of this pilot study is to evaluate qualitative responses and factors affecting planned return to work following significant trauma, for which there is currently a poor evidence base. National ethical approval was obtained for routine prospective PROMs data collection, including EQ-5D, between Sept 2013 and March 2015 for trauma patients admitted to the Sussex Major Trauma Centre (n=92). 84 trauma patients disclosed their intended return to work at discharge. Additional open questions asked 'things done well' and 'things to be improved'. EQ-5D responses were valued using the time trade-off method. Statistical analysis between multiple variables was completed by ANOVA, and with categorical categories by Chi squared analysis. Only 18/68 of patients working at admission anticipated returning to work within 14days post-discharge. The injury severity scores (ISS) of those predicting return to work within two weeks and those predicting return to work longer than two weeks were 14.17 and 13.59, respectively. Increased physicality of work showed a trend towards poorer return to work outcomes, although non-significant in Chi-squared test in groups predicting return in less than or greater than two weeks (4.621, p=0.2017ns). No significant difference was demonstrated in the comparative incomes of patients with different estimated return to work outcomes (ANOVA r2=0.001, P=0.9590ns). EQ-5D scores were higher in those predicting return to work within two weeks when compared to greater than two weeks. Qualitative thematic content analysis of open responses was possible for 66/92 of respondents. Prominent positive themes were: care, staff, professionalism, and communication. Prominent negative themes were: food, ward response time, and communication. This pilot study highlights the importance of qualitative PROMs analysis in leading patient-driven improvements in trauma care. We provide standard deviations for ISS scores and EQ-5D scores in our general trauma cohort, for use in sample size calculations for further studies analysing factors affecting return to work after trauma.

Power tool injuries to the hand and wrist.

Power tool injuries to the hand and wrist are complex injuries which can have a profound impact on the function of the patient. This article gives an overview of the principles, and provides a systematic approach, to the management and rehabilitation of the injured limb and patient required to minimize future disability.

Renal replacement therapy: implications for the surgeon.

Renal replacement therapy comprises peritoneal dialysis, haemodialysis and renal transplantation. Patients undergoing renal replacement therapy often require surgery for a number of different reasons. This review summarizes likely surgical procedures for these patients and some of the common complications.