Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Safety and efficacy of whole-body chlorhexidine gluconate cleansing with or without emollient in hospitalised neonates (NeoCHG): a multicentre, randomised, open-label, factorial pilot trial.

Background: Healthcare-associated infections account for substantial neonatal in-hospital mortality. Chlorhexidine gluconate (CHG) whole body skin application could reduce sepsis by lowering bacterial colonisation density, although safety and optimal application regimen is unclear. Emollients, including sunflower oil, may independently improve skin condition, thereby reducing sepsis. We aimed to inform which concentration and frequency of CHG, with or without emollient, would best balance safety and the surrogate marker of efficacy of reduction in bacterial colonisation, to be taken forward in a future pragmatic trial evaluating clinical outcomes of sepsis and mortality. Methods: In this multicentre, randomised, open-label, factorial pilot trial, neonates in two hospital sites (South Africa, Bangladesh) aged 1-6 days with gestational age ≥ 28 weeks and birthweight 1000-1999 g were randomly assigned in a factorial design stratified by site to three different concentrations of CHG (0.5%, 1%, and 2%), with or without emollient (sunflower oil) applied on working days vs alternate working days. A control arm received neither product. Caregivers were unblinded although laboratory staff were blinded to randomisation Co-primary outcomes were safety (change in neonatal skin condition score incorporating dryness, erythema, and skin breakdown) and efficacy in reducing bacterial colonisation density (change in total skin bacterial log10 CFU from randomisation to day-3 and day-8). The trial is registered at the ISRCTN registry, ISRCTN 69836999. Findings: Between Apr 12 2021 and Jan 18 2022, 208 infants were randomised and 198 were included in the final analysis. Skin condition scores were low with mean 0.1 (sd = 0.3; N = 208) at baseline, 0.1 (sd = 0.3; N = 199) at day 3 and 0.1 (sd = 0.3; N = 189) at day 8, with no evidence of differences between concentration (1% CHG vs 0.5% estimate = -0.3, 95% CI = (-1.2, 0.6), p = 0.55. 2% CHG vs 0.5% CHG estimate = 0.5 (-0.4, 1.4), p = 0.30), increasing frequency (estimate = -0.4; 95% CI = (-1.1, 0.4), p = 0.33), emollient (estimate = -0.5, (-1.2, 0.3), p = 0.23) or with control (estimate = -0.9, (-2.3, 0.4), p = 0.18). Mean log10 CFU was 4.9 (sd = 3.0; N = 208) at baseline, 6.3 (sd = 3.1; N = 198) at day 3 and 8.4 (sd = 2.6; N = 183) with no evidence of differences between concentration (1% CHG vs 0.5% estimate = -0.4; 95% CI = (-1.1, 0.23); p = 0.23. 2% CHG vs 0.5% CHG estimate = 0.0 (-0.6, 0.6), p = 0.96), with increasing frequency (estimate = -0.4; 95% CI = (-0.9, 0.2); p = 0.17), with emollient (estimate = 0.4, 95% CI = (-0.2, 0.9); p = 0.18) or with control (estimate = -0.2, 95% CI = (-1.3, 0.9); p = 0.73). By day-8, overall 158/183 (86%) of neonates were colonised with Enterobacterales, and 72/183 (39%) and 69/183 (9%) with Klebsiella spp resistant to third-generation cephalosporin and carbapenems, respectively. There were no CHG-related SAEs, emollient-related SAEs, grade 3 or 4 skin scores or grade 3 or 4 hypothermias. Interpretation: In this pilot trial of CHG with or without sunflower oil, no safety issues were identified, and further trials examining clinical outcomes are warranted. The relatively late start application of emollient, at a mean of 3.8 days of life, may have reduced the impact of the intervention although no subgroup effects were detected. There was no clear evidence in favour of a specific concentration of chlorhexidine, and there was rapid colonisation with Enterobacterales with frequent antimicrobial resistance, regardless of skin application regimen. Funding: The MRC Joint Applied Global Health award, the Global Antibiotic Research and Development Partnership (GARDP), MRC Clinical Trials Unit core funding (UKRI) and St. George's, University of London.

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Global, regional, and national estimates of the impact of a maternal Klebsiella pneumoniae vaccine: A Bayesian modeling analysis.

BACKGROUND: Despite significant global progress in reducing neonatal mortality, bacterial sepsis remains a major cause of neonatal deaths. Klebsiella pneumoniae (K. pneumoniae) is the leading pathogen globally underlying cases of neonatal sepsis and is frequently resistant to antibiotic treatment regimens recommended by the World Health Organization (WHO), including first-line therapy with ampicillin and gentamicin, second-line therapy with amikacin and ceftazidime, and meropenem. Maternal vaccination to prevent neonatal infection could reduce the burden of K. pneumoniae neonatal sepsis in low- and middle-income countries (LMICs), but the potential impact of vaccination remains poorly quantified. We estimated the potential impact of such vaccination on cases and deaths of K. pneumoniae neonatal sepsis and project the global effects of routine immunization of pregnant women with the K. pneumoniae vaccine as antimicrobial resistance (AMR) increases. METHODS AND FINDINGS: We developed a Bayesian mixture-modeling framework to estimate the effects of a hypothetical K. pneumoniae maternal vaccine with 70% efficacy administered with coverage equivalent to that of the maternal tetanus vaccine on neonatal sepsis infections and mortality. To parameterize our model, we used data from 3 global studies of neonatal sepsis and/or mortality-with 2,330 neonates who died with sepsis surveilled from 2016 to 2020 undertaken in 18 mainly LMICs across all WHO regions (Ethiopia, Kenya, Mali, Mozambique, Nigeria, Rwanda, Sierra Leone, South Africa, Uganda, Brazil, Italy, Greece, Pakistan, Bangladesh, India, Thailand, China, and Vietnam). Within these studies, 26.95% of fatal neonatal sepsis cases were culture-positive for K. pneumoniae. We analyzed 9,070 K. pneumoniae genomes from human isolates gathered globally from 2001 to 2020 to quantify the temporal rate of acquisition of AMR genes in K. pneumoniae isolates to predict the future number of drug-resistant cases and deaths that could be averted by vaccination. Resistance rates to carbapenems are increasing most rapidly and 22.43% [95th percentile Bayesian credible interval (CrI): 5.24 to 41.42] of neonatal sepsis deaths are caused by meropenem-resistant K. pneumoniae. Globally, we estimate that maternal vaccination could avert 80,258 [CrI: 18,084 to 189,040] neonatal deaths and 399,015 [CrI: 334,523 to 485,442] neonatal sepsis cases yearly worldwide, accounting for more than 3.40% [CrI: 0.75 to 8.01] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert over 6% of all neonatal deaths. Nevertheless, our modeling only considers country-level trends in K. pneumoniae neonatal sepsis deaths and is unable to consider within-country variability in bacterial prevalence that may impact the projected burden of sepsis. CONCLUSIONS: A K. pneumoniae maternal vaccine could have widespread, sustained global benefits as AMR in K. pneumoniae continues to increase.

Effect of food on the pharmacokinetics of zoliflodacin granules for oral suspension: Phase I open-label randomized cross-over study in healthy subjects.

Gonorrhea is a sexually transmitted infection for which antibiotic treatment options have declined due to increasing antibiotic resistance. Zoliflodacin, an investigational oral spiropyrimidinetrione antibiotic with activity against Neisseria gonorrhoeae strains that are multidrug-resistant, including to third-generation cephalosporins, is in phase III development for uncomplicated gonorrhea. This phase I, parallel, open-label, randomized, crossover study in healthy adults evaluated the effect of food on the pharmacokinetics of single 3 or 4 g doses of zoliflodacin administered as granules for oral suspension in the fasted state or after consumption of a standardized high-fat meal. Forty-seven out of 48 randomized subjects completed the study. Oral administration of zoliflodacin with food delayed the absorption rate, compared with fasted state, with time to maximum concentration (Tmax ) increasing from 3 to 6 h for the 3 g dose, and 2.5 to 4 h for the 4 g dose, but had no impact on the elimination of zoliflodacin. The maximum concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-24) ) significantly increased with food by 52% and 94% for the 3 g dose, and by 89% and 108% for the 4 g dose. Forty-two percent of participants reported a total of 34 treatment-emergent adverse events (TEAEs), which were all considered mild in severity. Headache was the most common TEAE (22/48 subjects, 45.8%) and the only TEAE reported in more than one subject. In conclusion, administration of single 3 and 4 g doses of zoliflodacin as granules for oral suspension, with a high-fat meal was well-tolerated and resulted in statistically significant increases in peak and overall systemic exposure to zoliflodacin.

Decision regret after primary hip and knee replacement surgery.

BACKGROUND: Decision regret (DR) is a recognised patient centered outcome measure following a therapeutic intervention. This study aimed to measure DR following primary total hip and knee arthroplasty (THA/TKA), to assess for differences between these patients and explore possible contributory factors. METHOD: DR was measured using the DR scale in a group of THA and TKA patients, between February 2017 and December 2018, who had made a decision to have joint replacement surgery within the previous year and were able to reflect on their outcomes. RESULTS: On analysis a significantly greater proportion of TKA patients reported moderate or severe (Mod/Sev) DR [17.1% (56/328)] compared to THA patients [4.8% (18/376)]. Conversely, a significantly reduced proportion of TKA patients reported having No DR [42.1% (138/328)] compared to THA patients [66.7% (251/376)]. On multivariate logistic regression analysis joint replacement type (TKA/THA) and change in Oxford score were significant predictors of DR with gender, age, BMI and ASA grade not significantly associated. TKA patients were more than twice as likely to have Mod/Sev DR compared THA patients (Odds Ratio = 2.33 (95% CI 1.24-4.39)). Patients with poorer improvements in pain and function 1-year post-operatively (measured by Oxford scores) reported greater levels of DR. CONCLUSION: TKA patients were significantly more likely to report greater levels of DR 1-year following surgery compared to THA patients. For both TKA and THA patients, greater levels of DR were associated with poorer Oxford scores. The use of decision aids to reduce post-operative DR in joint replacement patients should be examined especially for knee replacement patients.

Antibiotics needed to treat multidrug-resistant infections in neonates.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Les infections demeurent l'une des principales causes de décès chez les nouveau-nés. Les rares projets de développement d'antibiotiques et les défis posés par la recherche néonatale ont entraîné une pénurie d'antibiotiques efficaces spécialement étudiés pour traiter les infections multirésistantes (MR) chez les nouveau-nés, en dépit d'une mortalité galopante due à une résistance accrue aux antimicrobiens. Sur 40 antibiotiques autorisés pour les adultes depuis 2000, quatre à peine sont munis d'un étiquetage indiquant la posologie adaptée aux nouveau-nés. Actuellement, 43 essais cliniques portant sur des antibiotiques recrutent des patients du côté des adultes, contre six seulement du côté des nouveau-nés. Dans le présent document, nous passons en revue la liste prioritaire d'agents pathogènes établie par l'Organisation mondiale de la Santé (OMS) pour soigner la septicémie néonatale et proposons de réunir, sous l'égide de l'OMS, des parties prenantes issues de plusieurs domaines d'expertise afin de promouvoir la création d'une liste prioritaire de développement d'antibiotiques destinés aux nouveau-nés. Objectif: parvenir à un consensus international et interdisciplinaire visant à accélérer le programme de mise au point d'antibiotiques à usage néonatal. Ce programme permettrait d'orienter les recherches vers des antibiotiques identifiés comme prioritaires pour les nouveau-nés, en vue de faire baisser les taux de morbidité et de mortalité excessifs qu'engendrent les infections MR au sein de cette population vulnérable.

Las infecciones siguen siendo una de las principales causas de muerte en los recién nacidos. Debido al escaso desarrollo de los antibióticos y a las dificultades para llevar a cabo la investigación neonatal, son pocos los antibióticos eficaces que se estudian de manera adecuada para tratar las infecciones multirresistentes (MR) en los recién nacidos, a pesar de la creciente carga de mortalidad mundial causada por la resistencia a los antimicrobianos. De los 40 antibióticos aprobados para su uso en adultos desde el 2000, solo cuatro han incluido información sobre la dosis para recién nacidos en su etiquetado. En la actualidad, 43 ensayos clínicos con antibióticos para adultos están reclutando pacientes, en comparación con solo seis ensayos que reclutan recién nacidos. Se revisa la lista de patógenos prioritarios de la Organización Mundial de la Salud (OMS) relevantes para la sepsis neonatal y se propone una reunión de la OMS con múltiples expertos para promover el desarrollo de una lista de antibióticos prioritarios para los recién nacidos. El objetivo es desarrollar un consenso internacional e interdisciplinario para establecer un programa acelerado de desarrollo de antibióticos neonatales. Este programa permitiría centrar la investigación en los antibióticos prioritarios identificados para los recién nacidos con el fin de reducir el exceso de morbilidad y mortalidad causado por las infecciones MR en esta población vulnerable.

The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium.

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.

A Nonprofit Drug Development Model Is Part of the Antimicrobial Resistance (AMR) Solution.

Antibiotics underpin modern medicine and are critical for pandemic preparedness. Push funding has revitalized the preclinical antimicrobial resistance (AMR) pipeline and government funding via CARB-X and BARDA, as well as private sector-led investment via the AMR Action Fund, will help several new antibiotics obtain regulatory approval. Nevertheless, revenues generated by new antibiotics are not considered sufficiently profitable by commercial developers to address unmet need. The question remains: Who could viably fund development and secure global equitable access for new antibiotics? Public health need should be the primary driver for antibiotic development. Improved prioritization and government oversight by funders who allocate public resources are a needed first step. In this framework, nonprofit research and development organizations, with support from public funders, and unconstrained by commercial profitability requirements are well positioned to work with public and private actors to viably provide new antibiotics to all in need.

Novel Phage-Derived Depolymerase with Activity against Proteus mirabilis Biofilms.

The adherence of Proteus mirabilis to the surface of urinary catheters leads to colonization and eventual blockage of the catheter lumen by unique crystalline biofilms produced by these opportunistic pathogens, making P. mirabilis one of the leading causes of catheter-associated urinary tract infections. The Proteus biofilms reduce efficiency of antibiotic-based treatment, which in turn increases the risk of antibiotic resistance development. Bacteriophages and their enzymes have recently become investigated as alternative treatment options. In this study, a novel Proteus bacteriophage (vB_PmiS_PM-CJR) was isolated from an environmental sample and fully characterized. The phage displayed depolymerase activity and the subsequent genome analysis revealed the presence of a pectate lyase domain in its tail spike protein. The protein was heterologously expressed and purified; the ability of the purified tail spike to degrade Proteus biofilms was tested. We showed that the application of the tail spike protein was able to reduce the adherence of bacterial biofilm to plastic pegs in a MBEC (minimum biofilm eradication concentration) assay and improve the survival of Galleria mellonella larvae infected with Proteus mirabilis. Our study is the first to successfully isolate and characterize a biofilm depolymerase from a Proteus phage, demonstrating the potential of this group of enzymes in treatment of Proteus infections.

Ten-year outcomes following a cohort of ASR XL total hip arthroplasties.

AIMS: To determine the outcome at 10 years of a cohort of ASR XL total hip arthroplasties (THAs) and reasons for revision. METHODS: Between November 2005 and May 2007, 122 ASR XL THAs were implanted. All patients had a routine review at 6 weeks and 1 year, followed by a review in 2009 because of clinical concern and thereafter annual review up to 10 years with MRI. Review also included functional scores, radiographs, pain scores and blood metal ions. RESULTS: 67 (54.9%) ASR XLs had been revised by 11.1 years. Reasons for revision included pain (89.6%), high levels of cobalt and chromium ions (50.7%) and radiographic or MRI changes (80.6%). All 3 factors were present in 23 (34.3%). Pain at 1 year did not predict revision, but pain at the 2009 review did. At 10 years the revised patients had an average Oxford Hip Score (OHS) of 25.38 (12-42) and the non-revised 23.61 (2-21), the difference was not significant (p = 0.48). 3 patients (4.5%) have had a further revision; 2 for a previously unrevised stem and the other for instability. CONCLUSIONS: Our arthroplasty care practitioner service allowed us to identify increased pain and stop using the ASR XL over 3 years before the implant was recalled. The revised patients had similar functional outcome to those unrevised. Poorly performing implants need to be identified earlier.

Psychosocial predictors of outcomes up to one year following total knee arthroplasty.

BACKGROUND: Total knee arthroplasty (TKA) aims to relieve pain and improve physical functioning of the knee, however, some patients continue to experience pain and impaired function following TKA which cannot be explained by surgical and implant factors. Psychological factors may influence the outcomes of TKA. The aim of this prospective study was to examine the psychosocial factors that predicted pain, stiffness and physical functioning up to one year following TKA. METHODS: One hundred and two patients completed pre-operative and one-year questionnaires which assessed a wide range of psychosocial and sociodemographic factors prior to surgery. The Oxford Knee Score (OKS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, Stiffness and Physical Functioning subscales were used as outcome measures. Pearson correlation analysis and multiple linear regression were conducted to examine relationships between predictor and outcome variables. RESULTS: Regression analysis showed that regarding variance in WOMAC outcome measures post TKA, our model predicted 31% for physical functioning, 25% for pain and 29% for stiffness at one year. Regarding variance in OKS post TKA, the model predicted 36% at one year. Greater levels of depressive symptoms and neuroticism and worse pre-operative scores significantly predicted poorer outcomes. CONCLUSIONS: The findings indicate that pre-operative psychosocial factors are important in understanding outcomes of TKA. Psychosocial factors could be considered during pre-operative assessment. Further research conducted on psychological interventions is needed within this population to determine whether early and one-year outcomes can be improved.

Observed effect of femoral component undersizing and a collarless design in the development of radiolucent lines in cementless total hip arthroplasty.

BACKGROUND: The objective of this study was to determine the prevalence of radiolucent lines (RLLs) around the femoral component in a cohort of patients who underwent well-functioning cementless total hip arthroplasty (THA). METHODS: A cohort of unrevised Corail (DePuy Synthes, Raynham, MA) femoral components (n = 636) were analyzed at a median follow-up of 6.0 years (interquartile range: 5.2-6.8) with the Oxford Hip Score (OHS) and radiographs. Two independent observers assessed the radiographs for the presence of RLLs. RESULTS: The overall prevalence of RLLs in zone 7 was 13% (83/636). Patients with RLLs in zone 7 had an average OHS of 40.3 (15-48), and those who did not have RLLs in zone 7 had an average OHS of 38 (6-48), P = .07. Both groups had an average pain score of 1.6 out of 5, P = .5. The prevalence of RLLs in zone 7 was much less in the collared femoral components (2.6% prevalence) than in the collarless components (23.6% prevalence), but there was heterogeneity between these 2 groups preventing comparison. Logistic regression analysis of only the collarless components identified undersizing as the only predictive (odds ratio = 2.6) factor for RLL development in zone 7. CONCLUSIONS: Undersizing the Corail stem is strongly predictive of developing RLLs in zone 7. Preoperative templating for the appropriate size is critical. We observed more RLLs in zone 7 with the collarless design Corail, but a comparison study with the same bearing couple is needed to investigate this further.

Foot drop following primary total hip arthroplasty.

INTRODUCTION: Foot drop is a potentially debilitating complication following injury to the sciatic nerve during primary total hip arthroplasty (THA). The aim of this study was to determine the incidence, risk factors and outcome of this complication within one large surgical practice. METHODS: We analysed the records of 10,624 primary THAs carried out between January 1993 and November 2017 using a posterior approach. All were under the care of the senior author. RESULTS: Overall, there were 47 cases (0.44%) of foot drop, but over time the incidence dropped from 0.6% to 0.3% (p = 0.033). Preoperative protrusio acetabulae (p < 0.001), female sex (p < 0.001) and junior grade of surgeon (p < 0.009) were all significant risk factors. In this series, dysplasia was not a risk factor. 1 year postoperatively, 25 (53.2%) had complete recovery, 12 (25.5%) had ongoing sensory deficit but normal power, and 10 (21.3%) had a residual sensory-motor deficit. CONCLUSION: Take home message:- In this series, protrusio acetabulae, female sex and junior grade of surgeon were significant risk factors for foot drop following primary THA.

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

Gut Check Time: Antibiotic Delivery Strategies to Reduce Antimicrobial Resistance.

Antimicrobial resistance (AMR) has developed into a huge threat to global health, and reducing it is an urgent priority for public health authorities. The importance of a healthy and balanced gut microbiome has been identified as a key protective factor against AMR development, but this can be significantly affected by antibiotic therapy, resulting in dysbiosis and reduction of taxonomic richness. The way in which antibiotics are administered could form an important part of future antimicrobial stewardship strategies, where drug delivery is ideally placed to play a key role in the fight against AMR. This review focuses on drug delivery strategies for antibiotic administration, including avoidance of the gut microbiome and targeted delivery approaches, which may reduce AMR.

A Prospective Randomized Study Comparing Postoperative Pain, Biological Fixation, and Clinical Outcomes Between Two Uncemented Rotating Platform Tibial Tray Designs.

BACKGROUND: With the demand for arthroplasty increasing worldwide year on year, there is a drive to improve prosthesis longevity. Biological fixation from cementless implants has been one method of trying to achieve this. We hypothesized that the addition of a hydroxyapatite (HA) coating and 4 pegs to a porous-coated tibial tray would provide a reduction in time to implant osseointegration, allowing for normal physiological stress transfer, thus improving early postoperative pain and rehabilitation as well as the elimination of radiolucent lines (RLLs). METHODS: A prospective, randomized controlled single-blinded study was undertaken, comparing postoperative pain, radiographic evidence of biological fixation, and clinical outcomes between patients undergoing primary total knee arthroplasty with either LCS Complete POROCOAT (porous coating only) or LCS Complete DUOFIX (porous coating plus HA and pegs) knee systems (DePuy Synthes, Warsaw, IN). In total, 197 patients (205 knees) were recruited into the study between November 2006 and November 2008 and have been followed for up to 10 years. RESULTS: There were no clinically significant differences in pain or patient-reported outcome measures when comparing the 2 designs but the tibial tray with pegs and HA showed fewer RLLs at all time points. There was no correlation between RLLs and pain and no instances of loosening or osteolysis in either group. There was 1 revision for infection in the porous coating only group. CONCLUSION: The tray design with HA and additional fixation pegs did not confer any benefit in terms of reduced early postoperative pain or improved patient-reported outcomes, although it did result in significantly fewer RLLs. Both implants demonstrated excellent survivorship. With a cementless porous-coated tibial component, nonprogressive RLLs should be considered normal.

Twenty-year survivorship of a cemented mobile bearing Total Knee Arthroplasty.

BACKGROUND: Increasing numbers of Total Knee Arthroplasty (TKA) operations are carried out worldwide each year. This brings with it an ever-increasing revision burden and it is therefore important to appreciate both the functional outcome and survivorship of established arthroplasties when considering new designs. We aim to evaluate the long-term survivorship of a fully cemented mobile bearing Total Knee Arthroplasty. METHODS: This study prospectively analyses the 20-year survivorship of a cohort of 487 consecutive patients who underwent cemented TKA under the care of a single surgeon using the Low Contact Stress (LCS) rotating platform (RP) implant. These patients were followed up prospectively with patient reported and functional outcomes recorded at regular intervals postoperatively. RESULTS: Five hundred and forty-two consecutive primary TKAs were carried out in 487 patients. A total of 139 knees (25.6%) were reviewed at 20 years post-operation. Overall cumulative survivorship, using revision for any reason as primary endpoint, was 98.0%. Mean Knee Society Scores for the patient cohort were 87.3 (Clinical score) and 52.5 (Functional score). Eleven (2.0%) were revised within 20 years - two for aseptic loosening, two for unexplained pain, five secondary patellar resurfacings for anterior knee pain, one for late infection and one liner exchange following spin-out. CONCLUSION: This series demonstrates excellent survivorship and satisfactory outcome of a cemented mobile bearing TKA at 20 years.

CSF Beta-amyloid 1-42 Concentration Predicts Delirium Following Elective Arthroplasty Surgery in an Observational Cohort Study.

OBJECTIVE: To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aß42, T-tau and P-tau would independently predict the risk of postoperative delirium. BACKGROUND: Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium. METHODS: This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium. RESULTS: Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aß42 (P < 0.01) were independent predictors of postoperative delirium. CONCLUSIONS: This study is the first to show an independent association between CSF Aß42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.