FDA, CDC, and NIH Co-sponsored Public Workshop Summary-Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.

There is an unmet need for developing drugs for the treatment of gonorrhea, due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets. On April 23, 2021, the U.S. Food and Drug Administration; Centers for Disease Control and Prevention; and National Institute of Allergy and Infectious Diseases, National Institutes of Health co-sponsored a workshop with stakeholders from academia, industry, and regulatory agencies to discuss the challenges and strategies, including potential collaborations and incentives, to facilitate the development of drugs for the treatment of gonorrhea. This article provides a summary of the workshop.

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.

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.

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.

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.

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.

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.

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.

Total Knee Arthroplasty in Severe Valgus Deformity Using a Modified Technique-A 10-Year Follow-Up Study.

BACKGROUND: Valgus knee deformity accounts for only 10% of total knee arthroplasties (TKAs), but is frequently considered the most challenging to manage. This study provides a 10-year follow-up on a previously reported series of severe valgus knees performed using an unconstrained mobile-bearing TKA with a modified technique to validate this technique. METHODS: A consecutive series of 275 predominantly cementless TKAs in 262 patients were performed for severe valgus (≥10°) deformity and prospectively followed to 10 years. Patient-reported outcome measures included the Oxford Knee Score, American Knee Society Score, Bartlett Patellar Score, and the Short Form 12 questionnaire. RESULTS: Average valgus deformity was reduced from 15.6° to 3.8° (P < .001). At a mean follow-up of 10.4 years (range, 9.5-14.1), 90 (34.4%) patients had died. Of the reviewed survivors, the mean Oxford Knee Score was 27.8 ± 9.8, with an American Knee Society clinical score of 85.6 ± 17.0 and a functional score of 65.1 ± 20.4, with 78% of patients reporting good to excellent results. To date, there has been 1 (0.36%) revision and 13 (4.73%) reoperations. Kaplan-Meier implant survival was 99.6% at 10 years. CONCLUSION: Despite its challenging nature, the valgus knee is associated with excellent survivorship and satisfactory long-term results using this modified technique. LEVEL OF EVIDENCE: Level IV.

Seventeen to Twenty Years of Follow-Up of the Low Contact Stress Rotating-Platform Total Knee Arthroplasty With a Cementless Tibia in All Cases.

BACKGROUND: Total knee arthroplasty designs can be categorized by bearing design and fixation method. The mobile-bearing concept was developed with the aim of increasing longevity and improving function by reduced polyethylene wear and closer replication of physiological knee motion. Cementless fixation has the goal of achieving a long-lasting "biological" fixation between prosthesis and bone. METHODS: Prospective analysis of the survivorship and patient-reported functional outcomes of a series of 500 low contact stress rotating-platform mobile-bearing total knee arthroplasties with a cementless tibial component with a minimum 17-year follow-up. RESULTS: Five hundred primary total knee arthroplasties were conducted in 467 patients. Mean follow-up was 18.1 (17.0-21.8) years and 141 (28.2%) knees were alive and available for review. Using revision for any cause as the end point, cumulative survivorship was 97.4%. Thirteen knees required revision: 3 for deep infection, 3 bearing only revisions for spinout, 3 for tibial tray subsidence, 2 secondary patella resurfacings, 1 aseptic loosening, and 1 for suspected aseptic loosening that was found to be well fixed. Mean American Knee Society Scores were 83 (evaluation) and 48 (function), Mean Oxford Knee Score was 32.1, and the mean Bartlett Patellar Score was 21.6. CONCLUSION: This series demonstrates excellent survivorship and acceptable patient-reported functional outcome scores of a mobile-bearing total knee arthroplasty with a cementless tibial tray at minimum 17-year follow-up.

A prospective evaluation of a largely cementless total knee arthroplasty cohort without patellar resurfacing: 10-year outcomes and survivorship.

BACKGROUND: The theoretical benefits of a mobile bearing design in Total Knee Arthroplasty (TKA) include increased articular surface conformity with a reduction in both polyethylene wear and implant interface shear. However, to date these theoretical advantages have not been translated into published evidence of superior survivorship. This paper presents the results of a prospective, non-comparative study evaluating the performance of the mobile bearing Low Contact Stress LCS Complete Rotating Platform TKA in a largely cementless cohort without patellar resurfacing. METHODS: 237 consecutive patients (240 knees) undergoing primary TKA were prospectively recruited. All received the LCS Complete Rotating Platform TKA (DePuy International, Leeds, UK). Clinical and radiographic assessments were performed at 3, 12, 60 and 120 months post-operatively. Radiographic evaluation was performed by an independent external surgeon. RESULTS: The mean age was 70.3 years. 77.5% of cases were cementless. Radiographic assessment suggested excellent femoral component fixation. 22 tibial radiolucent lines (RLLs) > 1 mm were observed in 12 knees. No RLLs were progressive. There have been two revisions; one for late infection and one for aseptic loosening. No patients underwent secondary patellar resurfacing. The cumulative implant survivorship, using component revision for any reason as the endpoint, was 98.9% (95% CI, 95.6 to 99.7%) at 10 years. CONCLUSIONS: The excellent survivorship at a minimum 10-year follow-up supports the use of uncemented porous coated fixation without patellar resurfacing with the non-posterior stabilized LCS Complete Rotating Platform TKA.

Postdischarge Unscheduled Care Burden After Lower Limb Arthroplasty.

BACKGROUND: In contrast to postdischarge arthroplasty readmission rates, the unscheduled reattendance burden to primary care is under-reported. Understanding reasons for reattendance would allow for implementation of strategies to reduce this burden. The present study aims to quantify the out-of-hours (OOH) general practitioner and emergency department (ED) service reattendance burden and readmission rate after primary total hip arthroplasty and total knee arthroplasty, with estimation of the associated costs. METHODS: This is a prospective consecutive cohort study. A prospective audit of all total hip arthroplasty and total knee arthroplasty patients in 2016 in a single high-volume UK arthroplasty unit was performed. Incidence and reasons for reattendance to OOH and ED service, as well as readmission rates, at both 30 and 90 days following discharge are reported. A multivariate analysis was performed to determine patient characteristics, which results in increased reattendance and readmission rates. RESULTS: A total of 2351 procedures resulted in 374 attendances of OOH service and 665 to ED with a total estimated cost of £190,000 within 90 days. The readmission rate was 6.8%. Risk factors for reattendance and readmission were increasing age and a prolonged length of stay. The use of a 5-day postdischarge phone call and a dedicated Arthroplasty Care Practitioner favors reduced reattendances but not the readmission rate, with the additional benefit of being cost-effective. CONCLUSION: The postdischarge arthroplasty reattendance burden is associated with significant costs, and strategies to reduce this should be developed. Further research is required to assess the effectiveness and cost-effectiveness of multicomponent strategies to reduce reattendance operating at scale.

Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population.

Introduction: delirium following surgery is common and is associated with negative outcomes. Preoperative cognitive impairment has been shown to be a risk factor for post-operative delirium. Often the cognitive tests used are cumbersome. This study tests the hypothesis that the quantification of brain vulnerability, using Apolipoprotein E (ApoE) status and neuropsychological tests, both traditional and more easily administered, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery. Methods: this observational cohort study recruited participants aged 65 years or older admitted prior to elective primary hip or knee arthroplasty. Baseline data was collected and participants underwent neuropsychological testing and had blood taken for ApoE genotyping preoperatively. Post-operatively participants were assessed daily for delirium using the Confusion Assessment Method (CAM) and charts were reviewed where possible for reports of delirium. Univariate and multivariate analyses of preoperative factors were undertaken to identify independent predictors of delirium. Results: between March 2012 and October 2014, 315 participants completed the study with an overall incidence of post-operative delirium of 40/315 (12.7%). Of these 18 fulfilled the CAM criteria for delirium and 22 were deemed delirious by consensus decision based on chart review. ApoE genotype was not associated with post-operative delirium in this cohort. Time taken to complete Colour Trails 2, errors in mini mental state examination and level of pain preoperatively were independent predictors of post-operative delirium. Conclusions: this study challenges the assertion that ApoE4 genotype predicts post-operative delirium. It replicates previous work suggesting cognitive impairment predicts post-operative delirium and shows for the 1st time that simple cognitive tests can be as effective as more detailed tests.

Meeting the societal need for new antibiotics: the challenges for the pharmaceutical industry.

The rise of antibiotic resistance is leading to clinicians being increasingly faced with clinical failure due to the lack of effective and safe treatment options. New antibiotics are needed now for current multi-drug resistant infections but also in preparation for emerging and anticipated threats. There are significant challenges for the pharmaceutical industry to discover and develop new antibiotics including a business model that balances reasonable reimbursement with appropriate use. This summary reviews the key challenges and collaborative interventions that may contribute to addressing a societal problem.

Development of a scale to assess performance following primary total knee arthroplasty.

BACKGROUND: Quantitative assessment of postsurgical knee motion provides sensitive measurements, but results are technical and may not be meaningful to patients. Although several knee-specific instruments exist, no patient-reported outcome (PRO) measure correlates function with improved stability, motion, satisfaction, and confidence. OBJECTIVE: To address both the above limitations by developing a PRO measure to assess the phenomenon of a "normal" knee after primary total knee arthroplasty (TKA). METHODS: A draft conceptual model linking the impact of clinical mechanics to hypothesized functional outcomes was generated after a literature review of available assessment tools. Participants aged 18 to 80 years having undergone TKA within the past 10 to 18 months were identified and screened by clinical sites to participate in phase 1 focus groups or phase 2 in-depth interviews. Participants were asked to describe their TKA experiences, including how their knee feels now, followed by cognitive debriefing of Patient's Knee Implant Performance (PKIP) draft items. RESULTS: Phase 1 results indicated that concepts of confidence, stability, and satisfaction in patients' replacement knee when performing certain activities were distinct and important in the patients' assessment of their TKA. Phase 2 efforts yielded a final version of the PKIP measure containing nine items assessing the broader concepts of stability, confidence, and satisfaction in association with activities. Presurgical and postsurgical versions of the measure were created. CONCLUSIONS: Results of this qualitative study support use of the PKIP as a complementary PRO measure to assess performance after primary TKA. Psychometric evaluation of the PKIP is planned.

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.

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.

Patient evaluation of early discharge after hip arthroplasty: development of a measure and comparison of three centres with differing durations of stay.

OBJECTIVE: We compared patients' evaluation of care between a surgical unit with a rapid discharge policy and two comparison units to test the hypothesis that the centre with rapid discharge has outcomes that are not inferior to those of the comparison sites. DESIGN: Cross-sectional cohort study. SUBJECTS: Consecutive consenting patients undergoing primary hip arthroplasty during 12 months in: a unit that had reduced postoperative stay to median three days; a specialised orthopaedic surgery treatment centre with median stay of five days; a traditional unit with median stay of six days (N = 316, 125, 119, respectively). METHODS: Six weeks postoperatively, patients completed a specially developed questionnaire measuring their evaluation of care and recovery, together with measures of function and quality of life for validation purposes. RESULTS: Factor analysis of questionnaire responses identified two independent components of patients' evaluation: problems in staff care and problems in physical recovery. Neither component was impaired in the unit with rapid discharge: similar proportions of patients reported recovery problems in each site (odds radios (ORs) for the two comparators versus unit with rapid discharge: 0.96, 1.18); and more patients reported care problems in the two comparator sites (ORs 2.97, 2.16). CONCLUSION: Duration of stay after primary hip arthroplasty can be reduced to three days without intensive pre- or postoperative care, without detriment to patient evaluation.