Population pharmacokinetics of a single daily intramuscular dose of gentamicin in children with severe malnutrition

Article published in Journal of Antimicrobial ChemotherapyObjectives: The World Health Organization recommends that all children admitted with severe malnutrition should routinely receive parenteral ampicillin and gentamicin; despite this, mortality remains high. Since this population group is at risk of altered volume of distribution, we aimed to study the population pharmacokinetics of once daily gentamicin (7.5 mg/kg) in children with severe malnutrition and to evaluate clinical factors affecting pharmacokinetic parameters. Methods: Thirty-four children aged 0.5–10 years were studied. One hundred and thirty-two gentamicin concentrations (median of four per patient), drawn 0.4–24.6 h after administration of the intramuscular dose, were analysed. The data were fitted by a two-compartment model using the population package NONMEMw. Results: Gentamicin was rapidly absorbed and all concentrations measured within the first 2 h after administration were >8 mg/L (indicating that satisfactory peak concentrations were achieved). Ninetyeight percent of samples measured more than 20 h after the dose were <1 mg/L. The best model included weight, and it was found that high base deficit, high creatinine concentration and low temperature (all markers of hypovolaemic shock) reduced clearance (CL/F). Weight influenced volume of the central (V1/F) and peripheral (V2/F) compartments, and high base deficit reduced V2/F and intercompartmental CL (Q/F). Interindividual variability in CL was 26%, in V1/F 33% and in V2/F and Q/F was 52%. Individual estimates of CL/F ranged from 0.02 to 0.16 (median 0.10) L/h/kg and those of Vss/F from 0.26 to 1.31 (median 0.67) L/kg. Initial half-lives had a median of 1.4 h and elimination half-lives and a median of 14.9 h. Excessive concentrations were observed in one patient who had signs of renal impairment and shock. Conclusions: Although a daily dose of 7.5 mg/kg achieves satisfactory gentamicin concentrations in the majority of patients, patients with renal impairment and shock may be at risk of accumulation with 24 hourly dosing. Further studies of gentamicin pharmacokinetics in this group are now needed to inform future international guideline recommendations

Woodland, cropland and hedgerows promote pollinator abundance in intensive grassland landscapes, with saturating benefits of flower cover

1. Pollinating insects provide economic value by improving crop yield. They are also functionally and culturally important across ecosystems outside of cropland. To understand landscape-level drivers of pollinator declines, and guide policy and intervention to reverse declines, studies must cover (a) multiple insect and plant taxa and (b) a range of agricultural and semi-natural land uses. Furthermore, in an era of woodland restoration initiatives and rewilding ideologies, the contribution of woodland and woody linear features (WLFs; e.g. hedgerows) to pollinator abundance demands further investigation. 2. We demonstrate fine-scale analysis of high-quality, co-located measurements from a national environmental survey. We relate pollinator transect counts to ground-truth habitat and WLF maps across 300 1 km squares in Wales, UK. We look at effects of habitat type, flower cover, WLF density and habitat diversity on summer abundance (July and August) of eight insect groups, representing three insect orders (Lepidoptera, Hymenoptera and Diptera). 3. Compared with improved grassland (the dominant habitat in Wales), pollinator abundance is consistently higher in cropland and woodland—especially broadleaved woodland. For mining bees and two hoverfly groups, abundance is predicted to be at least 1.5× higher in woodland ecosystems than elsewhere. Furthermore, we estimate contributions of WLFs to abundance in agriculturally improved habitats to be up to 14% for honeybees and up to 21% for hoverflies. 4. The abundance of all insect groups increases with flower cover, which is a key mechanism through which woodland, cropland and grassland support pollinators. Importantly, we observe diminishing returns of increasing flower cover for abundance of non-Apis pollinator groups, expecting roughly twice the increase in abundance per % flower cover from 0% to 5%, as compared with 10% to 15%. However, the shape of the relationship was inverted for honeybees, which showed steeper increases in abundance at higher flower cover. 4. Synthesis and applications: We provide a holistic view of the drivers of pollinator abundance in Wales, in which flower cover, woodland, hedgerows and cropland are critical. We propose a key role for woodland creation, hedge-laying and farmland heterogeneity within future land management incentive schemes. Finally, we suggest targeting of interventions to maximise benefits for non-Apis pollinators. Specifically, increasing floral provision in areas where existing flower cover is low—for example, in flower-poor improved grasslands—could effectively increase pollinator abundance and diversity while prioritising wild over managed species

Integrated ecological monitoring in Wales: the Glastir Monitoring and Evaluation Programme field survey

The Glastir Monitoring and Evaluation Programme (GMEP) ran from 2013 until 2016 and was probably the most comprehensive programme of ecological study ever undertaken at a national scale in Wales. The programme aimed to (1) set up an evaluation of the environmental effects of the Glastir agri-environment scheme and (2) quantify environmental status and trends across the wider countryside of Wales. The focus was on outcomes for climate change mitigation, biodiversity, soil and water quality, woodland expansion, and cultural landscapes. As such, GMEP included a large field-survey component, collecting data on a range of elements including vegetation, land cover and use, soils, freshwaters, birds, and insect pollinators from up to three-hundred 1 km survey squares throughout Wales. The field survey capitalised upon the UK Centre for Ecology & Hydrology (UKCEH) Countryside Survey of Great Britain, which has provided an extensive set of repeated, standardised ecological measurements since 1978. The design of both GMEP and the UKCEH Countryside Survey involved stratified-random sampling of squares from a 1 km grid, ensuring proportional representation from land classes with distinct climate, geology and physical geography. Data were collected from different land cover types and landscape features by trained professional surveyors, following standardised and published protocols. Thus, GMEP was designed so that surveys could be repeated at regular intervals to monitor the Welsh environment, including the impacts of agri-environment interventions. One such repeat survey is scheduled for 2021 under the Environment and Rural Affairs Monitoring & Modelling Programme (ERAMMP). Data from GMEP have been used to address many applied policy questions, but there is major potential for further analyses. The precise locations of data collection are not publicly available, largely for reasons of landowner confidentiality. However, the wide variety of available datasets can be (1) analysed at coarse spatial resolutions and (2) linked to each other based on square-level and plot-level identifiers, allowing exploration of relationships, trade-offs and synergies. This paper describes the key sets of raw data arising from the field survey at co-located sites (2013 to 2016). Data from each of these survey elements are available with the following digital object identifiers (DOIs): Landscape features (Maskell et al., 2020a–c), https://doi.org/10.5285/82c63533-529e-47b9-8e78-51b27028cc7f, https://doi.org/10.5285/9f8d9cc6-b552-4c8b-af09-e92743cdd3de, https://doi.org/10.5285/f481c6bf-5774-4df8-8776-c4d7bf059d40; Vegetation plots (Smart et al., 2020), https://doi.org/10.5285/71d3619c-4439-4c9e-84dc-3ca873d7f5cc; Topsoil physico-chemical properties (Robinson et al., 2019), https://doi.org/10.5285/0fa51dc6-1537-4ad6-9d06-e476c137ed09; Topsoil meso-fauna (Keith et al., 2019), https://doi.org/10.5285/1c5cf317-2f03-4fef-b060-9eccbb4d9c21; Topsoil particle size distribution (Lebron et al., 2020), https://doi.org/10.5285/d6c3cc3c-a7b7-48b2-9e61-d07454639656; Headwater stream quality metrics (Scarlett et al., 2020a), https://doi.org/10.5285/e305fa80-3d38-4576-beef-f6546fad5d45; Pond quality metrics (Scarlett et al., 2020b), https://doi.org/10.5285/687b38d3-2278-41a0-9317-2c7595d6b882; Insect pollinator and flower data (Botham et al., 2020), https://doi.org/10.5285/3c8f4e46-bf6c-4ea1-9340-571fede26ee8; and Bird counts (Siriwardena et al., 2020), https://doi.org/10.5285/31da0a94-62be-47b3-b76e-4bdef3037360

Oral versus intravenous antibiotics for bone and joint infection

BACKGROUND The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927. opens in new tab.

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose