Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials.

BACKGROUND: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections. METHODS: EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥105 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <103 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed. FINDINGS: Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred. INTERPRETATION: Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients. FUNDING: GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.

Antimicrobial Activity of Gepotidacin Tested against Escherichia coli and Staphylococcus saprophyticus Isolates Causing Urinary Tract Infections in Medical Centers Worldwide (2019 to 2020).

The in vitro activities of gepotidacin and comparator agents against 3,560 Escherichia coli and 344 Staphylococcus saprophyticus collected from female (81.1%) and male (18.9%) patients with urinary tract infections (UTIs) in a global prospective surveillance program in 2019 to 2020 were determined. Isolates collected from 92 medical centers in 25 countries, including the United States, Europe, Latin America, and Japan, were tested for susceptibility by reference methods in a central monitoring laboratory. Gepotidacin inhibited 98.0% (3,488/3,560 isolates) of E. coli and 100% (344/344 isolates) of S. saprophyticus at gepotidacin concentrations of ≤4 µg/mL and ≤0.25 µg/mL, respectively. This activity was largely unaffected with isolates that demonstrated resistance phenotypes to other oral standard-of-care antibiotics, including amoxicillin-clavulanic acid, cephalosporins, fluoroquinolones, fosfomycin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Gepotidacin also inhibited 94.3% (581/616 isolates) of E. coli isolates with an extended-spectrum ß-lactamase-producing phenotype, 97.2% (1,085/1,129 isolates) of E. coli isolates resistant to ciprofloxacin, 96.1% (874/899) of E. coli isolates resistant to trimethoprim-sulfamethoxazole, and 96.3% (235/244 isolates) of multidrug-resistant E. coli isolates at gepotidacin concentrations of ≤4 µg/mL. In summary, gepotidacin demonstrated potent activity against a large collection of contemporary UTI E. coli and S. saprophyticus strains collected from patients worldwide. These data support the further clinical development of gepotidacin as a potential treatment option for patients with uncomplicated UTIs.

In vitro activity of gepotidacin against urine isolates of Escherichia coli from outpatient departments in Germany.

BACKGROUND: Escherichia coli is the leading pathogen of community-acquired urinary tract infections. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene oral antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action that confers activity against most strains of target pathogens, such as E. coli, Staphylococcus saprophyticus and Neisseria gonorrhoeae, including those resistant to other antibiotics. OBJECTIVES: This study assessed the in vitro activity of gepotidacin in comparison with ciprofloxacin and other oral standard-of-care antibiotics using a large collection of urine isolates of E. coli obtained from outpatients in Germany. METHODS: Four hundred and sixty E. coli collected from 23 laboratories during a surveillance study in 2019/2020 were tested. Forty-six isolates (10.0%) produced an ESBL of the CTX-M family, half of which belonged to MDR clonal subgroups of E. coli ST131. Antibiotic susceptibilities were tested at a reference laboratory by broth microdilution according to the standard ISO 20776-1. RESULTS: Fifty-three (11.5%) isolates were ciprofloxacin resistant, 25 (47.2%) of which also produced an ESBL. Overall, MIC50/90 values for gepotidacin were 2/4 mg/L (MIC range 0.125-16 mg/L), with no differences in activity between ciprofloxacin-susceptible and ciprofloxacin-resistant isolates, ESBL-producing and non-ESBL isolates, O25b-ST131 isolates, and isolates susceptible or resistant to fosfomycin, mecillinam or nitrofurantoin. CONCLUSIONS: Gepotidacin showed promising in vitro activity against urine isolates of E. coli, including ciprofloxacin-resistant isolates, ESBL-producing isolates and isolates resistant to oral standard-of-care antibiotics.

Innovative features and functionalities of an artificial pancreas system: What do youth and parents want?

AIMS: Participant-driven solutions may help youth and families better engage and maintain use of diabetes technologies. We explored innovative features and functionalities of an ideal artificial pancreas (AP) system suggested by youth with type 1 diabetes and parents. METHODS: Semi-structured interviews were conducted with 39 youth, ages 10-25 years, and 44 parents. Interviews were recorded, transcribed and coded using thematic analysis. RESULTS: Youth (72% female, 82% non-Hispanic white) were (M ± SD) ages 17.0 ± 4.7 years, with diabetes for 9.4 ± 4.9 years, and HbA1c of 68 ± 11 mmol/mol (8.4 ± 1.1%); 79% were pump-treated and 82% were continuous glucose monitor users. Of parents, 91% were mothers and 86% were non-Hispanic white, with a child 10.6 ± 4.5 years old. Youth and parents suggested a variety of innovative features and functionalities for an ideal AP system related to (1) enhancing the appeal of user interface, (2) increasing automation of new glucose management functionalities, and (3) innovative and commercial add-ons for greater convenience. Youth and parents offered many similar suggestions, including integration of ketone testing, voice activation, and location-tracking into the system. Youth seemed more driven by increasing convenience and normalcy while parents expressed more concerns with safety. CONCLUSIONS: Youth and parents expressed creative solutions for an ideal AP system to increase ease of use, enhance normalcy, and reduce burden of management. Designers of AP systems will likely benefit from incorporating the desired preferences by end users to optimize acceptance and usability by young persons with diabetes.

Mental Health Providers' Assessment of Parents' Reactions to their Children's Elevated Depressive Symptoms.

This study assessed parental reactions to the report of elevated depressive symptoms in a sample of 29 youth with type 1 diabetes (ages 8-17 years; 48% female) who scored ≥15 on the Center for Epidemiologic Studies Depression Scale for Children (CES-DC). We also assessed parental depressive symptoms and how the presence of such symptoms was linked to parental reactions to the report of a positive screening score in their children and subsequent acceptance of a mental health referral. Mental health professionals contacted parents to discuss elevated scores and offer a mental health referral. Two coders reviewed the documentation of phone contacts made by mental health professionals and categorized parental responses to their child's elevated CES-DC score and the disposition plan. Youth and parent depressive symptoms were modestly correlated (r = 0.21, P = .01). About half (55%, 16/29) of parents were unaware of their child's depressive symptoms. Only 14% (4/29) of youth were already receiving mental health care while 28% (8/29) of parents accepted a referral. Parents with depressive symptoms were frequently unaware of their child's symptoms. Findings provide insight into parental reactions to learning of their child's depressive symptoms and highlight the need for more research on parental mood and reactions to their child's positive screen for depressive symptoms, as a potential barrier to mental health referral acceptance.

Youth and parent preferences for an ideal AP system: It is all about reducing burden.

BACKGROUND: As new diabetes technologies improve to better manage glucose levels, users' priorities for future technologies may shift to prioritize burden reduction and ease of use. We used qualitative methods to explore youth and parent desired features of an "ideal" artificial pancreas (AP) system. METHODS: We conducted semi-structured interviews with 39 youth, ages 10-25 years, and 44 parents. Interviews were audio-recorded, transcribed, and coded using thematic analysis. RESULTS: Youth (79% female, 82% non-Hispanic white) were (M ± SD) ages 17.0 ± 4.7 years, with diabetes for 9.4 ± 4.9 years, and HbA1c of 8.4 ± 1.1%; 79% were pump-treated and 82% used CGM. Of parents, 91% were mothers and 86% were non-Hispanic white. Participants suggested various ways in which an ideal AP system could reduce physical and emotional burdens of diabetes. Physical burdens could be reduced by lessening user responsibilities to manage glucose for food and exercise, and wear or carry devices. Emotional burden could be reduced by mitigating negative emotional reactions to sound and frequency of alerts, while increasing feelings of normalcy. Youth and parents differed in their suggestions to reduce emotional burden. Participants suggested features that would improve glycemia, but nearly always in the context of how the feature would directly reduce their diabetes-specific burden. CONCLUSIONS: Although participants expressed interest in improving glucose levels, the pervasive desire among suggested features of an ideal AP system was to minimize the burden of diabetes. Understanding and addressing users' priorities to reduce physical and emotional burden will be necessary to enhance uptake and maintain use of future AP systems.

Necessary but not sufficient: identifying conditions for effective feedback during internal medicine residents' clinical education.

Competency-based medical education and programmatic assessment intend to increase the opportunities for meaningful feedback, yet these conversations remain elusive. By comparing resident and faculty perceptions of feedback opportunities within one internal medicine residency training program, we sought to understand whether and how principles underlying meaningful feedback could be supported or constrained across a variety of feedback opportunities. Using case-study qualitative methodology, interviews and focus groups were conducted to explore 19 internal medicine residents' and 7 faculty members' perceptions of feedback across a variety of feedback opportunities: coaching, mini-CEXs, in-training evaluation reports and routine clinical supervision. Our data analysis moved iteratively between developing conceptual understandings and fine-grained analyses, while attending to both deductive and inductive analysis. Our results suggest that all feedback opportunities, including those created through formalized assessments, can foster meaningful feedback if faculty establish a trusting relationship with the resident, base their feedback on direct observation and support resident learning. However, formalized assessments were often perceived as inhibiting the conditions for meaningful feedback. A coaching program provided a context in which meaningful feedback could arise, in part because faculty were supported in shifting their focus from patient to resident. Meaningful feedback in clinical education may be fostered across a variety of feedback opportunities, however, it is often constrained by assessment. We must consider whether increasing the frequency of formative assessments may inhibit efforts to improve our feedback cultures while, in contrast, freeing up faculty to focus on supporting resident learning could improve these cultures.

Working in the dead of night: exploring the transition to after-hours duty.

CONTEXT: Transitions, although often difficult, represent integral components of medical training. New postgraduate trainees (first-year residents) find themselves in an especially challenging transition as they are expected to fulfil both learning and service expectations concurrently. Workplace learning theory has been suggested as a lens through which to understand this unique educational, yet service-oriented, role. This tension may be further amplified overnight when residents are on-call with little to no support. OBJECTIVES: The aims of this study were to explore the transition from medical student to resident with respect to the on-call experience, and to provide theory-based suggestions to enhance learning during this unique transition. METHODS: We conducted an interpretivist qualitative study by interviewing eight medical students and 10 first-year residents from six different specialty training programmes across four academic sites. Each semi-structured interview was transcribed verbatim and anonymised. Resident interview transcripts were initially coded for major themes, after which medical student interview transcripts were coded for consistencies and discrepancies. RESULTS: Four interrelated themes were identified in students' and residents' descriptions of on-call experiences: (i) shift in responsibility; (ii) supervisory support; (iii) contextual conditions, and (iv) clarity of expectations. Generally, students were not able to anticipate the challenges they would face as residents on-call, and residents perceived the transition as sudden with little emphasis placed on learning. CONCLUSIONS: First-year residents face multiple challenges during on-call, which may prevent optimal learning in this setting. These challenges are amplified by the large gap between the respective roles of medical students and residents. We identified promoters of and barriers to effective learning in this environment and, by using workplace learning theory, provide recommendations for how we might be able to enhance medical students' preparation for and first-year residents' learning during experiences of being on-call.

Associations between major life events and adherence, glycemic control, and psychosocial characteristics in teens with type 1 diabetes.

AIMS: This cross-sectional study assessed the type of major life events occurring in a contemporary sample of teens with type 1 diabetes and the association between event frequency and demographic, diabetes management, and psychosocial characteristics. METHODS: Parents of 178 teens completed the Life Events Checklist to report major events teens had experienced in the last year: 42% experienced 0 to 1 event (n = 75), 32% experienced 2 to 3 events (n = 57), and 26% experienced 4+ events (n = 46). Teens and parents completed validated measures of treatment adherence, diabetes-specific self-efficacy, quality of life, and diabetes-specific family conflict. Parent-youth interview and chart review provided demographics and diabetes management data. RESULTS: Mean number of events/teen was 2.6 ± 2.7 (range = 0-15). The most common events were "Hospitalization of a family member" (24%), "Getting a bad report card" (20%), "Serious arguments between parents" (19%), and "Serious illness/injury in a family member" (19%). Compared with teens experiencing 0 to 1 event, teens experiencing 4+ events were less likely to have married parents (P = .01) and a parent with a college degree (P = .006). Teens with 4+ events had significantly poorer adherence (P = .002 teen, P = .02 parent), lower self-efficacy (P = .03 teen, P < .0001 parent), poorer quality of life (P < .0001 teen, P < .0001 parent), and more conflict (P = .006 teen, P = .02 parent) than teens with fewer events. In a multivariate model (R 2 = 0.21, P < .0001) controlling for demographic and diabetes management characteristics, fewer events was associated with lower A1c (P = .0009). CONCLUSIONS: Occurrence of more major life events was associated with poorer diabetes care and A1c and more negative psychosocial qualities in teens with type 1 diabetes.

Low uptake of Aboriginal interpreters in healthcare: exploration of current use in Australia's Northern Territory.

BACKGROUND: In Australia's Northern Territory, most Aboriginal people primarily speak an Aboriginal language. Poor communication between healthcare providers and Aboriginal people results in adverse outcomes including death. This study aimed to identify remediable barriers to utilisation of Aboriginal Interpreter services at the Northern Territory's tertiary hospital, which currently manages over 25,000 Aboriginal inpatients annually. METHODS: This is a multi-method study using key stakeholder discussions, medical file audit, bookings data from the Aboriginal Interpreter Service 2000-2015 and an online cross-sectional staff survey. The Donabedian framework was used to categorise findings into structure, process and outcome. RESULTS: Six key stakeholder meetings each with approximately 15 participants were conducted. A key structural barrier identified was lack of onsite interpreters. Interpreter bookings data revealed that only 7603 requests were made during the 15-year period, with completion of requests decreasing from 337/362 (93.1%) in 2003-4 to 649/831 (78.1%) in 2014-15 (p < 0.001). Non-completion was more common for minority languages (p < 0.001). Medical files of 103 Aboriginal inpatients were audited. Language was documented for 13/103 (12.6%). Up to 60/103 (58.3%) spoke an Aboriginal language primarily. Of 422 staff who participated in the survey, 18.0% had not received 'cultural competency' training; of those who did, 58/222 (26.2%) indicated it was insufficient. The Aboriginal Interpreter Service effectiveness was reported to be good by 209/368 (56.8%), but only 101/367 (27.5%) found it timely. Key process barriers identified by staff included booking complexities, time constraints, inadequate delivery of tools and training, and greater convenience of unofficial interpreters. CONCLUSION: We identified multiple structural and process barriers resulting in the outcomes of poor language documentation and low rates of interpreter bookings. Findings are now informing interventions to improve communication.

Investigating conditions for meaningful feedback in the context of an evidence-based feedback programme.

CONTEXT: We developed, implemented and evaluated an evidence-based programme of feedback designed to address limitations identified in the current literature. OBJECTIVES: We sought to advance understanding about how and why feedback processes might be more effective in clinical education. METHODS: Three faculty members and nine first-year internal medicine residents participated in the pilot programme. To counter challenges identified in the literature, feedback was based on direct observation, grounded in longitudinal faculty-resident relationships, and devoid of summative assessment. We used a qualitative case study design to address three research questions: (i) What benefits did the participants describe? (ii) What elements of the programme facilitated these benefits? (iii) What were the limitations and challenges of the programme? Collected data included audiotapes of interactions between faculty members and residents, field notes written during observations, and semi-structured interviews and focus groups with resident participants. Data analysis moved cyclically and iteratively through inductive and deductive analysis. RESULTS: Residents described benefits relating to their ways of working (clinical skills), ways of learning (accountability for learning) and ways of feeling (emotional well-being). According to participants, specific elements of the programme that achieved these benefits included the direct observation of authentic clinical work, the longitudinal relationship with a faculty member and the emergence of feedback as a conversation between the faculty member and learner. CONCLUSIONS: We conclude that the conditions established within our pilot feedback programme influenced the learning culture for first-year internal medicine residents by grounding direct observation in authentic clinical work and setting the observations in the context of a longitudinal, non-assessment-based relationship between a faculty member and resident. These conditions appeared to influence residents' participation in the feedback process, their ways of approaching their daily clinical work, their emotional well-being and their engagement in their own learning.

Cellular pharmacokinetics and intracellular activity of the novel peptide deformylase inhibitor GSK1322322 against Staphylococcus aureus laboratory and clinical strains with various resistance phenotypes: studies with human THP-1 monocytes and J774 murine macrophages.

GSK1322322 is a peptide deformylase inhibitor active against Staphylococcus aureus strains resistant to currently marketed antibiotics. Our aim was to assess the activity of GSK1322322 against intracellular S. aureus using an in vitro pharmacodynamic model and, in parallel, to examine its cellular pharmacokinetics and intracellular disposition. For intracellular activity analysis, we used an established model of human THP-1 monocytes and tested one fully susceptible S. aureus strain (ATCC 25923) and 8 clinical strains with resistance to oxacillin, vancomycin, daptomycin, macrolides, clindamycin, linezolid, or moxifloxacin. Uptake, accumulation, release, and subcellular distribution (cell fractionation) of [(14)C]GSK1322322 were examined in uninfected murine J774 macrophages and uninfected and infected THP-1 monocytes. GSK1322322 demonstrated a uniform activity against the intracellular forms of all S. aureus strains tested, disregarding their resistance phenotypes, with a maximal relative efficacy (E max) of a 0.5 to 1 log10 CFU decrease compared to the original inoculum within 24 h and a static concentration (C s) close to its MIC in broth. Influx and efflux were very fast (<5 min to equilibrium), and accumulation was about 4-fold, with no or a minimal effect of the broad-spectrum eukaryotic efflux transporter inhibitors gemfibrozil and verapamil. GSK1322322 was recovered in the cell-soluble fraction and was dissociated from the main subcellular organelles and from bacteria (in infected cells). The results of this study show that GSK1322322, as a typical novel deformylase inhibitor, may act against intracellular forms of S. aureus. They also suggest that GSK1322322 has the ability to freely diffuse into and out of eukaryotic cells as well as within subcellular compartments.

In vitro and intracellular activities of peptide deformylase inhibitor GSK1322322 against Legionella pneumophila isolates.

GSK1322322, a novel peptide deformylase inhibitor currently in development as an oral and intravenous agent for the treatment of hospitalized community-acquired bacterial pneumonia, showed poor in vitro activity against a panel of 50 Legionella pneumophila strains, with MICs ranging from 1 to 16 µg/ml and an MIC90 of 16 µg/ml, but very potent intracellular activity, with the minimum extracellular concentrations capable of inhibiting intracellular proliferation (MIECs) ranging from 0.12 to 2 µg/ml and 98% of the strains being inhibited by concentrations of ≤ 1 µg/ml.

Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae.

The continuous emergence of multidrug-resistant pathogenic bacteria is compromising the successful treatment of serious microbial infections. GSK1322322, a novel peptide deformylase (PDF) inhibitor, shows good in vitro antibacterial activity and has demonstrated safety and efficacy in human proof-of-concept clinical studies. In vitro studies were performed to determine the frequency of resistance (FoR) to this antimicrobial agent in major pathogens that cause respiratory tract and skin infections. Resistance to GSK1322322 occurred at high frequency through loss-of-function mutations in the formyl-methionyl transferase (FMT) protein in Staphylococcus aureus (4/4 strains) and Streptococcus pyogenes (4/4 strains) and via missense mutations in Streptococcus pneumoniae (6/21 strains), but the mutations were associated with severe in vitro and/or in vivo fitness costs. The overall FoR to GSK1322322 was very low in Haemophilus influenzae, with only one PDF mutant being identified in one of four strains. No target-based mutants were identified from S. pyogenes, and only one or no PDF mutants were isolated in three of the four S. aureus strains studied. In S. pneumoniae, PDF mutants were isolated from only six of 21 strains tested; an additional 10 strains did not yield colonies on GSK1322322-containing plates. Most of the PDF mutants characterized from those three organisms (35/37 mutants) carried mutations in residues at or in close proximity to one of three highly conserved motifs that are part of the active site of the PDF protein, with 30 of the 35 mutations occurring at position V71 (using the S. pneumoniae numbering system).

Improving dietary quality in youth with type 1 diabetes: randomized clinical trial of a family-based behavioral intervention.

BACKGROUND: Diets of children with type 1 diabetes are low in fruits, vegetables, and whole grains, and high in foods of minimal nutritional value, increasing risk for future adverse health outcomes. This 18-month randomized clinical trial tested the effect of a family-based behavioral intervention integrating motivational interviewing, active learning, and applied problem-solving on the primary outcomes of dietary intake and glycemic control among youth with type 1 diabetes. METHODS: A parallel-group study with equal randomization was conducted at an outpatient, free-standing, multidisciplinary tertiary diabetes center in the United States. Eligible youth were those age 8-16 years with type 1 diabetes diagnosis ≥1 year and hemoglobin A1c (HbA1c) ≥6.5% and ≤10.0%. Participants were 136 parent-youth dyads (treatment n = 66, control n = 70). The intervention consisted of 9 in-clinic sessions delivered to the child and parent; control condition comprised equivalent assessments and number of contacts without dietary advice. Dietary intake was assessed using 3-day diet records at 6 time points across the 18-month study. Dietary outcomes included the Healthy Eating Index-2005 (HEI2005; index measuring conformance to the 2005 United States Dietary Guidelines for Americans) and Whole Plant Food Density (WPFD; number of cup or ounce equivalents per 1000 kcal of whole grains, whole fruit, vegetables, legumes, nuts, and seeds consumed). HbA1c was obtained every 3 months. Overall comparison of outcome variables between intervention and usual care groups was conducted using permutation tests. RESULTS: There was a positive intervention effect across the study duration for HEI2005 (p = .015) and WPFD (p = .004). At 18 months, HEI2005 was 7.2 greater (mean ± SE 64.6 ± 2.0 versus 57.4 ± 1.6), and WPFD was 0.5 greater (2.2 ± 0.1 versus 1.7 ± 0.1) in the intervention group versus control. There was no difference between groups in HbA1c across the study duration. CONCLUSIONS: This behavioral nutrition intervention improved dietary quality among youth with type 1 diabetes, but did not impact glycemic control. Findings indicate the potential utility of incorporating such strategies into clinical care, and suggest that improvement in diet quality can be achieved in families living with this burdensome disease. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT00999375.

Potent sub-MIC effect of GSK1322322 and other peptide deformylase inhibitors on in vitro growth of Staphylococcus aureus.

Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus in vitro growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected S. aureus strains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant S. aureus.

Family-based psychoeducation and Care Ambassador intervention to improve glycemic control in youth with type 1 diabetes: a randomized trial.

OBJECTIVE: Youth with type 1 diabetes frequently do not achieve glycemic targets. We aimed to improve glycemic control with a Care Ambassador (CA) and family-focused psychoeducational intervention. RESEARCH DESIGN AND METHODS: In a 2-yr, randomized, clinical trial, we compared three groups: (i) standard care, (ii) monthly outreach by a CA, and (iii) monthly outreach by a CA plus a quarterly clinic-based psychoeducational intervention. The psychoeducational intervention provided realistic expectations and problem-solving strategies related to family diabetes management. Data on diabetes management and A1c were collected, and participants completed surveys assessing parental involvement in management, diabetes-specific family conflict, and youth quality of life (QOL). The primary outcome was A1c at 2 yr; secondary outcomes included maintaining parent involvement and avoiding deterioration in glycemic control. RESULTS: We studied 153 youth (56% female, median age 12.9 yr) with type 1 diabetes (mean A1c 8.4 ± 1.4%). There were no differences in A1c across treatment groups. Among youth with suboptimal baseline A1c ≥ 8%, more youth in the psychoeducation group maintained or improved their A1c and maintained or increased parent involvement than youth in the other two groups combined (77 vs. 52%, p = 0.03; 36 vs. 11%, p = 0.01, respectively) without negative impact on youth QOL or increased diabetes-specific family conflict. CONCLUSIONS: No differences in A1c were detected among the three groups at 2 yr. The psychoeducational intervention was effective in maintaining or improving A1c and parent involvement in youth with suboptimal baseline glycemic control.

Dispensing antimicrobials to farmers in Wales: The roles and experiences of veterinary practice staff.

BACKGROUND: Veterinary practice staff are directly involved in the dispensing of prescription veterinary medicines (POM-Vs) to farmers as prescribed by registered veterinary surgeons to animals 'under their care'. The role of veterinary practice staff has, to date, been underresearched. The objective of this study was to investigate the roles played by veterinary practice staff, exploring their expectations and perceptions of the front-of-house (FoH) role, their interactions with clients in day-to-day veterinary practice and their experiences relating to the dispensing of POM-Vs. METHODS: Thematic analysis was used to analyse data from 20 semi-structured interviews of veterinary practice staff. Participants were recruited from 80% of the large animal or mixed species veterinary practices across Wales. RESULTS: Four key themes-'piggy in the middle', learning on the job, practice organisation and facilitating change-were identified, illustrating the multifaceted and diverse nature of this type of employment. LIMITATIONS: This study is not intended to be representative of the perceptions of FoH staff on the dispensing of antimicrobials. Larger-scale studies are required to substantiate these findings. CONCLUSION: Understanding the roles of non-clinical veterinary staff allows practice managers and veterinary surgeons to better identify and meet training and staffing needs and improves recognition of this key area of practice work.

Intermethod comparability analyses of gepotidacin antimicrobial susceptibility tests using a large collection of globally collected Escherichia coli and Staphylococcus saprophyticus clinical isolates.

Gepotidacin (GSK2140944) is a novel, bactericidal, first in class triazaacenaphthylene bacterial type II topoisomerase inhibitor in development for the treatment of uncomplicated urinary tract infections and gonorrhea. The performance of several antimicrobial susceptibility methods (broth microdilution, gradient diffusion, and disk diffusion) for gepotidacin were evaluated using over 5800 recent Escherichia coli and Staphylococcus saprophyticus clinical isolates. Reference broth microdilution gepotidacin MICs showed an essential agreement of 95.9 % and 98.1 % with MICs by gradient diffusion for E. coli and S. saprophyticus isolates, respectively. Gepotidacin susceptibility using disks produced by 2 manufacturers had good agreement with an R2 values of 0.95 and 99.2 % of overall zone diameters agreeing within 3 mm. A correlation with an overall R2 value of 0.72 between MICs by broth microdilution and zone diameters by disk diffusion was observed. This data should assist in the clinical development of gepotidacin and provide reliable susceptibility methods to evaluate its activity.

Comparative analysis of the antibacterial activity of a novel peptide deformylase inhibitor, GSK1322322.

GSK1322322 is a novel peptide deformylase (PDF) inhibitor being developed for the intravenous and oral treatment of acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae (n = 2,370), Moraxella catarrhalis (n = 115), Streptococcus pneumoniae (n = 947), Streptococcus pyogenes (n = 617), and Staphylococcus aureus (n = 940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC(90) of 1 µg/ml against M. catarrhalis and 4 µg/ml against H. influenzae, with 88.8% of ß-lactamase-positive strains showing growth inhibition at that concentration. All S. pneumoniae strains were inhibited by ≤ 4 µg/ml of GSK1322322, with an MIC(90) of 2 µg/ml. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC(90) of 1 µg/ml for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK1322322 was very potent against S. pyogenes strains, with an MIC(90) of 0.5 µg/ml, irrespective of their macrolide resistance phenotype. This PDF inhibitor was also active against S. aureus strains regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with an MIC(90) of 4 µg/ml in all cases. Time-kill studies showed that GSK1322322 had bactericidal activity against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a ≥ 3-log(10) decrease in the number of CFU/ml at 4× MIC within 24 h in 29 of the 33 strains tested. Given the antibacterial potency demonstrated against this panel of organisms, GSK1322322 represents a valuable alternative therapy for the treatment of infectious diseases caused by drug-resistant pathogens.