Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics.

Enteral ibuprofen was first approved as a prescription drug in 1974 for the US market. An intravenous (IV) ibuprofen formulation is approved for use in children older than 6 months of age, but there are limited studies specifically evaluating the pharmacokinetics and safety in children 1-6 months of age. The primary purpose of this study was to evaluate the pharmacokinetics of IV ibuprofen in infants younger than 6 months of age. The secondary objective was to evaluate the safety of single and repeated doses of IV ibuprofen in infants younger than 6 months of age. This was an industry-sponsored multi-center study. Institutional Review Board approval and informed parental consent were obtained prior to enrollment. Hospitalized neonates and infants younger than 6 months of age with fever or expected postoperative pain were eligible. Enrolled patients received 10 mg/kg of IV ibuprofen every 6 h, with up to four doses per day. Patients were randomized to two sparse sampling technique pharmacokinetic sample time groups. Group 1 samples were drawn at 0, 30 min, and 2 h, while group 2 samples were drawn at 0 min, 1, and 4 h after administration. A total of 24 children were enrolled in the study, with 15 male patients and 9 female patients. The median age of the cohort was 4.4 months (range 1.1-5.9 months), and the median weight was 5.9 kg (range 2.3-8.8 kg). The arithmetic mean and standard error for peak plasma ibuprofen concentration was 56.28 ± 2.77 µg/mL. Plasma levels declined rapidly with a mean elimination half-life of 1.30 h. Time to peak ibuprofen effect and concentration were similar when compared with older pediatric patients. Clearance and volume of distribution were also similar to those reported in older pediatric patients. No drug-related adverse events were reported. The pharmacokinetic and short-term safety profiles of IV ibuprofen in pediatric patients 1-6 months of age are comparable to those in children older than 6 months of age. Clinicaltrials.gov Trial Registration number and date: NCT02583399-Registered July 2017.

Poor patient-reported outcomes (PROs) are common in cirrhosis, including poor sleep and health-related quality of life (HRQOL). HE is a major driver of poor PROs. Many clinicians initiate lactulose therapy to address poor PROs. PRO-triggered therapy, however, has not been studied till date. We conducted a 28-day randomized trial of crystalline lactulose therapy (20g BID) compared with no HE-directed therapy in 52 patients with cirrhosis, portal hypertension, no prior HE, and high Work Productivity and Activity Impairment scores (0-10) attributed to cirrhosis. The primary outcome was change in global HRQOL measured with Short Form-8 Health Survey. Secondary outcomes included change in Animal Naming Test score, Work Productivity and Activity Impairment, and sleep quality (scored "very bad" to "very good"). Overall, 52 patients underwent randomization; 3 subjects withdrew from the crystalline lactulose arm (1 before medication initiation, 1 due to an unrelated condition, and 1 due to high baseline bowel movements). The average age was 60 years, the average Model for Endstage Liver Disease-Sodium score was 10.5, and 56% of the patients had ascites. Baseline bowel movements were 2.3/day, with 35% of the patients having Bristol Stool Scale >4. At 28 days, there was no improvement in HRQOL: patients receiving crystalline lactulose had an 8.1-point (95% CI: 3.7-12.4) increase compared with 6.6 (95% CI: 2.3-10.8) in the control group ( p = 0.6). Lactulose was associated with a significantly ( p = 0.002) increased Animal Naming Test score (3.7, 95% CI: 2.1-5.4) versus the control group (0.2, 95% CI: -1.7, 1.4). Lactulose users reported more good sleep (92% vs. 52%, p = 0.001) and lower activity impairment (3.0 vs. 4.8, p = 0.02). Lactulose improves sleep and activity impairment in patients with poor PROs. We did not observe any improvement in global HRQOL after 28 days using the Short Form-8 Health Survey instrument.

AbstractAnthrax, caused by the bacteriumBacillus anthracis, is a zoonotic disease that manifests in various forms in human infection, depending on the route of infection. Inhalation anthrax, the most detrimental form of the disease, comes about from the inhalation of anthrax spores and progresses to severe life-threatening conditions late in infection. Notably, there are FDA-approved antibiotics that are effective at treating the disease when administered promptly; however, these antibiotics would be rendered useless against strains ofB. anthracisthat were genetically modified to be resistant to these antibiotics. Consequently, the search for new and effective therapeutics to combat anthrax infection continues. In this study, telavancin (Vibativ®), a semisynthetic lipoglycopeptide antibiotic, was assessed forin vitroactivity against 17B. anthracisstrains and tested for the protective efficacy against inhalation anthrax infection in the rabbit model. Telavancin demonstrated potentin vitroactivity againstB. anthraciswhich led us to test its efficacy in the rabbit inhalation anthrax model. Rabbits were infected with a lethal dose of anthrax spores via the inhalation route and treated intravenously with telavancin at 30 mg/kg every 12 hours, a dose that mimics the levels measured in the serum of humans, for 5 days upon detection of antigenemia. Blood samples were collected at various times post-infection to assess the level of bacteremia and antibody production, and tissues were collected to determine bacterial load. The animals’ body temperatures were also recorded. Telavancin conveyed 100% survival in this model. Moreover, the dosage of telavancin used for the study effectively clearedB. anthracisfrom the bloodstream and organ tissues, even more effectively than a humanized dose of levofloxacin. Collectively, the low MICs against all strains tested and rapid bactericidalin vivoactivity demonstrate that telavancin has the potential to be an effective alternative for the treatment or prophylaxis of anthrax infection.Author SummaryBacillus anthracis, the causative agent of anthrax, continues to interest the research community due to its past and future potential use as bioweapon. Importantly, as a bacterial pathogen,B. anthracisis capable of developing resistance to the antibiotics currently used to treat the infection, either naturally or by deliberate, nefarious means. Consequently, there remains a need to discover, develop, and/or repurpose new antibiotics that would be effective at treating anthrax infection. In this study, we evaluated the antibacterial activity of telavancin, a semisynthetic glycopeptide antibiotic clinically approved to treat complicated skin and skin structure infections, against various strains ofB. anthracis in vitro, and we assessed the protective efficacy of telavancin against inhalation anthrax infection in the rabbit model. We show that telavancin is very potent against numerousB. anthracisstrainsin vitro, and its level of potency surpassed that of another antibiotic currently approved and used to prevent anthrax infection. Moreover, we show that telavancin protects against inhalation anthrax infectionin vivo. Overall, our findings support the use of telavancin as an effective therapeutic for anthrax infection.

Introduction: Von Willebrand Factor (VWF) is a ubiquitous component of thrombi extracted by endovascular thrombectomy from patients with large vessel occlusion (LVO) stroke. BB-031 is a modified RNA aptamer that targets von Willebrand Factor (VWF) that lyses occlusive thrombi and improves outcomes in pre-clinical models of acute ischemic stroke (AIS). Hypothesis: BB-031 is safe, tolerable, and inhibits both VWF binding and activity in a dose-dependent manner. Methods: Healthy participants were randomized to receive BB-031 or placebo (6:2) by intravenous bolus injection at single ascending doses (SAD) of 0.1, 0.3, 1.0, 2.0 and 4.0 mg/kg (total n=40). Serial Clinical assessment, and blood sample collection for pharmacokinetic (PK) and pharmacodynamic (PD) analysis were performed. Non-compartmental PK analysis was conducted using Phoenix WinNonlin. PD evaluation included measurement of VWF inhibition and whole blood thrombosis (Platelet Function Analyzer [PFA-200]). Results: BB-031 was safe and well-tolerated for 28 days following single IV doses up to 4.0 mg/kg. There were no significant adverse events (SAEs), or treatment-emergent adverse events (TEAEs) leading to dose discontinuation. Minor events included bleeding at an IV site in 1 participant, and minor bleeding of an ulcer on the tongue in 1 participant. None of the minor TEAEs were dose-dependent. BB-031 demonstrated nonlinear, dose-dependent plasma PK across the dose range tested, with an apparent mean terminal half-life (t 1/2 ) of 18 min at 0.1 mg/kg to 67 min at 4.0 mg/kg. Dose-dependent changes in VWF binding were observed; >95% maximal mean change from baseline was reached following a single IV dose of 4.0 mg/kg. Finally, PFA-200 results showed complete inhibition of clot formation (closing time ≥300 seconds) at all doses tested with a dose-dependent duration of inhibition and return to normal range. Conclusion: This first-in-human SAD study of BB-031 demonstrated safety following a single IV dose of 0.1 to 4 mg/kg, and dose-dependent patterns of VWF binding and platelet function changes. These results lay the foundation for future studies in patients suffering from thrombotic conditions including AIS.

BackgroundAssessment and feedback is a common implementation strategy to improve healthcare provider fidelity to clinical guidelines. For immunization guidelines, fidelity is often measured with doses administered during eligible visits. Adding a patient refusal measure captures provider fidelity more completely (i.e., all instances of a provider recommending a vaccine, resulting in vaccination or refusal) and enables providers to track patient vaccine hesitancy patterns. However, many electronic health record (EHR) systems have no structured field to document multiple instances of refusals for specific vaccines, and existing billing codes for refusal are not vaccine specific. This study assessed the feasibility of a novel method for refusal documentation used in a study focused on human papillomavirus (HPV) vaccine.MethodsAn observational, descriptive-comparative, mixed-methods study design was used to conduct secondary data analysis from an implementation-effectiveness trial. The parent trial compared coach-based versus web-based practice facilitation, including assessment and feedback, to increase HPV vaccination in 21 community-based private pediatric practices. Providers were instructed to document initial HPV vaccine refusals in the EHR's immunization forms and subsequent refusals using dummy procedure codes, for use in assessment and feedback reports. This analysis examined adoption and maintenance of the refusal documentation method during eligible well visits, identified barriers and facilitators to documentation and described demographic patterns in patient refusals.ResultsSeven practices adopted the refusal documentation method. Among adopter practices, documented refusals started at 2.4% of eligible well visits at baseline, increased to 14.2% at the start of implementation, peaked at 24.0%, then declined to 18.8%. Barriers to refusal documentation included low prioritization, workflow integration and complication of the billing process. Facilitators included high motivation, documentation instructions and coach support. Among adopter practices, odds of refusing HPV vaccine were 25% higher for patients aged 15–17 years versus 11–12 years, and 18% lower for males versus females.ConclusionsWe demonstrated the value of patient refusal documentation for measuring HPV vaccination guideline fidelity and ways that it can be improved in future research. Creation of vaccine-specific refusal billing codes or EHR adaptations to enable documenting multiple instances of specific vaccine refusals would facilitate consistent refusal documentation.Trial Registration NCT03399396 Registered in ClinicalTrials.gov on 1/16/2018.

To improve appropriate antibiotic prescribing for children in Tennessee. We performed a before-and-after intervention study with 3 comparison periods: period 1 (P1, baseline) May 2018-September 2019; period 2 (P2, intervention before the COVID-19 pandemic) November 11, 2019-March 20, 2020; and period 3 (P3, intervention during the coronavirus disease 2019 [COVID-19] pandemic) March 21, 2020-November 10, 2020. We additionally surveyed participating providers to assess acceptance of the intervention. Community general pediatrics practices. In total, 81 general pediatricians, family medicine physicians, and nurse practitioners in 5 general pediatrics practices participated in this study. Each practice identified a practice and operations champion for the project. Practices chose 2-4 implementation strategies previously shown to be effective at reducing outpatient antibiotic use to implement in their practice throughout the study intervention period. Study personnel also held quarterly meetings with all providers to review deidentified peer comparison feedback both across practices enrolled in the study and at the provider level within each practice. We detected improvements in guideline-concordant antibiotic use in the pre-COVID-19 intervention period, and they were sustained in the study period during the pandemic (P3): otitis media (P1 72.14% vs P2 81.42% vs P3 86.11%), group A streptococcal pharyngitis (P1 66.13% vs P2 81.56% vs P3 80.44%), pneumonia (P1 70.6% vs P2 76.2% vs P3 100%), sinusitis (P1 76.2% vs P2 83.78% vs P3 82.86%), skin and soft-tissue infections (P1 97.18% vs P2 100% vs P3 100%). Bundled implementation strategies led to significant increases in guideline-concordant antibiotic prescribing for all diagnoses. Survey results demonstrate that the bundled implementation strategies were well-accepted by providers.

The COVID-19 pandemic led to rapid expansion of telemedicine services. We surveyed parent/guardians from March 10 to June 29, 2020, in an academic and community pediatric practice, and community pediatric providers from June 5 to July 13, 2020, to better understand their perceptions of telemedicine and compare parent/guardian satisfaction between in-person and telemedicine encounters. Overall patient satisfaction scores were high in both settings and did not differ between in-person and telemedicine visits (community setting: 93.36 ± 12.87 in-person vs. 88.04 ± 22.04 telemedicine; academic setting: 92.25 ± 11.2 vs. 95.37 ± 8.21). Most providers (82.5%) would be willing to use telemedicine in a nonpandemic situation. Telemedicine should remain available for primary care pediatrics during and after resolution of the pandemic.