First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults.

VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC24) and maximum concentration (Cmax). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.

Exploring pharmacists' perceptions regarding influenza and streptococcal testing within a chain pharmacy.

OBJECTIVES: To assess pharmacists' perceptions of point-of-care testing (POCT) and treatment for influenza and streptococcus pharyngitis in a community pharmacy setting. A secondary objective was to explore the correlation between demographic data and survey responses. METHODS: An anonymous electronic Likert-type-scale questionnaire was sent to pharmacists in a division of a large national supermarket chain pharmacy in western Tennessee, Mississippi, and Arkansas. This survey was e-mailed with the use of Qualtrics Survey Software and administered from November 28, 2016, to December 31, 2016. It included questions that explored pharmacists' willingness to perform influenza and streptococcus pharyngitis POCT as well as to recommend and provide appropriate treatment. The survey also collected demographic information including age, education, and number of years practicing at current site. The survey was reviewed by a convenience sample of pharmacists in a large national supermarket chain and revised based on their feedback. Descriptive statistics were used to evaluate quantitative participant responses. RESULTS: The electronic survey was distributed to 379 pharmacists, and the response rate for the survey was 39% (146/379). This study found that 69% either strongly agreed or agreed to be willing to perform POCT in a community pharmacy setting, and 86% either strongly agreed or agreed to be willing to recommend appropriate treatment for influenza and streptococcal pharyngitis. Secondarily, the majority of participants either strongly agreed (27%) or agreed (52%) that they possessed the clinical knowledge to treat these infections. In addition, 32% strongly agreed and 52% agreed that their staff could be trained to assist with these services. Finally, 66% either strongly agreed or agreed there were barriers to implementing this service. CONCLUSION: This survey provided insight into pharmacists' perceptions of providing influenza and streptococcal pharyngitis POCT in their pharmacy and demonstrated that a majority were willing to provide treatment.

Patient Satisfaction With a Comprehensive Medication Review Provided by a Community Pharmacist.

Background: The comprehensive medication review (CMR) is one of the most commonly delivered medication therapy management services, and it is a required service to be provided to Medicare Part D beneficiaries. Despite the large body of evidence available on medication therapy management benefits, and the growing value placed on it by payers, there has been little research assessing patient satisfaction with these services. Objectives: The primary objective of this study was to determine patient satisfaction with a face-to-face or telephonic CMR provided by a chain community pharmacist. The study secondarily assessed patients' perceived value of the service while also collecting demographic information. Methods: A Likert-type satisfaction survey was distributed to patients on completion of a face-to-face or telephonic CMR in either Outcomes or Mirixa by members of a clinical team (7 clinical pharmacists and 4 residents) within a chain community pharmacy. Participants were asked to return the survey in a self-addressed stamped envelope within 1 week of the CMR. Results: The response rate for the survey was 33% (31 of 95 surveys returned). The study found that approximately 70% (21 of 31) strongly agreed with being overall satisfied with the CMR. Conclusion: This research study provided insight to patients' perceptions of a CMR provided by a community pharmacist. Patient views of the CMR were positive, with patients finding CMR delivery in a community pharmacy valuable. Further investigation of specific interventions and approaches during a medication review could help identify ways to increase patient satisfaction.

Training and retaining community pharmacy leaders: Career pathways after completing a PGY1 community pharmacy residency affiliated with a large supermarket chain.

OBJECTIVE: To determine pharmacist career paths and resident perceptions after completion of a PGY1 community pharmacy residency with a national supermarket pharmacy chain. METHODS: Cross-sectional nationwide survey. RESULTS: Overall, 65% (n = 24) of residents who responded accepted a position with Kroger immediately after graduation. When asked about the degree of value the residency had on obtaining the resident's ideal position, 29 (76%) reported that it was "very valuable" and the remaining 9 (24%) reported that it was "somewhat valuable." Positions that these pharmacists held immediately after residency completion were: clinical pharmacist (clinical coordinators, patient care specialists, or patient care managers; 54%), staff pharmacist (21%), split/mixed (mixed clinical and staffing components; 21%), and pharmacy manager (4%). CONCLUSION: Residency trained pharmacists were retained by the pharmacy chain where they practiced, and the majority of those pharmacists held split or full-time clinical pharmacist roles within the chain supermarket pharmacy.

Exploring Pharmacy Technician Roles in the Implementation of an Appointment-Based Medication Synchronization Program.

The objective of this study was to qualitatively explore the role of pharmacy technicians in the implementation of an appointment-based model (ABM) medication synchronization program. The purposeful sampling of technicians working within six different locations of a supermarket chain pharmacy in Mississippi and Tennessee was carried out, and the technicians were interviewed between January and April 2018. A semi-structured interview guide was developed based on the Consolidated Framework for Implementation Research (CFIR). Questions gathered information around pharmacy technician demographics and CFIR domains (process, inner setting, outer setting and intervention characteristics). Interviews were audiotaped and transcribed. Two members of the research team performed thematic content analysis. Six full-time, certified pharmacy technicians with 8.3 ± 2.7 years of experience were interviewed. Findings suggest that including hands-on experience with program software is needed during training to successfully implement ABM. A barrier to implementation was the time needed to complete ABM tasks as compared to other tasks. Although some barriers exist regarding implementation, technicians believe that overall, this program has positive benefits for patients. Results from this study signify that ABM implementation can be challenging. Better ABM portal integration with the pharmacy patient profile and appropriate workforce budgeting are key to continued success.

Density Functional and Electrostatic Calculations of Manganese Superoxide Dismutase Active Site Complexes in Protein Environments.

Density functional and electrostatic methods have been applied to calculate active site geometries and the redox potential of manganese superoxide dismutase (MnSOD). The initial active site clusters were built up by including only first-shell side chain ligands and then augmented by second-shell ligands. The density functional optimized Mn-ligand bond lengths for the reduced complexes in general compared fairly well with protein crystallography data; however, large deviations for calculated Mn-OH distances were found for the oxidized active site clusters. Our calculations suggest that this deviation can be attributed to the redox heterogeneity of the oxidized protein in X-ray crystallography studies. The redox potential was calculated by treating the protein environment and the solvent bulk by a semimacroscopic electrostatic model. The protein structures were taken from the Thermus thermophilus enzyme. The calculated coupled redox potentials converge toward experimental values with increasing size of the active site cluster models, and the final calculated value was +0.06 V, compared to experimental values of +0.26 V determined for Bacillus stearothermophilus and +0.31 V in Escherichia coli enzymes. Using an energy decomposition scheme, the effects of the second-shell ligands and the protein and reaction fields have been analyzed.

CuZn Superoxide Dismutase Geometry Optimization, Energetics, and Redox Potential Calculations by Density Functional and Electrostatic Methods.

The structures, energetics, and orbital- and charge-dependent properties of copper zinc superoxide dismutase (CuZnSOD) have been studied using density functional and electrostatic methods. The CuZnSOD was represented with a model consisting of copper and zinc sites connected by a bridging histidine ligand. In addition to the bridge, three histidine ligands and one water molecule were bonded to the Cu ion in the copper site as first-shell ligands. Two histidine ligands and an aspartate were coordinated to the zinc ion in the zinc site. Full optimization of the model was performed using different functionals, both local and nonlocal. Geometrical parameters calculated with the nonlocal functionals agree well with the experimental X-ray data. In our calculated results, the His61 Nepsilon-Cu bond in the active site breaks during the reduction and protonation, consistent with a number of X-ray structures and with EXAFS and NMR evidence. The reduction potential and pK(a) of the coupled electron/proton reaction catalyzed by CuZnSOD were determined using different models for the extended environment-from an electrostatic representation of continuum solvent, to the full protein/solvent environment using a Poisson-Boltzmann method. The predicted redox potential and pK(a) values determined using the model with the full protein/solvent environment are in excellent agreement with experiment. Inclusion of the full protein environment is essential for an accurate description of the redox process. Although the zinc ion does not play a direct redox role in the dismutation, its electronic contribution is very important for the catalytic mechanism.

Identifying relationships between high-risk sexual behaviors and screening positive for chlamydia and gonorrhea in school-wide screening events.

BACKGROUND: This article describes a school-wide sexually transmitted infection (STI) screening to identify adolescent high-risk sexual behaviors, STI history/incidence, and presence of chlamydia and gonorrhea, and examines relationships between high-risk behaviors and screening positive for chlamydia and gonorrhea in an alternative high school setting. METHODS: School-wide chlamydia and gonorrhea education and screening was provided to 869 adolescents; 226 males and 282 females 14-20 years (mean age = 17.07) consented to urine screening. Relationships were examined between screening positive, history of STIs, and high-risk sexual behaviors. RESULTS: A majority (69%) of the adolescents consented to screening: 17.76% (92) had a history of STI; 8.83% (46) tested positive at screening. More females than males tested positive (p = .001). Significant relationships existed between history of STIs and ≥ 4 sexual partners (p = .0022), no condom use (p = .06), and sexual intercourse in last 3 months (p = .03). CONCLUSIONS: School-Based Health Center (SBHC) screening was well accepted by students and staff. Sexually transmitted infection history was correlated with all identified high-risk sexual behaviors supporting the need for in-depth assessment, counseling, and testing of adolescents wherever they present for care. This study also provides an example of the role SBHCs can play in the national strategy to control chlamydia and gonorrhea in adolescents.

Antibiotic use in Thailand: quantifying impact on blood culture yield and estimates of pneumococcal bacteremia incidence.

No studies have quantified the impact of pre-culture antibiotic use on the recovery of individual blood-borne pathogens or on population-level incidence estimates for Streptococcus pneumoniae. We conducted bloodstream infection surveillance in Thailand during November 2005-June 2008. Pre-culture antibiotic use was assessed by reported use and by serum antimicrobial activity. Of 35,639 patient blood cultures, 27% had reported pre-culture antibiotic use and 24% (of 24,538 tested) had serum antimicrobial activity. Pathogen isolation was half as common in patients with versus without antibiotic use; S. pneumoniae isolation was 4- to 9-fold less common (0.09% versus 0.37% by reported antibiotic use; 0.05% versus 0.45% by serum antimicrobial activity, P < 0.01). Pre-culture antibiotic use by serum antimicrobial activity reduced pneumococcal bacteremia incidence by 32% overall and 39% in children < 5 years of age. Our findings highlight the limitations of culture-based detection methods to estimate invasive pneumococcal disease incidence in settings where pre-culture antibiotic use is common.

Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin.

BACKGROUND: Development of vaccines against highly pathogenic avian influenza virus H5N1 subtypes posing a pandemic threat remains a priority. Limitations in manufacturing capacity and production time of conventional inactivated vaccines highlight the need for additional approaches. METHODS: We conducted two double-blind, placebo-controlled phase 1 studies involving a total of 103 healthy adults who received two intramuscular injections of Vaxfectin-adjuvanted plasmid DNA vaccine or placebo 21 days apart. Vaccine cohorts received either a monovalent vaccine containing an A/Vietnam/1203/04 H5 hemagglutinin-encoding plasmid or a trivalent vaccine with plasmids encoding H5, NP, and M2 proteins in doses from 0.1 to 1mg of DNA/injection. RESULTS: All doses were well tolerated without vaccine-related serious adverse events or discontinuations. In the monovalent cohorts, hemagglutination inhibition (HI) titers of > or =40 and 4-fold rises from baseline were achieved in 47-67% of subjects and H5-specific T-cell responses in 75-100%. Trivalent cohorts had lower HI response rates (< or = 20%), but 72% of subjects achieved T-cell and/or antibody responses to one or more antigens. CONCLUSIONS: Vaxfectin-adjuvanted monovalent H5 DNA vaccines were well tolerated and induced HI response rates and titers in the reported range of inactivated protein-based H5 vaccines, suggesting that adjuvanted DNA vaccines with rapid vaccine production could be useful for pandemic control.