Sustained Virologic Response of Patients Hospitalized Compared With Those Not Hospitalized During Treatment for Hepatitis C Virus With Direct-Acting Antivirals.

BACKGROUND: Direct-acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) have resulted in great success through high attainment of sustained virologic response (SVR). Risk factors for DAA treatment failure are important to identify because of worsened outcomes with failure and high treatment cost. OBJECTIVE: We sought to identify whether hospitalization during treatment affects SVR. The primary outcome was the difference in SVR at 12 weeks after treatment. METHODS: This multicenter, single health system retrospective cohort review compared achievement of SVR between patients hospitalized during DAA treatment for HCV with those not hospitalized during treatment. RESULTS: Patients in the hospitalized cohort (n = 94) had more severe disease at baseline than nonhospitalized patients (n = 167) as indicated through higher Model for End-Stage Liver Disease (MELD) scores, Fibrosis-4 scores, and imaging-suggested or biopsy-confirmed cirrhosis. Patients hospitalized during treatment had lower SVR rates compared with those not hospitalized (87.2% vs 95.2%; P = 0.043) but failed to reach significance when inpatient mortality was excluded on secondary analysis (91.1% vs 95.2%; P = 0.195). Patients who were hospitalized and did not achieve SVR had higher MELD scores, were more likely to have intensive care unit stay, and had longer hospital stay compared with those who achieved SVR. Of 94 patients, 93 provided home supply of DAAs during hospitalization. CONCLUSION AND RELEVANCE: Patients hospitalized during DAA treatment for HCV had reduced rates of SVR. This reduced SVR rate may be driven by inpatient mortality and severity of liver disease. Patient education to bring home supply of medication for use during admission is an effective intervention.

p38 MAPK activation, JNK inhibition, neoplastic growth inhibition, and increased gap junction communication in human lung carcinoma and Ras-transformed cells by 4-phenyl-3-butenoic acid.

Human lung neoplasms frequently express mutations that down-regulate expression of various tumor suppressor molecules, including mitogen-activated protein kinases such as p38 MAPK. Conversely, activation of p38 MAPK in tumor cells results in cancer cell cycle inhibition or apoptosis initiated by chemotherapeutic agents such as retinoids or cisplatin, and is therefore an attractive approach for experimental anti-tumor therapies. We now report that 4-phenyl-3-butenoic acid (PBA), an experimental compound that reverses the transformed phenotype at non-cytotoxic concentrations, activates p38 MAPK in tumorigenic cells at concentrations and treatment times that correlate with decreased cell growth and increased cell-cell communication. H2009 human lung carcinoma cells and ras-transformed rat liver epithelial cells treated with PBA showed increased activation of p38 MAPK and its downstream effectors which occurred after 4 h and lasted beyond 48 h. Untransformed plasmid control cells showed low activation of p38 MAPK compared to ras-transformed and H2009 carcinoma cells, which correlates with the reduced effect of PBA on untransformed cell growth. The p38 MAPK inhibitor, SB203580, negated PBA's activation of p38 MAPK downstream effectors. PBA also increased cell-cell communication and connexin 43 phosphorylation in ras-transformed cells, which were prevented by SB203580. In addition, PBA decreased activation of JNK, which is upregulated in many cancers. Taken together, these results suggest that PBA exerts its growth regulatory effect in tumorigenic cells by concomitant up-regulation of p38 MAPK activity, altered connexin 43 expression, and down-regulation of JNK activity. PBA may therefore be an effective therapeutic agent in human cancers that exhibit down-regulated p38 MAPK activity and/or activated JNK and altered cell-cell communication.

A clinical pathway for community-acquired pneumonia: an observational cohort study.

BACKGROUND: Six hospitals instituted a voluntary, system-wide, pathway for community acquired pneumonia (CAP). We proposed this study to determine the impact of pathway antibiotics on patient survival, hospital length of stay (LOS), and total hospital cost. METHODS: Data were collected for adults from six U.S. hospitals with a principal CAP discharge diagnosis code, a chest infiltrate, and medical notes indicative of CAP from 2005-2007. Pathway and non-pathway cohorts were assigned according to antibiotics received within 48 hours of admission. Pathway antibiotics included levofloxacin 750 mg monotherapy or ceftriaxone 1000 mg plus azithromycin 500 mg daily. Multivariable regression models assessed 90-day mortality, hospital LOS, total hospital cost, and total pharmacy cost. RESULTS: Overall, 792 patients met study criteria. Of these, 505 (64%) received pathway antibiotics and 287 (36%) received non-pathway antibiotics. Adjusted means and p-values were derived from Least Squares regression models that included Pneumonia Severity Index risk class, patient age, heart failure, chronic obstructive pulmonary disease, and admitting hospital as covariates. After adjustment, patients who received pathway antibiotics experienced lower adjusted 90-day mortality (p = 0.02), shorter mean hospital LOS (3.9 vs. 5.0 days, p < 0.01), lower mean hospital costs ($2,485 vs. $3,281, p = 0.02), and similar mean pharmacy costs ($356 vs. $442, p = 0.11). CONCLUSIONS: Pathway antibiotics were associated with improved patient survival, hospital LOS, and total hospital cost for patients admitted to the hospital with CAP.

Insight into development of a mentorship program in a professional pharmacy organization.

INTRODUCTION: The American Association of Colleges of Pharmacy Pharmacy Practice Section appointed a task force charged with developing a formal, national mentorship program for association section members. This manuscript provides insight into the creation of a mentorship program in a professional organization. METHODS: Eighteen task force volunteers were divided into four sub-teams, along with a chair and vice chair. Sub-team responsibilities were segmented into the following: (1) mission and vision development, (2) structure and content, (3) assessment and impact, and (4) dissemination and scholarship. Task force members were surveyed to generate recommendations for creating a formal mentorship program within a professional organization and reflect on the process. RESULTS: Seven of 14 eligible task force members completed the questionnaire (50% response rate). Most participants were mid-career, involved in a range of development aspects, and represented both committee members and leadership within the task force. The average time commitment was 15-19 hours over the year. The most common resource utilized was published literature and guidance documents. Identified needs included validated assessment tools, a wider range of exemplary programs to review, and guidance on broader organizational support. Strengths included organization and sub-team structure. Areas for improvement included coordination between sub-teams and resources available. Participants noted the challenges of creating a program to meet the diverse needs of a large membership. CONCLUSIONS: This manuscript demonstrates the feasibility and evidence-based approach in creation of a mentorship program within a national organization.

Risk factors for development of initial Clostridioides difficile infection.

OBJECTIVES: The purpose of this study was to identify risk factors for initial complicated Clostridioides difficile infection (CDI). METHODS: This retrospective cross-sectional study included adult patients with initial episodes of CDI who received ≥72 h of CDI-active antimicrobials. Patients were categorised into one of two groups: complicated CDI or uncomplicated CDI. A total of 513 patients were screened for inclusion, with complicated CDI patients exhibiting abnormal abdominal CT findings or experiencing death within 30 days post-CDI diagnosis. RESULTS: A total of 203 patients met the inclusion criteria, comprising 143 (70.4%) with uncomplicated CDI and 60 (29.6%) with complicated CDI. Complicated CDI patients were more likely to have been exposed to fluoroquinolones (48.3% vs. 30.8%; P = 0.017) and to carbapenems for a longer duration prior to CDI diagnosis (7 days vs. 3 days; P = 0.019). They were more likely to receive oral vancomycin (65.0% vs. 46.9%; P = 0.018) and rectal vancomycin (5.0% vs. 0%; P = 0.025) compared with uncomplicated CDI patients. Logistic regression identified previous fluoroquinolone exposure increased the risk of complicated CDI, while previous abdominal surgery decreased the risk. CONCLUSION: Almost one-third of included patients experienced a complicated episode of CDI as their initial episode. Further research is warranted to elucidate the extent of influence of prior antibiotics on the development of complicated CDI.

Ceftriaxone as an Alternative Therapy for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia after Initial Clearance of Bloodstream Infection.

INTRODUCTION: Staphylococcus spp. represent the leading cause of hospital-acquired infections and second-most frequent pathogen in bloodstream infections. Methicillin-susceptible S. aureus (MSSA) comprise approximately half of all S. aureus isolates. Standard-of-care therapies (SOCTs) display high treatment success but require frequent dosing, are problematic in penicillin allergic patients, and are nephrotoxic. Ceftriaxone may represent an alternative treatment option. METHODS: Adult patients hospitalized from January 2015 through June 2016 with positive MSSA blood cultures and treated with SOCT or ceftriaxone for ≥48 hours were included. Exclusion criteria were receipt of vancomycin or concomitant systemic antimicrobials with activity against MSSA, polymicrobial infections, and pregnant patients. Additional data collected included demographics, source/site of infection, and treatment. The primary endpoint was clinical cure (normalization of white blood cell count and temperature within 7 days and clearance of bloodstream within 7 days). Readmission within 60 days, length of stay, and discharge disposition were collected. RESULTS: A total of 43 patients were included: 23 receiving SOCT and 20 receiving ceftriaxone group. Sixteen patients received SOCT prior to ceftriaxone while 4 patients were initiated on ceftriaxone. Clinical cure was observed in 18/23 (78%) and 10/20 (50%), respectively (P=0.052). Clinical failure was driven by leukocytosis despite clearance of their bloodstream infection in 3/23 (13%) SOCT group compared to 8/20 (40%) in the ceftriaxone group (P=0.043). Six patients (SOCT: 2, ceftriaxone: 4; p=0.669) had infection-related readmissions, and 1 death per group was observed. CONCLUSION: Ceftriaxone poses a reasonable alternative to consider for MSSA bacteremia when cost and feasibility are concerns for outpatient parenteral therapy after initial clearance of bloodstream infections.

Newest lipoglycopeptides for the management of acute bacterial skin and skin structure infections.

Acute bacterial skin and skin structure infections (ABSSSIs) are some of the most commonly encountered infections worldwide. Hospitalizations as a result of ABSSSIs are associated with high mortality. This article discusses the role of oritavancin and dalbavancin, the two newest lipoglycopeptides, in the context of the other available I.V. infusion standard therapy options.

Managing acute bacterial skin and skin structure infections: Focus on new lipoglycopeptides.

Acute bacterial skin and skin structure infections (ABSSSI) are some of the most commonly encountered infections worldwide. Hospitalizations as a result of ABSSSI are associated with high mortality. This article discusses the role of oritavancin and dalbavancin, two new lipoglycopeptides, in the context of the other I.V. available standard therapy options.

Acute hepatic injury with amphotericin B deoxycholate in an immunocompetent patient.

Amphotericin B deoxycholate (AmBd) is rarely used due to its adverse effect profile, which includes nephrotoxicity, infusion-related reactions, and hepatotoxicity. The incidence of hepatotoxicity related to AmBd is 18-23%, but the reports of this adverse effect are mainly in immunocompromised patients receiving chemotherapy. We report a case of AmBd-related acute hepatic injury in an immunocompetent male with multiple medical problems. The patient initially had acute hepatic injury likely caused by poor nutritional status and a diagnosis of failure to thrive, but was recovering. He was also diagnosed with bilateral renal fungal mycetomas and received systemic treatment initially with micafungin and then fluconazole after urine cultures returned with the growth of Candida glabrata. Therapy was expanded to systemic AmBd when the fungal balls persisted. The patient subsequently developed hepatic re-injury with 1 dose of AmBd, and the therapy was discontinued. Caution should be exerted when utilizing AmBd in treating patients with previous hepatic injury.

Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C.

Hepatitis C virus (HCV) is estimated to affect up to 150 million people worldwide. Despite worldwide prevalence, treatment modalities prior to 2011 remained suboptimal, with low virologic response rates and intolerable side effect profiles. Fortunately, the landscape of treatment for chronic hepatitis C has rapidly evolved since the introduction of HCV NS3/4 protease inhibitors in 2011. Elbasvir, a NS5A inhibitor, combined with grazoprevir, a NS3/4A protease inhibitor, is the latest FDA-approved therapy for patients with genotype 1 or 4 chronic hepatitis C, with or without compensated cirrhosis. This review will focus on the current literature and clinical evidence supporting elbasvir/grazoprevir as first-line therapy in patients with genotypes 1 and 4 chronic hepatitis C.

Intravenous Vancomycin Dosing in the Elderly: A Focus on Clinical Issues and Practical Application.

The elderly population can be divided into three distinct age groups: 65-74 years (young-old), 75-84 years (middle-old), and 85+ years (old-old). Despite evidence of a shift in leading causes for mortality in the elderly from infectious diseases to chronic conditions, infections are still a serious cause of death in this population. These patients are at increased risk due to weakened immune systems, an increased prevalence of underlying comorbidities, and decreased physiologic reserves to fight infection. Additionally, elderly patients, especially adults in institutional settings, are at an increased risk of colonization and subsequent infection with methicillin-resistant Staphylococcus aureus at a rate that is five times higher than in younger individuals, causing an increase in empiric and definitive vancomycin use. Elderly patients have unique characteristics that make dosing vancomycin a challenge for clinicians, such as increased volume of distribution and decreased renal function. Using the best available evidence, it is recommended to initiate lower empiric maintenance doses and monitor vancomycin serum concentrations earlier than steady state to accurately calculate drug elimination and make appropriate dose adjustments.

Impact of piperacillin-tazobactam shortage on meropenem use: implications for antimicrobial stewardship programs.

Drug shortages pose a clear detriment to antimicrobial stewardship (AS) efforts. Our objective was to evaluate the effect of a piperacillin-tazobactam shortage on meropenem use, related costs, and associated changes in AS activity. A quasi-experimental quality improvement review compared adult patients receiving meropenem ≥72h three months pre-shortage and three months during the shortage. 320 patients were included (pre-shortage: 103; shortage: 217). Baseline characteristics were similar, but the length of stay was slightly longer in pre-shortage [19 (11-32) days] versus shortage [16 (11-32) days] (p=0.094). In pre-shortage and shortage, median days of therapy and estimated meropenem cost were 7 (5-11) and 7 (5-10) and $309.93 ($173.60-$507.03) and $255.30 ($204.24-$424.31), respectively (p=0.411 and p=0.050). Frequency of ID consultation was similar (16.8% in pre- and 25.3% in shortage, p=0.091). AS interventions increased during the shortage period (99 in pre-shortage and 205 in shortage). De-escalation occurred in 19.4% versus 32.7% of the patients in pre-shortage and shortage (p=0.014). The piperacillin-tazobactam shortage was associated with a 111% increase in meropenem prescriptions despite active AS, but was not associated with changes in mortality, length of therapy, or meropenem costs. AS should be aware that shortages may require proactive countermeasures to avoid inappropriate antimicrobial use during shortage periods.

Pathways to Improve Student Pharmacists' Experience in Research.

OBJECTIVE: To describe the implementation of a student research program and to provide outcomes from the initial 4 years' experience. DESIGN: Students conducted individual research projects in a 4-year longitudinal program (known as Pathway), with faculty member advising and peer mentoring. A prospective assessment compared perceptions of those who completed the Pathway program with those of students who did not. Descriptive statistics, t tests, and analysis of variance (ANOVA) were used. ASSESSMENT: The class of 2013 was the first to complete the Pathway program. In the Pathway assessment project, 59% (n=47) of students who responded reached self-set goals. Pathway students agreed that this research experience improved their ability to work/think independently, evaluate literature, and distinguish themselves from other students. CONCLUSION: The Pathway program helped students understand the research process and reach other self-set goals.

Pharmacologic therapy for nonalcoholic fatty liver disease in adults.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in hepatocytes in the absence of excessive alcohol intake, ranging in severity from simple steatosis to nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis can ultimately progress to cirrhosis and hepatocellular carcinoma. NAFLD is associated with cardiometabolic risk factors and is the most common chronic liver disease among adults in the Western Hemisphere. Although simple steatosis is generally considered a self-limiting disease, evidence suggests an increased risk of cardiovascular disease, and, less conclusively, mortality, among individuals with NAFLD and/or NASH. The current standard of care for the treatment of patients with NAFLD focuses on lifestyle interventions, particularly diet and exercise. There is a lack of consensus regarding the most effective and appropriate pharmacologic therapy. A PubMed search was conducted using the medical subject heading terms "fatty liver" and "steatohepatitis." This review focuses on the current pharmacologic options available for treating adults with NAFLD and/or NASH. Continued investigation of drugs or combinations that improve NAFLD progression is crucial. Clinicians, particularly pharmacists, must take an active role in identification and appropriate selection of pharmacotherapy for NAFLD.