Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza.

Baloxavir marboxil (formerly S-033188) is a prodrug of baloxavir acid (S-033447) and inhibits cap-dependent endonuclease, an essential protein involved in the initiation of viral transcription by cleaving capped mRNA bound to PB2. Its adverse event profile is comparable to oseltamivir but is still vulnerable to resistance. The single-dose baloxavir marboxil is an appealing antiviral regimen for the treatment of influenza among outpatients when compared with longer, twice-daily regimens of oral and inhaled neuraminidase inhibitors. This review focuses on the mode of action, antiviral activity, pharmacokinetics, clinical indications, and safety profiles of this drug. Considerations for formulary addition and its place in therapy are also discussed.

The Effect of Molecular Rapid Diagnostic Testing on Clinical Outcomes in Bloodstream Infections: A Systematic Review and Meta-analysis.

BACKGROUND: Previous reports on molecular rapid diagnostic testing (mRDT) do not consistently demonstrate improved clinical outcomes in bloodstream infections (BSIs). This meta-analysis seeks to evaluate the impact of mRDT in improving clinical outcomes in BSIs. METHODS: We searched PubMed, CINAHL, Web of Science, and EMBASE through May 2016 for BSI studies comparing clinical outcomes between mRDT and conventional microbiology methods. RESULTS: Thirty-one studies were included with 5920 patients. The mortality risk was significantly lower with mRDT than with conventional microbiology methods (odds ratio [OR], 0.66; 95% confidence interval [CI], .54-.80), yielding a number needed to treat of 20. The mortality risk was slightly lower with mRDT in studies with antimicrobial stewardship programs (ASPs) (OR, 0.64; 95% CI, .51-.79), and non-ASP studies failed to demonstrate a significant decrease in mortality risk (0.72; .46-1.12). Significant decreases in mortality risk were observed with both gram-positive (OR, 0.73; 95% CI, .55-.97) and gram-negative organisms (0.51; .33-.78) but not yeast (0.90; .49-1.67). Time to effective therapy decreased by a weighted mean difference of -5.03 hours (95% CI, -8.60 to -1.45 hours), and length of stay decreased by -2.48 days (-3.90 to -1.06 days). CONCLUSIONS: For BSIs, mRDT was associated with significant decreases in mortality risk in the presence of a ASP, but not in its absence. mRDT also decreased the time to effective therapy and the length of stay. mRDT should be considered as part of the standard of care in patients with BSIs.

Antimicrobial Resistance of Escherichia coli Urinary Isolates in the Veterans Affairs Health Care System.

We reviewed data for almost 300,000 clinical Escherichia coli urinary isolates (collected in 2009 through 2013) from 127 inpatient and outpatient facilities, to assess antibiotic resistance among Veterans Affairs health care system patients using Clinical and Laboratory Standards Institute and Centers for Disease Control and Prevention National Healthcare Safety Network definitions or guidance. Rates of resistance to amoxicillin or ampicillin/ß-lactamase inhibitors were approximately 40% and rates of resistance to fluoroquinolones and trimethoprim-sulfamethoxazole approached 30%. Rates of resistance to nitrofurantoin, antipseudomonal penicillin/ß-lactamase inhibitors, and carbapenems remained less than 10%. The percentage of isolates that were considered multidrug resistant varied (4% to 37%), depending on the definitions used.

Consensus of recommendations guiding comparative effectiveness research methods.

PURPOSE: Because of an increasing demand for quality comparative effectiveness research (CER), methods guidance documents have been published, such as those from the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI). Our objective was to identify CER methods guidance documents and compare them to produce a summary of important recommendations which could serve as a consensus of CER method recommendations. METHODS: We conducted a systematic literature review to identify CER methods guidance documents published through 2014. Identified documents were analyzed for methods guidance recommendations. Individual recommendations were categorized to determine the degree of overlap. RESULTS: We identified nine methods guidance documents, which contained a total of 312 recommendations, 97% of which were present in two or more documents. All nine documents recommended transparency and adaptation for relevant stakeholders in the interpretation and dissemination of results. Other frequently shared CER methods recommendations included: study design and operational definitions should be developed a priori and allow for replication (n = 8 documents); focus on areas with gaps in current clinical knowledge that are relevant to decision-makers (n = 7); validity of measures, instruments, and data should be assessed and discussed (n = 7); outcomes, including benefits and harms, should be clinically meaningful, and objectively measured (n = 7). Assessment for and strategies to minimize bias (n = 6 documents), confounding (n = 6), and heterogeneity (n = 4) were also commonly shared recommendations between documents. CONCLUSIONS: We offer a field-consensus guide based on nine CER methods guidance documents that will aid researchers in designing CER studies and applying CER methods. Copyright © 2016 John Wiley & Sons, Ltd.

Risk stacking of pneumococcal vaccination indications increases mortality in unvaccinated adults with Streptococcus pneumoniae infections.

BACKGROUND: Several chronic disease states have been identified as pneumococcal vaccination indications due to their ability to increase pneumococcal disease development and subsequent mortality. However, the risk of mortality according to the number of these disease states present is unknown. We sought to determine the impact of concomitant, multiple risk factors (stacked risks) for pneumococcal disease on 30-day mortality in adults. METHODS: This was a national case-control study of unvaccinated older Veterans (≥50years of age) admitted to Veterans Affairs medical centers from 2002 to 2011 with serious pneumococcal infections (pneumonia, bacteremia, meningitis) based on positive S. pneumoniae blood, cerebrospinal fluid, or respiratory cultures, respectively. Cases were those not alive 30days following culture, while controls were alive. Using logistic regression, we quantified risk of 30-day mortality among patients with stacked risk factors, including age ≥65years, alcohol abuse, chronic heart disease, chronic liver disease, chronic respiratory disease, diabetes mellitus, immunodeficiency, and smoking. RESULTS: We identified 9730 serious pneumococcal infections, with an overall 30-day mortality rate of 18.6% (1764 cases, 7966 controls). Infection types included pneumonia (62%), bacteremia (26%), and bacteremic pneumonia (11%). Along with eight individual risk factors, we assessed 247 combinations of risk factors. Most cases (85%) and controls (74%) had at least two risk factors. Mortality increased as risks were stacked, up to six risk factors (one: OR 1.5, CI 1.08-2.07; two: OR 2.01, CI 1.47-2.75; three: OR 2.71, CI 1.99-3.69; four: OR 3.27, CI 2.39-4.47; five: OR 3.63, CI 2.60-5.07; six: OR 4.23, CI 2.69-6.65), with each additional risk factor increasing mortality an average of 55% (±13%). CONCLUSIONS: Among adults ≥50years with serious pneumococcal disease, mortality risk increased approximately 55% as vaccination indications present increased. Mortality with six stacked indications was double that of two indications.

Predictors of Mortality Among U.S. Veterans With Streptococcus Pneumoniae Infections.

INTRODUCTION: Serious Streptococcus pneumoniae infections, encompassing pneumonia, bacteremia, and meningitis, are a major cause of mortality. However, literature regarding mortality is often limited to invasive pneumococcal disease, excluding pneumonia. This study sought to identify predictors of mortality among adults with serious pneumococcal disease, including pneumonia and invasive pneumococcal disease. METHODS: This was a nested case-control study of unvaccinated older Veterans with positive S. pneumoniae cultures (blood, cerebrospinal fluid, respiratory) admitted to Veterans Affairs medical centers nationally between 2002 and 2011. Patients vaccinated against pneumococcal disease were excluded. Using multivariable logistic regression, predictors of 30-day mortality were identified, including patient demographics, comorbidities during admission, and medical history within the previous year. RESULTS: Among 9,468 patients, there were 9,730 serious pneumococcal infections; 1,764 (18.6%) resulted in death within 30 days (cases), whereas 7,966 did not (controls). Pneumonia accounted for half (49.4%, n=871) of all deaths. Mortality predictors consistent with vaccine recommendations included dialysis (during hospitalization, OR=3.35, 95% CI=2.37, 4.72), moderate to severe liver disease (during hospitalization, OR=2.47, 95% CI=1.53, 3.99; within 1 year, OR=1.49, 95% CI=1.01, 2.20), and neutropenia (during hospitalization, OR=2.67, 95% CI=1.32, 5.42). Predictors not included in current recommendations included dementia (during hospitalization, OR=1.8, 95% CI=1.23, 2.61) and neurologic disorders (during hospitalization, OR=1.86, 95% CI=1.42, 2.45; within 1 year, OR=1.28, 95% CI=1.02, 1.59). CONCLUSIONS: Several mortality predictors among unvaccinated Veterans with serious pneumococcal disease were consistent with pneumococcal vaccine recommendations, including organ or immune system dysfunction-related conditions. Other predictors, including neurologic disorders or dementia, may warrant expanded vaccination recommendations.