β-Lactamase–Producing Bacteria in Upper Respiratory Tract Infections

β-Lactamase–producing bacteria (BLPB) can play an important role in respiratory infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme β-lactamase. BLPB not only may survive penicillin therapy, but as demonstrated by in vitro and in vivo studies, can also protect other penicillin-susceptible bacteria from penicillin by releasing the free enzyme into their environment. The clinical in vitro and in vivo evidence supporting the role of these organisms in the increased failure rate of penicillin in eradication of these infections and the implication of that increased rate on the management of infections is discussed.     

Neurogenic Bladder: Recurrent Urinary Tract Infections—Beyond Antibiotics

Purpose of Review

Our goal was to identify evidenced-based strategies to prevent and treat patients with neurogenic bladder who suffer from recurrent urinary tract infections. We focused on therapy beyond standard antibiotics to address a multitude of factors implicated in these complex infections.

Recent Findings

Anatomic and functional components specific to neurogenic bladder contribute to the risk of infection and require close clinical monitoring. The host-pathogen interaction is one that allows for colonization of bacteria in the bladder. We recognize that bacteriuria in the neurogenic bladder population does not equate with infection. Local antibiotic treatment and oral supplements are often not adequate to eliminate infection nor prevent recurrent infection due to biofilms. However, novel medical therapies, such as photodynamic therapy, bacterial interference, and infrared laser therapy to augment local immune cells, are promising options to prevent and treat symptomatic infection.

Summary

A combination approach including management of anatomic and functional factors with medical intervention can significantly improve frequency of urinary infection. Further study of non-antibiotic therapeutic strategies is much needed as we recognize the complexity of the urinary biomes and the limitations of antibiotic therapies.

     

Prevention of Recurrent Thrombosis in Antiphospholipid Syndrome: Different from the General Population?

Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis with or without pregnancy morbidity in the presence of autoantibodies targeting proteins that associate with membrane phospholipids, termed “antiphospholipid antibodies” (aPL). Management of arterial and venous thromboses shares some similarities with management of arterial and venous thromboses in the general population; however, there are key differences. The majority of studies addressing management of thrombotic APS focus on secondary prevention. Vitamin K antagonists (VKA) are typically used for secondary prevention of venous thromboembolism in APS. Optimal management of isolated arterial thrombosis, in particular ischemic stroke, in patients with APS is controversial, and proposed therapeutic options have included antiplatelet agents and VKA. Primary prophylaxis in aPL-positive patients should be an individualized decision taking into account patient-specific risks. There may be a role for adjuvant therapies such as hydroxychloroquine, vitamin D, statins, or novel therapeutics in specific patient populations.     

Is There a Role for Genetics in the Prevention of Sudden Cardiac Death?

The identification of patients at risk for sudden cardiac death (SCD) is fundamental for both acquired cardiovascular diseases (such as coronary artery diseases, CAD) and inherited arrhythmia syndromes (such as the long‐QT syndrome, LQTS). Genetics may play a role in both situations, although the potential to exploit this information to reduce the burden of SCD varies among these two groups. Concerning acquired cardiovascular diseases, which affect most of the general population, preliminary data suggest an association between genetics and the risk of dying suddenly. The maximal utility, instead, is reached in inherited arrhythmia syndromes, where the discovery of monogenic diseases such as LQTS tracked the way for the first genotype‐phenotype correlations. The aim of this review is to provide a general overview focusing on the current genetic knowledge and on the present and future applicability for prevention in these two populations at risk for SCD.     

How Do Community Practitioners Decide Whether to Prescribe Antibiotics for Acute Respiratory Tract Infections?

BACKGROUND  Overuse of antibiotics in the treatment of acute respiratory tract infection (ARI) contributes to the growing problem of antibiotic-resistant infections. OBJECTIVE  To identify factors that influence community practitioners to prescribe antibiotics and examine how they differ from the recommendations of the Centers for Disease Control and Prevention (CDC) guideline for treatment of ARI. DESIGN  Paper case vignette study using a fractional factorial design. PARTICIPANTS  One hundred one community practitioners and eight faculty members. MAIN MEASUREMENTS  We asked community practitioners to estimate how likely they would be to prescribe antibiotics in each of 20 cases of ARI and then used multiple regression to infer the importance weights of each of nine clinical findings. We then compared practitioners’ weights with those of a panel of eight faculty physicians who evaluated the cases following the CDC guidelines rather than their own judgments. MAIN RESULTS  Practitioners prescribed antibiotics in 44.5% of cases, over twice the percentage treated by the panel using the CDC guidelines (20%). In deciding to prescribe antibiotic treatment, practitioners gave little or no weight to patient factors such as whether the patients wanted antibiotics. Although weighting patterns differed among practitioners, the majority (72%) gave the greatest weight to duration of illness. When illness duration was short, the rate of prescribing (20.1%) was the same as the rate of the faculty panel (20%). CONCLUSIONS  Based on hypothetical cases of ARI, community practitioners prescribed antibiotics at twice the rate of faculty following CDC practice guidelines. Practitioners were most strongly influenced by duration of illness. The effect of duration was strongest when accompanied by fever or productive cough, suggesting that these situations would be important areas for practitioner education and further clinical studies.     

Is There a Role for Probiotics in the Prevention or Treatment of Food Allergy?

A balanced gut microbiota is crucial for the development of healthy immunoregulation and gut barrier function to allow brisk immune responses to pathogens and systemic hyporesponsiveness to harmless antigens such as food. Although the first allergic disease to manifest itself, atopic eczema, is not equivalent to food allergy, pre- and postnatal administration of specific probiotic strains has emerged as a promising tool for the prevention of this condition, with potential implications for food allergy development. For food allergy proper, however, we lack markers and risk factors and mechanisms, i.e., targets for preventive measures. The focus here is therefore on the treatment. Indeed, the potential of specific probiotic strains to alleviate food allergy resides in their ability to modify antigens, repair gut barrier functions, balance altered microbiota, and restore local and systemic immune regulation. In patients with multiple food allergies, induction of oral tolerance by specific probiotics continues to attract research interest.     

Genetics—Current and Future Role in the Prevention and Management of Coronary Artery Disease

Purpose of Review

The purpose of this study is to review genetic risk variants for coronary artery disease (CAD) and how they will change the management and prevention of CAD currently and in the future.

Recent Findings

Through the efforts of international consortia, 58 genetic risk variants for CAD of genome-wide significance have been replicated in appropriate independent populations. Only one third of these variants mediate their risk through known conventional risk factors for CAD. Thus, unknown mechanisms contribute to CAD. Secondly, the genetic risk is proportional to the total number of risk variants rather than the intensity of any risk factor. Thirdly, the availability of the genetic risk variants enables one to perform Mendelian randomization (MR) studies since they are randomized at conception, not confounded, fixed for life, and can be used to determine if a risk factor is causative or just a marker. MR can also be used to determine the safety and efficacy of a gene product targeted for drug therapy. Genetic risk variants have been shown to successfully risk stratify for CAD in both primary and secondary preventions.

Summary

Contrary to dogma, MR documents that plasma HDL-C is not protective of CAD. The use of genetic risk score (GRS) for CAD is shown to be more effective in risk stratifying for CAD than the Framingham risk score and independent of the conventional risk factors including family history. Furthermore, the GRS predicts the response to statin therapy in primary and secondary preventions. The use of GRS could represent a paradigm shift in the prevention of CAD.

     

Development of ST-246® for Treatment of Poxvirus Infections

ST-246 (Tecovirimat) is a small synthetic antiviral compound being developed to treat pathogenic orthopoxvirus infections of humans. The compound was discovered as part of a high throughput screen designed to identify inhibitors of vaccinia virus-induced cytopathic effects. The antiviral activity is specific for orthopoxviruses and the compound does not inhibit the replication of other RNA- and DNA-containing viruses or inhibit cell proliferation at concentrations of compound that are antiviral. ST-246 targets vaccinia virus p37, a viral protein required for envelopment and secretion of extracellular forms of virus. The compound is orally bioavailable and protects multiple animal species from lethal orthopoxvirus challenge. Preclinical safety pharmacology studies in mice and non-human primates indicate that ST-246 is readily absorbed by the oral route and well tolerated with the no observable adverse effect level (NOAEL) in mice measured at 2000 mg/kg and the no observable effect level (NOEL) in non-human primates measured at 300 mg/kg. Drug substance and drug product processes have been developed and commercial scale batches have been produced using Good Manufacturing Processes (GMP). Human phase I clinical trials have shown that ST-246 is safe and well tolerated in healthy human volunteers. Based on the results of the clinical evaluation, once a day dosing should provide plasma drug exposure in the range predicted to be antiviral based on data from efficacy studies in animal models of orthopoxvirus disease. These data support the use of ST-246 as a therapeutic to treat pathogenic orthopoxvirus infections of humans.