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Objectives To evaluate the activity of fosfomycin against a group of MRSA strains, including isolates with reduced susceptibility or resistance to vancomycin, daptomycin, linezolid and ceftaroline and to determine the effect of combining various combinations of antimicrobial agents used in the therapy of serious Gram-positive infections. Methods Broth microdilution testing was used to determine the MICs of fosfomycin, vancomycin, daptomycin, linezolid, ceftaroline and cefazolin. Isolates were selected for further evaluations to determine in vitro synergy between fosfomycin and select antimicrobial agents using chequerboard broth microdilution testing. Fosfomycin was tested in combination with vancomycin, linezolid, daptomycin, ceftaroline and cefazolin. Results Fosfomycin maintained activity against 100% of strains of vancomycin-resistant Staphylococcus aureus (VRSA) and linezolid-resistant S. aureus (LRSA), 86% of VISA and 95% of daptomycin-resistant S. aureus (DRSA) strains. The combination of fosfomycin with ceftaroline consistently demonstrated synergy among all 18 isolates against the strains tested. The next most potent combination regimen was linezolid with fosfomycin, which demonstrated synergy in 16 of the 18 strains. Daptomycin demonstrated synergy in only 7 of the 18 strains tested when combined with fosfomycin. Cefazolin demonstrated synergy in 6 of 6 strains and vancomycin demonstrated no interaction in 6 of 6 strains tested. Conclusions Fosfomycin demonstrated excellent activity against MRSA as well as isolates with resistance or reduced activity to other anti-MRSA drugs including vancomycin, daptomycin and linezolid. When combined with linezolid or daptomycin, fosfomycin demonstrated synergy for all or most strains tested. Thus, these combinations may have potential clinical utility when treating patients with serious infections caused by MRSA.

At a crucial time with rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant globally, the United States Food and Drug Administration has issued an emergency use authorization for 2 oral antivirals, molnupiravir (in persons aged ≥18 years) and nirmatrelvir-ritonavir (Paxlovid) (in persons aged ≥12 years weighing ≥40 kg), for the outpatient treatment of patients with mild to moderate coronavirus disease 2019 (COVID–19) who are at risk for progression. Molnupiravir is a nucleoside analogue, whereas nirmatrelvir is a SARS-CoV-2 main protease inhibitor, and ritonavir is a human immunodeficiency virus type 1 protease inhibitor. Drug interactions are a major concern for nirmatrelvir-ritonavir. Nirmatrelvir-ritonavir demonstrated a greater risk reduction in hospitalization and death than molnupiravir compared to placebo. Both drugs need to be started within 5 days of symptoms onset and given for 5 days’ duration. This article reviews the 2 oral COVID-19 antiviral drugs including the mechanisms of action, antiviral activity, pharmacokinetics, drug interactions, clinical experience including trials, adverse events, recommended indications, and formulary considerations.

BACKGROUND: Coronavirus disease 19 (COVID-19) can have a severe presentation characterized by a dysregulated immune response requiring admission to the intensive care unit (ICU). Immunomodulatory treatments like tocilizumab were found to improve inflammatory markers and lung injury over time. We aim to evaluate the effectiveness of tocilizumab treatment on critically ill patients with severe COVID-19. MATERIALS AND METHODS: We conducted a multi-center retrospective cohort study of 154 adult patients admitted to the ICU for severe COVID-19 pneumonia between March 15 and May 8, 2020. Data were obtained by electronic medical record (EMR) review. The primary outcome of interest was mortality. RESULTS: Of 154 patients, 34 (21.4%) received tocilizumab. Compared to the non-treated group, the treated group was significantly younger, had fewer comorbidities, lower creatinine and procalcitonin levels, and higher alanine aminotransferase levels on admission. The treated group was more likely to receive supportive measures in the context of critical illness. The overall case fatality rate was 71.4%, and it was significantly lower in the treated than the non-treated (52.9 vs. 76.7%, p = 0.007). In multivariable survival analysis, tocilizumab treatment was associated with a 2.1 times lower hazard of mortality when compared to those who were not treated (hazard ratio: 0.47; 95% CI: 0.27, 0.83; p = 0.009). The prevalence of secondary infection was higher in the treated group compared to the non-treated without significant difference (p = 0.17). CONCLUSION: Tocilizumab treatment for critically ill patients with COVID-19 resulted in a lower likelihood of mortality.

Background: Many patients who have been suffering by Covid-19 suffer of long-Covid syndrome, with symptoms of fatigue and muscular weakness that characterize post-acute sequelae SARS-CoV-2 infection (PASC). However, there is limited knowledge about the molecular pathophysiology, and about the serum profile of these patients.Methods: We studied the blood serum profile of 75 selected patients, with previous confirmed Covid-19, 2 months after hospital discharge, who reported new-onset fatigue, muscle weakness and/or dyspnea not present prior to the virus infection and independently from concomitant diseases and/or clinical conditions.Results: All patients had very high serum concentrations of ferritin and D-Dimer. 87 and 72% of patients had clinically significant low levels of hemoglobin and albumin, respectively. Seventy three percentage had elevations in erythrocyte sedimentation rate and CRP. Twenty seven percentage had elevations in LDH.Conclusions: The co-existence of patient symptoms along with blood markers of coagulation, protein disarrangement and inflammation suggests ongoing alterations in the metabolism, promoting an inflammatory/hypercatabolic state which maintains a vicious circles implicated in the persistence of PASC. The persistence of altered D-Dimer levels raises the possibility of long-term risks of thromboembolic disease. All these markers levels should be accurately evaluated in the long-term follow-up, with individualized consideration for prophylactic nutritional, anti-inflammatory and/or anticoagulant therapy if indicated.

This is a retrospective analysis of patients with osteomyelitis who received telavancin at some time during their treatment course. The primary outcome was the percent of patients cured or improved at the end of telavancin therapy (EOTT). The secondary outcome was the percent of patients cured or improved three months after discontinuation of telavancin therapy. There were 32 cases of osteomyelitis with methicillin-resistant Staphylococcus aureus identified in 17 (56.7%), methicillin-sensitive Staphylococcus aureus 2(6.6%), coagulase negative staphylococci 6 (20.0%) and other pathogens, 5 (16.7%). At EOTT, 87.5% of patients had their osteomyelitis cured and 94.6% had the infection cured at three months after telavancin was completed. The most common adverse events associated with telavancin were gastrointestinal in nature (nausea (25.8%), vomiting (9.7%) and diarrhea (3.2%)) followed by metallic taste (6.5%). A favorable outcome was achieved for many patients receiving the antimicrobial regimen that included telavancin for the treatment of osteomyelitis.

In this systematic review article, we aim to summarize the most up-to-date evidence regarding elevations of cardiac troponin, especially in clinical scenarios other than obstructive coronary artery disease. The accurate interpretation of raised cardiac troponin is challenging because it relies on unconfirmed postulations and dogmatic knowledge (e.g., the exclusive provenience of cardiac troponin from cardiac myocytes), based on which every troponin elevation is assumed to definitely indicate myocardial damage. Indeed, the investigation of the pathophysiologic mechanism leading to the release in the bloodstream of cardiac biomarkers should be the first step of the diagnostic process to fully understand the clinical significance of the elevated serum levels and identify the best management. A prominent effort should be put in place to identify the contribution of potential confounding factors, both cardiac and non-cardiac in etiology, with the ability to affect synthesis and clearance of cardiac biomarkers. Regardless of the underlying cause, it is well established that cardiovascular biomarkers are increasingly useful to further risk stratification and prognosticate patients. Accordingly, we sought to clarify the meaning and impact of elevated cardiac troponin in those frequently encountered real-world scenarios presenting clinicians with a diagnostic dilemma, with the final goal of facilitating the diagnosis and help optimize individually tailored treatment strategies.

BACKGROUND Urocortin (Ucn) is a member of the hypothalamic corticotrophin-releasing factor family and has been shown to reduce cell death in the heart caused by ischemia/reperfusion (I/R) injury. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor known to function as a pro-survival and anti-apoptotic factor, whose activation depends on a variety of cytokines, including IL-6. A recent study demonstrated that urocortin induced IL-6 release from cardiomyocytes in a CRF-R2-dependent manner, suggesting a possible link between CRF-R2 stimulation and STAT3 activation. MATERIAL AND METHODS Experimental work was carried out in HL-1 cardiac myocytes exposed to serum starvation for 16-24 h. RESULTS Ucn stimulation led to IL-6 expression and release from mouse atrial HL-1 cardiomyocytes. Ucn treatment led to rapid phosphorylation of JAK2, which was blocked by the protein synthesis inhibitor cycloheximide or the JAK inhibitor AG490. Urocortin treatment induced STAT3 phosphorylation at Y705 and S727 through transactivation of JAK2 in an IL-6-dependent manner, but had no effect on STAT1 activity. Kinase inhibition experiments revealed that urocortin induces STAT3 S727 phosphorylation through ERK1/2 and Y705 phosphorylation through Src tyrosine kinase. In line with this finding, urocortin failed to induce phosphorylation of Y705 residue in SYF cells bearing null mutation of Src, while phosphorylation of S727 residue was unchanged. CONCLUSIONS Here, we have shown that Ucn induces activation of STAT3 through diverging signaling pathways. Full understanding of these signaling pathways will help fully exploit the cardioprotective properties of endogenous and exogenous Ucn.

BACKGROUND Although originally described as a survival mechanism, it is unknown whether and to what extent autophagy is implicated in the terminal stages of heart failure. Here, we studied magnitude and evolution of autophagy in patients with intractable heart failure. MATERIAL AND METHODS Myocardial samples were obtained from 22 patients with ischemic cardiomyopathy and idiopathic dilated cardiomyopathy who were undergoing cardiac transplantation. Hearts from 11 patients who died from non-cardiac causes were used as control samples. Autophagy was evaluated by immunostaining with a monoclonal microtubule associated protein light chain 3 (LC3)-II antibody, while the relationship of autophagy with apoptosis and oncosis was assessed by double staining with TUNEL (terminal deoxynucleotidyl transferase - mediated deoxyuridine triphosphate nick end labeling) assay and complement 9 (C9) immunological staining, respectively. In addition, several necroptotic markers, including RIP1 and RIP3 (receptor interacting protein kinase 1 and 3), anti-C3 (cleaved-caspase-3), and anti-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) were assessed by immunohistochemistry. RESULTS Anti-LC3-II staining was detected in 8.7±1.6% of the heart failure patient heart samples and in 1.2±0.3% of control patient heart samples. Vacuole formation started at one nuclear pole, before becoming bipolar and involving the cytosol. Subsequently, the autophagic process extended also to the nuclei, which underwent a progressive vacuolization and disintegration, assuming a peculiar "strawberry like appearance". Myocytes with extensive vacuole formation exhibited nuclear degeneration, which was associated with TUNEL, C3, C9, RIP1, and RIP3 positive staining. Conversely, myocytes with less extensive vacuole formation showed RIP1 and NF-κB positive staining, though not positivity for other cell death markers. CONCLUSIONS Autophagy was extensively detected in end-stage heart failure and its progression, resulted in secondary cell death, with occurrence of oncosis and necroptosis exceeding that of apoptosis. Conversely, activation of the RIP1/NF-κB pathway was associated with cell survival.

Background: Sex-disaggregated data for coronavirus disease 2019 (COVID-19) reported higher hospitalized fatality rates among men than women. Objective: To determine whether the risk factors for in-hospital mortality from COVID-19, present at the time of hospital admission, differed by patient sex. Design and setting: Single-center, retrospective cohort study at a tertiary-care urban academic center. Methods: We reviewed the electronic medical records of patients positive for COVID-19 via qualitative polymerase chain reaction (PCR) assay, admitted between March 8 and June 14, 2020. Patients were stratified by sex to assess the association of variables present on admission with in-hospital mortality. Results: The overall inpatient case fatality rate (CFR) was 30.4% (172 of 565). The CFR among male patients was higher than among female patients: 99 (33.7%) versus 73 (26.9%), respectively (P = .08). Among males, comorbid conditions associated with in-hospital mortality were chronic pulmonary disease (P = .02) and connective tissue disease (P = .03). Among females, these comorbid conditions were congestive heart failure (P = .03), diabetes with complication (P = .05), and hemiplegia (P = .02). Variables that remained independently associated with death in males included age >70 years, public insurance, incremental increase in quick sepsis-related organ failure assessment (qSOFA) and C-reactive protein (CRP), lymphocytopenia, and thrombocytopenia. Among females, variables that remained independently associated with mortality included public insurance, incremental increase in Charlson weighted index of comorbidity (CWIC) score, qSOFA, and CRP. Conclusions: Risk factors for in-hospital mortality by sex included public insurance type, incremental increase in qSOFA and CRP in both sexes. For male patients, older age, lymphocytopenia and thrombocytopenia were also associated with mortality, whereas a higher Charlson score was associated with in-hospital mortality in female patients.

We conducted a retrospective chart review examining the demographics, clinical history, physical findings, and comorbidities of patients with influenza and patients with coronavirus disease 2019 (COVID-19). Older patients, male patients, patients reporting fever, and patients with higher body mass indexes (BMIs) were more likely to have COVID-19 than influenza.

Introduction 2019 novel coronavirus (COVID‐19) patients frequently develop QT interval prolongation that predisposes them to Torsades de Pointes and sudden cardiac death. Continuous cardiac monitoring has been recommended for any COVID‐19 patient with a Tisdale Score of seven or more. This recommendation, however, has not been validated. Methods We included 178 COVID‐19 patients admitted to a non‐intensive care unit setting of a tertiary academic medical center. A receiver operating characteristics curve was plotted to determine the accuracy of the Tisdale Score to predict QT interval prolongation. Multivariable analysis was performed to identify additional predictors. Results The area under the curve of the Tisdale Score was 0.60 (CI 95%, 0.46–0.75). Using the cutoff of seven to stratify COVID‐19, patients had a sensitivity of 85.7% and a specificity of 7.6%. Risk factors independently associated with QT interval prolongation included a history of end‐stage renal disease (ESRD) (OR, 6.42; CI 95%, 1.28–32.13), QTc ≥450 ms on admission (OR, 5.90; CI 95%, 1.62–21.50), and serum potassium ≤3.5 mmol/L during hospitalization (OR, 4.97; CI 95%, 1.51–16.36). Conclusion The Tisdale Score is not a useful tool to stratify hospitalized non‐critical COVID‐19 patients based on their risks of developing QT interval prolongation. Clinicians should initiate continuous cardiac monitoring for patients who present with a history of ESRD, QTc ≥450 ms on admission or serum potassium ≤3.5 mmol/L.

Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.

Patient: Male, 58-year-old Final Diagnosis: Lymphoma Symptoms: Shortness of breath Medication:— Clinical Procedure: — Specialty: Cardiology • Oncology • Pathology Objective: Unusual clinical course Background: In humans, wood dust is a carcinogen. Indeed, a strong association between wood dust and lung cancer risk has been reported in woodworkers, as well as in the general population. Case Report: The patient was a 58-year-old man with follicular B-cell lymphoma. In the 10 years preceding the cancer diagnosis, he lived within 1/4 mile of a paper mill, where wood was processed. Computed tomography of the chest, abdomen, and pelvis revealed right hilar, mediastinal, abdominal, and retroperitoneal lymphadenopathy, bilateral pleural effusions, and a large soft-tissue mass infiltrating the small bowel mesentery. Analysis of the pleural fluid revealed the presence of a web of thin filopodia-like filaments, which trapped clusters of mesothelial cells and atypical lymphocytes. Single tubular filaments, morphologically similar to tunneling nanotubes, were seen originating from atypical lymphocytes and reaching neighboring cells. Furthermore, long, thick, cylindrical fibers of unknown nature, probably from the external environment, were also observed. Conclusions: Because the patient lived in an unhealthy environment for many years, the possibility that his clinical condition was related to exposure to toxic emissions should be entertained. Considered in this context, the foreign fibers in his pleural fluid could be a direct consequence of inhalation of contaminants in the polluted air.

As members of the American Board of Internal Medicine’s (ABIM) Infectious Disease (ID) Board we’ve heard from many of our colleagues asking for greater flexibility in maintaining their ABIM Board Certification. The ID Board—and ABIM as a whole—has engaged with the physician community over the past several years to gain a deeper understanding of what is most important to them, and how an enhanced Maintenance of Certification (MOC) program could support their commitment to keeping up with advances in medical knowledge. This article serves as an update about how ABIM has evolved its assessments over time and on our progress in developing a new longitudinal pathway that is anticipated to become available in most specialties in 2022, and will launch in ID in 2023.

Background Delafloxacin is a recently approved anionic fluoroquinolone antibiotic with broad-spectrum activity against Gram-positive and Gram-negative organisms. The drug has been approved for patients with acute bacterial skin and skin structure infections including those caused by MRSA. There are limited data available against MRSA blood isolates (MRSABIs), vancomycin-intermediate strains (VISA), vancomycin-resistant strains (VRSA), daptomycin-non-susceptible strains (DNSSA) and linezolid-resistant Staphylococcus aureus (LRSA). Methods Antimicrobial activity of delafloxacin, levofloxacin, vancomycin, daptomycin and linezolid was determined against 110 MRSABIs, 15 VRSA, 35 VISA, 40 DNSSA and 6 LRSA. Microdilution testing using CAMHB was used to determine MIC according to CLSI guidelines. FDA breakpoints were used to determine delafloxacin susceptibility, and CLSI breakpoints were used for all other antibiotics. PCR testing for molecular markers was performed. Results Delafloxacin demonstrated activity against MRSABIs with an MIC90 of 1 mg/L and 68% susceptibility. Against the other groups the MIC90 and susceptibility were 1 mg/L and 40%, respectively, for VISA, 4 mg/L and 7% for VRSA and 1 mg/L and 38% for DNSSA. None of the LRSA isolates was susceptible to delafloxacin. Delafloxacin was active against 94% of MRSA blood isolates that were genotype SCC IVa. For MRSABIs with a levofloxacin MIC ≥8 mg/L (55/110), suggesting multiple mutations in the QRDR, delafloxacin MIC90 was 1 mg/L with a 36.4% susceptibility rate. Conclusions Delafloxacin demonstrates superior activity to levofloxacin against recent MRSA blood isolates, VISA, VRSA and DNSSA, and demonstrates good activity against blood isolates most commonly found in the community.

The development of new synthetic antimicrobial peptides like LTX-109 provides a new class of drugs for the treatment of Staphylococcus aureus infections. We evaluated LTX-109 and mupirocin for pharmacodynamic parameters against 10 methicillin-resistant S. aureus isolates. The postantibiotic effect (PAE) is defined as the length of time that bacterial growth is suppressed following a brief exposure to an antibiotic. We also determined the sub-MIC effect (SME) which measures the direct effect of subinhibitory levels on strains that have not previously been exposed to antibiotics. The postantibiotic sub-MIC effect (PA-SME) is a combination of the PAE and SME. LTX-109 had an average PAE of 5·51 h vs 1·04 h for mupirocin. The PA-SME of LTX-109 ranged from 2·51 to 9·33 h as the concentration increased from 0·2 to 0·4 times the minimal inhibitory concentration (MIC). The PA-SME range for mupirocin was 0·93-2·58 h. LTX-109, as compared to mupirocin, demonstrated prolonged time of effect for these pharmacodynamic parameters, which supports persistent activity for several hours after the drug is no longer present or is below the MIC. The pharmacodynamic parameters studied here suggest that LTX-109 is less likely than mupirocin to generate resistance to S. aureus. Significance and impact of the study Resistant bacterial infections continue to be a challenge for clinicians. Identification of antibiotics with pharmacodynamic advantages may be beneficial in the treatment of these infections. An antibiotic with a longer postantibiotic effect may be able to be administered less frequently resulting in improved adherence. In this study, a new synthetic antimicrobial peptide, LTX-109, demonstrated a more prolonged time for LTX-109 than mupirocin against methicillin-resistant Staphylococcus aureus.

Background Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials. Aim of Study To test the effects of CFZ (10− 9 to 10− 7 mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta. Methods and Results CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10 min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p, Highlights • In the isolated aorta, carfilzomib increased basal tone and vasospastic action of KCl, noradrenaline and angiotensin II. • In the isolated aorta, carfilzomib impaired the anti-spasmogenic activity of nitroglycerin, nifedipine and acetylcholine. • In the isolated heart, carfilzomib increased coronary perfusion pressure, and mildly left ventricular pressure and heart rate. Carfilzomib is a new chemotherapeutic agent used for the treatment of multiple myeloma. Our study shows that carfilzomib increases coronary perfusion pressure, resting vasoconstricting tone, and the spasmogenic effect of noradrenaline and angiotensin II, while it curbs the vasodilatory action of nitroglycerine and nifedipine. Our findings are relevant to human health as they warrant caution in the use of carfilzomib in elderly patients with cardiovascular risk factors and, even more importantly, in those with preexisting heart conditions, who are also eligible to receive carfilzomib, even though they were excluded from the safety trials, based on which carfilzomib use was approved.

We report a rare case of Mycobacterium avium complex cutaneous infection in a non-HIV patient with a report of 13 other cases of M. avium complex cutaneous infection in non-HIV patients found in the literature since 1992.

Background Telavancin—a lipoglycopeptide antibacterial agent active against Gram-positive pathogens including methicillin-sensitive and -resistant Staphylococcus aureus (MRSA)—is approved in the USA for once-daily intravenous use. This registry study captured patient characteristics, prescribing patterns, and treatment outcomes associated with telavancin use in real-world clinical practice. Objective This prospective, multicenter, observational study will characterize current real-world practice patterns for the use of telavancin in the USA by describing demographic and clinical conditions, examining the process of care and rationale for use, and describing the clinical effectiveness and selected safety outcomes among patients treated with telavancin. Methods The Telavancin Observational Use Registry (TOUR™) is an observational multicenter registry study. Clinical data—including patient demographics, pathogens, telavancin dosing and treatment duration, and adverse events—along with investigators’ assessments of outcome, were collected through retrospective medical chart review. Results Data from 1063 patients were collected from 45 US sites. Of these patients, 29.4% were ≥ 65 years of age [mean age ± standard deviation, 55.2 ± 15.4 years; median age (interquartile range), 57.0 (46.0–66.0)], 53.4% were male, and 83.4% were White. The primary infections in these patients included complicated skin and skin-structure infection (48.7%), bone and joint infections (27.4%), bacteremia and endocarditis (14.2%), and lower respiratory tract infections (8.5%). The predominant pathogen identified was MRSA (37.7%). The mean telavancin dose and duration of treatment were 741.7 ± 194.3 mg and 17 ± 17 days, respectively. Of the 964 (90.7%) patients for whom an end-of-treatment assessment was available, 77.7% had a positive clinical response, 10.1% failed treatment, and 12.2% had indeterminate outcomes. Conclusions Real-world data collected from the TOUR study show once-daily telavancin is being used for the treatment of a variety of Gram-positive infections with generally positive clinical outcomes. Electronic supplementary material The online version of this article (10.1007/s40801-019-00165-8) contains supplementary material, which is available to authorized users.

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.

Plazomicin (ACHN-490) is a novel parenteral aminoglycoside developed to target multidrug-resistant Enterobacteriaceae. It has recently been approved by the Food and Drug Administration for the management of complicated urinary tract infections and pyelonephritis caused by susceptible organisms. When compared with meropenem, plazomicin was not inferior. The adverse-event profile for plazomicin was comparable to meropenem except for an increased additional rise in serum creatinine in the plazomicin arm compared with the meropenem arm. This review focuses on the mode of action, antimicrobial activity, pharmacokinetics, clinical indications, and safety profile of this drug. Considerations for formulary addition and its place in therapy are also discussed.

Background Human immunodeficiency virus (HIV) infection is now considered a chronic infection manageable on antiretroviral therapy. If trained in HIV care, primary care physicians would be well suited to work in consultation with infectious disease specialists to provide care for HIV patients. Methods Human immunodeficiency virus training was incorporated into our internal medicine residency program. All residents were given an internally developed preprogram survey about HIV infection to establish a baseline level of HIV knowledge; at the end of 1 year, a postprogram survey was distributed. These results were compared. Human immunodeficiency virus didactic lectures were mandatory for attendance. Human immunodeficiency virus training included methods of testing, treatment including all classes of antiretroviral therapy, and prevention methods. Additional, mandatory online training modules were used. All program year-2 residents were assigned to an outpatient HIV clinical rotation. Results Eighty-three residents participated. Residents received either 1 or 2 years of training. Results of preprogram scores and postprogram scores were calculated for each resident. Year 1-test scores preprogram were 52.2% vs postprogram 87.1%; year 2-test scores preprogram were 56.3% vs postprogram 89.8% (both P < .0001). There was no difference in posttest scores among residents who attended a clinical rotation. Conclusions Residents showed significant improvement in HIV knowledge between preprogram and postprogram test scores. Postgraduate surveys showed among those who completed the survey, and most found the program helpful to in their current practice.

We present a case of a 48 years old male with Gemella morbillorum native mitral valve endocarditis. Due to poor growth of the organism, antimicrobial susceptibility test (AST) could not be performed using the CLSI approved method. AST was determined using Etest© strips and the patient was successfully treated with mitral valve replacement and intravenous ceftriaxone.

We present a case of a 35-year-old male patient with a 12-hour history of sudden-onset, crushing chest pain and associated complaints of profuse diaphoresis, nausea and vomiting. The patient was transferred to our institution from an outside hospital for evaluation and possible emergent catheterization. Left heart catheterization was conclusive for normal coronary arteries and a ventriculogram revealed a left ventricular ejection fraction of approximately 45%. Due to a suspicion of myocarditis based on clinical history, pertinent serology tests were ordered, which were found to be negative. Cardiac magnetic resonance on delayed enhancement imaging showed typical sub-epicardial enhancement in a pattern most consistent with myocarditis. The patient was eventually diagnosed with myocarditis and discharged home later, without needing a myocardial biopsy. We present and discuss here the indications of myocardial biopsy and compare the relative utility of cardiac magnetic resonance imaging in formulating the diagnosis of myocarditis.

Telavancin was evaluated against S. aureus isolates with reduced susceptibility to other antimicrobial agents using two broth microdilution methods and Etest® strips. The three methods provided comparable results. Differences in telavancin susceptibility versus non-susceptibility were noted mainly in the VISA-daptomycin non-susceptible group of isolates. In this group the percent susceptibility was 38% for the Etest® method and 50% and 54% for the 2 broth microdilution methods. All differences in susceptibility were within one 2-fold dilution.

Delafloxacin (ABT 492) is a new fluoroquinolone available in both oral and parenteral formulations. It has recently been approved by the Food and Drug Administration for the management of acute bacterial skin and skin structure infections. When compared to combination therapy of vancomycin and aztreonam, delafloxacin was not inferior and had a favorable adverse event profile. Furthermore, its anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and favorable clinical response in MRSA infections distinguishes it from other fluoroquinolones. This review focuses on the mode of action, antimicrobial activity, pharmacokinetics and pharmacodynamics, clinical indications, and safety profile of this drug. Considerations for formulary addition and its place in therapy are also discussed.

Colonic duplication cysts are a rare congenital abnormality commonly presenting before two years of age. In adults, it has been rarely reported, most often as an incidental finding. We report a case of 42-year-old female complaining of constipation and lower abdominal pain. Patient’s CT scan of the abdomen showed a cystic lesion at hepatic flexure and the diagnosis was confirmed endoscopically using endoscopic ultrasound (EUS). The cyst was treated employing hot snare to expose the cyst cavity. On our literature search, there have been no reported cases of colonic duplication cyst treated endoscopically. We here discuss incidence, diagnosis, characteristics, and treatment of duplication cysts with special emphasis on endoscopic therapy.

Background Delafloxacin is a recently approved anionic fluoroquinolone antibiotic with broad-spectrum activity against Gram-positive and Gram-negative organisms. The drug has been approved for patients with acute bacterial skin and skin structure infections including those caused by methicillin-resistant S. aureus. There is limited data available against methicillin-resistant S. aureus blood isolates (MRSABI), vancomycin intermediate strains (VISA), vancomycin-resistant strains (VRSA), daptomycin non-susceptible strains (DNSSA) and linezolid-resistant S. aureus (LRSA). Methods Antimicrobial activity of delafloxacin, levofloxacin, vancomycin, daptomycin, ceftaroline, and linezolid was determined against recent (2016–2018) MRSABI (110), VRSA (15), VISA (35), DNSSA (40), and LRSA (6). Broth microdilution testing using Mueller–Hinton broth was used to determine minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) according to CLSI guidelines. FDA breakpoints were used to determine delafloxacin susceptibility, and CLSI breakpoints were used for all other antibiotics. Results Antimicrobial MIC90 expressed in mg/L and (% susceptible) None of the LRSA were susceptible to delafloxacin or levofloxacin. All strains that were susceptible to the antimicrobial agents above had an MBC that was the same as the MIC or one dilution greater except for linezolid which demonstrated an MBC that was more than eight-fold greater than the MIC. For MRSABI isolates with a levofloxacin MIC ≥ 8 mg/L (55/110) suggesting multiple mutations in the quinolone-resistant determining region, the delafloxacin MIC90 was 1 mg/L with a 36.4% susceptibility rate. Conclusion Delafloxacin demonstrates superior activity to levofloxacin against recent MRSA blood isolates, VISA, VRSA, and DNSSA. Disclosures All authors: No reported disclosures.

With each successive year, the number of Emergency Department (ED) visits related to illicit drug abuse has progressively increased. Cocaine is the most common illegal drug to cause a visit to the ED. Cocaine use results in a variety of pathophysiological changes with regards to the cardiovascular system, such as constriction of coronary vessels, dysfunction of vascular endothelium, decreased aortic elasticity, hemodynamic disruptions, a hypercoagulable state, and direct toxicity to myocardial and vascular tissue. The clinical course of patients with cocaine-induced chest pain (CCP) is often challenging, and electrocardiographic findings can be potentially misleading in terms of diagnosing a myocardial infarction. In addition, there is no current satisfactory study regarding outcomes of use of various pharmacological drug therapies to manage CCP. At present, calcium-channel blockers and nitroglycerin are two pharmacological agents that are advocated as first-line drugs for CCP management, although the role of labetalol has been controversial and warrants further investigation. We performed an extensive search of available literature through a large number of scholarly articles previously published and listed on Index Medicus. In this review, we put forward a concise summary of the current approach to a patient presenting to the ED with CCP and management of the clinical scenario. The purpose of this review is to summarize the understanding of cocaine's cardiovascular pathophysiology and to examine the current approach for proper evaluation and management of CCP.

The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo , TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF 3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-of-care drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development.

ABSTRACT Deep insight into the complex mechanisms of myocardial ischemia–reperfusion injury has been attained in the past years. Minocycline is a second-generation tetracycline with US FDA approval for clinical use in various infections. Lately, several noninfectious cytoprotective activities of minocycline have been discovered as well. There now exists encouraging evidence of its protective role in cardiovascular pathology and its activity against myocardial ischemia–reperfusion injury. In this article, an overview of the major mechanisms involved in myocardial ischemia–reperfusion injury is presented. This is followed by an analysis of the mechanisms by which minocycline exerts its cytoprotective role and of studies that have been conducted in order to analyze minocycline, along with a review of the scope and limitations of its role as a cytoprotective agent.

We report a retrospective study of 173 patients with vertebral osteomyelitis evaluating the effect of antibiotics administered prior to percutaneous and open biopsy cultures. Antibiotics given prior to these biopsies did not have a significant effect on the yield of cultures.

ObjectivesThe present study investigated the cardioprotective role of urocortin (Ucn) and its relationship with protein kinase C (PKC)ε and PKCδ in patients with (DMPs) and without (NDMPs) diabetes mellitus after on-pump cardiac surgery (OPCS). The molecular mechanisms responsible for the reported worse outcomes of DMP after OPCS remain unknown.MethodsTwo sequential biopsy specimens were obtained from the right atrium of 27 DMPs and 22 NDMPs before and after cardiopulmonary bypass.ResultsPostcardioplegic induction of Ucn in NDMPs (P

The quad pill is the newest single-pill, once-daily option for the treatment of human immunodeficiency virus (HIV) type 1 infection. In addition to tenofovir difumarate (TDF) and emtricitabine (FTC), the quad pill includes cobicistat (COBI; an inactivator of cytochrome P450 isoenzyme CYP3A without anti-HIV activity) and a new integrase inhibitor, elvitegravir (EVG). The quad does not have drug interactions with H2-receptor antagonists or proton pump inhibitors, does not cause central nervous system (CNS) side effects, and is pregnancy category B. It does have substantial drug interactions with medications that are metabolized using CYP3A and causes reversible declines in estimated glomerular filtration rate (eGFR) owing to inhibition of renal tubule transport of creatinine. In clinical trials, the virologic and immunologic efficacy of the quad pill is equivalent to that of other comparator regimens with low rates of discontinuation. The major side effect is nauseam which is self-limited, and the primary mutations associated with treatment failure frequently lead to cross-resistance with raltegravir (RAL).

The CHADS(2) score is widely used to assess the risk of stroke in patients with atrial fibrillation (AF). Patients with score of 0 and 1 are considered 'low risk' and are often treated with aspirin. In a Danish Study, the CHA(2)DS(2)--VASc score was shown to identify low and high-risk subgroups among patients with CHADS(2) score of 0 and 1, with annual risk ranging from 0.84 to 8.18%. This study seeks to assess whether using CHA(2)DS(2)--VASc score will identify high-risk subset of patients with low CHADS(2) scores in an American population. This pilot study examined data from our cardiology fellowship ambulatory clinics from January 2009 to May 2012 using the NCDR-PINNACLE registry. Each cardiology fellow entered patients' data using on-line software developed by the American College of Cardiology. Among 2,048 patients followed at our clinics, 478 had AF. Of those, 161 patients had CHADS(2) score of 0 (44 patients) or 1 (117 patients). Calculating the CHA(2)DS(2)--VASc score in these patients, 12 (7.4%) had score of 0, 50 (31.1%) had score of 1, 66(41%) had score of 2, 31 (19.3%) had score of 3 and 2 (1.2%) had score of 4. Using original CHADS(2) recommendation, warfarin would not be strongly recommended in any of these patients. Utilizing the CHA(2)DS(2)--VASc score, 61.5% of the 161 patients would have a score of 2 or more signifying increased risk where anticoagulation may be indicated. Compared to CHADS(2), CHA(2)DS(2)--VASc may more precisely predict the risk of stroke and anticoagulation strategy in low-risk patients with non-valvular AF.

Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St John's wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (

LTX-109 and eight other antimicrobial agents were evaluated against 155 methicillin-resistant Staphylococcus aureus (MRSA) isolates, including strains resistant to vancomycin and strains with decreased susceptibility to daptomycin and linezolid, by microdilution tests to determine MICs. Time-kill assays were performed against representative MRSA, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA) isolates. LTX-109 demonstrated a MIC range of 2 to 4 μg/ml and dose-dependent rapid bactericidal activity against S. aureus . This activity was not influenced by resistance to other antistaphylococcal agents.

Background and Objectives.Peripheral venous catheters (PVCs) can be associated with serious infectious complications. We evaluated the effect of education and feedback on process measures to improve PVC care and infectious complications.Design.Quasi-experimental controlled crossover study with sampling before and after education.Setting.An 804-bed tertiary care teaching hospital.Participants.Nurses and patients in 10 non-intensive care units.Methods.We implemented a process to improve PVC care in 10 non-intensive care units. The 4 periods (each 3 months in duration) included a preintervention period and a staggered educational intervention among nurses. During intervention period 1, 5 units participated in the intervention (group A), and 5 units served as a control group (group B). Group B underwent the intervention during intervention period 2, and both groups A and B received feedback on performance during intervention period 3. Process measures were evaluated twice monthly, and feedback was given to nurses directly and to the unit manager on a monthly basis.Results.During the preintervention period, there were no significant differences between groups A and B. Of 4,904 intravascular catheters evaluated, 4,434 (90.4%) were peripheral. By the end of the study, there were significant improvements in processes, compared with the preintervention period, including accurate documentation of dressing (from 442 cases [38%] to 718 cases [59%]; PPP P = .016).Conclusions.Education and real-time feedback to nurses increases and sustains compliance with processes to reduce the risk of infection from PVCs.

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.