A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus.

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

In-depth analysis of T2Bacteria positive results in patients with concurrent negative blood culture: a case series.

BACKGROUND: T2Bacteria assay uses T2 magnetic resonance (T2MR) technology for the rapid diagnosis of bacterial bloodstream infections (BSIs). This FDA cleared technology can detect 5 of the most prevalent pathogens causing bacteremia (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecium). Because the significance of discordant results between the T2Bacteria assay and blood culture (BC) remains a challenge, in this case series we reviewed the medical records of patients who had a positive T2Bacteria test and a concurrent negative BC. METHODS: Among 233 participants, we identified 20 patients with 21 (9%) discordant T2Bacteria-positive/BC-negative (T2+/BC-) results. We classified these results based on clinical cultures and clinical evidence. RESULTS: When we analyzed these 21 discordant results in-depth, 11 (52.5%) fulfilled criteria for probable BSI, 4 (19%) for possible BSI, and 6 (28.5%) were presumptive false positives. Among the probable/possible BSIs, discordant results were often associated with patients diagnosed with closed space and localized infections [pyelonephritis (n = 7), abscess (n = 4), pneumonia (n = 1), infected hematoma (n = 1), and osteomyelitis (n = 1)]. Also, within the preceding 2 days of the T2+/BC- blood sample, 80% (16/20) of the patients had received at least one dose of an antimicrobial agent which was active against the T2Bacteria-detected pathogen. CONCLUSIONS: In the majority of discrepant results, the T2Bacteria assay detected a plausible pathogen that was supported by clinical and/or microbiologic data. Discrepancies appear to be associated with closed space and localized infections and the recent use of effective antibacterial agents. The clinical significance and potential implications of such discordant results should be further investigated.

Insight into different phenotypic presentations of heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for half of all HF diagnoses, and its prevalence is increasing at an alarming rate. Lately, it has been recognized as a clinical syndrome due to diverse underlying etiology and pathophysiological mechanisms. The classic echocardiographic features of HFpEF have been well described as preserved ejection fraction (≥50%), left ventricular hypertrophy, and left atrial enlargement. However, echocardiography can play a key role in identifying the principal underlying mechanism responsible for HFpEF in the individual patient. The recognition of different phenotypic presentations of HFpEF (infiltrative, metabolic, genetic, and inflammatory) can assist the clinician in tailoring the appropriate management, and offer prognostic information. The goal of this review is to highlight several key phenotypes of HFpEF and illustrate the classic clinical scenario and echocardiographic features of each phenotype with real patient cases.

Association between dementia and psychiatric disorders in long-term care residents: An observational clinical study.

We examine the relationship between dementia and psychiatric disorder diagnoses among long-term care residents in nursing homes across the state of Rhode Island (RI), USA.Observational clinical study.Two hundred fifty-five residents with and without the diagnosis of dementia were included in this study.Prevalence analysis was used to elucidate information on psychiatric disorders in the overall cohort, and among residents with dementia. Questions from the quality of life questionnaire (EQ-5D-3L) that provides information on self-care, anxiety/depression, and resident's view of how healthy they are, were used to evaluate their association with dementia and psychiatric disorders. A logistic regression analysis was conducted to understand the relationship between dementia and mental illness diagnoses in long-term care facilities. Finally, a subgroup logistic regression analysis was performed for residents with Alzheimer disease.65.1% of all residents suffered from at least 1 psychiatric disorder. Anxiety was the most common diagnosis (36.5%), followed by depression (28.6%), and insomnia (14.9%). There was a positive and statistically significant association between any mental illness diagnosis and dementia (adjusted OR: 3.73; 95% CI: 1.34-10.41). Bipolar disorder and insomnia were negatively and statistically significantly associated with dementia (adjusted OR: 0.17; 95% CI: 0.03-0.89 AND adjusted OR: 0.39; 95% CI: 0.16-0.96 respectively). Age and COPD were also statistically associated with dementia (adjusted OR: 1.07; 95% CI: 1.03-1.11 AND adjusted OR: 0.28, 95% CI: 0.12-0.66). Alzheimer disease was positively and significantly associated with the diagnosis of any mental illness (adjusted OR: 3.77; 95% CI: 1.17-12.20).We studied the relationship between dementia and diagnoses of psychiatric disorders present in long-term care residents. We found that residents with a diagnosis of dementia were more likely to suffer from at least 1 psychiatric disorder. Further work is needed to establish the neuropathophysiological relationship between psychiatric disorders and dementia.

The process of obtaining informed consent to research in long term care facilities (LTCFs): An Observational Clinical Study.

We examined the process of obtaining informed consent (IC) for clinical research purposes in long-term care facilities (LTCFs) in Rhode Island (RI), USA. We assessed factors that were associated with resident ability to consent, such as Brief Interview for Mental Status scores. We used a self-administered questionnaire to further understand the effect of LTCF staff evaluation of ability to consent on residents' autonomy and control over their medical decision making.Observational clinical studyLong-term care setting.LTCF personnel provided us with residents' names, as well as their professional assessment of resident ability to consent. We used Brief Interview for Mental Status (BIMS) scores to assess the cognitive capacity of all residents to assess, and compare it to the assessment provided by LTCF personnel. A logistic regression analysis was performed to determine the relationship between LTCF assessment of resident ability to consent and BIMS score or confirmed diagnosis of dementia as seen from residents' medical charts. A self-administered questionnaire was filled out by the personnel of 10 LTCFs across RI, USA.LTCF personnel in 9 out of 10 recruited facilities reported that their assessment of resident ability to consent was based on subjective assessment of the resident as alert and oriented. There was a statistically significant relationship between the LTCF assessment of resident ability to consent and previously diagnosed dementia (OR: 0.211, 95% CI 0.107-0.415). Therefore, as BIMS scores increased, the likelihood that the resident would be deemed able to consent by LTCF personnel also increased. Furthermore, there was a statistically significant relationship between LTCF assessment of resident ability to consent and BIMS scores (OR: 1.430, 95% CI 1.274-1.605).There is no standard on obtaining IC for research studies conducted in LTCFs. We recommend that standardizing the process of obtaining IC in LTCFs can enhance the ability to perform research with LTCF residents.

The cost-effectiveness of empirical antibiotic treatments for high-risk febrile neutropenic patients: A decision analytic model.

PURPOSE: Febrile neutropenia has a significant clinical and economic impact on cancer patients. This study evaluates the cost-effectiveness of different current empiric antibiotic treatments. METHODS: A decision analytic model was constructed to compare the use of cefepime, meropenem, imipenem/cilastatin, and piperacillin/tazobactam for treatment of high-risk patients. The analysis was performed from the perspective of U.S.-based hospitals. The time horizon was defined to be a single febrile neutropenia episode. Cost-effectiveness was determined by calculating costs and deaths averted. Cost-effectiveness acceptability curves for various willingness-to-pay thresholds (WTP), were used to address the uncertainty in cost-effectiveness. RESULTS: The base-case analysis results showed that treatments were equally effective but differed mainly in their cost. In increasing order: treatment with imipenem/cilastatin cost $52,647, cefepime $57,270, piperacillin/tazobactam $57,277, and meropenem $63,778. In the probabilistic analysis, mean costs were $52,554 (CI: $52,242-$52,866) for imipenem/cilastatin, $57,272 (CI: $56,951-$57,593) for cefepime, $57,294 (CI: $56,978-$57,611) for piperacillin/tazobactam, and $63,690 (CI: $63,370-$64,009) for meropenem. Furthermore, with a WTP set at $0 to $50,000, imipenem/cilastatin was cost-effective in 66.2% to 66.3% of simulations compared to all other high-risk options. DISCUSSION: Imipenem/cilastatin is a cost-effective strategy and results in considerable health care cost-savings at various WTP thresholds. Cost-effectiveness analyses can be used to differentiate the treatments of febrile neutropenia in high-risk patients.

Strategies against methicillin-resistant Staphylococcus aureus persisters.

Chronic Staphylococcus aureus infections are complicated by frequent relapses not only from the development of drug resistance to conventional antibiotics, but also through the formation of persister bacterial cells. Bacterial persisters are in a transient, metabolically inactive state, making conventional antibiotics that target essential cellular growth processes ineffective, resulting in high clinical failure rates of antibiotic chemotherapy. The development of new antibiotics against persistent S. aureus is an urgent issue. Over the last decade, new strategies to identify S. aureus persister-active compounds have been proposed. This review summarizes the proposed targets, antipersister compounds and innovative methods that may augment conventional antibiotics against S. aureus persisters. The reviewed antipersister strategies can be summarized as two broad categories; directly targeting growth-independent targets and potentiating existing, ineffective antibiotics by aiding uptake or accessibility.

Colonization With Vancomycin-Resistant Enterococci and Risk for Bloodstream Infection Among Patients With Malignancy: A Systematic Review and Meta-Analysis.

BACKGROUND: Vancomycin-resistant enterococci (VRE) cause severe infections among patients with malignancy, and these infections are usually preceded by gastrointestinal colonization. METHODS: We searched the PubMed and EMBASE databases (up to May 26, 2016) to identify studies that reported data on VRE gastrointestinal colonization among patients with solid or hematologic malignancy. RESULTS: Thirty-four studies, reporting data on 8391 patients with malignancy, were included in our analysis. The pooled prevalence of VRE colonization in this population was 20% (95% confidence interval [CI], 14%-26%). Among patients with hematologic malignancy, 24% (95% CI, 16%-34%) were colonized with VRE, whereas no studies reported data solely on patients with solid malignancy. Patients with acute leukemia were at higher risk for VRE colonization (risk ratio [RR] = 1.95; 95% CI, 1.17-3.26). Vancomycin use or hospitalization within 3 months were associated with increased colonization risk (RR = 1.92, 95% CI = 1.06-3.45 and RR = 4.68, 95% CI = 1.66-13.21, respectively). Among the different geographic regions, VRE colonization rate was 21% in North America (95% CI, 13%-31%), 20% in Europe (95% CI, 9%-34%), 23% in Asia (95% CI, 13%-38%), and 4% in Oceania (95% CI, 2%-6%). More importantly, colonized patients were 24.15 (95% CI, 10.27-56.79) times more likely to develop a bloodstream infection due to VRE than noncolonized patients. CONCLUSIONS: A substantial VRE colonization burden exists among patients with malignancy, and colonization greatly increases the risk for subsequent VRE bloodstream infection. Adherence to antimicrobial stewardship is needed, and a re-evaluation of the use of vancomycin as empiric therapy in this patient population may be warranted.