Effect of Different Media on the Bactericidal Activity of Colistin and on the Synergistic Combination With Azidothymidine Against mcr-1-Positive Colistin-Resistant Escherichia coli

Antimicrobial susceptibility testing (AST) performed according to defined guidelines is important to identify resistance and to predict the clinical success or failure of specific antibiotic therapy. However, these guidelines do not cover all physiological conditions that can have a tremendous impact on in vivo resistance. In this study, we tested the susceptibility of thirteen mcr-1-positive Escherichia coli strains against colistin, one of the last resort antibiotics for treating multi-drug resistant pathogens, in media recommended for ASTs as well as – physiologically more relevant – in human serum and artificial urine (AU). Minimal inhibitory concentration (MIC) values in heat-inactivated human serum were similar to those in cation-adjusted Mueller-Hinton broth (CAMHB), but reduced in native serum for almost all strains that could grow in this media. In AU MIC values for mcr-1 positive E. coli were increased significantly up to 16-fold compared to that in CAMBH, which did not apply to the colistin-susceptible E. coli strains tested. Although different growth media could affect the MIC of colistin alone, their impact on the synergistic effect of the combination with the antiviral drug azidothymidine was minimal. The higher divalent cation concentration combined with acidic pH values is most likely responsible for the increased MIC values of the mcr-1 harboring E. coli strains tested against colistin in AU compared to that in CAMHB. Antimicrobial susceptibility screening procedures for colistin using CAMHB only could lead to an underestimation of resistance under different physiological conditions. Therefore, not only pharmacokinetic but also pharmacodynamic studies in urine are as important as in serum or plasma

Pattern of Presentation of Coronary Artery Disease in Hypertensive Patients

Background: Hypertension is a major risk factor for coronary artery disease (CAD) and left ventricular hypertrophy (LVH). Hypertensives have a threefold increase in cardiac death (due to either CAD or to cardiac failure).In Sudan hypertension complications were increasing in incidence and prevalence. Evaluating chest pain in hypertensive patients presents challenges because of left ventricular hypertrophy as a cause of chest pain besides CAD. There are limited data on different aspects of hypertensioncomplications.Objectives: To assess the CAD as a cause of chest pain, to see the pattern and severity of CAD and to find the correlation between ECG, ECHO and coronary angiography findings in hypertensive patientsMethodology: 135 known hypertensive patients presented with chest pain were assessed through ECG, ECHO and coronary angiography.Results: The participants’ ages ranged between 39 and 90 years, with mean age of 59 years .73.3% of them were found to have CAD. The left anterior descending (LAD) artery was the most involved one. Left main (LM) artery was the least involved. Electrocardiography (ECG) showed that LVH is found in more than 50%of patients with CAD. BMI was >25 in 41.5%. Percutaneous coronary intervention (PCI) was recommended in (31.4%), coronary artery bypass graft (CABG) in(21.6%). 33% and 25% of these consecutively have hypertension for 10 years or more.Conclusion: CAD is the main cause of chest pain in hypertensives. Aging, body mass index, duration and magnitude of hypertension and LVH have strong and frequent association with CAD

Influence of infection on the distribution patterns of NIH-Chronic Prostatitis Symptom Index scores in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex condition for which the etiological determinants are still poorly defined. To better characterize the diagnostic and therapeutic profile of patients, an algorithm known as UPOINT was created, addressing six major phenotypic domains of CP/CPPS, specifically the urinary (U), psycho-social (P), organ-specific (O), infection (I), neurological/systemic (N) and muscular tenderness (T) domains. An additional sexual dysfunction domain may be included in the UPOINT(S) system. The impact of the infection domain on the severity of CP/CPPS symptoms is a controversial issue, due to the contradictory results of different trials. The aim of the present retrospective study was to further analyze the extent to which a positive infection domain of UPOINTS may modify the pattern of CP/CPPS symptom scores, assessed with the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI). In a cohort of 935 patients that was divided on the basis of the presence or absence of prostatic infection, more severe clinical symptoms were shown by the patients with infection (median NIH total score: 24 versus 20 points in uninfected patients; P<0.001). Moreover, NIH-CPSI score distribution curves were shifted towards more severe symptoms in patients with a positive infection domain. Division of the patients into the six most prominent phenotypic clusters of UPOINTS revealed that the 'prostate infection-related sexual dysfunction' cluster, including the highest proportion of patients with evidence of infection (80%), scored the highest number of NIH-CPSI points among all the clusters. To assess the influence of the infection domain on the severity of patients' symptoms, all subjects with evidence of infection were withdrawn from the 'prostate infection-related sexual dysfunction' cluster. This modified cluster showed symptom scores significantly less severe than the original cluster, and the CPSI values became comparable to the scores of the five other clusters, which were virtually devoid of patients with evidence of infection. These results suggest that the presence of pathogens in the prostate gland may significantly affect the clinical presentation of patients affected by CP/CPPS, and that the infection domain may be a determinant of the severity of CP/CPPS symptoms in clusters of patients phenotyped with the UPOINTS system. This evidence may convey considerable therapeutic implications

Serum bactericidal activity of colistin and azidothymidine combinations against mcr-1 positive colistin-resistant Escherichia coli.

To examine the serum bactericidal activity of colistin-sulphate (CS) and azidothymidine (AZT) combinations, time-kill curves were performed in native and heat-inactivated human serum with five colistin-resistant and four colistin-susceptible Gram-negative strains. The serum samples were spiked according to the median and minimum plasma peak concentrations measured in a phase 1 clinical study, in which seven healthy subjects received 3-times (q12) 1h-IV-infusions of 4, 2 and 2 million international units (MIU) colistin-methanesulfonate (CMS) co-administered with 200, 100 and 100 mg AZT, respectively. This trial was performed to assess the pharmacokinetics and safety of CMS/AZT-combination therapy. Minimal bactericidal concentrations of CS in native, but not heat-inactivated serum, were strongly reduced compared to Mueller-Hinton-Broth for all tested Enterobacteriaceae, except one colistin-resistant (serum-resistant) strain. For colistin-susceptible strains, the minimum CS concentration after 2 MIU CMS dosage was already bactericidal in native and heat-inactivated serum. Median, but not minimum, CS concentrations after 2 MIU CMS dosage were sufficient to kill the serum-resistant, colistin-resistant E.coli strain in native serum. In heat-inactivated serum, even the median CS concentration after 2 MIU CMS dosage was not bactericidal for all colistin-resistant strains. In general, combinations with AZT accelerated killing of colistin-resistant E.coli or showed bactericidal activity even if the substances alone were not bactericidal. Thus, the combination with AZT potentiates the bactericidal effect of colistin against colistin-resistant E.coli strains. Although the dosage of 2 MIU CMS plus AZT may be sufficient to treat infections with colistin-susceptible strains, for infections caused by colistin-resistant E.coli the dosing should be further optimized

The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma.

BackgroundAlkaptonuria (AKU) is a disorder of tyrosine/protein metabolism leading to accumulation of homogentisic acid. Clinical management historically recommended reducing dietary protein intake, especially in childhood, which has since been discredited in the literature. For the first time, analysis of baseline cross-sectional nutritional surveillance data from a large cohort of AKU patients is presented, which has clinical implications in all aspects of treatment planning.MethodSeventy-four patients (mean 55 years) admitted to the National Alkaptonuria Centre (NAC), underwent a global nutritional assessment, which included objective anthropometry, bioimpedance measures, habitual nutritional intake using a 7-day food diary and key nutritional biomarkers, including 24 hours urinary nitrogen, serum albumin, total protein and total 25-hydroxy vitamin D. All data was compared with cohort norms or recommended nutrient intakes for health (RNI). The potential beneficial impact of protein and anti-inflammatory nutrients such as vitamin C, selenium, and zinc were statistically interrogated against the AKU severity score index (AKUSSI)-a validated measure of disease progression stratified by age.ResultsFifty percent of AKU patients reported some level of protein restriction at some point in their lives. In comparison with national data sets, AKU patients present with significantly lower than predicted mid-upper arm circumference, grip strength, BMI, total energy and protein intake, and higher than predicted percentage body fat. They therefore meet the ESPEN criteria as "clinically undernourished." Severity fluctuates over the life course. No statistical association is identified between protein intake, expressed as %RNI or g/kg, or anti-inflammatory nutrients, including vitamin C as a high dose supplement on the severity of the disease, when correlated against the validated AKUSSI score.ConclusionAKU patients are at risk of protein depletion associated with a "perfect storm" of risk factors: historical, poorly evidenced recommendations to reduce total protein intake; limited mobility as the condition progresses, compromising muscle integrity; frequent hospital admissions for major surgery associated with multiple joint replacements, creating pinch points of high metabolic demand and the potential impact of the disease itself. As this is the first time this risk has been identified, the authors consider the dietetic implications of nitisinone treatment, which requires dietary protein control to manage the acquired tyrosinaemia. The lack of statistically significant evidence to support dietary manipulation of any kind to impede disease progression in AKU is demonstrated

Vitamin D Status and Longitudinal Changes in Body Composition in Patients with Chronic Obstructive Pulmonary Disease &ndash; A Prospective Observational Study

Maria Minter,1,2 Jenny van Odijk,1 Hanna Augustin,1 Felipe VC Machado,3,4 Frits ME Franssen,5,6 Martijn A Spruit,5,6 Lowie EGW Vanfleteren1,5 1Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 405 30, Sweden; 2Department of Lung Medicine, Angered Hospital, SV Hospital Group, Angered, 424 22, Sweden; 3Rehabilitation Research Center (REVAL), Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium; 4Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; 5Department of Research and Development, Ciro, Horn, the Netherlands; Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands; 6Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine, and Life Sciences, Maastricht University Medical Centre+, Maastricht, the NetherlandsCorrespondence: Maria Minter, Department of Lung Medicine, Angered Hospital, SV Hospital Group, Angered, 424 22, Sweden, Email [email protected]: Alterations in body weight and composition are common in patients with chronic obstructive pulmonary disease (COPD) and are independent predictors for morbidity and mortality. Low vitamin D status is also more prevalent in patients with COPD compared to controls and has been related to lower lung function, muscle atrophy and impaired musculoskeletal function. This study aimed to evaluate the association between vitamin D levels and status with body composition (BC), as well as with its changes over time.Patients and Methods: Patients with COPD and controls without COPD, participating in the Individualized COPD Evaluation in relation to Ageing (ICE‐Age) study, a prospective observational study, were included. Plasma 25-hydroxyvitamin D (25(OH)D) was measured at baseline and BC was measured by dual‐energy X‐ray absorptiometry scan, at baseline and after two years of follow-up. Multiple linear regression analyses were performed to assess the relationships between 25(OH)D (nmol/l) and longitudinal changes in BMI, fat-free mass index (FFMI), fat mas index (FMI) and bone mineral density (BMD).Results: A total of 192 patients with COPD (57% males, mean ± SD age, 62 ± 7, FEV1, 49 ± 16% predicted) and 199 controls (45% males, mean ± SD age 61 ± 7) were included in this study. Vitamin D levels were significantly lower in patients with COPD (64 ± 26 nmol/L, 95% CI 60– 68 nmol/L versus 75 ± 25 nmol/L, 95% CI 72– 79 nmol/L) compared to controls. Both patients and controls presented a significant decline in FFMI and T-score hip, but vitamin D level or status did not determine differences in BC or changes in BC over time in either COPD or controls.Conclusion: Vitamin D status was not associated with BC or longitudinal changes in BC. However, vitamin D insufficiency and low BMD were more prevalent in patients with COPD compared to controls.Keywords: chronic obstructive pulmonary disease, body composition, vitamin D, longitudinal changes, fat-free mass, bone mineral densit