In vivo efficacy and pharmacokinetics of AC98-6446, a novel cyclic glycopeptide, in experimental infection models

AC98-6446 is a novel semisynthetic derivative of a natural product related to the mannopeptimycins produced by Streptomyces hygroscopicus. Naturally occurring esterified mannopeptimycins exhibited excellent in vitro activity but only moderate in vivo efficacy against staphylococcal infection. The in vivo efficacy and pharmacokinetics of AC98-6446 were investigated in murine acute lethal, bacterial thigh and rat endocarditis infections. Pharmacokinetics were performed in mice, rats, monkeys, and dogs. Acute lethal infections were performed with several gram-positive isolates: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant staphylococci), vancomycin-resistant Enterococcus faecalis, and penicillin-susceptible and -resistant Streptococcus pneumoniae. The 50% effective dose for all isolates tested ranged from 0.05 to 0.39 mg/kg of body weight after intravenous (i.v.) administration. Vancomycin was more than fivefold less efficacious against all of these same infections. Results of the thigh infection with S. aureus showed a static dose for AC98-6446 of 0.4 mg/kg by i.v. administration. Reduction of counts in the thigh of >2 log(10) CFU were achieved with doses of 1 mg/kg. i.v. administration of 3 mg/kg twice a day for 3 days resulted in a >3 log(10) reduction in bacterial counts of vancomycin-susceptible and -resistant E. faecalis in a rat endocarditis model. Pharmacokinetics of AC98-6446 showed an increase in exposure (area under the concentration-time curve) from mouse to dog species. The i.v. half-life (t(1/2)) increased threefold between rodents and the higher species dosed. Efficacy of AC98-6446 has been demonstrated in several models of infection with resistant gram-positive pathogens. This glycopeptide exhibited bactericidal activity in these models, resulting in efficacy at low doses with reduction in bacterial load.     

Influenza virus RNA recovered from droplets and droplet nuclei emitted by adults in an acute care setting

Transmission in hospital settings of seasonal influenza viruses and novel agents such as the Middle East respiratory syndrome coronavirus (MERS-CoV) is well-described but poorly understood. The characterization of potentially infectious bio-aerosols in the healthcare setting remains an important yet ill-defined factor in the transmission of respiratory viruses. Empiric data describing the distribution of bio-aerosols enable discernment of potential exposure risk to respiratory viruses. We sought to determine the distribution of influenza virus RNA emitted into the air by participants with laboratory-confirmed influenza, and whether these emissions had the potential to reach healthcare workers’ breathing zones. Two-stage cyclone bio-aerosol samplers from the Centers for Disease Control and Prevention – National Institute for Occupational Safety and Health were placed 0.5–1.0 m (near field) and 2.1–2.5 m (far field) from infected patient participants, as well as in the corridor immediately outside their rooms. In addition, healthcare worker participants providing care to infected participants were recruited to wear a polytetrafluoroethylene (PTFE) filter cassette in their breathing zones. Viral RNA was detected from the air emitted by 37.5% of the 16 participants infected with influenza virus and distributed both in near and far fields and in all tested particle sizes (<1 µm, 1–4 µm, and >4 µm). Viral RNA was recovered in droplet nuclei and beyond 1 m from naturally-infected participants in the healthcare setting and from the breathing zone of one healthcare worker. There was no correlation between patient participant nasal viral load and recovery of viral RNA from the air, and we did not identify any significant association between RNA detection from the air and patient demographics or clinical presentation. A more substantial study is required to identify patient determinants of virus emission into the air and delineate implications for evidence-based policy for prevention and control.     

The significance of protective factors in the assessment of risk

Background Few studies have explored protective factors in the assessment of risk, despite acknowledgement that protective factors may play an important role. Aim To examine the significance of protective factors in assessment of risk using the Structured Assessment of Violence Risk in Youth (SAVRY). Method The SAVRY was completed on 135 male adolescents in custody in the UK. Data on previous offending and childhood psychopathology were collected. Participants were prospectively followed up at 12 months using data from the Home Office Police National Computer (HOPNC). Results Participants with protective factors were older when first arrested, were less prolific offenders and had fewer psychopathological problems. The number of protective factors present was significantly higher for participants who did not re‐offend during the follow‐up. The total number of SAVRY protective factors significantly predicted desistance at follow‐up and resilient personality traits constituted the only significant individual protective factor. Conclusions and implications Protective factors might buffer the effects of risk factors and a resilient personality may be crucial. Recognition of protective factors should be an essential part of the risk management process and for interventions with high‐risk adolescents to reduce re‐offending. Copyright © 2010 John Wiley & Sons, Ltd.     

Transition Phase Nutrition Recommendations: A Missing Link in the Nutrition Management of Preterm Infants

Background: Despite the availability of international nutrition recommendations, preterm infants remain vulnerable to suboptimal nutrition. The standard approach of assessing nutrient intakes chronologically may make it difficult to identify the origin of nutrient deficits and/or excesses. Objective: To develop a “nutrition phase” approach to evaluating nutrition support, enabling analysis of nutrient intakes during the period of weaning from parenteral nutrition (PN) to enteral nutrition (EN), called the transition (TN) phase, and compare the data with those analyzed using the standard “chronological age” approach to assess whether the identification of nutrient deficits and/or excesses can be improved. Methods: Analysis of a comprehensive nutrition database developed using actual nutrient intake data collected on an hourly basis in 59 preterm infants (birth weight ≤1500 g, gestation <34 weeks) over the period of PN delivery (range, 2–21 days). Results: The nutrition phase analysis approach revealed substantial macronutrient and energy deficits during the TN phase. In particular, deficits were identified as maximal during the EN‐dominant TN phase (enteral feeds ≥80 mL/kg/d) of the infant’s nutrition course. In contrast, the chronological age analysis approach did not reveal a corresponding pattern of deficit occurrence but rather intakes that approximated or exceeded recommendations. Conclusion: Actual intakes of nutrients, analyzed using a nutrition phase approach to evaluating nutrition support, enabled a more infant‐driven rather than age‐driven application of nutrition recommendations. This approach unmasked nutrient deficits occurring during the transition phase. Overcoming nutrient deficits in this nutrition phase should be prioritized to improve the nutrition management of preterm infants.     

Relationships between acceptance of sour taste and fruit intakes in 18-month-old infants

The present study examined whether infants show an acceptance for extreme sour tastes and whether acceptance of sour taste is related to infants' fruit intake. Fruit intake of fifty-three infants at 6, 12 and 18 months was assessed using 3 d food records. Sour acceptance of these infants was studied at 18.1 (SD 1.5) months. Acceptance for four solutions differing in citric acid concentrations (0.00 M, 0.013 M, 0.029 M and 0.065 M) was measured by allowing infants ad libitum ingestion of each solution over brief time periods. The base solution to which citric acid was added was blackcurrant squash diluted in water. Infants' relative intake of each solution was used as a measure of sour acceptance. At 18 months, twelve infants readily accepted the two highest citric acid concentrations, whereas the remaining infants rejected these. Infants who accepted the most sour solutions had a significantly higher fruit intake (P = 0.025) and a higher fruit variety (P = 0.015) at 18 months than the infants who rejected the highly sour taste. Furthermore, infants who accepted the most sour solutions consumed fruits more frequently at 18 months (chi2 5.1; P = 0.024). Infants who accepted the sourest solutions also had a higher fruit intake at 6 months, and a significantly higher increase in their fruit intake from 12 to 18 months. This is the first scientific study that demonstrates the acceptance of sour tastes in some infants at the age of 18 months. Furthermore, the present results suggest a relationship between acceptance of sour tastes and infants' fruit intakes.     

Urban overdose hotspots: a 12-month prospective study in Dublin ambulance services

Background

Opioid overdose (OD) is the primary cause of death among drug users globally. Personal and social determinants of overdose have been studied before, but the environmental factors lacked research attention. Area deprivation or presence of addiction clinics may contribute to overdose.

Objectives

The objective of the study is to examine the baseline incidence of all new ODs in an ambulance service and their relationship with urban deprivation and presence of addiction services.

Methods

A prospective chart review of prehospital advanced life support patients was performed on confirmed OD calls. Demographic, geographic, and clinical information, that is, presentation, treatment, and outcomes, was collected for each call. The census data were used to calculate deprivation. Geographical information software mapped the urban deprivation and addiction services against the overdose locations.

Results

There were 469 overdoses, 13 of which were fatal; most were male (80%), of a young age (32 years), with a high rate of repeated overdoses (26%) and common polydrug use (9.6%). Most occurred in daytime (275) and on the streets (212). Overdoses were more likely in more affluent areas (r = .15; P < .05) and in a 1000-m radius of addiction services. Residential overdoses were in more deprived areas than street overdoses (mean difference, 7.8; t₁₇₀ = 3.99; P < .001). Street overdoses were more common in the city center than suburbs (χ²(1) = 33.04; P < .001).

Conclusions

The identified clusters of increased incidence—urban overdose hotspots—suggest a link between environment characteristics and overdoses. This highlights a need to establish overdose education and naloxone distribution in the overdose hotspots.     

Low dose supplementation with two different marine oils does not reduce pro-inflammatory eicosanoids and cytokines in vivo

In view of the reported potential anti-inflammatory activity of the New Zealand green lipped mussel (NZGLM), we aimed to compare the effect of low dose marine oil supplementation, from mussels and fish, in reducing blood markers of inflammation. Thirty apparently healthy males and females were recruited from the general public in Melbourne, Australia to participate in a double blind, randomised, parallel intervention study. Subjects were consuming approximately 73 mg of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) daily in their background diet prior to the commencement of the intervention. Subjects were randomly assigned to consume either 2 mL/day of the NZGLM oil preparation (mixed with olive oil and dl-alpha-tocopherol) or fish oil preparation (also mixed with olive oil and dl-alpha-tocopherol) for six weeks. Two mL of the oils contained 241 mg and 181 mg of n-3 LCPUFA, respectively. Neutrophil phospholipid fatty acids, serum thromboxane B2 (TXB2), stimulated monocyte production of prostaglandin E2 (PGE2), interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNFalpha) were measured. During the intervention, the total intakes of n-3 LCPUFA from the background diet and the supplements were 199 mg/d and 173 mg/day for the NZGLM and FO groups, respectively. Following six weeks of supplementation, both groups showed a small, but significant increase in neutrophil phospholipid proportion of eicosapentaenoic acid. The NZGLM group also showed a significant increase in docosahexaenoic acid levels. There were no significant changes with time or treatment for TXB2, PGE2, IL-1 beta or TNFalpha. This study showed that low dose supplementation with n-3 LCPUFA from two different marine oil preparations showed no difference in inflammatory markers in this group of healthy individuals. Further studies are warranted including dose response trials and studies in populations with inflammatory conditions.