An evaluation of the epidemiology of medication discrepancies and clinical significance of medicines reconciliation in children admitted to hospital

Aims: To determine the incidence of unintended medication discrepancies in paediatric patients at the time of hospital admission; evaluate the process of medicines reconciliation; assess the benefit of medicines reconciliation in preventing clinical harm. Method: A 5 month prospective multisite study. Pharmacists at four English hospitals conducted admission medicines reconciliation in children using a standardised data collection form. A discrepancy was defined as a difference between the patient's preadmission medication (PAM), compared with the initial admission medication orders written by the hospital doctor. The discrepancies were classified into intentional and unintentional discrepancies. The unintentional discrepancies were assessed for potential clinical harm by a team of healthcare professionals, which included doctors, pharmacists and nurses. Results: Medicines reconciliation was conducted in 244 children admitted to hospital. 45% (109/244) of the children had at least one unintentional medication discrepancy between the PAM and admission medication order. The overall results indicated that 32% (78/244) of patients had at least one clinically significant unintentional medication discrepancy with potential to cause moderate 20% (50/244) or severe 11% (28/244) harm. No single source of information provided all the relevant details of a patient's medication history. Parents/carers provided the most accurate details of a patient's medication history in 81% of cases. Conclusions: This study demonstrates that in the absence of medicines reconciliation, children admitted to hospitals across England are at risk of harm from unintended medication discrepancies at the transition of care from the community to hospital. No single source of information provided a reliable medication history.

Lipoplexes formulation and optimisation:in vitro transfection studies reveal no correlation with in vivo vaccination studies

The aim of these studies was to compare the effect of liposome composition on physico-chemical characteristics and transfection efficacy of cationic liposomes both in vitro and in vivo. Comparison between 4 popularly used cationic lipids, showed 3b-N-(dimethylaminoethyl)carbamate (DC-Chol) to promote the highest transfect levels in cells in vitro with levels being at least 6 times higher than those of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA). 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and dimethyldioctadecylammonium (DDA) and approximately twice as efficient as dipalmitoyl-trimethylammonium-propane (DPTAP). To establish the role of the helper lipid, DC-Chol liposomes were formulated in combination with either 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) or cholesterol (Chol) (1:1 molar ratio) with and without the addition of phosphatidyl choline. The choice of helper lipid incorporated within the bilayer was found to influence the formation of complexes, their resultant structure and their transfection efficiency in vitro, with SUV-DNA complexes containing optimum levels of DOPE giving higher transfection than those containing cholesterol. The inclusion of PC within the formulation also reduced transfection efficiency in vitro. However, when administered in vivo, SUV-DNA complexes composed of PC:Chol:DC-Chol at a molar ratio of 16:8:4 micromole/ml were the most effective at inducing splenocyte proliferation upon exposure to antigen in comparison to control spleens. These results demonstrate that there is no in vitro/in vivo correlation between the transfection efficacy of these liposome formulations and in vitro transfection in the above cell model cannot be taken as a reliable indicator for in vivo efficacy of DNA vaccines.

Epidemiology, clinical and laboratory characteristics of Staphylococcus aureus bacteraemia in a university hospital in UK

There has been a persistent increase in the number of meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-susceptible Staphylococcus aureus (MSSA) bacteraemia in the UK. This prospective study included 147 episodes of S. aureus bacteraemia in 139 patients over a 14 month period, from 1 November 2001 to 31 December 2002. Eighty-seven (59%) episodes in 84 patients and 60 (41%) in 56 patients were due to MRSA and MSSA, respectively. An intra-vascular device (29, 33%) and a soft-tissue (15, 25%) source were the commonest identifiable foci for bacteraemia in the MRSA and MSSA groups, respectively. Attributable mortality in the MRSA group was higher than the MSSA group (33% vs 16%; P = 0.03) but there was no statistical difference for either attributable (P = 0.35) or crude (P = 0.39) mortality between the two groups, when adjusted for age, respiratory focus and inappropriate antibiotic therapy. A respiratory source (P = 0.02) and inappropriate antibiotic therapy (P = 0.02) were associated with attributable mortality in the MRSA group whereas advanced age was the only risk factor (P = 0.02) in the MSSA group. The present study shows that S. aureus bacteraemia continues to be a serious infection mostly affecting the elderly and emphasizes the need for improved strategy in the control and management of this condition. © 2006 The Hospital Infection Society.

Spatial aspects of MRSA epidemiology:A case study using stochastic simulation, kernel estimation and SaTScan

The identification of disease clusters in space or space-time is of vital importance for public health policy and action. In the case of methicillin-resistant Staphylococcus aureus (MRSA), it is particularly important to distinguish between community and health care-associated infections, and to identify reservoirs of infection. 832 cases of MRSA in the West Midlands (UK) were tested for clustering and evidence of community transmission, after being geo-located to the centroids of UK unit postcodes (postal areas roughly equivalent to Zip+4 zip code areas). An age-stratified analysis was also carried out at the coarser spatial resolution of UK Census Output Areas. Stochastic simulation and kernel density estimation were combined to identify significant local clusters of MRSA (p<0.025), which were supported by SaTScan spatial and spatio-temporal scan. In order to investigate local sampling effort, a spatial 'random labelling' approach was used, with MRSA as cases and MSSA (methicillin-sensitive S. aureus) as controls. Heavy sampling in general was a response to MRSA outbreaks, which in turn appeared to be associated with medical care environments. The significance of clusters identified by kernel estimation was independently supported by information on the locations and client groups of nursing homes, and by preliminary molecular typing of isolates. In the absence of occupational/ lifestyle data on patients, the assumption was made that an individual's location and consequent risk is adequately represented by their residential postcode. The problems of this assumption are discussed, with recommendations for future data collection.

Improving diagnosis and oral vaccination strategies against bovine tuberculosis

In this work peptide antigens [ESAT-6,p45 in water (1ml, 1mg/ml)] have been adsorbed onto 10mg inorganic substrates (hydroxyapatite (MHA P201;P120, CHA), polystyrene, calcium carbonate and glass microspheres) and in vitro release characteristics were determined. The aim of formulation was to enhance the interaction of peptides with antigen presenting cells and to achieve rapid peptide release from the carrier compartment system in a mildly acidic environment. Hydroxyapatite microparticle P201 has a greater surface area and thus has the largest peptide adsorption compared to the P120. CHA gave a further higher adsorption due to larger surface area than that available on microparticles. These particles were incorporated into the BOVIGAMTM assay to determine if they improve the sensitivity. After overnight incubation the blood plasma was removed and the amount of IFN-g in each plasma sample was estimated. CHA and MHA P201 gave a significantly higher immune response at low peptide concentration compared to the free peptide, thus indicating that these systems can be used to evaluate Tuberculosis (TB) amongst cattle using the BOVIGAMTM assay. Badgers are a source of TB and pass infection to cattle. At the moment vaccination against TB in badgers is via the parenteral route and requires a trained veterinary surgeon as well as catching the badgers. This process is expensive and time consuming; consequently an oral delivery system for delivery of BCG vaccines is easier and cheaper. The initial stage involved addition of various surfactants and suspending agents to disperse BCG and the second stage involved testing for BCG viability. Various copolymers of Eudragit were used as enteric coating systems to protect BCG against the acidic environment of the stomach (SGF, 0.1M HCl pH 1.2 at 37oC) while dissolving completely in the alkaline environment of the small intestine (SIF, IM PBS solution pH 7.4 at 37oC). Eudragit L100 dispersed in 2ml PBS solution and 0.9ml Tween 80 (0.1%w/v) gave the best results remaining intact in SGF loosing only approximately 10-15% of the initial weight and dissolving completely within 3 hours. BCG was incorporated within the matrix formulation adjusted to pH 7 at the initial formulation stage containing PBS solution and Tween 80. It gave viability of x106 cfu/ml at initial formulation stage, freezing and freeze-drying stages. After this stage the matrix was compressed at 4 tons for 3 mins and placed in SGF for 2 hours and then in SIF until dissolved. The BCG viability dropped to x106 cfu/ml. There is potential to develop it further for oral delivery of BCG vaccine.

Immuno-potentiating activity of surfactant vesicles in DNA and subunit vaccination

Enhanced immune responses for DNA and subunit vaccines potentiated by surfactant vesicle based delivery systems outlined in the present study, provides proof of principle for the beneficial aspects of vesicle mediated vaccination. The dehydration-rehydration technique was used to entrap plasmid DNA or subunit antigens into lipid-based (liposomes) or non-ionic surfactant-based (niosomes) dehydration-rehydration vesicles (DRV). Using this procedure, it was shown that both these types of antigens can be effectively entrapped in DRV liposomes and DRV niosomes. The vesicle size of DRV niosomes was shown to be twice the diameter (~2µm) of that of their liposome counterparts. Incorporation of cryoprotectants such as sucrose in the DRV procedure resulted in reduced vesicle sizes while retaining high DNA incorporation efficiency (~95%). Transfection studies in COS 7 cells demonstrated that the choice of cationic lipid, the helper lipid, and the method of preparation, all influenced transfection efficiency indicating a strong interdependency of these factors. This phenomenon has been further reinforced when 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE): cholesteryl 3b- [N-(N’ ,N’ -dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol)/DNA complexes were supplemented with non-ionic surfactants. Morphological analysis of these complexes using transmission electron microscopy and environmental scanning electron microscopy (ESEM) revealed the presence of heterogeneous structures which may be essential for an efficient transfection in addition to the fusogenic properties of DOPE. In vivo evaluation of these DNA incorporated vesicle systems in BALB/c mice showed weak antibody and cell-mediated immune (CMI) responses. Subsequent mock challenge with hepatitis B antigen demonstrated that, 1-monopalmitoyl glycerol (MP) based DRV, is a more promising DNA vaccine adjuvant. Studying these DRV systems as adjuvants for the Hepatitis B subunit antigen (HBsAg) revealed a balanced antibody/CMI response profile on the basis of the HBsAg specific antibody and cytokine responses which were higher than unadjuvated antigen. The effect of addition of MP, cholesterol and trehalose 6,6’-dibehenate (TDB) on the stability and immuno-efficacy of dimethyldioctadecylammonium bromide (DDA) vesicles was investigated. Differential scanning calorimetry showed a reduction in transition temperature of DDA vesicles by ~12°C when incorporated with surfactants. ESEM of MP based DRV system indicated an increased vesicle stability upon incorporation of antigen. Adjuvant activity of these systems tested in C57BL/6j mice against three subunit antigens i.e., mycobacterial fusion protein- Ag85B-ESAT-6, and two malarial antigens - merozoite surface protein-1, (MSP1), and glutamate rich protein, (GLURP) revealed that while MP and DDA based systems induced comparable antibody responses, DDA based systems induced powerful CMI responses.

Epidemiology of myopia in a United Kingdom urban child population

The Aston Eye Study (AES) was instigated in October 2005 to determine the distribution of refractive error and associated ocular biometry in a sample of UK urban school children. The AES is the first study to compare outcome measures separately in White, South Asian and Black children. Children were selected from two age groups (Year 2 children aged 6/7 years, Year8 children aged 12/13 years of age) using random cluster sampling of schools in Birmingham, West Midlands UK. To date, the AES has examined 598 children (302 Year 2,296 Year 8). Using open-field cycloplegic autorefraction, the overall prevalence of myopia (=-0.50D SER in either eye) determined was 19.6%, with a higher prevalence in older (29.4%) compared to younger (9.9%) children (p<0.001). Using multiple logistic regression models, the risk of myopia was higher in Year 8 South Asian compared to White children and higher in children attending grammar schools relative to comprehensive schools. In addition, the prevalence of uncorrected ametropia was found to be high (Year 8: 12.84%, Year 2: 15.23%), which will be of concern to bodies responsible for the implementation of school vision screening strategies. Biometric data using non-contact partial coherence interferometry revealed a contributory effect of axial length (AL) and central corneal radius (CR) on myopic refraction, resulting in a strong coefficient of determination of the AL/CR ratio on refractive error. Ocular biometric measures did not vary significantly as a function of ethnicity, suggesting a greater miscorrelation of components in susceptible ethnic groups to account for their higher myopia prevalence. Corneal radius was found to be steeper in myopes in both age groups, but was found to flatten with increasing axial length. Due to the inextricable link between myopia and axial elongation, the paradoxical finding of the cornea demands further longitudinal investigation, particularly in relation to myopia onset. Questionnaire analysis revealed a history of myopia in parents and siblings to be significantly associated with myopia in Year 8 children, with a dose-dependent rise in the odds ratio of myopia evident with increasing number of myopic parents. By classifying socioeconomic status (SES) using Index of Multiple Deprivation values, it was found that Year 8 children from moderately deprived backgrounds were more at risk of myopia compared with children located at both extremities of the deprivation spectrum. However, the main effect of SES weakened following multivariate analysis, with South Asian ethnicity and grammar schooling remaining associated with Year 8 myopia after adjustment.

Epidemiology of community-acquired meticillin-resistant Staphylococcus aureus obtained from the UK West Midlands region

Between January 2005 and December 2005, 199 meticillin-resistant Staphylococcus aureus (MRSA) isolates were obtained from nonhospitalised patients presenting skin and soft tissue infections to local general practitioners. The study area incorporated 57 surgeries from three Primary Care Trusts in the Lichfield, Tamworth, Burntwood, North and East Birmingham regions of Central England, UK. Following antibiotic susceptibility testing, pulsed-field gel electrophoresis, Panton-Valentine leukocidin gene detection and SCCmec element assignment, 95% of the isolates were shown to be related to hospital epidemic strains EMRSA-15 and EMRSA-16. In total 87% of the isolate population harboured SCCmec IV, 9% had SCCmec II and 4% were identified as carrying novel SCCmec IIIa-mecI. When mapped to patient home postcode, a diverse distribution of isolates harbouring SCCmec II and SCCmec IV was observed; however, the majority of isolates harbouring SCCmec IIIa-mecI were from patients residing in the north-west of the study region, highlighting a possible localised clonal group. Transmission of MRSA from the hospital setting into the surrounding community population, as demonstrated by this study, warrants the need for targeted patient screening and decolonisation in both the clinical and community environments.

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4(+)CD25(+) regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4(+) T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4(+) T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.

Liposome (Lipodine™)-mediated DNA vaccination by the oral route

Plasmid DNA pRc/CMV HBS encoding the S (small) region of hepatitis B surface antigen (HBsAg) was incorporated by the dehydration-rehydration method into Lipodine™ liposomes composed of 16 μmoles phosphatidylcholine (PC) or distearoyl phosphatidylcholine (DSPC), 8 μmoles of (dioleoyl phosphatidylethanolamine (DOPE) or cholesterol and 4 μmoles of the cationic lipid 1,2-dioleoyl-3-(trimethylammonium propane (DOTAP) (molar ratios 1:0.5:0.25). Incorporation efficiency was high (89-93% of the amount of DNA used) in all four formulations tested and incorporated DNA was shown to be resistant to displacement in the presence of the competing anionic sodium dodecyl sulphate molecules. This is consistent with the notion that most of the DNA is incorporated within the multilamellar vesicles structure rather than being vesicle surface-complexed. Stability studies performed in simulated intestinal media also demonstrated that dehydration-rehydration vesicles (DRV) incorporating DNA (DRV(DNA)) were able to retain significantly more of their DNA content compared to DNA complexed with preformed small unilamellar vesicles (SUV-DNA) of the same composition. Moreover, after 4h incubation in the media, DNA loss for DSPC DRV(DNA) was only minimal, suggesting this to be the most stable formulation. Oral (intragastric) liposome-mediated DNA immunisation studies employing a variety of DRV(DNA) formulations as well as naked DNA revealed that secreted IgA responses against the encoded HBsAg were (as early as three weeks after the first dose) substantially higher after dosing with 100 μg liposome-entrapped DNA compared to naked DNA. Throughout the fourteen week investigation, IgA responses in mice were consistently higher with the DSPC DRV(DNA) liposomes compared to naked DNA and correlated well with their improved DNA retention when exposed to model intestinal fluids. To investigate gene expression after oral (intragastric) administration, mice were given 100 μg of naked or DSPC DRV liposome-entrapped plasmid DNA expressing the enhanced green fluorescent protein (pCMV.EGFP). Expression of the gene, in terms of fluorescence intensity in the draining mesenteric lymph nodes, was much greater in mice dosed with liposomal DNA than in animals dosed with the naked DNA. These results suggest that DSPC DRV liposomes containing DNA (Lipodine™) may be a useful system for the oral delivery of DNA vaccines.

Methicillin-resistant Staphylococcus aureus bacteremia:epidemiology, outcome, and laboratory characteristics in a tertiary referral center in the UK

Objective: To analyze the recent epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in a UK tertiary referral center. Methods: We collected epidemiological and laboratory data on all cases of MRSA bacteremia from September 1, 2005 to December 31, 2007. Results: There were 195 clinically significant episodes. Most were hospital-acquired. Only one episode occurred in patients without a history of hospital admission in the previous 12 months. An intravascular device was the most common focus of infection (37%), with no identifiable source found in 35% of episodes. Twenty-eight percent of patients died within 30 days of bacteremia. Mortality was significantly higher in the absence of an identifiable focus. Failure to include an antibiotic active against MRSA in the empirical treatment was only significantly associated with death in patients showing signs of hemodynamic instability (p < 0.001). No isolates had a minimum inhibitory concentration to vancomycin above 1.5. mg/l and no heteroresistance to glycopeptide antibiotics (heteroresistant vancomycin-intermediate Staphylococcus aureus; hVISA) was detected. All isolates were sensitive to daptomycin, tigecycline, and linezolid. Conclusions: Despite improvement in infection control measures, medical devices remain the most common source of infection. Inappropriate empirical antibiotic usage is associated with a poor outcome in patients with signs of severe sepsis. Susceptibility to glycopeptides and newer antibiotics remains good. © 2010 International Society for Infectious Diseases.

Epidemiology of medication discrepancies upon hospital admission in children - a systematic review

Objectives: NICE/NPSA excluded children under 16 from their guidance concerning medicines reconciliation (MR) upon admission.1 Our aims and objectives of conducting the literature review was to identify the epidemiology of medication discrepancies upon admission, transfer and discharge in children, and if they require MR. Method: Six bibliographical databases (Medline, Embase, CINAHL, International Pharmaceutical Abstracts, Web of Science and Biosis Previews) and selected key words were used to find epidemiological studies on medication discrepancies in children upon hospital admission, transfer and discharge (key words included ‘medication discrepancy’; ‘medication reconciliation’; ‘hospital admission’; ‘hospital discharge’; ‘hospital transfer’); studies where the data for children could be extracted were included. Results: From the 1239 articles found (in May 2011), eight of the articles had extractable paediatric information, (five from Canada, two from USA, one from UK). Five of the studies involved discrepancies on admission, one involved discrepancies on admission and transfer, one involved discrepancies at transfer and one considered discharge. The reference point used to compare against the admission, transfer and the discharge order differed in each of the studies. Four studies used a rating scale to assess the clinical significance of the discrepancies to demonstrate the potential adverse clinical outcome of patients in the absence of clinical intervention. Two studies2 3 used a rating scale that was used in adults.4 A study of paediatric neurosurgical patients found that initial hospital prescriptions for children differed from the preadmission prescriptions in 39% of occasions and 50% of all prescribing variations had the potential to cause moderate or severe discomfort or clinical deterioration.2 A study by Coffey et al in general paediatric admissions in Canada showed 22% of patients experienced at least one discrepancy and 29% of the discrepancies had the potential to cause moderate or severe discomfort or clinical deterioration.3 By comparison an epidemiological study in discrepancies in adults on admission had 38.6% of the discrepancies identified with a potential to cause moderate or severe discomfort or clinical deterioration.4 All the studies involved small samples or specific patient groups such as medically complex patients. However all of the studies demonstrated that discrepancies occurred among paediatric populations during transitions in care settings and mentioned MR as an intervention. Conclusion: The results have shown that discrepancies of medication upon hospital admission, transfer and discharge occur regularly in children. With only one published study in the UK looking at hospital admission in children, and no published articles on the incidence and epidemiology of medication discrepancies upon hospital transfer or discharge further research is required in a wider paediatric population. Further work is also required to define the required interventions to improve practice.