Essential medicines containing ethanol elevate blood acetaldehyde concentrations in neonates.

UNLABELLED: Neonates administered ethanol-containing medicines are potentially at risk of dose-dependent injury through exposure to ethanol and its metabolite, acetaldehyde. Here, we determine blood ethanol and acetaldehyde concentrations in 49 preterm infants (median birth weight = 1190 g) dosed with iron or furosemide, medicines that contain different amounts of ethanol, and in 11 control group infants (median birth weight = 1920 g) who were not on any medications. Median ethanol concentrations in neonates administered iron or furosemide were 0.33 (range = 0-4.92) mg/L, 0.39 (range = 0-72.77) mg/L and in control group infants were 0.15 (range = 0.03-5.4) mg/L. Median acetaldehyde concentrations in neonates administered iron or furosemide were 0.16 (range = 0-8.89) mg/L, 0.21 (range = 0-2.43) mg/L and in control group infants were 0.01 (range = 0-0.14) mg/L. There was no discernible relationship between blood ethanol or acetaldehyde concentrations and time after medication dose. CONCLUSION: Although infants dosed with iron or furosemide had low blood ethanol concentrations, blood acetaldehyde concentrations were consistent with moderate alcohol exposure. The data suggest the need to account for the effects of acetaldehyde in the benefit-risk analysis of administering ethanol-containing medicines to neonates. WHAT IS KNOWN: • Neonates are commonly treated with ethanol-containing medicines, such as iron and furosemide. • However, there is no data on whether this leads to appreciable increases in blood concentrations of ethanol or its metabolite, acetaldehyde. What is New: • In this study, we find low blood ethanol concentrations in neonates administered iron and/or furosemide but markedly elevated blood acetaldehyde concentrations in some infants receiving these medicines. • Our data suggest that ethanol in drugs may cause elevation of blood acetaldehyde, a potentially toxic metabolite.

Tackling the problem of blood culture contamination in the intensive care unit using an educational intervention.

Blood culture contamination (BCC) has been associated with unnecessary antibiotic use, additional laboratory tests and increased length of hospital stay thus incurring significant extra hospital costs. We set out to assess the impact of a staff educational intervention programme on decreasing intensive care unit (ICU) BCC rates to <3% (American Society for Microbiology standard). BCC rates during the pre-intervention period (January 2006-May 2011) were compared with the intervention period (June 2011-December 2012) using run chart and regression analysis. Monthly ICU BCC rates during the intervention period were reduced to a mean of 3.7%, compared to 9.5% during the baseline period (P < 0.001) with an estimated potential annual cost savings of about £250,100. The approach used was simple in design, flexible in delivery and efficient in outcomes, and may encourage its translation into clinical practice in different healthcare settings.

Hospital antibiotic use and its relationship to age-adjusted comorbidity and alcohol-based hand rub consumption.

The objective of this study was to evaluate the effect of age-adjusted comorbidity and alcohol-based hand rub on monthly hospital antibiotic usage, retrospectively. A multivariate autoregressive integrated moving average (ARIMA) model was built to relate the monthly use of all antibiotics grouped together with age-adjusted comorbidity and alcohol-based hand rub over a 5-year period (April 2005-March 2010). The results showed that monthly antibiotic use was positively related to the age-adjusted comorbidity index (concomitant effect, coefficient 1·103, P = 0·0002), and negatively related to the use of alcohol-based hand rub (2-month delay, coefficient -0·069, P = 0·0533). Alcohol-based hand rub is considered a modifiable factor and as such can be identified as a target for quality improvement programmes. Time-series analysis may provide a suitable methodology for identifying possible predictive variables that explain antibiotic use in healthcare settings. Future research should examine the relationship between infection control practices and antibiotic use, identify other infection control predictive factors for hospital antibiotic use, and evaluate the impact of enhancing different infection control practices on antibiotic use in a healthcare setting.

Impact of an enhanced antibiotic stewardship on reducing methicillin-resistant Staphylococcus aureus in primary and secondary healthcare settings.

The objective of this study was to evaluate the impact of restricting high-risk antibiotics on methicillin-resistant Staphylococcus aureus (MRSA) incidence rates in a hospital setting. A secondary objective was to assess the impact of reducing fluoroquinolone use in the primary-care setting on MRSA incidence in the community. This was an interventional, retrospective, ecological investigation in both hospital and community (January 2006 to June 2010). Segmented regression analysis of interrupted time-series was employed to evaluate the intervention. The restriction of high-risk antibiotics was associated with a significant change in hospital MRSA incidence trend (coefficient=-0·00561, P=0·0057). Analysis showed that the intervention relating to reducing fluoroquinolone use in the community was associated with a significant trend change in MRSA incidence in community (coefficient=-0·00004, P=0·0299). The reduction in high-risk antibiotic use and fluoroquinolone use contributed to both a reduction in incidence rates of MRSA in hospital and community (primary-care) settings.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

A simple bioanalytical method for the quantification of antiepileptic drugs in dried blood spots.

An increasing number of publications on the dried blood spot (DBS) sampling approach for the quantification of drugs and metabolites have been spurred on by the inherent advantages of this sampling technique. In the present research, a selective and sensitive high-performance liquid chromatography method for the concurrent determination of multiple antiepileptic drugs (AEDs) [levetiracetam (LVT), lamotrigine (LTG), phenobarbital (PHB)], carbamazepine (CBZ) and its active metabolite carbamazepine-10,11 epoxide (CBZE)] in a single DBS has been developed and validated. Whole blood was spotted onto Guthrie cards and dried. Using a standard punch (6mm diameter), a circular disc was punched from the card and extracted with methanol: acetonitrile (3:1, v/v) containing hexobarbital (Internal Standard) and sonicated prior to evaporation. The extract was then dissolved in water and vortex mixed before undergoing solid phase extraction using HLB cartridges. Chromatographic separation of the AEDs was achieved using Waters XBridge™ C18 column with a gradient system. The developed method was linear over the concentration ranges studied with r≥0.995 for all compounds. The lower limits of quantification (LLOQs) were 2, 1, 2, 0.5 and 1 µg/mL for LVT, LTG, PHB, CBZE and CBZ, respectively. Accuracy (%RE) and precision (%CV) values for within and between day were <20% at the LLOQs and <15% at all other concentrations tested. This method was successfully applied to the analysis of the AEDs in DBS samples taken from children with epilepsy for the assessment of their adherence to prescribed treatments.

A point prevalence survey of antibiotic use in four acute-care teaching hospitals utilizing the European Surveillance of Antimicrobial Consumption (ESAC) audit tool.

The objective of this research was to assess current patterns of hospital antibiotic prescribing in Northern Ireland and to determine targets for improving the quality of antibiotic prescribing. A point prevalence survey was conducted in four acute teaching hospitals. The most commonly used antibiotics were combinations of penicillins including ß-lactamase inhibitors (33·6%), metronidazole (9·1%), and macrolides (8·1%). The indication for treatment was recorded in 84·3% of the prescribing episodes. A small fraction (3·9%) of the surgical prophylactic antibiotic prescriptions was for >24 h. The results showed that overall 52·4% of the prescribed antibiotics were in compliance with the hospital antibiotic guidelines. The findings identified the following indicators as targets for quality improvement: indication recorded in patient notes, the duration of surgical prophylaxis and compliance with hospital antibiotic guidelines. The results strongly suggest that antibiotic use could be improved by taking steps to address the identified targets for quality improvement.

Clinical and economic impact of contaminated blood cultures within the hospital setting.

Blood cultures have an important role in the diagnosis of serious infections, although contamination of blood cultures (i.e. false-positive blood cultures) is a common problem within the hospital setting. The objective of the present investigation was to determine the impact of the false-positive blood culture results on the following outcomes: length of stay, hotel costs, antimicrobial costs, and costs of laboratory and radiological investigation. A retrospective case-control study design was used in which 142 false-positive blood culture cases were matched with suitable controls (patients for whom cultures were reported as true negatives). The matching criteria included age, comorbidity score and month of admission to the hospital. The research covered a 13-month period (July 2007 to July 2008). The findings indicated that differences in means, between cases and controls, for the length of hospital stay and the total costs were 5.4 days [95% CI (confidence interval): 2.8-8.1 days; P<0.001] and £5,001.5 [$7,502.2; 95% CI: £3,283.9 ($4,925.8) to £6,719.1 ($10,078.6); P<0.001], respectively. Consequently, and considering that 254 false-positive blood cultures had occurred in the study site hospital over a one-year period, patients with false-positive blood cultures added 1372 extra hospital days and incurred detrimental additional hospital costs of £1,270,381 ($1,905,572) per year. The findings therefore demonstrate that false-positive blood cultures have a significant impact on increasing hospital length of stay, laboratory and pharmacy costs. These findings highlight the need to intervene to raise the standard of blood-culture-taking technique, thus improving both the quality of patient care and resource use.

Can the use of a rapid polymerase chain screening method decrease the incidence of nosocomial meticillin-resistant Staphylococcus aureus?

Rapid detection of MRSA may be important for the control of MRSA spread in hospitals. The aim of this investigation was to compare the use of a rapid polymerase chain reaction (PCR) screening method with standard culture for the detection of meticillin-resistant Staphylococcus aureus (MRSA) colonisation and to determine its impact on the incidence of MRSA in two hospital wards. During the first phase of the investigation (four months), patients in a surgical ward were screened using the rapid PCR technique and patients in a medical/cardiology ward were screened with standard culture methods. During the second phase of the investigation (four months), MRSA screening methods were switched between the two wards. An audit of infection control practices on each ward was made at the end of each phase in order to check whether any changes had occurred that might influence the risks of MRSA transmission. Use of the rapid PCR method significantly reduced the median time between swabs being taken, to the results being telephoned to the wards (excluding weekends), from 47 to 21 h (P<0.001). However, comparison of MRSA incidence during use of PCR (20/1000 bed-days) and culture methods (22.1/1000 bed-days) revealed no significant difference in incidence on the surgical ward (P=0.69). Regarding the medical/cardiology ward, analysis of data was complicated by an increase in the detection of MRSA during the PCR phase (P<0.05). The study demonstrated that rapid PCR can significantly reduce the turnaround times but reducing the time between swabs being taken to results being telephoned to the ward is still not sufficient to limit the transmission of MRSA.

Public awareness and views on unlicensed use of medicines in children.

AIMS: To explore awareness and views of the general public on unlicensed use of medicines in children and on the participation of children in clinical trials. METHODS: Members of the public completed a questionnaire survey administered by face-to-face interview in public areas in N. Ireland. The main outcome measures were the views on unlicensed use of medicines in children and on clinical trials in children. RESULTS: One thousand participants (59.2% female) took part; 610 were parents. Most participants (86%) had no previous knowledge about unlicensed use of medicines in children. Being a parent did not influence this nor did being a parent of a child who suffered from a health problem (P > 0.05). Most participants (92%) felt that parents should be told about unlicensed use of medicines, with the doctor most frequently selected as the person who should inform parents. At the outset, only 1.8% of participants felt that the use of medicines in children was unsafe. However, having been informed about unlicensed use of medicines, this proportion increased dramatically (62.4%; P < 0.001). Views on whether participants would enter a child of their own into a clinical trial varied according to the health status of the child (P < 0.05) i.e. a child in good health (3.9%) vs a child with a life-threatening condition (41.9%). CONCLUSIONS: There is limited public knowledge of unlicensed use of medicines in children and a general reluctance to involve children in clinical trials unless the child to be involved has a life-threatening condition.

Sputum antibiotic concentrations: implications for treatment of cystic fibrosis lung infection.

BACKGROUND: The success of antibiotic therapy may be predicted based on the achievement of pharmacodynamic indices (PDIs), which are determined by the susceptibility of the infecting bacteria and the concentrations of antibiotics achieved at the site of infection. The aim of this study was to determine whether PDIs associated with clinical effectiveness for ceftazidime and tobramycin were achieved at the site of infection in the lungs of cystic fibrosis (CF) patients following intravenous administration during treatment of an acute exacerbation. METHODS: Serum and sputum samples were collected from 14 CF patients and the concentration of both antibiotics in the samples determined. The susceptibility of bacteria cultured from sputum samples to both antibiotics alone and in combination was also determined. RESULTS: A total of 22 Pseudomonas aeruginosa isolates and 4 Burkholderia cepacia complex isolates were cultured from sputum samples with 55% and 4% of isolates susceptible to ceftazidime and tobramycin, respectively. Target PDIs for ceftazidime and tobramycin, an AUC/MIC ratio of 100 and a C(max)/MIC ratio of 10, respectively, were not achieved in serum or sputum simultaneously or even individually for any patient. Although the combination of ceftazidime and tobramycin was synergistic against 20 of the 26 isolates cultured, the concentrations of both antibiotics required for synergy were achieved simultaneously in only 38% of serum and 14% of sputum samples. CONCLUSION: Key PDIs associated with clinical effectiveness for ceftazidime and tobramycin were not achieved at the site of infection in the lungs of CF patients.

Development and validation of an HPLC method for the determination of spironolactone and its metabolites in paediatric plasma samples.

An HPLC method has been developed and validated for the determination of spironolactone, 7 alpha-thiomethylspirolactone and canrenone in paediatric plasma samples. The method utilises 200 microl of plasma and sample preparation involves protein precipitation followed by Solid Phase Extraction (SPE). Determination of standard curves of peak height ratio (PHR) against concentration was performed by weighted least squares linear regression using a weighting factor of 1/concentration2. The developed method was found to be linear over concentration ranges of 30-1000 ng/ml for spironolactone and 25-1000 ng/ml for 7 alpha-thiomethylspirolactone and canrenone. The lower limit of quantification for spironolactone, 7 alpha-thiomethylspirolactone and canrenone were calculated as 28, 20 and 25 ng/ml, respectively. The method was shown to be applicable to the determination of spironolactone, 7 alpha-thiomethylspirolactone and canrenone in paediatric plasma samples and also plasma from healthy human volunteers.

Pharmaceutical care of patients with heart failure.

AIM: The aim of this study was to investigate the impact of a pharmacist-led pharmaceutical care programme, involving optimization of drug treatment and intensive education and self-monitoring of patients with heart failure (HF) within the United Arab Emirates (UAE), on a range of clinical and humanistic outcome measures. METHODS: The study was a randomized, controlled, longitudinal, prospective clinical trial at Al-Ain Hospital, Al-Ain, UAE. Patients were recruited from the general medical wards and from cardiology and medical outpatient clinics. HF patients who fulfilled the entrance criteria, and had no exclusion criteria present, were identified for inclusion in the study. After recruitment, patients were randomly assigned to one of two groups: intervention group or control group. Intervention patients received a structured pharmaceutical care service while control patients received traditional services. Patient follow-up took place when patients attended scheduled outpatient clinics (every 3 months). A total of 104 patients in each group completed the trial (12 months). The patients were generally suffering from mild to moderate HF (NYHA Class 1, 29.5%; Class 2, 50.5%; Class 3, 16%; and Class 4, 4%). RESULTS: Over the study period, intervention patients showed significant (P < 0.05) improvements in a range of summary outcome measures [AUC (95% confidence limits)] including exercise tolerance [2-min walk test: 1607.2 (1474.9, 1739.5) m.month in intervention patients vs. 1403.3 (1256.5, 1549.8) in control patients], forced vital capacity [31.6 (30.8, 32.4) l.month in the intervention patients vs. 27.8 (26.8, 28.9) in control patients], health-related quality of life, as measured by the Minnesota living with heart failure questionnaire [463.5 (433.2, 493.9) unit.month in intervention patients vs. 637.5 (597.2, 677.7) in control patients; a lower score in this measure indicates better health-related quality of life]. The number of individual patients who reported adherence to prescribed medications was higher (P < 0.05) in the intervention group (85 vs. 35), as was adherence to lifestyle advice (75 vs. 29) at the final assessment (12 months). There was a tendency to have a higher incidence of casualty department visits by intervention patients, but a lower rate of hospitalization. CONCLUSIONS: The research provides clear evidence that the delivery of pharmaceutical care to patients with HF can lead to significant clinical and humanistic benefits.

Prevalence of over-the-counter drug-related overdoses at Accident and Emergency departments in Northern Ireland--a retrospective evaluation.

BACKGROUND AND OBJECTIVES: One major concern associated with misuse/abuse of over-the-counter (OTC) products is the potential for over-dosage. The aim of this research study was to evaluate, over a 3-month period, OTC medicine-related overdoses (those involving OTC drugs only and OTC drugs in combination with other drugs) that led to patients presenting at the Accident and Emergency (A & E) departments in four Belfast hospitals. METHODS: A data collection sheet was designed to capture the information required from the A & E records in each hospital. A retrospective week-by-week data collection, reviewing A & E records, took place over a 3-month period (starting on 1 December 2002). All data related to cases presenting at the A & E departments because of drug overdoses (either accidental or deliberate according to Read Clinical Classification) were included in the study. Data were coded and entered into a custom designed SPSS database for analysis, using Chi square and Fisher exact tests. RESULTS: OTC drug-related overdoses comprised 40.1% of all overdoses, of which 24.0% were OTC-only overdoses. Those who overdosed on OTC drugs (solely or combined with other drugs) were mainly female (62.3%) and in the age category 31-50 years (44.9%; P <0.05). The majority (n=215) of OTC-related overdoses were intentional, whereas only 28 were accidental. Of those who attended the A & E departments and had an overdose history, one-third overdosed on OTC-related products and two-thirds overdosed on OTC drugs only. CONCLUSIONS: OTC drugs accounted for a significant proportion of overdose presentations at the A & E departments in Northern Ireland. Higher awareness of the potential of OTC product use in overdose cases (intentional or accidental) is recommended for both the public and health care professionals.

Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study.

AIMS: To characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment. METHODS: Data were collected from 35 infants (gestational age 25-34 weeks; postnatal age 1-77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1-0.2 mg kg(-1)) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared. RESULTS: The concentration-time course of indometacin was best described by a one-compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h(-1) and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l(-1). Closure occurred in 75% of infants with a plasma concentration > or = 0.4 mg l(-1) 24 h after the last dose. CONCLUSIONS: Dosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration > or = 0.4 mg l(-1). Although the pharmacokinetic estimates will be affected by both interindividual and within-individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.

Liquid chromatographic determination including simultaneous "on-cartridge" separation of ranitidine cisapride drug combinations from paediatric plasma samples using an automated solid-phase extraction procedure.

HPLC methodology was investigated for the simultaneous determination of cisapride and ranitidine in small volume paediatric plasma samples. Such a simultaneous determination proved difficult due to the small sample volumes, the low concentrations of the drugs and the different log P values of the two compounds. The two drugs and their respective internal standards were separated "on-cartridge" using HLB Solid Phase Extraction cartridges and the samples quantified by individual HPLC methodologies. The technique has been applied successfully to 60 paediatric plasma samples containing both cisapride and ranitidine.

A HRG-based costing model for estimating pharmacy costs associated with surgical procedures.

OBJECTIVE: The present study addresses pharmacy expenditure within a surgical directorate in a UK hospital. The aim of the study was to develop a health care resource group (HRG)-based costing model that can be used to forecast pharmacy expenditure based on surgical casemix. Such a model will be of benefit as an expenditure projection tool at a time when hospitals are developing accelerated operation programmes in an attempt to decrease hospital waiting times. METHOD: During the period February-April 2000, nursing staff recorded all pharmacy sourced items for each individual operation in the theatres used for general surgery, ENT surgery and gynaecological procedures; each operation was also classified according to its HRG. The associated costs of the items per HRG were identified and the average pharmaceutical cost per HRG calculated and included in the costing model. The model derived costs over the study period were compared with the actual pharmacy expenditure which was obtained from the pharmacy computer system. Finally HRG data for operations carried out in February 2002 were costed using the model for validation purposes. RESULTS: The estimated pharmaceutical cost for surgery items for February-April 2000 was 121,235 UK pounds. This figure was 3.92% over the actual pharmaceutical expenditure as determined from computer records. The February 2002 casemix varied considerably from that of 2000. However, the model estimated pharmaceutical cost of surgery performed in February 2002 (38,054 UK pounds) was again very similar to the computer logged expenditure (1.09% under the actual expenditure for that period) indicating the robustness of the HRG-based costing approach.