Prioritizing research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper.

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team organization and policy levels, evidence from the behavioural sciences is underutilized in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimizing effective implementation of ASPs in hospital settings using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four HICs with publicly funded healthcare systems (e.g. Canada, Germany, Norway and the UK) met face-to-face to agree on broad research priority areas using a structured consensus method. Question addressed and recommendations: The consensus process assessing the ten identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimize effective implementation of ASPs for hospital inpatients in HICs with publicly funded healthcare systems. We suggest and detail behavioural science evidence-guided research efforts in the following areas: (a) comprehensively identifying barriers and facilitators to implementing ASPs and clinical recommendations intended to optimize antibiotic prescribing; (b) identifying actors ('who') and actions ('what needs to be done') of ASPs and clinical teams; (c) synthesizing available evidence to support future research and planning for ASPs; (d) specifying the activities in current ASPs with the purpose of defining a control group for comparison with new initiatives; (e) defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; (f) conducting robust evaluations of ASPs with built-in process evaluations and fidelity assessments; (g) defining and designing ASPs; (h) establishing the evidence base for impact of ASPs on resistance; (i) investigating the role and impact of government and policy contexts on ASPs; and (j) understanding what matters to patients in ASPs in hospitals. CONCLUSIONS: Assessment, revisions and updates of our priority-setting exercise should be considered at intervals of 2 years. To propose research priority areas in low- and middle-income countries, the methodology reported here could be applied.

Clinical evaluation of multiparameter correction equations for Goldmann applanation tonometry.

PURPOSE: To evaluate and compare the multiparameter equations in correcting intraocular pressure (IOP) measurements obtained using the Goldmann applanation tonometer (IOPG) for the effects of central corneal thickness (CCT), corneal curvature (R), and age in different ethnic populations. METHODS: Data of IOPG, CCT, R, and age were collected from three clinical centers. The sample size consisted of 945 eyes of 945 glaucoma patients or suspects (669 Europeans, 127 African Americans, and 149 Indians). The 'corrected IOP' was calculated using five multiparameter equations to decrease the association of CCT, R, and age with measured IOP. Regression analyses were performed to calculate variance (r(2)) and determine the association of CCT, R, and age with IOPG and corrected IOP (residual association). RESULTS: Overall, CCT accounted for the majority of variance in IOPG, while R and age had a much smaller effect, with the combined effect on IOPG ranging from 4.7 to 7.5% in the three data sets. The residual association of CCT, R, and age with corrected IOP in the three groups ranged from 0.2 to 1.3% and 0.5 to 1.8% with the application of the Elsheikh and the Chihara equations, respectively. The residual association of CCT, R, and age with corrected IOP calculated using the Ehlers, Orssengo and Pye, and Shimmoyo equations were 7-11.5, 1.8-11.7, and 4.6-8.3%, respectively. CONCLUSION: The Elsheikh and the Chihara equations better decreased the association of CCT, R, and age with measured IOP than the Ehlers, Orssengo and Pye, and Shimmoyo equations.

Prevalence and outcomes of use of potentially inappropriate medicines in older people: cohort study stratified by residence in nursing home or in the community.

OBJECTIVES: To compare the prevalence of use of potentially inappropriate medicines (PIMs) between older patients living in their own homes versus those living in nursing or residential homes, and to test the association between exposure to PIMs and mortality. DESIGN: Cohort study stratified by place of residence. SETTING: Tayside, Scotland. PARTICIPANTS: All people aged between 66 and 99 years who were resident or died in Tayside from 2005 to 2006. MAIN OUTCOME MEASURES: The exposure variable was PIM use as defined by Beers' Criteria. All cause mortality was the main outcome measure. RESULTS: 70,299 people were enrolled in the cohort of whom 96% were exposed to any medicine and 31% received a PIM. Place of residence was not associated with overall risk of receiving PIMs, adjusted OR 0.94, 95% CI 0.87 to 1.01. Exposure to five of the PIMs (including long-acting benzodiazepines) was significantly higher in nursing homes whereas exposure to five other PIMs (including amitriptyline and NSAIDs) was significantly lower. Exposure to PIMs was similar (20-46%) across all 71 general practices in Tayside and was not associated with increased risk of mortality after adjustment for age, gender and polypharmacy (adjusted OR 0.98, 95% CI 0.92 to 1.05). CONCLUSIONS: The authors question the validity of the full list of PIMs as an indicator of safety of medicines in older people because one-third of the population is exposed with little practice variation and no significant impact on mortality. Future studies should focus on management of a shorter list of genuinely high-risk medicines.

Burden of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli resistant to third-generation cephalosporins.

OBJECTIVES: This study determined excess mortality and length of hospital stay (LOS) attributable to bloodstream infection (BSI) caused by third-generation-cephalosporin-resistant Escherichia coli in Europe. METHODS: A prospective parallel matched cohort design was used. Cohort I consisted of patients with third-generation-cephalosporin-resistant E. coli BSI (REC) and cohort II consisted of patients with third-generation-cephalosporin-susceptible E. coli BSI (SEC). Patients in both cohorts were matched for LOS before infection with patients free of the respective BSI. Thirteen European tertiary care centres participated between July 2007 and June 2008. RESULTS: Cohort I consisted of 111 REC patients and 204 controls and cohort II consisted of 1110 SEC patients and 2084 controls. REC patients had a higher mortality at 30 days (adjusted odds ratio = 4.6) and a higher hospital mortality (adjusted hazard ratio = 5.7) than their controls. LOS was increased by 8 days. For SEC patients, these figures were adjusted odds ratio = 1.9, adjusted hazard ratio = 2.0 and excess LOS = 3 days. A 2.5 times [95% confidence interval (95% CI) 0.9-6.8] increase in all-cause mortality at 30 days and a 2.9 times (95% CI 1.2-6.9) increase in mortality during entire hospital stay as well as an excess LOS of 5 days (95% CI 0.4-10.2) could be attributed to resistance to third-generation cephalosporins in E. coli BSI. CONCLUSIONS: Morbidity and mortality attributable to third-generation-cephalosporin-resistant E. coli BSI is significant. If prevailing resistance trends continue, high societal and economic costs can be expected. Better management of infections caused by resistant E. coli is becoming essential.

Appropriate vs. inappropriate antimicrobial therapy.

Inappropriate antimicrobial treatment (defined as use of antimicrobial agent to which a pathogen is resistant) or a delay in starting appropriate treatment are both associated with increased morbidity and mortality. Studies of ventilator-associated pneumonia, intra-abdominal infections or bacteraemia document higher mortality in patients who received inappropriate therapy. In addition, the outcome in patients switched from inappropriate to appropriate therapy is better than for patients who remained on inappropriate therapy, but the benefit is not as great as for those who were started on appropriate therapy initially. While inappropriate therapy undoubtedly has an important influence on outcomes, it needs to be considered in the context of other patient risk-factors, such as co-morbid conditions, severity score measures, and functional status. When assessing the impact of inappropriate therapy on outcomes such as length of hospital stay, it is important to be as precise as possible about the time of onset of infection. Failure to do so may lead to inaccurate estimation of the effect of inappropriate therapy. While the likelihood that resistant pathogens can increase costs throughout the healthcare system is generally recognised, an under-appreciated aspect of resistance is its consequences for patients and their carers. Initiatives are underway to gauge the impact of resistance and strategies to combat its spread.

The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection.

The quality of research in hospital epidemiology (infection control) must be improved to be robust enough to influence policy and practice. In order to raise the standards of research and publication, a CONSORT equivalent for these largely quasi-experimental studies has been prepared by the authors of two relevant systematic reviews, following consultation with learned societies, editors of journals and researchers. It consists of a 22 item checklist, and a summary table. The emphasis is on transparency to improve the quality of reporting and on the use of appropriate statistical techniques. The statement has been endorsed by a number of professional special interest groups and societies. Like CONSORT, ORION should be considered a 'work in progress', which requires ongoing dialogue for successful promotion and dissemination. The statement is therefore offered for further public discussion. Journals and research councils are strongly recommended to incorporate it into their submission and reviewing processes. Feedback to the authors is encouraged and the statement will be revised in 2 years.

Presence of bacteriuria caused by trimethoprim resistant bacteria in patients prescribed antibiotics: multilevel model with practice and individual patient data.

OBJECTIVE: To look for evidence of a relation between antibiotic resistance and prescribing by general practitioners by analysis of prescribing at both practice and individual patient level. DESIGN: Repeated cross-sectional study in 1995 and 1996. SETTING: 28 general practices in the Ninewells Hospital laboratory catchment area, Tayside, Scotland. SUBJECTS REVIEWED: 8833 patients registered with the 28 practices who submitted urine samples for analysis. MAIN OUTCOME MEASURES: Resistance to trimethoprim in bacteria isolated from urine samples at practice and individual level simultaneously in a multilevel model. RESULTS: Practices showed considerable variation in both the prevalence of trimethoprim resistance (26-50% of bacteria isolated) and trimethoprim prescribing (67-357 prescriptions per 100 practice patients). Although variation in prescribing showed no association with resistance at the practice level after adjustment for other factors (P = 0.101), in the multilevel model resistance to trimethoprim was significantly associated with age, sex, and individual-level exposure to trimethoprim (P < 0.001) or to other antibiotics (P = 0.002). The association with trimethoprim resistance was strongest for people recently exposed to trimethoprim, and there was no association for people with trimethoprim exposure more than six months before the date of the urine sample. DISCUSSION: Analysis of practice level data obscured important associations between antibiotic prescribing and resistance. The results support efforts to reduce unnecessary prescribing of antibiotics in the community and show the added value of individual patient data for research on the outcomes of prescribing.

Hypothetical economic analysis of screening for left ventricular hypertrophy in high-risk normotensive populations.

BACKGROUND: Left ventricular hypertrophy (LVH) measured by echocardiography is a powerful independent marker of increased cardiovascular risk. The prevalence of echocardiographic LVH in patients with high cardiovascular risk appears to be high, even in patients currently considered normotensive. AIM: To ascertain the likely costs of screening for and treating echocardiographic LVH in normotensive patients at high risk of cardiovascular events. DESIGN: Hypothetical economic analysis. METHODS: Cost analyses were based on known costs of echocardiography, costs of selected cardiovascular medications and prevalence of normotensive LVH in at-risk populations, combined with treatment effect data from studies of hypertensive patients with echocardiographic LVH. RESULTS: Screening costs per case for echocardiographic LVH are likely to be low, because of the high prevalence of the condition and the low unit cost of echocardiography. Treatment costs are likely to be comparable to those currently deemed acceptable in treating high-risk cardiovascular populations, e.g. the HOPE study population. DISCUSSION: The costs of screening for and treating LVH in normotensive patients at risk of cardiovascular events do not appear to be prohibitively high. Trials of screening and treatment for normotensive LVH seem therefore to be warranted.

Cardiovascular prophylaxis with aspirin: costs of supply and management of upper gastrointestinal and renal toxicity.

AIMS: To determine the cost to the NHS of prescribed low-dose aspirin. METHODS: This was a population based observational cohort study. Patients from Tayside Scotland (17 244 new users of dispensed aspirin each with 10 matched comparators) were included. A pragmatic analysis totalled costs from the start to end of the study and compared these with a matched cohort of aspirin nonusers to estimate excess costs. Fastidious analyses were done of subjects with no prior history of upper gastrointestinal (UGI) or renal disease where the cost that occurred during aspirin exposure, the 30 days following aspirin exposure and subsequent nonexposure was calculated adjusting for risk factors in each period. RESULTS: Subjects took aspirin for only 1.18 of the 2.53 years follow-up (47% compliance). Aspirin use cost an additional 49.86 UK pounds per year (pragmatic analysis) made up of 1.96 UK pounds for aspirin tablets (4%), 5.49 UK pounds for dispensing costs (11%), 24.60 UK pounds for UGI complications (49%) and 17.81 UK pounds for renal complications (36%). The costs for managing complications were substantially lower in the fastidious analysis (2.66 UK pounds for UGI complications and 2.92 UK pounds for renal complications). Assuming that the antiplatelet trial meta-analysis is an accurate assessment of the benefits of aspirin, the costs of preventing one vascular event lay between 62 500 UK pounds (primary prevention, pragmatic analysis) and 867 UK pounds (secondary prevention, fastidious analysis). These costs may be underestimates due to the low compliance observed. CONCLUSIONS: Compliance with aspirin was poor. Serious adverse events were uncommon but despite this aspirin cost the NHS between 6 and 25 times the cost of aspirin tablets due to dispensing costs and the cost of managing adverse effects.

A pharmacoeconomic comparison of misoprostol/diclofenac with diclofenac.

OBJECTIVES: To estimate the economic impact of misoprostol/diclofenac in a fixed combination tablet compared with diclofenac. DESIGN: Cohort study with a prospectively constructed, population-based, record-linkage database containing details of exposure to all community dispensed NSAIDs and all admissions to hospital for upper gastrointestinal (GI) diagnoses. Costs associated with each study drug exposure were analysed using generalized linear models. SETTING: The population of Tayside, Scotland. SUBJECTS: Subjects aged 20 years and over who received misoprostol/diclofenac or any other NSAID between January 1989 and 31 December 1995. MAIN OUTCOME MEASURES: Total costs for the number of days of exposure to diclofenac and misoprostol/diclofenac, plus costs of concomitant ulcer healing drug therapy plus endoscopy procedures plus costs of admissions to hospital for upper GI diagnoses. RESULTS: The rate of hospitalization with gastrointestinal events was 30% higher among patients receiving diclofenac than that for patients receiving misoprostol/diclofenac. Among patients who received diclofenac and an ulcer-healing drug (UHD), the event rate was more than twice that for patients receiving misoprostol/diclofenac. In patients with a prior GI history, switching from diclofenac to misoprostol/diclofenac would reduce the costs of hospitalization. The resulting savings would more than offset the extra prescription costs. In patients without a prior GI history, the greatest potential saving would arise due to reduced use of UHDs and net savings would occur in subjects aged between 60 and 70 years of age or more. CONCLUSION: Use of misoprostol/diclofenac instead of diclofenac can produce cost savings due to reduced hospitalization rates and decreased use of UHDs in subjects with a prior history of GI disease and in older subjects without prior GI disease. These findings have implications for the management of patients who require treatment with NSAIDs.

Prior trimethoprim use and trimethoprim-resistant urinary tract infection: a nested case-control study with multivariate analysis for other risk factors.

Trimethoprim resistance is increasingly prevalent in community-acquired urinary infections. The objective of this study was to evaluate the association between exposure to community-prescribed trimethoprim and other risk factors in subjects and subsequent trimethoprim-resistant urinary tract infection. The design was a nested case-control study using a record-linkage database. Study subjects submitted a urine sample to the Ninewells Hospital Laboratory between July 1993 and December 1995. Antibiotic exposure in subjects with trimethoprim-resistant isolates (cases) was compared with antibiotic exposure in subjects with trimethoprim-susceptible isolates (controls). Study subjects were drawn from the catchment area of a large teaching hospital in Tayside, Scotland. There were 13765 males and females aged 1-106 years who submitted their first urine sample for culture during the study period. After adjustment for significant risk factors and confounding variables, logistic regression analysis showed exposure to trimethoprim [odds ratio (OR) 4.35] or any antibiotic other than trimethoprim (OR 1.32) to be predictive of resistance. The growth of Proteus spp. (OR 115.14) and bacterial growth other than Escherichia coli and Proteus spp. (OR 2.83) were also predictor variables. Hospitalization in the previous 6 months was not independently associated with trimethoprim resistance. In conclusion, trimethoprim resistance was independently associated with exposure to trimethoprim and to antibiotics other than trimethoprim. Reduction in trimethoprim prescribing alone may not reduce the prevalence of trimethoprim resistance.

Practice factors that influence antibiotic prescribing in general practice in Tayside.

A cohort design was used to evaluate antibiotic prescribing in relation to patient and general practice characteristics. The study included prescribing to all subjects resident in Tayside, from January to December 1994 and found 215217 antibiotic prescriptions dispensed to 118596 people. Training status of general practitioners (GPs) was found to be the characteristic most associated with prescribing. Adjusting for other GP characteristics had little effect on these results. Training practice status was the dominant factor associated with significant differences in rates of antibiotic prescribing, in class of antibiotic prescribed and in performance indicators of antibiotic prescribing.

Community antibiotic therapy, hospitalization and subsequent respiratory tract isolation of Haemophilus influenzae resistant to amoxycillin: a nested case-control study.

The study objective was to determine whether recent community antibiotic prescribing and hospitalization are associated with beta-lactam resistance in respiratory isolates of Haemophilus influenzae. Data obtained for hospitalization and community prescribing (in the previous 3 months) from 412 adults (>15 years) in whom an episode of respiratory tract infection had been described, during which H. influenzae was isolated, were analysed. Seventy-three (17.7%) isolates of H. influenzae were resistant to amoxycillin. Resistance was associated with recent hospitalization [odds ratio (OR) 3.2, 1.8-5.6] and antibiotic exposure in the community (2.1, 1.2-3.6). These variables were independently associated with amoxycillin resistance [hospitalization (OR 4.5, 1. 7-12.5) and community beta-lactam antibiotic exposure (3.9, 1.6-9. 8)]. Hospitalized patients probably received antibiotics during their admission although aquisition of the organism or the beta-lactamase via plasmids from other Gram-negative organisms in the hospital could also be a factor. Control measures to reduce the inappropriate use of antimicrobials in the community and in hospital need to be reinforced.

Selegiline and mortality in subjects with Parkinson's disease: a longitudinal community study.

OBJECTIVE: To estimate mortality by drug use in a cohort of patients with PD relative to age- and sex-matched comparators. METHODS: two longitudinal cohorts of patients with 7 and 11 years' duration of PD were constructed with matched comparators in Tayside, Scotland. Subjects were eligible for inclusion if they received a first prescription for an anti-Parkinson's drug from July 1989 to December 1995, with no PD drug prescription in the previous 6 months. Those who had previously taken a neuroleptic drug or were younger than 40 years of age were excluded. RESULTS: Overall, subjects with PD in relation to comparators had higher mortality with a rate ratio (RR) of 1.76 (95% CI 1.11, 2.81) in the 7-year cohort. There was significantly greater mortality in patients with PD who received levodopa monotherapy (RR = 2.45, 95% CI 1.42, 4.23) relative to the comparators, adjusting for previous cardiovascular drug use and diabetes. However, there was no significant difference in mortality in those with PD receiving combination therapy of selegiline with levodopa and other drugs in relation to the comparators (RR = 0.92, 95% CI 0.37, 2.31). CONCLUSIONS: Subjects with PD had twice the rate of mortality relative to age- and sex-matched comparators. However, those subjects who received selegiline at any time in combination with co-careldopa or co-beneldopa showed no significant difference in mortality compared with the comparators. Monotherapy with levodopa was associated with the highest mortality.

Continuity of prescribing with inhaled corticosteroids and control of asthma.

Purpose-Current asthma guidelines advocate early intervention with inhaled corticosteroids. The aim of the study was to examine the association between continuity of dispensed prescribing for inhaled corticosteroids, and hospitalization for asthma or use of high dose oral corticosteroids.Methods-Using the MEMO record-linkage database we identified subjects receiving inhaled corticosteroids (aged 12 - 45 years). Compliance was estimated by calculating the number of days, for which a subject could have taken an inhaled corticosteroid. In the 90-day exposure-window, subjects with 90 days therapy were considered to be 'compliant', those with 1 - 89 days to be 'partially compliant', and those with zero days to be 'non-compliant'.Results-There were 4535 subjects who had 88 occurrences of hospitalization for asthma, and 457 subjects with either hospitalization or high dose oral corticosteroids. The proportion of hospitalizations for compliant, partially compliant and noncompliant subjects was 9, 3 and 1%. The odds-ratios, versus compliance, were 0.34 (95% CI, 0.19 - 0.62) for partial compliance, and 0.10 (95% CI, 0.05, 0.19) for non-compliance. This association disappeared after adjustment for beta-agonists and other relief medication.Conclusions-As dispensed prescribing decreased, the incidence of hospitalization and high dose oral corticosteroids decreased. Patients with good continuity of prescribing had the highest rates of serious asthma-related outcomes. Copyright (c) 2000 John Wiley & Sons, Ltd.

Self-medication of antibacterials without prescription (also called 'over-the-counter' use). A report of a Working Party of the British Society for Antimicrobial Chemotherapy.

The availability of antimicrobial agents for self-medication may increase and could include antibacterial agents for oral or topical use. Wholesale deregulation of antibacterials would be undesirable and likely to encourage misuse of classes of agents currently important in the management of serious infections. Changed regulation from Prescription-Only Medicine (POM) to Pharmacy (P) medicine of selected agents with indications for short-term use in specific minor infections and illness is likely to have advantages to the user. However, safeguards to their use would need to be included in the Patient Information Leaflet (PIL). Agents and indications for self-medication are discussed. Any alteration in licensed status from POM to P will require careful risk-benefit assessment, including the likely impact on bacterial resistance. Safety issues also include concerns relating to age of the user, pregnancy, underlying disease and the potential for drug interactions. The importance of appropriate information with the PIL is emphasized, as is the role of the pharmacist, while ways of improving adverse event notification and monitoring are discussed. The paucity of good denominator-controlled data on the prevalence of in-vitro resistance is highlighted, and recommendations for improving the situation are made. There are currently no levels of resistance accepted by regulatory bodies on which to base a licensing decision, be it for granting a product licence, renewal of a licence or a change in licensed status from POM to P. Due consideration should be given to: the validation of user-defined indications in comparison with those medically defined; the enhancement of pharmacy advice in the purchase of such agents; improved safety monitoring; the establishment of systematic surveillance of susceptibility data.

Factors associated with trimethoprim-resistant bacteria isolated from urine samples.

Urine samples with trimethoprim-resistant or trimethoprim-sensitive Gram-negative bacteria and samples with no bacterial growth (NG) were identified. Age-sex matched community controls were generated with each trimethoprim-resistant case. These four groups were evaluated for exposure. Prior trimethoprim use was significantly more common in the trimethoprim-resistant group when compared with the trimethoprim-sensitive or the NG group. Prior hospitalization was significantly less common in the trimethoprim-resistant than the trimethoprim-sensitive group, but not with the NG group. Prior oestrogen exposure was associated with trimethoprim resistance. There were no associations found for diabetes or prior corticosteroid exposure. Community controls were found to be inappropriate controls for the study of trimethoprim-resistant bacteria in urine samples.