Iryna Schlackow

Decline of meticillin-resistant Staphylococcus aureus in Oxfordshire hospitals is strain-specific and preceded infection-control intensification

Background In the past, strains of Staphylococcus aureus have evolved, expanded, made a marked clinical impact and then disappeared over several years. Faced with rising meticillin-resistant S aureus (MRSA) rates, UK government-supported infection control interventions were rolled out in Oxford Radcliffe Hospitals NHS Trust from 2006 onwards. Methods Using an electronic Database, the authors identified isolation of MRS among 611 434 hospital inpatients admitted to acute hospitals in Oxford, UK, 1 April 1998 to 30 June 2010. Isolation rates were modelled using segmented negative binomial regression for three groups of isolates: from blood cultures, from samples suggesting invasion (eg, cerebrospinal fluid, joint fluid, pus samples) and from surface swabs (eg, from wounds). Findings MRSA isolation rates rose rapidly from 1998 to the end of 2003 (annual increase from blood cultures 23%, 95% CI 16% to 30%), and then declined. The decline accelerated from mid-2006 onwards (annual decrease post-2006 38% from blood cultures, 95% CI 29% to 45%, p=0.003 vs previous decline). Rates of meticillin-sensitive S aureus changed little by comparison, with no evidence for declines 2006 onward (p=0.40); by 2010, sensitive S aureus was far more common than MRSA (blood cultures: 2.9 vs 0.25; invasive samples 14.7 vs 2.0 per 10 000 bedstays). Interestingly, trends in isolation of erythromycin-sensitive and resistant MRSA differed. Erythromycin-sensitive strains rose significantly faster (eg, from blood cultures p=0.002), and declined significantly more slowly (p=0.002), than erythromycin-resistant strains (global p<0.0001). Bacterial typing suggests this reflects differential spread of two major UK MRSA strains (ST22/36), ST36 having declined markedly 2006–2010, with ST22 becoming the dominant MRSA strain. Conclusions MRSA isolation rates were falling before recent intensification of infection-control measures. This, together with strain-specific changes in MRSA isolation, strongly suggests that incompletely understood biological factors are responsible for the much recent variation in MRSA isolation. A major, mainly meticillin-sensitive, S aureus burden remains.

Increasing incidence of Escherichia coli bacteraemia is driven by an increase in antibiotic-resistant isolates: electronic database study in Oxfordshire 1999–2011

OBJECTIVES To investigate trends in Escherichia coli resistance, bacteraemia rates and post-bacteraemia outcomes over time. METHODS Trends in E. coli bacteraemia incidence were monitored from January 1999 to June 2011 using an infection surveillance database including microbiological, clinical risk factor, infection severity and outcome data in Oxfordshire, UK, with imported temperature/rainfall data. RESULTS A total of 2240 E. coli (from 2080 patients) were studied, of which 1728 (77%) were susceptible to co-amoxiclav, cefotaxime, ciprofloxacin and gentamicin. E. coli bacteraemia incidence increased from 3.4/10,000 bedstays in 1999 to 5.7/10,000 bedstays in 2011. The increase was fastest around 2006, and was essentially confined to organisms resistant to ciprofloxacin, co-amoxiclav, cefotaxime and/or aminoglycosides. Resistant E. coli isolation rates increased similarly in those with and without recent hospital contact. The sharp increase also occurred in urinary isolates, with similar timing. In addition to these long-term trends, increases in ambient temperature, but not rainfall, were associated with increased E. coli bacteraemia rates. It is unclear whether resistant E. coli bacteraemia rates are currently still increasing [incidence rate ratio = 1.07 per annum (95% CI = 0.99-1.16), P = 0.07], whereas current susceptible E. coli bacteraemia rates are not changing significantly [incidence rate ratio = 1.01 (95% CI = 0.99-1.02)]. However, neither mortality nor biomarkers associated with mortality (blood creatinine, urea/albumin concentrations, neutrophil counts) changed during the study. CONCLUSIONS E. coli bacteraemia rates have risen due to rising rates of resistant organisms; little change occurred in susceptible E. coli. Although the severity of resistant infections, and their outcome, appear similar to susceptible E. coli in the setting studied, the increasing burden of highly resistant organisms is alarming and merits on-going surveillance.

What is the impact of chronic kidney disease stage and cardiovascular disease on the annual cost of hospital care in moderate-to-severe kidney disease?

BackgroundReliable estimates of the impacts of chronic kidney disease (CKD) stage, with and without cardiovascular disease, on hospital costs are needed to inform health policy.MethodsThe Study of Heart and Renal Protection (SHARP) randomized trial prospectively collected information on kidney disease progression, serious adverse events and hospital care use in a cohort of patients with moderate-to-severe CKD. In a secondary analysis of SHARP data, the impact of participants’ CKD stage, non-fatal cardiovascular events and deaths on annual hospital costs (i.e. all hospital admissions, routine dialysis treatments and recorded outpatient/day-case attendances in United Kingdom 2011 prices) were estimated using linear regression.Results7,246 SHARP patients (2,498 on dialysis at baseline) from Europe, North America, and Australasia contributed 28,261 years of data. CKD patients without diabetes or vascular disease incurred annual hospital care costs ranging from £403 (95% confidence interval: 345-462) in CKD stages 1-3B to £525 (449-602) in CKD stage 5 (not on dialysis). Patients in receipt of maintenance dialysis incurred annual hospital costs of £18,986 (18,620-19,352) in the year of initiation and £23,326 (23,231-23,421) annually thereafter. Patients with a functioning kidney transplant incurred £24,602 (24,027-25,178) in hospital care costs in the year of transplantation and £1,148 (978-1,318) annually thereafter. Non-fatal major vascular events increased annual costs in the year of the event by £6,133 (5,608-6,658) for patients on dialysis and by £4,350 (3,819-4,880) for patients not on dialysis, and were associated with increased costs, though to a lesser extent, in subsequent years.ConclusionsRenal replacement therapy and major vascular events are the main contributors to the high hospital care costs in moderate-to-severe CKD. These estimates of hospital costs can be used to inform health policy in moderate-to-severe CKD.

Mapping from the Parkinson’s Disease Questionnaire PDQ-39 to the Generic EuroQol EQ-5D-3L: The Value of Mixture Models

Objective. To compare a range of statistical models to enable the estimation of EQ-5D-3L utilities from responses to the Parkinson’s Disease Questionnaire 39 (PDQ-39). Methods. Linear regression, beta regression, mixtures of linear regressions and beta regressions, and multinomial logistic regression were compared in terms of their ability to accurately predict EQ-5D-3L utilities from responses to the PDQ-39 using mean error (ME), mean absolute error (MAE), and mean square error (MSE), overall and by Hoehn and Yahr stage. Models were estimated using data from the PD MED trial (n = 9123) and assessed on both the estimation data as well as external data from the PD SURG trial (n = 917). Results. Overall, the differences in the metrics of fit between models were small in both data sets, with performance poorer for all models in PD SURG. The performance across Hoehn and Yahr stages 1 to 3 were also similar, but multinomial logistic regression was found to exhibit less bias and better individual-level predictive accuracy in PD MED for those in Hoehn and Yahr stages 4 or 5. Overall, the multinomial logistic regression reported an ME of 0.038 out of sample and MAEs of 0.128 and 0.164 and MSEs of 0.030 and 0.044 in the estimation and external data sets, respectively. Poorer levels of the mobility domain score of the PDQ-39 were associated with increased odds of reporting problems for all EQ-5D domains except anxiety/depression. Conclusions. Finite mixture models with only few components can approximate the distribution of EQ-5D-3L utilities well but did not demonstrate improvements in predictive accuracy compared with multinomial logistic regression in the present data set.

Impact of Educational Attainment on Health Outcomes in Moderate to Severe CKD

Background The inverse association between educational attainment and mortality is well established, but its relevance to vascular events and renal progression in a population with chronic kidney disease (CKD) is less clear. This study aims to determine the association between highest educational attainment and risk of vascular events, cause-specific mortality, and CKD progression. Study Design Prospective epidemiologic analysis among participants in the Study of Heart and Renal Protection (SHARP), a randomized controlled trial. Setting & Participants 9,270 adults with moderate to severe CKD (6,245 not receiving dialysis at baseline) and no history of myocardial infarction or coronary revascularization recruited in Europe, North America, Asia, Australia, and New Zealand. Predictor Highest educational attainment measured at study entry using 6 levels that ranged from “no formal education” to “tertiary education.” Outcomes Any vascular event (any fatal or nonfatal cardiac, cerebrovascular, or peripheral vascular event), cause-specific mortality, and CKD progression during 4.9 years’ median follow-up. Results There was a significant trend (P < 0.001) toward increased vascular risk with decreasing levels of education. Participants with no formal education were at a 46% higher risk of vascular events (relative risk [RR], 1.46; 95% CI, 1.14-1.86) compared with participants with tertiary education. The trend for mortality across education levels was also significant (P < 0.001): all-cause mortality was twice as high among those with no formal education compared with tertiary-educated individuals (RR, 2.05; 95% CI, 1.62-2.58), and significant increases were seen for both vascular (RR, 1.84; 95% CI, 1.21-2.81) and nonvascular (RR, 2.15; 95% CI, 1.60-2.89) deaths. Lifestyle factors and prior disease explain most of the excess mortality risk. Among 6,245 participants not receiving dialysis at baseline, education level was not significantly associated with progression to end-stage renal disease or doubling of creatinine level (P for trend = 0.4). Limitations No data for employment or health insurance coverage. Conclusions Lower educational attainment is associated with increased risk of adverse health outcomes in individuals with CKD.

Cost-effectiveness of Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD: Results of the Study of Heart and Renal Protection (SHARP).

Background Simvastatin, 20 mg, plus ezetimibe, 10 mg, daily (simvastatin plus ezetimibe) reduced major atherosclerotic events in patients with moderate to severe chronic kidney disease (CKD) in the Study of Heart and Renal Protection (SHARP), but its cost-effectiveness is unknown. Study Design Cost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial. Setting & Population 9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, <10%; medium, 10%-<20%; or high, ≥20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy). Model, Perspective, & Timeline Assessment during SHARP follow-up from the UK perspective; long-term projections. Intervention Simvastatin plus ezetimibe (2015 UK £1.19 per day) during 4.9 years’ median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK £0.05-£1.06 per day). Outcomes Additional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained. Results In SHARP, the proportional reductions per 1 mmol/L of low-density lipoprotein (LDL) cholesterol reduction with simvastatin plus ezetimibe in all major atherosclerotic events of 20% (95% CI, 6%-32%) and in the costs of vascular hospital episodes of 17% (95% CI, 4%-28%) were similar across participant categories by cardiovascular risk and CKD stage. The 5-year reduction in major atherosclerotic events per 1,000 participants ranged from 10 in low-risk to 58 in high-risk patients and from 28 in CKD stage 3 to 36 in patients on dialysis therapy. The net cost per major atherosclerotic event avoided with simvastatin plus ezetimibe compared to no LDL-lowering regimen ranged from £157,060 in patients at low risk to £15,230 in those at high risk (£30,500-£39,600 per QALY); and from £47,280 in CKD stage 3 to £28,180 in patients on dialysis therapy (£13,000-£43,300 per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost. Limitations High-intensity statin-alone regimens were not studied in SHARP. Conclusions Simvastatin plus ezetimibe prevented atherosclerotic events in SHARP, but other less costly statin regimens are likely to be more cost-effective for reducing cardiovascular risk in CKD.

Surveillance of infection severity: a registry study of laboratory diagnosed Clostridium difficile.

Iryna Schlackow and colleagues investigated whether electronic systems providing early warning of changing severity of infectious conditions can be established using routinely collected laboratory hospital data. They showed that for Clostridium difficile infection, these systems perform better than those monitoring mortality.

A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease

Objective To present a long-term policy model of cardiovascular disease (CVD) in moderate-to-advanced chronic kidney disease (CKD). Methods A Markov model with transitions between CKD stages (3B, 4, 5, on dialysis, with kidney transplant) and cardiovascular events (major atherosclerotic events, haemorrhagic stroke, vascular death) was developed with individualised CKD and CVD risks estimated using the 5 years’ follow-up data of the 9270 patients with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP) and multivariate parametric survival analysis. The model was assessed in three further CKD cohorts and compared with currently used risk scores. Results Higher age, previous cardiovascular events and advanced CKD were the main contributors to increased individual disease risks. CKD and CVD risks predicted by the state-transition model corresponded well to risks observed in SHARP and external cohorts. The model’s predictions of vascular risk and progression to end-stage renal disease were better than, or comparable to, those produced by other risk scores. As an illustration, at age 60–69 years, projected survival for SHARP participants in CKD stage 3B was 13.5 years (10.6 quality-adjusted life years (QALYs)) in men and 14.8 years (10.7 QALYs) in women. Corresponding projections for participants on dialysis were 7.5 (5.6 QALYs) and 7.8 years (5.4 QALYs). A non-fatal major atherosclerotic event reduced life expectancy by about 2 years in stage 3B and by 1 year in dialysis. Conclusions The SHARP CKD-CVD model is a novel resource for evaluating health outcomes and cost-effectiveness of interventions in CKD. Trial registration number NCT00125593 and ISRCTN54137607; Post-results.

Impact of CKD on Household Income

Introduction The impact of chronic kidney disease (CKD) on income is unclear. We sought to determine whether CKD severity, serious adverse events, and CKD progression affected household income. Methods Analyses were undertaken in a prospective cohort of adults with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP), with household income information available at baseline screening and study end. Logistic regressions, adjusted for sociodemographic characteristics, smoking, and prior diseases at baseline, estimated associations during the 5-year follow-up, among (i) baseline CKD severity, (ii) incident nonfatal serious adverse events (vascular or cancer), and (iii) CKD treatment modality (predialysis, dialysis, or transplanted) at study end and the outcome “fall into relative poverty.” This was defined as household income <50% of country median income. Results A total of 2914 SHARP participants from 14 countries were included in the main analysis. Of these, 933 (32%) were in relative poverty at screening; of the remaining 1981, 436 (22%) fell into relative poverty by study end. Compared with participants with stage 3 CKD at baseline, the odds of falling into poverty were 51% higher for those with stage 4 (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.09–2.10), 66% higher for those with stage 5 (OR: 1.66; 95% CI: 1.11–2.47), and 78% higher for those on dialysis at baseline (OR: 1.78, 95% CI: 1.22–2.60). Participants with kidney transplant at study end had approximately half the risk of those on dialysis or those with CKD stages 3 to 5. Conclusion More advanced CKD is associated with increased odds of falling into poverty. Kidney transplantation may have a role in reducing this risk.

Developing a lifetime disease model from RCT data using parametric models with time-updated covariates

Aims Patients with moderate to advanced chronic kidney disease (CKD) are at increased risk of cardiovascular (CV) events, which, in turn, accelerate CKD progression. We use data from the 9,270-patient Study of Heart and Renal Protection (SHARP) to develop a disease model that takes into account the interdependence between CKD progression and CV risk over time and can be used to simulate disease outcomes and life expectancy over lifetime.