Jesper Smit

Prevalence of infective endocarditis in patients with Staphylococcus aureus bacteraemia: the value of screening with echocardiography

AIMS Staphylococcus aureus infective endocarditis (IE) is a critical medical condition associated with a high morbidity and mortality. In the present study, we prospectively evaluated the importance of screening with echocardiography in an unselected S. aureus bacteraemia (SAB) population. METHODS AND RESULTS From 1 January 2009 to 31 August 2010, a total of 244 patients with SAB at six Danish hospitals underwent screening echocardiography. The inclusion rate was 73% of all eligible patients (n= 336), and 53 of the 244 included patients (22%; 95% CI: 17-27%) were diagnosed with definite IE. In patients with native heart valves the prevalence was 19% (95% CI: 14-25%) compared with 38% (95% CI: 20-55%) in patients with prosthetic heart valves and/or cardiac rhythm management devices (P= 0.02). No difference was found between Main Regional Hospitals and Tertiary Cardiac Hospitals, 20 vs. 23%, respectively (NS). The prevalence of IE in high-risk patients with one or more predisposing condition or clinical evidence of IE were significantly higher compared with low-risk patients with no additional risk factors (38 vs. 5%; P < 0.001). IE was associated with a higher 6 months mortality, 14(26%) vs. 28(15%) in SAB patients without IE, respectively (P < 0.05). CONCLUSION SAB patients carry a high risk for development of IE, which is associated with a worse prognosis compared with uncomplicated SAB. The presenting symptoms and clinical findings associated with IE are often non-specific and echocardiography should always be considered as part of the initial evaluation of SAB patients.

Infections associated with permanent pacemakers and implanted cardioverter-defibrillator devices. A 10-year regional study in Denmark.

Abstract Endocarditis and localized pocket infections are recognized as serious adverse events in patients with implanted cardiac impulse generators. We have undertaken a 10-y retrospective study in North Denmark Region (population 0.5 million) in order to elucidate the clinical spectrum, causative microorganisms, management and outcome. Infections associated with permanent pacemakers (PPM) and implanted cardioverter-defibrillator (ICD) devices were identified by searching hospital databases. Ninety-one incident cases were recorded in 1999 through 2008: 26 patients had endocarditis, 39 patients had a localized pocket infection, and 9 patients developed surgical sepsis with or without local signs immediately after implantation or reoperation; the device was the likely but unconfirmed focus of infection in 17 patients with bacteraemia. Staphylococcus aureus, coagulase-negative staphylococci and other Gram-positive bacteria were the predominant causative agents; only 6 cases were culture-negative. Management included device and lead extraction and individualized antibiotic therapy. The all-cause 30-day case-fatality was 11%. Only 3 recurrences were recorded during 2 y of follow-up. In conclusion, infections associated with permanent impulse generators have a broader clinical spectrum than often reported in the literature. Most cases are culture-positive with staphylococcal predominance. The short-term mortality is notably high, but the risk of recurrence is low.

Diabetes and risk of community-acquired Staphylococcus aureus bacteremia: A population-based case-control study

OBJECTIVE Patients with diabetes may experience higher risk of Staphylococcus aureus bacteremia (SAB) than patients without diabetes due to decreased immunity or coexisting morbidities. We investigated the risk of community-acquired (CA) SAB in persons with and without diabetes. DESIGN Using population-based medical databases, we conducted a case-control study of all adults with first-time CA-SAB and matched population controls in Northern Denmark, 2000-2011. METHODS Based on conditional logistic regression, we computed odds ratios (ORs) of CA-SAB according to diabetes. We further assessed whether the risk of CA-SAB differed according to various diabetes-related characteristics (e.g. duration of diabetes, glycemic control, and presence of diabetes complications). RESULTS We identified 2638 patients with incident CA-SAB, of whom 713 (27.0%) had diabetes, and 26,379 matched population controls (2495 or 9.5% with diabetes). Individuals with diabetes had a substantially increased risk of CA-SAB compared with population controls (adjusted OR = 2.8 (95% confidence interval (CI): 2.5-3.1)). Duration of diabetes of ≥10 years and poor glycemic control conferred higher risk estimates, with an adjusted OR = 2.3 (95% CI: 1.9-2.7) for diabetes with Hba1c < 7% (< 53 mmol/mol) and an adjusted OR = 5.7 (95% CI: 4.2-7.7) for diabetes with Hba1c ≥9% (≥75 mmol/mol). The risk of CA-SAB was particularly high in patient with diabetes complications: adjusted OR = 5.5 (95% CI: 4.2-7.2) with presence of microvascular complications and OR = 7.0 (95% CI: 5.4-9.0) with combined macro- and microvascular complications. CONCLUSIONS Diabetes is associated with a substantially increased risk of CA-SAB, particularly in patients with diabetes of long duration, poor glycemic control, and diabetes complications.

Classification of Healthcare-Associated Staphylococcus aureus Bacteremia: Influence of Different Definitions on Prevalence, Patient Characteristics, and Outcome

We investigated whether different definitions of healthcare-associated infection influenced the prevalence, characteristics, and mortality of patients with Staphylococcus aureus bacteremia. With different definitions, the proportion of patients classified as having healthcare-associated S. aureus bacteremia varied substantially and the distribution of patient characteristics was influenced, whereas 30-day mortality remained robust.

Statin Use and Risk of Community-Acquired Staphylococcus aureus Bacteremia: A Population-Based Case-Control Study

Objective: To ascertain whether persons treated with statins experience a decreased risk of community‐acquired Staphylococcus aureus bacteremia (CA‐SAB) as compared with nonusers. Patients and Methods: Using population‐based medical registries, we conducted a case‐control study including all adults with first‐time CA‐SAB and population controls matched on age, sex, and residence in Northern Denmark from January 1, 2000, through December 31, 2011. Statin users were categorized as current users (new or long‐term use), former users, and nonusers. We used conditional logistic regression to compute odds ratios (ORs) for CA‐SAB according to statin exposure, overall and stratified by intensity (<20, 20–39, ≥40 mg/d) and duration of use (<365, 365–1094, ≥1095 days). Results: We identified 2638 patients with first‐time CA‐SAB and 26,379 matched population controls. Compared with nonusers, current statin users experienced markedly decreased risk of CA‐SAB (adjusted OR, 0.73; 95% CI, 0.63–0.84). The adjusted OR was 0.96 (95% CI, 0.60–1.51) for new users, 0.71 (95% CI, 0.62–0.82) for long‐term users, and 1.12 (95% CI, 0.94–1.32) for former users as compared with nonusers. The CA‐SAB risk decreased with increasing intensity of statin use; thus, compared with nonusers, the adjusted OR was 0.84 (95% CI, 0.68–1.04) for current users with daily dosages of less than 20 mg/d, 0.71 (95% CI, 0.58–0.87) for 20 to 39 mg/d, and 0.63 (95% CI, 0.49–0.81) for 40 mg/d or more. Conversely, we observed no differences in the risk of CA‐SAB with successive increases in the duration of statin use. Conclusion: Statin use was associated with a decreased risk of CA‐SAB, particularly in long‐term users.

Use of Glucocorticoids and Risk of Community-Acquired Staphylococcus aureus Bacteremia: A Population-Based Case-Control Study

OBJECTIVE To investigate whether the use of systemic glucocorticoids is a risk factor for community-acquired Staphylococcus aureus bacteremia (CA-SAB). PATIENTS AND METHODS We used population-based medical registries in Northern Denmark to conduct a case-control study including all adults with first-time CA-SAB and matched population controls from January 1, 2000, through December 31, 2011. Glucocorticoid users were categorized as current users (new or long-term use), former users, and nonusers. Using conditional logistic regression, we computed odds ratios (ORs) of CA-SAB according to glucocorticoid exposure, overall and by 90-day prednisolone-equivalent cumulative dose. RESULTS We identified 2638 patients with first-time CA-SAB and 26,379 matched population controls. Current glucocorticoid users experienced considerably increased risk of CA-SAB compared with nonusers (adjusted OR=2.48; 95% CI, 2.12-2.90). The adjusted OR was 2.73 (95% CI, 2.17-3.45) in new users, 2.31 (95% CI, 1.90-2.82) in long-term users, and much lower at 1.33 (95% CI, 0.98-1.81) in former users of glucocorticoids compared with nonusers. The risk of CA-SAB increased with higher 90-day cumulative doses. Compared with nonusers of glucocorticoids, the adjusted OR was 1.32 (95% CI, 1.01-1.72) for persons with a cumulative dose of 150 mg or less, 2.42 (95% CI, 1.76-3.33) for persons whose cumulative dose was greater than 500 to 1000 mg, and 6.25 (95% CI, 4.74-8.23) for persons with a cumulative dose greater than 1000 mg. CONCLUSION Glucocorticoid use was associated with a substantially increased risk of CA-SAB. The risk increased with higher cumulative dose, revealing a distinct dose-response relation.

Vogt–Koyanagi–Harada syndrome: A rare but important differential diagnosis of viral meningitis

Abstract Vogt–Koyanagi–Harada syndrome (VKHS) is an inflammatory syndrome affecting melanocyte-containing organs. The clinical onset is often acute with neurological and ophthalmological symptoms and there is considerable risk of sequelae if the condition is not promptly diagnosed and treated. We present a case illustrating that VKHS is a rare but important differential diagnosis of viral meningitis.

Onset of symptoms, diagnostic confirmation, and occurrence of multiple infective foci in patients with Staphylococcus aureus bloodstream infection: a look into the order of events and potential clinical implications

PurposeData on the systemic dissemination in Staphylococcus aureus bloodstream infection (SAB) remain sparse. We investigated the timing and the sequence of clinical symptoms, diagnostic confirmation, and occurrence of multiple infective foci in relation to three major infective foci.MethodsFrom 2006 to 2011, all adult patients with first-time SAB in Cologne and Freiburg, Germany were followed prospectively. The study was restricted to patients with short-term central venous catheter (CVC)-related SAB, vertebral osteomyelitis (VO), and infective endocarditis (IE). The collection date of the first positive blood culture was used as reference point for determining time to onset of clinical symptoms, microbiological findings, imaging results compatible with focal infection, and occurrence of additional infective foci.ResultsWe included 266 patients with first-time SAB. Among patients with CVC-related SAB, clinical onset, collection of the first positive blood culture, and microbiological confirmation almost coincided. In contrast, among patients with VO or IE, the onset of clinical symptoms most often preceded the collection of the first positive blood culture, and imaging and microbiological confirmation were most frequently obtained subsequent to the SAB diagnosis. CVC-related SAB was infrequently associated with further foci (n = 15/15.5%). Conversely, more than one infective focus was observed in 44 (56.4%) patient with VO and 68 (64.8%) patients with IE.ConclusionsThe sequence of clinical symptoms, diagnostic confirmation, and occurrence of multiple infective foci varied considerably with different infective foci in SAB. Based on these results, we propose a pragmatic and evidence-based terminology for the clinical course of SAB and suggest the terms “portal of entry”, “infective focus”, “multiple infective foci”, and “dominant infective focus”.

Outcome of Community-Acquired Staphylococcus aureus Bacteraemia in Patients with Diabetes: A Historical Population-Based Cohort Study

Background Patients with diabetes (DM) experience increased risk of Staphylococcus aureus bacteraemia (SAB), but the prognostic impact of diabetes in patients with SAB remain unclear. Therefore, we investigated 30-day all-cause mortality in patients with and without DM. Methods Population-based medical databases were used to conduct a cohort study of all adult patients with community-acquired SAB in Northern Denmark, 2000–2011. Using Cox proportional hazards regression, we computed hazard ratios as estimates of 30-day mortality rate ratios (MRRs) among patients with and without DM. We further investigated whether the prognostic impact of DM differed among patients with and without recent preadmission healthcare contacts (within 30 days of the current hospitalization) and by age, sex, marital status, level of comorbidity, and DM-related characteristics (e.g., duration of DM and presence of DM complications). Results Among 2638 SAB patients, 713 (27.0%) had DM. Thirty-day cumulative mortality was 25.8% in patients with DM and 24.3% in patients without DM, for an adjusted MRR (aMRR) of 1.01 (95% confidence interval (CI), 0.84–1.20). In analyses with and without recent healthcare contacts, the corresponding aMRRs were 0.84 (95% CI, 0.62–1.14) and 1.13 (95% CI, 0.91–1.41), respectively. Compared to patients without DM, the aMRR was 0.94 (95% CI, 0.74–1.20) for male patients with DM and 1.13 (95% CI, 0.87–1.47) for female patients with DM. The prognostic influence of DM on mortality did not differ notably with age, level of comorbidity, or characteristics of patients with DM. Conclusion Patients with DM and community-acquired SAB did not experience higher 30-day mortality than patients without DM.

Use of Glucocorticoids and Risk of Community-Acquired Staphylococcus aureus Bacteraemia: A Population-Based Case-Control Study

Background: Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor for liver, pancreatic, and colorectal cancer. T2DM patients show higher incidences of these cancers compared to the non-diabetic (non-DM) population. Current evidence, however, is inconsistent with respect to the incidences of other gastrointestinal (GI) malignancies. Objectives: To determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. Methods: A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) during 1988-2012. A T2DM cohort of antidiabetic drug users was matched to a non-DM reference cohort, by age, sex, and practice. Crude incidence rates (IRs) per 100,000 person-years (105 py) and 95% confidence intervals (CI) were calculated, stratified by age, sex, and calendar period. IRs were compared using the normal theory test. Results: 333,438 T2DM subjects and 333,438 non- DM subjects were analyzed, with a total duration of follow-up of >3.6 million py and 10,977 observed GI cancer cases. Overall, IRs of any GI cancer (IR 330 vs. 276 per 105 py), liver cancer (IR 26 vs. 8.9 per 105 py), pancreatic cancer (IR 65 vs. 31 per 105 py), and colon cancer (IR 119 vs. 109 per 105 py) were significantly higher in the T2DM cohort compared to the non-DM cohort, whereas the IR of esophageal cancer was significantly lower (IR 41 vs. 47 per 105 py, pBackground: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, whi ...The article investigates the special features of state control over international transfer of special-purpose and dual-use goods. It was established what international organizations was created in the international community to determine the principles of control over international transfer of special-purpose and dual-use goods, as well as the question of Ukraines joining the circle of member-states of such organizations. The structure of the system of export control bodies in Ukraine was defined, as well as the main powers of the State Service of Export Control of Ukraine in the sphere of control over international transfer of goods. The essence and the concept of goods over which international transfer state export control is carried out in accordance with the Ukrainian legislation were revealed, as well as special aspects of the procedure of state control over their international transfer.Background: Different antiplatelet regimens are used for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA), but studies on the relative effectiveness and safety of each regimen in daily practice are lacking. Objectives: To assess the relative effectiveness and safety of several antiplatelet regimens as secondary prevention in patients after an IS/TIA in clinical practice. Methods: A cohort study was conducted using the Clinical Practice Research Datalink. Patients aged ≥ 18 years with a first diagnosis of IS/TIA in 1998- 2013 were identified. Antiplatelet exposure was categorized into aspirin-dipyridamole, aspirin-only, clopidogrel-only, aspirin-clopidogrel, other regimens, and no-antiplatelet exposure. The primary effectiveness outcome was a composite endpoint of nonfatal IS, nonfatal myocardial infarction (MI), or cardiovascular (CV) death; and the safety outcome was major bleeding. Time-dependent Cox regression analysis was used to assess the association between antiplatelet regimens and CV effectiveness and major bleeding outcomes. Results: We followed 20,552 IS/TIA patients for a median duration of 2.3 years. There were 5,714 composite events during follow-up. All regimens were effective in reducing the primary effectiveness outcome compared to no-antiplatelet exposure. Aspirin-only, clopidogrel-only, aspirin-clopidogrel and other regimens were significantly (p <0.05) less effective compared to aspirin-dipyridamole (HR: 1.35, 1.12, 1.40, and 1.27, respectively), adjusted for age, sex, lifestyle factors, disease history and CV comedications. All other regimens were also significantly (p <0.05) associated with a higher relative risk of major bleeding compared to aspirin-dipyridamole (HR: 1.21, 1.32, 1.78, and 1.37, respectively), adjusted for age, sex, alcohol use, liver and renal disease, major bleeding history and comedications. Conclusions: Compared to aspirin-dipyridamole, all other antiplatelet regimens are less effective in reducing the risk of nonfatal IS, nonfatal MI or CV death, and associated with a higher risk of major bleeding in patients with IS/TIA.Characteristics of Patients at Initiation of Treatment for Primary Chronic Immune ThrombocytopeniaBackground: Guidelines for cardiovascular secondary prevention are based on evidence from relatively old clinical trials and need to be evaluated in daily clinical practice. Objectives: To evaluate effectiveness of the recommended drug classes after an acute coronary syndrome (ACS) for secondary prevention of cardiovascular diseases and all-cause mortality. Methods: This cohort study used data from a representative sample of the French national healthcare insurance system database (EGB). Patients hospitalised for an incident ACS between 2006 and 2011, and aged ≥ 20 years at time of ACS were included in the study. Patients non-exposed to any of the four recommended drug classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting-enzyme inhibitors, ACEI, or angiotensin II receptor blockers, ARB) in the first 3 months following ACS or who died during this period were not included in the cohort. Exposure status was determined daily during follow-up. Effectiveness of the four therapeutic classes in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke, or all-cause-death was estimated using a time-dependent Cox proportional hazards model, which was adjusted for time-fixed confounders measured at baseline (general characteristics and characteristics of the initial ACS) and time-dependent confounders during follow-up (co-morbidities and co-medications). Results: Of the 2874 patients included in the study, 33.9% were women and the median age was 67 years (interquartile range, IQR: 56-77). The median time of follow-up was 3.6 years (IQR: 2.2-5.3). The risk of the composite outcome decreased with use of antiplatelet agents (adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63; 0.91), use of statins (aHR 0.71, 95%CI 0.57; 0.87), and use of ACEI/ARB (aHR 0.67, 95%CI 0.57; 0.80). Use of beta-blockers was not associated with a lower risk of the composite outcome (aHR, 0.90, 95%CI 0.74; 1.09]). Conclusions: Use of antiplatelet agents, statins, and ACEI/ARB after an ACS, but not beta-blockers, was associated with a lower risk of cardiovascular morbidity and all-cause mortality.Abstracts of the 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management, The Convention Centre Dublin, Dublin, Ireland August 25–28, 2016Background: Cough and angioedema are adverse events associated with especially angiotensinconverting enzyme (ACE) inhibitors but also reported with angiotensin receptor blockers (ARBs) and aliskiren, a direct renin inhibitor (DRI). Susceptibility of developing cough/angioedema with ACE inhibitors depends on ethnicity, which is not documented in spontaneous reporting systems of drug safety. Objectives: To assess the impact of ethnicity on the occurrence of cough/angioedema with renin angiotensin system (RAS) inhibitors using information reported to the the World Health Organization database (VigiBase). Methods: A case/non-case study was performed in VigiBase. Cases were defined as reports of cough/angioedema and non-cases were all reports of other adverse events. The reporting countries were divided into three categories: black African countries, East Asian countries and other countries. Logistic regression analysis was used to assess the association between reporting of cough/angioedema with each class of RAS inhibitors stratified by country group and to control for confounding. Results: The reporting of cough with ACE inhibitors was significantly higher in East Asian countries than black African countries and other countries (adjusted reporting odds ratios (RORs): 256, 95%CI (236-278), 48.9, 95%CI (42.7-56.1) and 35.4, 95%CI (34.8- 35.9), respectively. The reporting of angioedema with ACE inhibitors was significantly higher in black African countries than East Asian countries and other countries (adjusted RORs: 55.3, 95%CI (45.5-67.2), 5.29, 95%CI(3.89-7.21) and 16.5, 95%CI (16.1- 16.8), respectively. There was no difference in reporting of cough/angioedema with ARBs and DRI between black African countries, East Asian countries and other countries. Conclusions: Our results by grouping countries according to ethnicity in VigiBase are consistent with previous results in the literature suggesting that the occurrence of cough with ACE inhibitors is higher in East Asian patients and the occurrence of angioedema with ACE inhibitors is higher in black patients. These findings indicate that ethnicity should be included as scientific parameter in pharmacovigilance.An Automatized Model for Sequential Monitoring of Effectiveness of New Drugs using Dronedarone as ExampleGeneral Pharmacological Treatments Preceding A Primary Chronic Immune Thrombocytopenia DiagnosisBackground: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. There is limited information available about the association of type 1 diabetes (T1D) and psychiatric disorders in children and adolescents. Objectives: To assess the extent of psychiatric medication use before and after the onset of T1D in children and adolescents compared with a reference cohort without T1D. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children and adolescents <19 years) with at least two insulin dispensings between 1999 and 2009 were identified as a T1D cohort (N=925) and matched with an up to four times larger diabetes-free reference cohort (N=3591) by age and sex. The period prevalences of psychiatric medication use (psycholeptics (ATC N05) and psychoanaleptics (ATC N06)) were calculated by dividing the number of patients with at least one dispensing by the number of patients available in the cohort during that time. Prevalences were calculated from 5 years before until 5 years after the onset of T1D (the index date in both cohorts) and stratified by age, sex, medication subgroup, and before/after the onset of T1D. Results: The mean age of the study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2 vs. 4.7%, respectively, p=0.002). The same pattern was observed for the period after developing T1D (10.4 vs. 7.9% in the T1D and reference cohort respectively, p=0.015). In both cohorts adolescents (15-19 years) and boys had higher prevalences of psychiatric medication use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (mainly anxiolytics). Conclusions: Children with T1D were more likely to use psychiatric medication in the years before and after the onset of type 1 diabetes. This increased use was mainly driven by psycholeptics both before and after onset of T1D.