Patients with Obesity Should be Recognised as a Special Patient Population During Drug Development of Antibacterial and Antifungal Agents; A Call to Action.

Individuals with obesity are at increased risk of developing infectious diseases. Timely administration of an effective dose of an antimicrobial agent is paramount to safeguard optimal therapy. For this purpose, special patient populations at risk for altered exposure such as renal or hepatic impairment are studied during drug development. Strikingly, there is no such evaluation in individuals with obesity despite a potential influence on exposure and a global obesity prevalence of 13 %. Optimal clinical decision making in patients with obesity is impossible without prior study of the drug of interest in this population. This statement is strengthened by an evaluation of 19 antimicrobial agents that showed tremendous variability in the influence of weight on clearance. In contrast to patient with renal or hepatic impairment who are mainly at risk of overexposure, individuals with obesity can be at risk of both under- and overexposure. Gaining knowledge on the influence of body weight on clearance during early phases of drug development may allow for optimisation of other phases of research, potentially increasing success rate of the drug, and can provide clinicians with vital information as soon as the drug reaches the market. Antimicrobial therapy should be tailored to obesity-related (patho)physiological changes and to reach this goal, obese individuals should be studied during drug development.

Dihydropyrimidine dehydrogenase phenotype in peripheral blood mononuclear cells is related to adverse events of fluoropyrimidine-therapy.

PURPOSE: The primary objective of this study was to determine if dihydropyrimidine dehydrogenase (DPD) activity measured in peripheral blood mononuclear cells (PBMCs) is related to adverse events during fluoropyrimidine therapy. METHODS: A retrospective cohort study was conducted. The study population included 481 patients who received fluoropyrimidine treatment and for whom relevant patient characteristics were known and adverse events were noted in the electronic health records. Factors besides DPD phenotype that could affect the incidence of adverse events were corrected for using log regression. These log regression models were used to identify an association between the DPD phenotype measured in PBMCs and adverse events. RESULTS: Patients with a decreased DPD activity measured in PBMCs suffered more adverse events. Results from log regression data show that this effect remains significant after correcting for dosage, chemotherapy regimen and relevant patient characteristics. CONCLUSION: A significant correlation was found between reduced DPD enzyme activity in PBMCs and adverse events. The findings in this paper support further exploring DPD phenotyping as a method for preventing fluoropyrimidine-related adverse events. Further assessment of DPD phenotyping will require clinical validation in a prospective study.

Impact of mucositis on oral bioavailability and systemic exposure of ciprofloxacin Gram-negative infection prophylaxis in patients with haematological malignancies.

BACKGROUND: Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis. OBJECTIVES: We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure. METHODS: Adult haematological patients from two Dutch University Medical Centres received 500 mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling. RESULTS: In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30 days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16 µmol/L (12-23)]. The time to Cmax was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2 L/h, respectively. CONCLUSIONS: This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake.

Sex differences associated with adverse drug reactions resulting in hospital admissions.

BACKGROUND: Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5-1.7 times more likely to develop ADRs. The main objective was to identify sex differences in the types and number of ADRs leading to hospital admission. METHODS: ADR-related hospital admissions between 2005 and 2017 were identified from the PHARMO Database Network using hospital discharge diagnoses. Patients aged ≥ 16 years with a drug possibly responsible for the ADR and dispensed within 3 months before admission were included. Age-adjusted odds ratios (OR) with 95% CIs for drug-ADR combinations for women versus men were calculated. RESULTS: A total of 18,469 ADR-related hospital admissions involving women (0.35% of all women admitted) and 14,678 admissions involving men (0.35% of all men admitted) were included. Most substantial differences were seen in ADRs due to anticoagulants and diuretics. Anticoagulants showed a lower risk of admission with persistent haematuria (ORadj 0.31; 95%CI 0.21, 0.45) haemoptysis (ORadj 0.47, 95%CI 0.30,0.74) and subdural haemorrhage (ORadj 0.61; 95%CI 0.42,0.88) in women than in men and a higher risk of rectal bleeding in women (ORadj 1.48; 95%CI 1.04,2.11). Also, there was a higher risk of admission in women using thiazide diuretics causing hypokalaemia (ORadj 3.03; 95%CI 1.58, 5.79) and hyponatraemia (ORadj 3.33, 95%CI 2.31, 4.81) than in men. CONCLUSIONS: There are sex-related differences in the risk of hospital admission in specific drug-ADR combinations. The most substantial differences were due to anticoagulants and diuretics.

A multicentre cluster-randomized clinical trial to improve antibiotic use and reduce length of stay in hospitals: comparison of three measurement and feedback methods.

BACKGROUND: Various metrics of hospital antibiotic use might assist in guiding antimicrobial stewardship (AMS). OBJECTIVES: To compare patient outcomes in association with three methods to measure and feedback information on hospital antibiotic use when used in developing an AMS intervention. METHODS: Three methods were randomly allocated to 42 clusters from 21 Dutch hospitals: (1) feedback on quantity of antibiotic use [DDD, days-of-therapy (DOT) from hospital pharmacy data], versus feedback on (2) validated, or (3) non-validated quality indicators from point prevalence studies. Using this feedback together with an implementation tool, stewardship teams systematically developed and performed improvement strategies. The hospital length of stay (LOS) was the primary outcome and secondary outcomes included DOT, ICU stay and hospital mortality. Data were collected before (February-May 2015) and after (February-May 2017) the intervention period. RESULTS: The geometric mean hospital LOS decreased from 9.5 days (95% CI 8.9-10.1, 4245 patients) at baseline to 9.0 days (95% CI 8.5-9.6, 4195 patients) after intervention (P < 0.001). No differences in effect on LOS or secondary outcomes were found between methods. Feedback on quality of antibiotic use was used more often to identify improvement targets and was preferred over feedback on quantity of use. Consistent use of the implementation tool seemed to increase effectiveness of the AMS intervention. CONCLUSIONS: The decrease in LOS versus baseline likely reflects improvement in the quality of antibiotic use with the stewardship intervention. While the outcomes with the three methods were otherwise similar, stewardship teams preferred data on the quality over the quantity of antibiotic use.

Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study.

OBJECTIVE: Short-course aminoglycosides as adjunctive empirical therapy to ß-lactams in patients with a clinical suspicion of sepsis are used to broaden antibiotic susceptibility coverage and to enhance bacterial killing. We quantified the impact of this approach on 30-day mortality in a subset of sepsis patients with a Gram-negative bloodstream infection. METHODS: From a prospective cohort study conducted in seven hospitals in the Netherlands between June 2013 and November 2015, we selected all patients with Gram-negative bloodstream infection (GN-BSI). Short-course aminoglycoside therapy was defined as tobramycin, gentamicin or amikacin initiated within a 48-hour time window around blood-culture obtainment, and prescribed for a maximum of 2 days. The outcome of interest was 30-day all-cause mortality. Confounders were selected a priori for adjustment using a propensity score analysis with inverse probability weighting. RESULTS: A total of 626 individuals with GN-BSI who received ß-lactams were included; 156 (24.9%) also received aminoglycosides for a median of 1 day. Patients receiving aminoglycosides more often had septic shock (31/156, 19.9% versus 34/470, 7.2%) and had an eight-fold lower risk of inappropriate treatment (3/156, 1.9% versus 69/470, 14.7%). Thirty-day mortality was 17.3% (27/156) and 13.6% (64/470) for patients receiving and not receiving aminoglycosides, respectively; yielding crude and adjusted odds ratios for 30-day mortality for patients treated with aminoglycosides of 1.33 (95% CI 0.80-2.15) and 1.57 (0.84-2.93), respectively. CONCLUSIONS: Short-course adjunctive aminoglycoside treatment as part of empirical therapy with ß-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.

[Hydroxychloroquine and chloroquine for COVID-19: no evidence of effectiveness]. / Hydroxychloroquine en chloroquine bij COVID-19.

On 3 March 2020, the document 'Drug treatment options for patients with COVID-19 (infections with SARS-CoV-2)' was published on the website of the Dutch Working Party on Antibiotic Policy (StichtingWerkgroepAntibioticabeleid, SWAB). Based on a 7-step analysis of the literature, hydroxychloroquine (HCQ) and chloroquine (CQ) were initially included in the SWAB document as possible drug treatments for hospitalised adult COVID-19 patients. However, recent weeks have seen the publication of the results of various studies into the effectiveness of treatment with HCQ and CQ in patients with COVID-19. On the basis of these results, we conclude that there is insufficient evidence to consider HCQ and CQ as meaningful treatment options in patients with COVID-19. Clinically relevant QTc prolongation occurs in at least 1 in 10 COVID-19 patients treated with HCQ or HQ.

Human resources required for antimicrobial stewardship teams: a Dutch consensus report.

SCOPE: Antimicrobial stewardship teams are responsible for implementing antimicrobial stewardship programmes (ASP). However, in many countries, lack of funding challenges this obligation. A consensus procedure was performed to investigate which structural activities need to be performed by Dutch stewardship teams and how much time (and thus full-time equivalent (FTE) labor) is needed to perform these activities. METHODS: In 2015, an electronic survey, based on a nonsystematic literature search and interviews with seven experienced stewardship teams, was sent to 21 stewardship teams that performed an ASP. This was followed by a semistructured face-to-face consensus meeting. Fourteen stewardship teams completed the survey (18% of Dutch acute-care hospitals), and 13 participated in the consensus meeting. RECOMMENDATIONS: The hours needed each year are dependent on hospital size and number of stewardship objectives monitored. If all activities are performed at a minimal base (one stewardship objective; minimal staffing standard), time investment was estimated to be 1393 to 2680 hours annually in the early phase, corresponding with 0.87 (300 beds) to 1.68 FTE (1200 beds), with a further increase to minimally 1.25 to 3.18 FTE in the following years with three stewardship objectives monitored (optimal staffing standards during the first few years of implementing an ASP). This consensus on required human resources provides a directive for structural financial support of stewardship teams in the Dutch context. Some stewardship activities (and related time investments) might be specific to the Dutch context and hospital setting. To develop standards for other settings, our methodology could be applied.

Development of diagnostic prediction tools for bacteraemia caused by third-generation cephalosporin-resistant enterobacteria in suspected bacterial infections: a nested case-control study.

OBJECTIVES: Current guidelines for the empirical antibiotic treatment predict the presence of third-generation cephalosporin-resistant enterobacterial bacteraemia (3GCR-E-Bac) in case of infection only poorly, thereby increasing unnecessary carbapenem use. We aimed to develop diagnostic scoring systems which can better predict the presence of 3GCR-E-Bac. METHODS: A retrospective nested case-control study was performed that included patients ≥18 years of age from eight Dutch hospitals in whom blood cultures were obtained and intravenous antibiotics were initiated. Each patient with 3GCR-E-Bac was matched to four control infection episodes within the same hospital, based on blood-culture date and onset location (community or hospital). Starting from 32 commonly described clinical risk factors at infection onset, selection strategies were used to derive scoring systems for the probability of community- and hospital-onset 3GCR-E-Bac. RESULTS: 3GCR-E-Bac occurred in 90 of 22 506 (0.4%) community-onset infections and in 82 of 8110 (1.0%) hospital-onset infections, and these cases were matched to 360 community-onset and 328 hospital-onset control episodes. The derived community-onset and hospital-onset scoring systems consisted of six and nine predictors, respectively. With selected score cut-offs, the models identified 3GCR-E-Bac with sensitivity equal to existing guidelines (community-onset: 54.3%; hospital-onset: 81.5%). However, they reduced the proportion of patients classified as at risk for 3GCR-E-Bac (i.e. eligible for empirical carbapenem therapy) with 40% (95%CI 21-56%) and 49% (95%CI 39-58%) in, respectively, community-onset and hospital-onset infections. CONCLUSIONS: These prediction scores for 3GCR-E-Bac, specifically geared towards the initiation of empirical antibiotic treatment, may improve the balance between inappropriate antibiotics and carbapenem overuse.

Intensification of antibiotic use within acute care hospitals in the Netherlands.

OBJECTIVES: To report and analyse trends in antibiotic use in Dutch university hospitals, large teaching hospitals and general hospitals over the period 2003 to 2009. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDDs) per 100 patient-days, per 100 admissions and per 1000 inhabitants per day. The latter was achieved by extrapolating sample data by means of imputation and up-scaling. RESULTS: From 2003 to 2009, the mean length of hospital stay decreased from 6.27 to 4.50 days (-28%). Total systemic antibiotic use significantly increased from 52.3 to 69.8 DDDs per 100 patient-days (P < 0.001). Despite the overall constant use when expressed in DDDs per 100 admissions, we found a significant increase in the total use of piperacillin/tazobactam, cefazolin, ceftriaxone, meropenem, azithromycin, gentamicin, ciprofloxacin and vancomycin. Mean total systemic use expressed in DDDs per 1000 inhabitants per day gradually increased by 38% from 0.73 in 2003 to 1.01 in 2009. CONCLUSIONS: Total hospital antibiotic consumption is still low in the Netherlands compared with other European countries. Also, between 2003 and 2009 the use of antibiotics in individual hospitalized patients remained stable. However, since they remained in the hospital for a shorter period of time, the number of DDDs per 100 patient-days increased. This results in an intensification of antibiotic treatment per hospital bed, leading to a possible increase in selection pressure towards resistance. This may create a problem for future patients. To limit the emergence and transmission of antimicrobial-resistant bacteria, effective antibiotic stewardship is essential.

Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and fentanyl in labour.

BACKGROUND: To compare the analgesic efficacy of remifentanil with meperidine and fentanyl in a patient-controlled setting (patient-controlled analgesia, PCA). METHODS: Parturients (n=159) were randomly assigned to receive remifentanil (n=52), meperidine (n=53), or fentanyl (n=54). Pain scores and an observer sedation scores were assessed hourly. Fetal outcome was evaluated with Apgar score, cord blood gas analysis and the Neurologic and Adaptive Capacity Score. RESULTS: Pain scores decreased in all groups, the decrease varying from mild to moderate, average pain scores remaining above 4.5 cm in all groups. Remifentanil PCA was associated with the greatest decrease in pain scores, but the difference was significant only at 1 h. Pain scores returned towards baseline over time; 3 h after the initiation of treatment, pain scores no longer differed significantly from baseline values in any of the groups. Significantly more parturients receiving meperidine crossed over to epidural analgesia. Overall satisfaction scores were higher with remifentanil, but remifentanil produced more sedation and itching. More periods of desaturation (Sa(o(2)) <95%) were observed during administration of remifentanil and fentanyl. There were no significant differences in fetal outcome between the three groups. CONCLUSIONS: The efficacy of meperidine, fentanyl, and remifentanil PCA for labour analgesia varied from mild to moderate. Remifentanil PCA provided better analgesia than meperidine and fentanyl PCA, but only during the first hour of treatment. In all groups, pain scores returned to pre-treatment values within 3 h after the initiation of treatment.

Changes in antibiotic use in Dutch hospitals over a six-year period: 1997 to 2002.

OBJECTIVE: To analyse trends in antibiotic use in Dutch hospitals over the period 1997 to 2002. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDD) per 100 patient-days and as DDD per 100 admissions. RESULTS: Between 1997 and 2002, the mean length of stay decreased by 18%. The mean number of admissions remained almost constant. Total antibiotic use significantly increased by 24%, from 47.2 in 1997 to 58.5 DDD per 100 patient-days in 2002 (p<0.01), whereas expressed as DDD per admissions it remained constant. Antibiotic use varied greatly between the hospitals. Moreover, the mean number of DDD per hospital of amoxicillin with clavulanic acid, clarithromycin, cefazolin, clindamycin and ciprofloxacin increased by 16, 38, 39, 50 and 52%, respectively. Total antibiotic use was higher in university hospitals than in general hospitals. CONCLUSIONS: Between 1997 and 2002, patients hospitalised in the Netherlands did not receive more antibiotics but, since they remained in the hospital for fewer days, the number of DDD per 100 patient-days increased. For macrolides, lincosamides and fluoroquinolones increases in both DDD per 100 patient-days and in DDD per 100 admissions were observed. It is arguable whether these trends result in an increase in selection pressure towards resistance in the hospitals. Continuous surveillance of antibiotic use and resistance is warranted to maintain efficacy and safety of antibiotic treatment.

An additional measure for quantifying antibiotic use in hospitals.

OBJECTIVES: The number of defined daily doses (DDD) per 100 patient days is often used as an indicator for the selection pressure exerted by antibiotics in the hospital setting. However, this unit of measurement does not fully describe the selection pressure and is sensitive to changes in hospital resource indicators. Additional information is required to facilitate interpretation of this indicator. The number of DDD per 100 admissions could be a valuable additional tool. The aim of this study is to investigate the importance of units of measurement in quantifying antibiotic use data with regards to antibiotic resistance risks. PATIENTS AND METHODS: Trends in antibiotic use in acute care Dutch hospitals between 1997-2001 were studied. Antibiotic use was expressed in DDD per 100 patient days and in DDD per 100 admissions. RESULTS: From 1997 to 2001, total systemic antibiotic use significantly increased from 47.2 to 54.7 DDD per 100 patient days, whereas expressed in DDD per 100 admissions it remained constant. Some individual antibiotics increases in DDD per 100 patient days were not accompanied by increases in DDD per 100 admissions and vice versa. The mean number of total DDD per hospital decreased (not significantly) between 1997 and 2001. The mean number of patient days, admissions and length of stay decreased significantly. CONCLUSIONS: Knowledge of variation in resource indicators and additional expression of the data in DDD per 100 admissions is imperative for a meaningful understanding of observed trends in antibiotic use expressed in DDD per 100 patient days. Further research is needed to determine the correlation between different measures of antibiotic use and the level of antibiotic resistance.

Efficacy and safety of methylphenidate in 45 adults with attention-deficit/hyperactivity disorder. A randomized placebo-controlled double-blind cross-over trial.

BACKGROUND: Data on the efficacy and safety of methylphenidate in adults with attention deficit/ hyperactivity disorder (ADHD) are lacking in Europe. This study was undertaken to report on the efficacy and safety of methylphenidate in an adult out-patient population with ADHD, and to compare results with US data. METHOD: A double-blind randomized cross-over trial comparing methylphenidate and placebo in 45 adults with ADHD with childhood onset was performed in a dose-titration design. Methylphenidate was titrated from 0.5 mg/kg per day in week 1 up to 1.0 mg/kg per day in week 3. RESULTS: Response rates using methylphenidate varied between 38 and 51%, and using placebo between 7 and 18% (p<0.05), depending on outcome measure used. Although the overall percentage of subjects having any side effect on both methylphenidate and placebo was rather high, side effects on methylphenidate over and above those on placebo were few and mild. CONCLUSIONS: Methylphenidate proves to be an effective and well tolerated treatment for symptoms of ADHD in adults in the short term. Future research should study the long-term response and clarify the impact of gender, co-morbidity, socio-economic status and IQ on response rates in adults with ADHD.

Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study.

The association between the use of calcium channel blockers (CCB) and cancer has received ample attention, but is still controversial. In this study, we have tested the hypothesis that the observed association between CCB and cancer in earlier studies could be explained by residual confounding or by misclassification of exposure because of the use of cross-sectional data on drug use. Data from the Rotterdam Study, a prospective population-based cohort study in the municipal area Ommoord, were used. The study population consisted of a cohort of 3204 participants aged 71 years or older who were followed from a baseline interview in the period 1991-1993 for the occurrence of incident cancer. Data on drug use were gathered at baseline and through the seven community pharmacies which served the Ommoord region during the study period between 1 January 1991 and 1 January 1999. Incident cancer events were gathered from a nationwide registry of hospitalisation data and from a specialised cancer centre in the Rotterdam region. We performed three analyses. First, we followed the method, and adjusted for the same risk factors, as in the earlier studies. In the second analysis, we included all risk factors that were univariately associated with cancer in the Rotterdam Study. In the third analysis, we included exposure to CCBs as time-varying co-variates, while adjusting for potential confounders. The relative risk (RR) of cancer associated with CCB was 1.4 (95% Confidence Interval (CI): 0.9-2.0) in the first analysis and lowered to 1.2 (95% CI: 0.8-1.8) upon adjustment for the different co-variates in the second. In both analyses, however, verapamil was significantly associated with cancer with RRs of 2.1 (95% CI: 1.1-4.0) and 2.0 (1.01-3.9), respectively, whereas no associations were found with the other CCB in this study, i.e. diltiazem and nifedipine. A significantly increased risk of cancer was found for intermediate daily doses of verapamil and diltiazem. Intake of other antihypertensives such as beta-blocking agents, diuretics and ACE-inhibitors was not associated with cancer. In the third analysis with exposure to CCB as time-varying co-variates, the risk increase was non-significant for use of 2 years or less, 1.0 (95% CI: 0.7-1.5), and for use for a cumulative period of more than 2 years, 1.3 (95% CI: 0.8-2.0). However, in all models the hazard ratio was statistically significantly increased for verapamil, but not for diltiazem and nifedipine. On the basis of these analyses, we found no increase in cancer in users of diltiazem and nifedipine, nor in users of other antihypertensives. In line with earlier studies, however, we found an increased risk of cancer in users of verapamil. At variance with the conclusions from several other studies, we think that it is too early to conclude that CCB are not associated with cancer.

Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands.

OBJECTIVES: Many drugs used in paediatric care are not licensed for that use or are prescribed outside the terms of the product license (off-label). Studies in the UK and Europe showed a large number of unlicensed and off-label drug prescription in specialised paediatric health care centres. We determined the extent and nature of use of unlicensed drugs and off-label prescriptions in children in a general hospital in the Netherlands. METHODS: We conducted a longitudinal prospective cohort study in a dynamic population consisting of patients admitted to the paediatric ward and the neonatology unit of a general hospital during a 19-week period. Drug-licensing status of all prescriptions given to these patients was determined. RESULTS: A total of 1017 prescriptions was administered to 293 paediatric patients for 114 different drugs. The median number of prescriptions per patient was three (interquartile range 2-5). The most commonly administered drugs were acetaminophen (14%), cefotaxime (8%), amoxicillin (7%), caffeine (4%) and prednisolone (4%). Four hundred and forty-three (44%) prescriptions were off-label, and 285 (28%) were for unlicensed drugs. Ninety-two percent of patients received one or more unlicensed or off-label prescriptions, and this proportion was significantly higher in children below 6 months of age than in older children. CONCLUSIONS: This study shows that the extent of unlicensed and off-label drug prescription in a paediatric ward and neonatology unit of a general hospital is large and not smaller than in an academic paediatric setting. Lack of paediatric drug labelling is therefore not solely a problem with drugs used in university hospitals, but also in general hospitals. Efforts must be taken to change the current situation.

Impaired cognitive function and compliance with antihypertensive drugs in elderly: the Rotterdam Study.

BACKGROUND: To our knowledge, there are no epidemiologic studies on the association between cognitive impairment and noncompliance with antihypertensive therapy. We studied compliance with antihypertensive treatment in elderly patients with cognitive impairment. METHODS: The Rotterdam Study is a prospective community-based cohort study of 7983 residents > or = 55 years old. We studied 1979 participants in the study who had 2 consecutive Mini Mental State Examination (MMSE) assessments in the period from 1991 to 1996, who did not have dementia at baseline, and who had received 3 or more consecutive antihypertensive prescriptions for at least 6 months. We compared persons with MMSE scores < or = 25 on both assessments to persons with MMSE scores > 25 on both occasions. Compliance was estimated by dividing the number of days the subjects took antihypertensive drugs by the follow-up period in days, and it was expressed as a ratio between 0 and 1. We defined patients as compliant if they had a compliance ratio > or = 0.80 and as noncompliant if they had a compliance ratio < or = 0.50 during the study period. RESULTS: We followed-up on 1573 patients (mean age, 68 years) during an average period of 1609 days. The risk of noncompliance in cognitively impaired elderly subjects was 2.0 (95% confidence interval, 1.4 to 2.8) after adjustment for age, sex, education, income, living situation, and smoking. Stratification by living situation showed that the risk increase predominantly occurred in those who lived alone (odds ratio, 2.9; 95% confidence interval, 1.2 to 7.5). CONCLUSIONS: Cognitive function is an independent predictor of compliance with antihypertensive drugs in elderly patients who are living alone.

Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands.

INTRODUCTION: Shortly after their introduction, fluoroquinolones were associated with reports of tendinitis and tendon rupture. During the past years, the number of reports has risen, possibly because of an increased use of fluoroquinolones. In this study, we describe the use of fluoroquinolones in the Dutch community and the possible public health effects of an association between fluoroquinolone use and tendon ruptures. METHODS: In the PHARMO drug database we identified all prescriptions for fluoroquinolones in the period 1991-1996. The incidence of fluoroquinolone use was expressed as the number of fluoroquinolone episodes per 1000 inhabitants in one year, and extrapolated to the Dutch population after standardisation on age and gender. The annual incidence of non-traumatic tendon ruptures in the period 1991-1996 was calculated with data from the nation-wide hospital registry. The expected number of fluoroquinolone attributable tendon ruptures was calculated on the basis of the use of fluoroquinolones, the number of non-traumatic tendon ruptures and an assumed relative risk of 1.5-10. RESULTS: In 1996, approximately 251,000 patients experienced 318,000 episodes of fluoroquinolone use in the Netherlands. Females used more often fluoroquinolones than males, and the number of episodes increased exponentially with age. In the period 1991 through 1996, the absolute number of fluoroquinolone episodes increased by 160%, from 122,000 to 318,000. The absolute number of hospitalised tendon ruptures increased with 28%, from 768 in 1991 to 984 in 1996. Assuming a relative risk of 1.5 to 10.0, 1 to 15 tendon ruptures could be attributed to fluoroquinolone use in 1996. Only 7% of the observed increase could be attributed to the increased use of fluoroquinolones. If the total increase of hospitalised non-traumatic tendon ruptures would be attributable to the increase in fluoroquinolone use, this would mean that the risk of non traumatic tendon ruptures to fluoroquinolones would be more than 250 times the risk during non-use. CONCLUSION: In the Netherlands, a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996. Assuming a relative risk of 1.5 to 10.0 for tendon ruptures during fluoroquinolone use, only 0.5 to 7% of the increase in non-traumatic tendon ruptures could be attributed to the increased fluoroquinolone use. The increase in the incidence of non-traumatic hospitalised tendon ruptures in the Netherlands is not likely to be explained solely by the increased use of fluoroquinolones.