Timo Klaukka

The Effect of Changes in the Consumption of Macrolide Antibiotics on Erythromycin Resistance in Group A Streptococci in Finland

BACKGROUND In the early 1990s there was an increase in erythromycin resistance among group A streptococci in Finland. In response, policies regarding outpatient antibiotic therapy were changed, and nationwide recommendations were issued that called for reductions in the use of macrolide antibiotics for respiratory and skin infections in outpatients. We studied the effect of this policy on the pattern of erythromycin resistance throughout Finland. METHODS From 1991 through 1996, a total of 39,247 group A streptococcal isolates from throat swabs (82 percent of the isolates) and pus samples (18 percent) and 290 isolates from blood cultures were studied in regional microbiology laboratories. The susceptibility of the isolates to erythromycin was tested by the disk-diffusion or the screening-plate method. RESULTS Consumption of macrolide antibiotics decreased from 2.40 defined daily doses per 1000 inhabitants per day in 1991 to 1.38 in 1992 (P=0.007) and remained near the lower level during the study period. The change in consumption was followed by a steady decrease in the frequency of erythromycin resistance among group A streptococcal isolates from throat swabs and pus samples, from 16.5 percent in 1992 to 8.6 percent in 1996 (odds ratio for 1996 as compared with 1992, 0.5; 95 percent confidence interval, 0.4 to 0.5). CONCLUSIONS In Finland, after nationwide reductions in the use of macrolide antibiotics for outpatient therapy, there was a significant decline in the frequency of erythromycin resistance among group A streptococci isolated from throat swabs and pus samples.

11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)

BACKGROUND The introduction of second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia. Our aim was to establish the long-term contribution of antipsychotic drugs to mortality in such patients. METHODS Nationwide registers in Finland were used to compare the cause-specific mortality in 66 881 patients versus the total population (5.2 million) between 1996, and 2006, and to link these data with the use of antipsychotic drugs. We measured the all-cause mortality of patients with schizophrenia in outpatient care during current and cumulative exposure to any antipsychotic drug versus no use of these drugs, and exposure to the six most frequently used antipsychotic drugs compared with perphenazine use. FINDINGS Although the proportional use of second-generation antipsychotic drugs rose from 13% to 64% during follow-up, the gap in life expectancy between patients with schizophrenia and the general population did not widen between 1996 (25 years), and 2006 (22.5 years). Compared with current use of perphenazine, the highest risk for overall mortality was recorded for quetiapine (adjusted hazard ratio [HR] 1.41, 95% CI 1.09-1.82), and the lowest risk for clozapine (0.74, 0.60-0.91; p=0.0045 for the difference between clozapine vs perphenazine, and p<0.0001 for all other antipsychotic drugs). Long-term cumulative exposure (7-11 years) to any antipsychotic treatment was associated with lower mortality than was no drug use (0.81, 0.77-0.84). In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted (HR for trend per exposure year 0.991; 0.985-0.997). INTERPRETATION Long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. Second-generation drugs are a highly heterogeneous group, and clozapine seems to be associated with a substantially lower mortality than any other antipsychotics. Restrictions on the use of clozapine should be reassessed. FUNDING Annual EVO Financing (Special government subsidies from the Ministry of Health and Welfare, Finland).

Use of medications and polypharmacy are increasing among the elderly.

To assess changes in medicine use and polypharmacy, two cross-sectional surveys were carried out among community-dwelling persons aged 64 years or over in 1990-91 (n = 1,131) and 1998-99 (n = 1,197) in the municipality of Lieto in southwestern Finland. In addition to drug use, the questionnaire included items on social background, quality of life, and home nursing services. Among those surveyed, 78% in 1990-1991 and 88% in 1998-1999 (P =.001) used prescription drugs during 7 days prior to the interview. The most commonly used medications were for the cardiovascular and central nervous systems. The number of medications per person increased from 3.1 (SD 2.8) to 3.8 (SD 3.1) (P =.0001), and polypharmacy (concominant use of over five medications) increased from 19 to 25% (P =.006). These changes were most prominent among persons aged 85 years or over, especially among women. Polypharmacy is a complex and worrying phenomenon that merits more research.

Resistance to Erythromycin in Group A Streptococci

BACKGROUND The use of erythromycin in Finland nearly tripled from 1979 to 1989. In 1988, we observed an unusually high frequency of resistance to erythromycin in group A streptococci in one geographic region. Because routine testing does not detect the sensitivity of these organisms to antibiotics, we initiated a national study to evaluate the extent of this resistance. METHODS We studied 272 isolates of group A streptococci obtained from blood cultures from 1988 through 1990. In 1990 we collected from six regional laboratories 3087 consecutive isolates from throat swabs and 1349 isolates from pus samples. Resistance was indicated by growth on blood agar containing 2 micrograms of erythromycin per milliliter after incubation in 5 percent carbon dioxide. We also evaluated the clinical importance of erythromycin resistance in a retrospective study of consecutive patients with pharyngitis. RESULTS The frequency of resistance to erythromycin in group A streptococci from blood cultures increased from 4 percent in 1988 to 24 percent in 1990. From January to December 1990, the frequency of resistance in isolates from throat swabs increased from 7 percent to 20 percent, and resistance in isolates from pus increased from 11 percent to 31 percent. In four communities within 50 km of each other, the frequency of erythromycin resistance ranged from 2 to 5 percent to 26 to 44 percent. Several distinct DNA restriction profiles and serotypes were found among resistant isolates from the same area, suggesting a multiclonal origin. The treatment of pharyngitis with erythromycin failed in 9 of 19 patients infected with erythromycin-resistant group A streptococci, as compared with 1 of 26 patients with erythromycin-susceptible isolates (47 percent vs. 4 percent, P = 0.008). CONCLUSIONS In Finland since 1988 there has been a rapid and substantial increase in resistance to erythromycin in group A streptococci. The extent of this resistance is particularly serious since there are only a few alternative antibiotics available for peroral treatment of group A streptococcal infections.

Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study

Abstract Objective To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community. Design Prospective cohort study using national central registers. Setting Community care in Finland. Participants Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001. Main outcome measures Rates of discontinuation of drugs (all causes), rates of rehospitalisation, and mortality associated with monotherapy with the 10 most commonly used antipsychotic drugs. Multivariate models and propensity score methods were used to adjust estimates of effectiveness. Results Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276). Conclusions The effectiveness of first and second generation antipsychotics varies greatly in the community. Patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation or discontinuation (for any reason) of their initial treatment than do patients treated with haloperidol. Excess mortality is seen mostly in patients not using antipsychotic drugs.

Reliability and validity of interview data on chronic diseases The mini-Finland health survey

The Mini-Finland Health Survey was designed to obtain a comprehensive picture of health and of the need for care in Finnish adults, and to develop methods for monitoring health in the population as a whole. Out of a nationally representative sample of 8000 people aged 30 or over, 7217 (90%) were both interviewed at home by local public health nurses using simple open-ended questions and, independently of this interview, subsequently examined in a two-phase health examination. The estimate of chronic morbidity based on the health interview (56%) was close to the prevalence of definite somatic diseases diagnosed in the health examination (54%), and the agreement between the two methods was moderate (kappa = 0.53). The estimated prevalence of cardiovascular diseases was the same (23%) in the health interview and in the health examination; the agreement was substantial (kappa = 0.74). The prevalence of respiratory and musculoskeletal diseases and mental disorders was underestimated in the interview by 52, 25 and 78%, respectively; the agreement between results of the two methods was relatively low (kappa = 0.43, 0.38 and 0.30, respectively). These results suggest that both the health examination and the health interview methods, as used in this survey, have useful applications in monitoring the populations health.

Risks associated with selective serotonin reuptake inhibitors in pregnancy.

OBJECTIVE: To study the effects of selective serotonin reuptake inhibitors (SSRIs) on pregnancy outcome. METHODS: We performed a population-based study of women exposed to SSRIs during pregnancy (n = 1782). Data were derived from a national project in Finland, established by 3 governmental organizations. In that project, the Drug Reimbursement Register, the Medical Birth Register, the Register of Congenital Malformations, and the Register of Induced Abortions have been linked. Comparisons were made between women with SSRI purchases to matched controls and between women with purchases in different trimesters. Only singleton pregnancies were included. Primary outcomes were major malformations, preterm birth, small for gestational age, low birth weight, and treatment in neonatal special or intensive care unit. Analyses were based on logistic models. RESULTS: Major malformations were not more common in infants or fetuses of women with first trimester SSRI purchases (n = 1,398) when compared with controls with no drug purchases (P = .4). Of infants born to mothers with SSRI purchases in the 3rd trimester, 15.7% were treated in special or intensive care unit compared with 11.2% of infants exposed only during the 1st trimester (P = .009, adjusted odds ratio 1.6, 95% confidence interval 1.1–2.2). We found no increased risk of preterm birth (< 37 weeks), birth 32 weeks of gestation or less, small for gestational age, or low birth weight in women with purchases in each trimester or during the 2nd and 3rd trimesters when compared with women with only 1st trimester purchases CONCLUSION: Use of SSRIs during pregnancy is not independently associated with increased risk of adverse perinatal outcome other than need for treatment in neonatal special or intensive care unit. LEVEL OF EVIDENCE: II-2

Perinatal Factors and the Risk of Asthma in Childhood—A Population-based Register Study in Finland

The aim of the study was to assess whether perinatal factors are associated with the risk of asthma in childhood in a register-based, nested case-control study in Finland. All children born between January 1, 1996, and April 30, 2004, who were entitled to a special reimbursement for antiasthmatic drugs (i.e., had diagnosed asthma by 2006 and had purchased inhaled corticosteroids or montelukast at least once), were identified (n = 21,038). For each case, one matched control child was selected. The associations between perinatal factors, derived from the Finnish Medical Birth Register, and the risk of asthma were analyzed by conditional logistic regression. In the final multivariate model, maternal asthma, young age, smoking, previous miscarriages, and a high number of previous deliveries, as well as cesarean section, low gestational age, and low ponderal index, were associated with an increased risk of asthma in children diagnosed before the age of 3 years. Among children diagnosed at the age of 3 years or later, maternal asthma, low gestational age, and low ponderal index were associated with an increased risk, and a high number of previous deliveries was associated with a decreased risk of asthma. In conclusion, perinatal factors play a role in the development of asthma in childhood, but the etiology may differ in early and late-onset asthma.

Incidence of cancer and statin usage—Record linkage study

The consumption of statins (HMG‐CoA reductase inhibitors) has been increasing, and a substantial part of the middle‐aged and elderly population use them continuously. Because a large fraction of the population is exposed, even a small excess of risk with respect to cancer should be considered. We carried out a record‐linkage study in Finland utilizing nationwide databases of reimbursed statin medication and cancer. The study population included all statin users in Finland who had purchased at least 1 prescription between 1996 and 2005 and who had no cancer diagnosis at the date of first purchase. A control population without statin usage was also included. Data consisted of 472,481 pairs of individuals that cumulated 4.2 million person years with an average of 8.8 years of follow‐up. Fifty thousand two hundred ninety‐four cancer cases were observed. Simvastatin and atorvastatin were the most used substances. The most frequent cancers were prostate, breast, lung, colon, and rectum cancer. In general, no association between the utilization of statins and cancer could be detected. In conclusion, this study adds large‐scale, population‐based results about the association between statin utilization and the incidence of cancer. We found neither beneficial nor harmful associations between the usage of statins and cancer.

Self-report as an indicator of incident disease.

PURPOSE Epidemiological studies use self-reports from repeated surveys to ascertain incident disease. However, the accuracy of such measurements remains unknown, as validity studies have typically relied on data from prevalent, rather than incident, disease. This study examined the validity of self-reports in the detection of new-onset disease with measurements at baseline and follow-up conditions. METHODS We conducted a prospective cohort study of 34,616 Finnish public-sector employees. Data from self-reported, physician-diagnosed diseases from two surveys approximately 4 years apart were compared with corresponding records in comprehensive national health registers used as the validity criterion. RESULTS There was a considerable degree of misclassification for self-reports as a measure of incident disease. The specificity of self-reports was equally high for the prevalent and incident diseases (range, 93%-99%), but the sensitivity of self-reports was considerably lower for incident than for prevalent diseases: hypertension (55% vs. 86%), diabetes (62% vs. 96%), asthma (63% vs. 91%), coronary heart disease (62% vs. 78%), and rheumatoid arthritis (63% vs. 83%). CONCLUSIONS This study suggests that the sensitivity of self-reports is substantially worse for incident than for prevalent diseases. Results from studies on self-reported incident chronic conditions should be interpreted with caution.