Fleroxacin (Ro 23-6240; AM-833) is a new trifluorinated quinolone exhibiting high activity against a broad spectrum of gram-negative and gram-positive bacteria. Healthy male volunteers received, according to a randomized scheme, oral doses of 200, 400, or 800 mg of fleroxacin in tablet form, an intravenous infusion of 100 mg, or 400 mg of fleroxacin orally together with 1,000 mg of probenecid. Fleroxacin is characterized pharmacokinetically by a long elimination half-life (9 to 10 h) and high concentrations in plasma (e.g., maximum concentration of 2.3 ,ig/ml after an oral dose of 200 mg). The volume of distribution clearly exceeds 1 liter/kg and suggests a good tissue penetration. Within 60 h, the cumulative urinary recovery of unchanged drug amounted to 50 to 60% of the dose. The renal clearance of unbound drug was 137 ml/min, and probenecid had no significant effect on renal elimination. A good linear correlation (r = 0.999) was found between doses from 100 to 800 mg and the resulting values of area under the concentration-time curve. The absolute bioavailability of the administered tablet was practically 100%. During oral multiple dosing of 800 or 1,200 mg of fleroxacin once a day over 10 consecutive days, the accumulation of the drug in plasma was close to the theoretically predicted value of 1.3 and reflected the persistence of linear pharmacokinetics. Early pharmacokinetic and tissue distribution studies in different animal species revealed that this new quinolone was rapidly and completely absorbed following oral administration and that drug levels in lungs, spleen, liver, and kidneys exceeded the corresponding levels in serum (9).Elimination half-lives (t4/2) were species dependent and reached more than 9 h in dogs.In this study the pharmacokinetics of fleroxacin in healthy volunteers were investigated after single and multiple dosing; factors studied included dose proportionality, absolute bioavailability of the used tablet, and the influence of probenecid on renal excretion.

Campylobacteriosis is the most frequently reported food borne infection in Switzerland. We investigated determinants of infections and illness experience in wintertime. A case–control study was conducted in Switzerland between December 2012 and February 2013. Cases were recruited among laboratory-confirmed campylobacteriosis patients. Population-based controls were matched according to age group, sex and canton of residence. We determined risk factors associated with campylobacteriosis, and help seeking behaviour and illness perception. The multivariable analysis identified two factors associated with an increased risk for campylobacteriosis: consumption of meat fondue (matched odds ratio [mOR] 4.0, 95 % confidence interval [CI] 2.3–7.1) and travelling abroad (mOR 2.7, 95 % CI 1.1–6.4). Univariable analysis among meat fondue consumers revealed chicken as the type of meat with the highest risk of disease (mOR 3.8, 95 % CI 1.1–13.5). Most frequently reported signs and symptoms among patients were diarrhoea (98 %), abdominal pain (81 %), fever (66 %), nausea (44 %) and vomiting (34 %). The median perceived disease severity was 8 on a 1-to-10 rating scale. Patients reported a median duration of illness of 7 days and 14 % were hospitalised. Meat fondues, mostly “Fondue chinoise”, traditionally consumed during the festive season in Switzerland, are the major driver of the epidemic campylobacteriosis peak in wintertime. At these meals, individual handling and consumption of chicken meat may play an important role in disease transmission. Laboratory-confirmed patients are severely ill and hospitalisation rate is considerable. Public health measures such as decontamination of chicken meat and improved food handling behaviour at the individual level are urgently needed.

The use of antibiotics is highest in primary care and directly associated with antibiotic resistance in the community. We assessed regional variations in antibiotic use in primary care in Switzerland and explored prescription patterns in relation to the use of point of care tests. Defined daily doses of antibiotics per 1000 inhabitants (DDD(1000pd) ) were calculated for the year 2007 from reimbursement data of the largest Swiss health insurer, based on the anatomic therapeutic chemical classification and the DDD methodology recommended by WHO. We present ecological associations by use of descriptive and regression analysis. We analysed data from 1 067 934 adults, representing 17.1% of the Swiss population. The rate of outpatient antibiotic prescriptions in the entire population was 8.5 DDD(1000pd) , and varied between 7.28 and 11.33 DDD(1000pd) for northwest Switzerland and the Lake Geneva region. DDD(1000pd) for the three most prescribed antibiotics were 2.90 for amoxicillin and amoxicillin-clavulanate, 1.77 for fluoroquinolones, and 1.34 for macrolides. Regions with higher DDD(1000pd) showed higher seasonal variability in antibiotic use and lower use of all point of care tests. In regression analysis for each class of antibiotics, the use of any point of care test was consistently associated with fewer antibiotic prescriptions. Prescription rates of primary care physicians showed variations between Swiss regions and were lower in northwest Switzerland and in physicians using point of care tests. Ecological studies are prone to bias and whether point of care tests reduce antibiotic use has to be investigated in pragmatic primary care trials.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Nasal application of midazolam has been studied for a variety of indications. Due to the limited application volume, highly concentrated formulations are required to reach clinically relevant concentrations in adult patients. No data on the pharmacokinetics and pharmacodynamics of nasal midazolam formulations based on cyclodextrin and chitosan are available. WHAT THIS STUDY ADDS• Clinically effective midazolam concentrations can be reached within less than 10 min after nasal administration of highly concentrated formulations containing an equimolar amount of the solubilizer randomly methylatedb-cyclodextrin combined with the absorption enhancer chitosan. Immediate non-invasive application of such formulations in emergency treatment of seizure patients by lay persons could offer clinical benefits in situations where intravenous access cannot be quickly established. AIMSTo investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml METHODSAn open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test. RESULTSMean bioavailability of midazolam after nasal administration ranged from 76 Ϯ 12% to 92 Ϯ 15%. With formulations delivering 1 mg midazolam, mean Cmax values between 28.1 Ϯ 9.1 and 30.1 Ϯ 6.6 ng ml -1 were reached after 9.4 Ϯ 3.2-11.3 Ϯ 4.4 min. With formulations delivering 3 mg midazolam, mean Cmax values were between 68.9 Ϯ 19.8 and 80.6 Ϯ 15.2 ng ml -1 after 7.2 Ϯ 0.7-13.0 Ϯ 4.3 min. Chitosan significantly increased Cmax and reduced tmax of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1′-hydroxymidazolam were between 0.97 Ϯ 0.15 and 1.06 Ϯ 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 Ϯ 78 ms and 19 Ϯ 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa. CONCLUSIONSEffective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMbCD combined with the absorption enhancer chitosan.

BackgroundThis was a systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Evidence mapping was used to reveal the effect of drug reminder packaging on medication adherence, to identify research gaps and to make suggestions for future research.MethodsPubMed, Embase, CINAHL and PsycINFO were searched with an end date of September 2013 using the Medical Subject Headings (MeSH) term ‘medication adherence’ and 20 different search terms for ‘drug reminder packaging’, limited to the English and German languages. Additional references were identified through cross-referencing. All prospective controlled trials with an intervention using drug reminder packaging for patients taking at least one medication without the assistance of a health-care professional were included in the evidence mapping of the effect of drug reminder packaging on adherence and outcomes according to the Economic, Clinical and Humanistic Outcomes (ECHO) model.ResultsA total of 30 studies met the inclusion criteria: 10 randomized controlled trials, 19 controlled clinical trials and 1 cohort study. Drug reminder packaging had a significant effect on at least one adherence parameter in 17 studies (57%). The methodological quality was strong in five studies. Two studies provided complete information. Clear research gaps emerged.ConclusionsOverall, the studies showed a positive effect of drug reminder packaging on adherence and clinical outcomes. However, poor reporting and important gaps like missing humanistic and economic outcomes and neglected safety issues limit the drawing of firm conclusions. Suggestions are made for future research.

Incorporation of teaching EBM in practice faces several barriers to implementation. Teaching EBM in clinical settings is most successful where EBM principles are culturally embedded and form part and parcel of everyday clinical decisions and medical practice.

Background: Evidence based medicine (EBM) is considered an integral part of medical training, but integration of teaching various EBM steps in everyday clinical practice is uncommon. Currently EBM is predominantly taught through theoretical courses, workshops and e-learning. However, clinical teachers lack confidence in teaching EBM in workplace and are often unsure of the existing opportunities for teaching EBM in the clinical setting. There is a need for continuing professional development (CPD) courses that train clinical trainers to teach EBM through on-the-job training by demonstration of applied EBM real time in clinical practice. We developed such a course to encourage clinically relevant teaching of EBM in post-graduate education in various clinical environments.

The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation containing the absorption-enhancer chitosan were studied in 12 healthy volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the β2 band (18-25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum-effect (E(max)) model indicated disequilibrium between plasma and effect-site concentrations, with equilibration half-lives of 2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out-of-hospital emergency settings with no immediate i.v. access.