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

Trends, seasonality and the association between outpatient antibiotic use and antimicrobial resistance among urinary bacteria in the Netherlands

OBJECTIVES: To determine trends, seasonality and the association between community antibiotic use and antimicrobial resistance (AMR) in Escherichia coli and Klebsiella pneumoniae in urinary tract infections. METHODS: We analysed Dutch national databases from January 2008 to December 2016 regarding antibiotic use and AMR for nitrofurantoin, trimethoprim, fosfomycin and ciprofloxacin. Antibiotic use was expressed as DDD/1000 inhabitant-days (DID) and AMR was expressed as the percentage of resistance from total tested isolates. Temporal trends and seasonality were analysed with autoregressive integrated moving average (ARIMA) models. Each antibiotic use-resistance combination was cross-correlated with a linear regression of the ARIMA residuals. RESULTS: The trends of DID increased for ciprofloxacin, fosfomycin and nitrofurantoin, but decreased for trimethoprim. Similar trends were found in E. coli and K. pneumoniae resistance to the same antibiotics, except for K. pneumoniae resistance to ciprofloxacin, which decreased. Resistance levels peaked in winter/spring, whereas antibiotic use peaked in summer/autumn. In univariate analysis, the strongest and most significant cross-correlations were approximately 0.20, and had a time delay of 3-6 months between changes in antibiotic use and changes in resistance. In multivariate analysis, significant effects of nitrofurantoin use and ciprofloxacin use on resistance to these antibiotics were found in E. coli and K. pneumoniae, respectively. There was a significant association of nitrofurantoin use with trimethoprim resistance in K. pneumoniae after adjusting for trimethoprim use. CONCLUSIONS: We found a relatively low use of antibiotics and resistance levels over a 9 year period. Although the correlations were weak, variations in antibiotic use for these four antibiotics were associated with subsequent variations in AMR in urinary pathogens

Quantifying antibiotic use in paediatrics: a proposal for neonatal DDDs

The defined daily dose (DDD) as defined by the World Health Organization (WHO) has been the most frequently used unit of measurement to measure antibiotic use. However, measuring antibiotic use in paediatrics is a problem as the WHO DDD methodology is not applicable in children (aged >1 month) due to the large variation in body weight within this population. Based on the narrow range of body weights in the neonatal population, we therefore aimed to develop a set of neonatal DDDs for antibiotics. Eight well-respected (inter)national sources for dosage recommendations of antibiotics in children and neonates were consulted for the assumed maintenance dose of the ten most frequently used antibiotics in neonatal intensive care units in its main indication for neonates. A set of neonatal DDDs for ten commonly used antibiotics in neonates based on an assumed neonatal weight of 2 kg was proposed. Primarily in children DDDs are not applicable to quantify antibiotic use since there is large variation in body weight. In the neonatal population, however, based on its narrow range of body weights and when access to patient level data is not available, neonatal DDDs can be used as a unit of measurement

Lack of the purinergic receptor P2X7 results in resistance to contact hypersensitivity

Engagement of P2X7 on mouse dendritic cells, presumably by ATP released in response to contact allergen, is needed for IL-1β production and the sensitization phase of contact hypersensitivity

Structure–activity relationships on the odor detectability of homologous carboxylic acids by humans

We measured concentration detection functions for the odor detectability of the homologs: formic, acetic, butyric, hexanoic, and octanoic acids. Subjects (14 ≤ n ≤ 18) comprised young (19–37 years), healthy, nonsmoker, and normosmic participants from both genders. Vapors were delivered by air dilution olfactometry, using a three-alternative forced-choice procedure against carbon-filtered air, and an ascending concentration approach. Delivered concentrations were established by gas chromatography (flame ionization detector) in parallel with testing. Group and individual olfactory functions were modeled by a sigmoid (logistic) equation from which two parameters are calculated: C, the odor detection threshold (ODT) and D, the steepness of the function. Thresholds declined with carbon chain length along formic, acetic, and butyric acid where they reached a minimum (ODTs = 514, 5.2, and 0.26 ppb by volume, respectively). Then, they increased for hexanoic (1.0 ppb) and octanoic (0.86 ppb) acid. Odor thresholds and interindividual differences in olfactory acuity among these young, normosmic participants were lower than traditionally thought and reported. No significant effects of gender on odor detectability were observed. The finding of an optimum molecular size for odor potency along homologs confirms a prediction made by a model of ODTs based on a solvation equation. We discuss the mechanistic implications of this model for the process of olfactory detection

Chemosensory Cues to Conspecific Emotional Stress Activate Amygdala in Humans

Alarm substances are airborne chemical signals, released by an individual into the environment, which communicate emotional stress between conspecifics. Here we tested whether humans, like other mammals, are able to detect emotional stress in others by chemosensory cues. Sweat samples collected from individuals undergoing an acute emotional stressor, with exercise as a control, were pooled and presented to a separate group of participants (blind to condition) during four experiments. In an fMRI experiment and its replication, we showed that scanned participants showed amygdala activation in response to samples obtained from donors undergoing an emotional, but not physical, stressor. An odor-discrimination experiment suggested the effect was primarily due to emotional, and not odor, differences between the two stimuli. A fourth experiment investigated behavioral effects, demonstrating that stress samples sharpened emotion-perception of ambiguous facial stimuli. Together, our findings suggest human chemosensory signaling of emotional stress, with neurobiological and behavioral effects

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades