Preclinical evaluation of performance, safety and usability of VAX-ID®, a novel intradermal injection device.

The recent SARS-Cov2 pandemic and mpox health emergency have led to renewed interest in intradermal vaccination due to its dose sparing potential. Indeed, intradermal vaccination is particularly of interest for use in mass vaccination campaigns, pandemic preparedness programs, and/or for vaccines that are expensive or in short supply. Moreover, the rich immune network in the skin makes it an attractive target not only for prophylactic vaccination, but also for therapeutic vaccination, like immunotherapy and (dendritic) cell-based therapies. The aim of the current paper was to provide an overview of preclinical data generated with VAX-ID®, a novel intradermal drug delivery device, to allow assessing it performance, safety and usability. The device can overcome challenges seen with the Mantoux technique whereby the needle needs to be inserted under a shallow angle. Various parameters of VAX-ID® were evaluated, including dead-space volume, dose accuracy, penetration depth & liquid deposit in piglets, as well as usability by healthcare professionals. The device has shown to have a low dead volume and a high dose accuracy. Importantly, the device performed successful injections at a predefined depth into the dermis with a high safety profile as confirmed by visual and histological evaluation in piglets. Moreover, the device was rated as easy to use by healthcare professionals. The combined preclinical performance and usability findings indicate that VAX-ID® can provide reliable, standardized and accurate drug delivery in the dermal layer of the skin with a high ease of use. The device offers a solution for injection of various prophylactic as well as therapeutic vaccines.

UAS™-A Urine Preservative for Oncology Applications.

Liquid biopsy is a revolutionary tool that is gaining momentum in the field of cancer research. As a body fluid, urine can be used in non-invasive diagnostics for various types of cancer. We investigated the performance of UAS™ as a preservative for urinary analytes. Firstly, the need for urine preservation was investigated using urine samples from healthy volunteers. Secondly, the performance of UAS™ was assessed for cell-free DNA (cfDNA) and host cell integrity during storage at room temperature (RT) and after freeze-thaw cycling. Finally, UAS™ was used in a clinical setting on samples from breast and prostate cancer patients. In the absence of a preservative, urinary cfDNA was degraded, and bacterial overgrowth occurred at RT. In urine samples stored in UAS™, no microbial growth was seen, and cfDNA and cellular integrity were maintained for up to 14 days at RT. After freeze-thaw cycling, the preservation of host cell integrity and cfDNA showed significant improvements when using UAS™ compared to unpreserved urine samples. Additionally, UAS™ was found to be compatible with several commercially available isolation methods.

Urine biomarkers in cancer detection: A systematic review of preanalytical parameters and applied methods.

The aim of this review was to explore the status of urine sampling as a liquid biopsy for noninvasive cancer research by reviewing used preanalytical parameters and protocols. We searched two main health sciences databases, PubMed and Web of Science. From all eligible publications (2010-2022), information was extracted regarding: (a) study population characteristics, (b) cancer type, (c) urine preanalytics, (d) analyte class, (e) isolation method, (f) detection method, (g) comparator used, (h) biomarker type, (i) conclusion and (j) sensitivity and specificity. The search query identified 7835 records, of which 924 unique publications remained after screening the title, abstract and full text. Our analysis demonstrated that many publications did not report information about the preanalytical parameters of their urine samples, even though several other studies have shown the importance of standardization of sample handling. Interestingly, it was noted that urine is used for many cancer types and not just cancers originating from the urogenital tract. Many different types of relevant analytes have been shown to be found in urine. Additionally, future considerations and recommendations are discussed: (a) the heterogeneous nature of urine, (b) the need for standardized practice protocols and (c) the road toward the clinic. Urine is an emerging liquid biopsy with broad applicability in different analytes and several cancer types. However, standard practice protocols for sample handling and processing would help to elaborate the clinical utility of urine in cancer research, detection and disease monitoring.

Impact of Collection Volume and DNA Extraction Method on the Detection of Biomarkers and HPV DNA in First-Void Urine.

The potential of first-void (FV) urine as a non-invasive liquid biopsy for detection of human papillomavirus (HPV) DNA and other biomarkers has been increasingly recognized over the past decade. In this study, we investigated whether the volume of this initial urine stream has an impact on the analytical performance of biomarkers. In parallel, we evaluated different DNA extraction protocols and introduced an internal control in the urine preservative. Twenty-five women, diagnosed with high-risk HPV, provided three home-collected FV urine samples using three FV urine collection devices (Colli-Pee) with collector tubes that differ in volume (4, 10, 20 mL). Each collector tube was prefilled with Urine Conservation Medium spiked with phocine herpesvirus 1 (PhHV-1) DNA as internal control. Five different DNA extraction protocols were compared, followed by PCR for GAPDH and PhHV-1 (qPCR), HPV DNA, and HBB (HPV-Risk Assay), and ACTB (methylation-specific qPCR). Results showed limited effects of collection volume on human and HPV DNA endpoints. In contrast, significant variations in yield for human endpoints were observed for different DNA extraction methods (p < 0.05). Additionally, the potential of PhHV-1 as internal control to monitor FV urine collection, storage, and processing was demonstrated.

Human papillomavirus detection in urine: Effect of a first-void urine collection device and timing of collection.

Great interest has been directed towards the use of first-void (FV) urine as a liquid biopsy for high-risk HPV DNA testing. The aim of this study was to investigate the potential effect of a first generation FV urine collection device on the detection of HPV DNA and to assess if the concentration of HPV DNA varies between FV urine collected in the morning and those collected later during the day. In this prospective cohort study, 33 self-reported HPV-positive women participated. An FV urine sample was collected by these women in the morning (first urine of the day) and another sample was collected later that day for four consecutive days using two different collection methods; i.e., the Colli-Pee® and a standard urine cup. Samples were collected at home and returned at ambient temperature to the laboratory by postal mail. HPV DNA testing was conducted with the Riatol qPCR HPV genotyping assay. Based on the combined generalized linear mixed model used, there was no significant impact of the timing of collection (morning versus later during the day) on copies of HPV DNA, whereas Colli-Pee® collected samples show higher HPV concentrations than cup collected samples. However, at high concentrations of hDNA, the benefit of the Colli-Pee® disappeared.

Assessment of Forces in Intradermal Injection Devices: Hydrodynamic Versus Human Factors.

PURPOSE: The force that has to be exerted on the plunger for administering a given amount of fluid in a given time, has an important influence on comfort for the subject and usability for the administrator in intradermal drug delivery. The purpose of this study is to model those forces that are subject-independent, by linking needle and syringe geometry to the force required for ejecting a given fluid at a given ejection rate. MATERIAL AND METHODS: We extend the well-known Hagen-Poiseuille formula to predict pressure drop induced by a fluid passing through a cylindrical body. The model investigates the relation between the pressure drop in needles and the theoretic Hagen-Poiseuille prediction and is validated in fifteen needles from 26G up to 33G suited for intradermal drug delivery. We also provide a method to assess forces exerted by operators in real world conditions. RESULTS: The model is highly linear in each individual needle with R-square values ranging from 75% up to 99.9%. Ten out of fifteen needles exhibit R-square values above 99%. A proof-of-concept for force assessment is provided by logging forces in operators in real life conditions. CONCLUSIONS: The force assessment method and the model can be used to pinpoint needle geometry for intradermal injection devices, tuning comfort for subjects and usability for operators.

Efficacy of Lactobacillus casei Shirota for patients with irritable bowel syndrome.

BACKGROUND AND AIMS: Meta-analyses point to a modest but significant effect of probiotics on symptoms in irritable bowel syndrome (IBS). We aimed to assess the effect of the probiotic Lactobacillus casei Shirota (LcS) on symptoms and quality of life in IBS patients in a randomized, double-blind, placebo-controlled intervention study. MATERIALS AND METHODS: IBS patients (Rome II) between 18 and 65 years of age were included. The study consisted of an 8-week intervention period in which the participants received probiotic (LcS) or placebo twice daily, followed by an 8-week follow-up period. Symptom diaries and quality of life were scored at weeks 0, 8 and 16. The primary outcome parameter was a decrease of at least 30% in a composite mean symptom score (MSS) at week 8 on the basis of an intention-to-treat analysis. RESULTS: Thirty-nine individuals (67% women) were included in the probiotic group and 41 individuals (71% women) were included in the placebo group. After the intervention period, the mean relative improvement did not reach 30% for MSS or any individual symptom score. After follow-up (week 16), a mean improvement of at least 30% was achieved for MSS in the probiotic group, but no significant difference was found between both treatment groups (mean±SD: 34±7%; 13±8%, P=0.06). CONCLUSION: After probiotic treatment with LcS, no improvement of 30% in MSS was observed after 8 weeks.

Assessment of acceptability and usability of new delivery prototype device for intradermal vaccination in healthy subjects.

The objectives of this study were to assess the acceptability and usability of a newly developed intradermal prototype device, VAX-ID™, in healthy subjects. In April 2012 an investigational study was conducted in healthy subjects aged 18 to 65 y. To compare injection site and route of administration, subjects were allocated to 4 subgroups, either receiving subsequently 2 intradermal (ID) injections (one in the forearm and one in the deltoid) or an ID (forearm) and an intramuscular (IM) (deltoid) injection. All injections contained saline solution. Acceptability was assessed with a subjects' questionnaire and a daily electronic diary for 5 d. Usability was assessed with a vaccinators' questionnaire and an expert panel. A 10-point Visual Analog Scale was used to score several statements on usability and acceptability. A total of 102 healthy subjects were enrolled in the study (age: 19-63). No statistically significant differences were seen in demographic characteristics between the ID and IM groups. Anxiety before injection, pain during injection and duration of injection were rated significantly lower for ID compared to IM. One day after the injections, redness was reported more often after ID injection in the forearm versus ID in the deltoid; pain at injection site was reported significantly more often after IM vs. ID injection. The new VAX-ID prototype device was found easy to handle, easy to use and safe. The new VAX-ID prototype device was shown to have a high degree of acceptability as well as usability. Further studies with VAX-ID will be conducted using vaccine antigen allowing assessment of immunogenicity and safety. Additionally, these studies will help to further improve VAX-ID in terms of accuracy of delivered dose and feedback to the vaccinator. (NCT01963338).

Reliability and Validity of the Dutch Physical Activity Questionnaires for Children (PAQ-C) and Adolescents (PAQ-A).

BACKGROUND: This study was designed to validate the Dutch Physical Activity Questionnaires for Children (PAQ-C) and Adolescents (PAQ-A). METHODS: After adjustment of the original Canadian PAQ-C and PAQ-A (i.e. translation/back-translation and evaluation by expert committee), content validity of both PAQs was assessed and calculated using item-level (I-CVI) and scale-level (S-CVI) content validity indexes. Inter-item and inter-rater reliability of 196 PAQ-C and 95 PAQ-A filled in by both children or adolescents and their parent, were evaluated. Inter-item reliability was calculated by Cronbach's alpha (α) and inter-rater reliability was examined by percent observed agreement and weighted kappa (κ). Concurrent validity of PAQ-A was examined in a subsample of 28 obese and 16 normal-weight children by comparing it with concurrently measured physical activity using a maximal cardiopulmonary exercise test for the assessment of peak oxygen uptake (VO2 peak). RESULTS: For both PAQs, I-CVI ranged 0.67-1.00. S-CVI was 0.89 for PAQ-C and 0.90 for PAQ-A. A total of 192 PAQ-C and 94 PAQ-A were fully completed by both child and parent. Cronbach's α was 0.777 for PAQ-C and 0.758 for PAQ-A. Percent agreement ranged 59.9-74.0% for PAQ-C and 51.1-77.7% for PAQ-A, and weighted κ ranged 0.48-0.69 for PAQ-C and 0.51-0.68 for PAQ-A. The correlation between total PAQ-A score and VO2 peak - corrected for age, gender, height and weight - was 0.516 (p = 0.001). CONCLUSIONS: Both PAQs have an excellent content validity, an acceptable inter-item reliability and a moderate to good strength of inter-rater agreement. In addition, total PAQ-A score showed a moderate positive correlation with VO2 peak. Both PAQs have an acceptable to good reliability and validity, however, further validity testing is recommended to provide a more complete assessment of both PAQs.

The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide.

BACKGROUND: The neonatal and pediatric antimicrobial point prevalence survey (PPS) of the Antibiotic Resistance and Prescribing in European Children project (http://www.arpecproject.eu/) aims to standardize a method for surveillance of antimicrobial use in children and neonates admitted to the hospital within Europe. This article describes the audit criteria used and reports overall country-specific proportions of antimicrobial use. An analytical review presents methodologies on antimicrobial use. METHODS: A 1-day PPS on antimicrobial use in hospitalized children was organized in September 2011, using a previously validated and standardized method. The survey included all inpatient pediatric and neonatal beds and identified all children receiving an antimicrobial treatment on the day of survey. Mandatory data were age, gender, (birth) weight, underlying diagnosis, antimicrobial agent, dose and indication for treatment. Data were entered through a web-based system for data-entry and reporting, based on the WebPPS program developed for the European Surveillance of Antimicrobial Consumption project. RESULTS: There were 2760 and 1565 pediatric versus 1154 and 589 neonatal inpatients reported among 50 European (n = 14 countries) and 23 non-European hospitals (n = 9 countries), respectively. Overall, antibiotic pediatric and neonatal use was significantly higher in non-European (43.8%; 95% confidence interval [CI]: 41.3-46.3% and 39.4%; 95% CI: 35.5-43.4%) compared with that in European hospitals (35.4; 95% CI: 33.6-37.2% and 21.8%; 95% CI: 19.4-24.2%). Proportions of antibiotic use were highest in hematology/oncology wards (61.3%; 95% CI: 56.2-66.4%) and pediatric intensive care units (55.8%; 95% CI: 50.3-61.3%). CONCLUSIONS: An Antibiotic Resistance and Prescribing in European Children standardized web-based method for a 1-day PPS was successfully developed and conducted in 73 hospitals worldwide. It offers a simple, feasible and sustainable way of data collection that can be used globally.

Differences in gut microbiota composition between obese and lean children: a cross-sectional study.

BACKGROUND: An altered gut microbiota composition has recently been linked to obesity. The principal aim of this study is to investigate and compare the gut microbiota composition in obese and lean children. Secondly, associations between analysed gut bacterial species, dietary compounds, energy intake and biochemical blood parameters are evaluated. METHODS: In this prospective cross-sectional study, 26 overweight/obese (mean BMI: 28.7 ± 6.5) and 27 lean (mean BMI: 16.5 ± 2.1) children aged 6 to 16 were included. Faecal samples were collected and subjected to selective plating and quantitative real-time PCR (qPCR) in order to determine the concentrations of bacterial species belonging to the genera: Bacteroides, Bifidobacterium, Clostridium, Staphylococcus and Lactobacillus. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied for an in-depth identification of species of Bacteroides fragilis group. Differences in the concentrations of gut bacterial species between obese and lean children were statistically analysed using Mann Whitney U test. Subsequently, random forest analysis and multiple linear regression analysis were performed in order to test associations between gut bacterial species, dietary compounds and blood parameters. RESULTS: Obese children showed an elevated Firmicutes-to-Bacteroidetes ratio compared with lean children. Furthermore, low relative proportions of B. vulgatus and high concentrations of Lactobacillus spp. were observed in the obese microbiota. In all children, Staphylococcus spp. were positively associated with energy intake. Additionally, in obese children, Lactobacillus spp. were positively associated with plasma hs-CRP. CONCLUSIONS: Our findings corroborate a significant difference in the gut microbiota composition of important bacterial species between obese and lean children. In future, non-invasive manipulation of gut microbiota composition in early infancy could offer a new approach to manage childhood obesity and associated disorders.

Food fermentations: microorganisms with technological beneficial use.

Microbial food cultures have directly or indirectly come under various regulatory frameworks in the course of the last decades. Several of those regulatory frameworks put emphasis on "the history of use", "traditional food", or "general recognition of safety". Authoritative lists of microorganisms with a documented use in food have therefore come into high demand. One such list was published in 2002 as a result of a joint project between the International Dairy Federation (IDF) and the European Food and Feed Cultures Association (EFFCA). The "2002 IDF inventory" has become a de facto reference for food cultures in practical use. However, as the focus mainly was on commercially available dairy cultures, there was an unmet need for a list with a wider scope. We present an updated inventory of microorganisms used in food fermentations covering a wide range of food matrices (dairy, meat, fish, vegetables, legumes, cereals, beverages, and vinegar). We have also reviewed and updated the taxonomy of the microorganisms used in food fermentations in order to bring the taxonomy in agreement with the current standing in nomenclature.

Indications for antimicrobial prescribing in European nursing homes: results from a point prevalence survey.

PURPOSE: In light of the emerging problem with multiresistant microorganisms in nursing homes (NHs), the European Surveillance of Antimicrobial Consumption NH subproject was set up to measure and describe antimicrobial use across Europe. The aim of this paper was to investigate the indications for antimicrobial use and hence identify targets for quality improvement. METHODS: Data were obtained from a point prevalence survey conducted in 323 NHs across 21 European countries. A resident questionnaire had to be completed for each resident receiving an antimicrobial, collecting data such as compound name and indication for antimicrobial prescribing. Four main indications for antimicrobial use were recorded: nasal decolonisation of methicillin-resistant Staphylococcus aureus (MRSA) carriage with mupirocin, prophylactic, empirical, and microbiologically documented treatments. The latter three treatment types were further subdivided according to the targeted infections. RESULTS: In total, 1966 residents were treated with 2046 antimicrobials. Empirical treatments were most common (54.4% of all antimicrobial therapies; prevalence: 3.39 per 100 eligible residents), followed by prophylactic (28.8%; prevalence: 1.87%) and microbiologically documented (16.1%; prevalence: 1.01%) regimes. MRSA decolonisation with nasal mupirocin (0.7%; prevalence: 0.02%) was uncommon. Antimicrobials were most frequently prescribed for the prevention or treatment of urinary (49.5%; prevalence: 3.23%) and respiratory (31.8%; prevalence: 1.81%) tract infections. A very high proportion of uroprophylaxis was reported (25.6% of all prescribed antimicrobials; prevalence: 1.67%). CONCLUSIONS: The indications for antimicrobial prescribing varied markedly between countries. We identified uroprophylaxis as a possible target for quality improvement.

Antimicrobial prescribing in hospitalized adults stratified by age: data from the ESAC point-prevalence surveys.

BACKGROUND: Geriatric infectious diseases are a major health care issue. Infections in the elderly occur more frequently than in younger adults, are often associated with higher morbidity and mortality, and may present atypically. Elderly patients are also often taking multiple medications, which increases the likelihood of drug-drug interactions. Dosing decisions should take into consideration the reduced lean body mass and declining renal function in this age group. OBJECTIVE: Antimicrobial prescribing in three age groups (65-74, 75-84 and ≥85 years) was compared with a reference age group (18-64 years), with the aim of identifying quality of care indicators specific to the elderly. METHODOLOGY: The ESAC (European Surveillance of Antimicrobial Consumption) final phase performed two hospital point-prevalence surveys in 2008 and 2009, respectively, using the defined daily dose (DDD) and Anatomical Therapeutic Chemical (ATC) classification system. The prescribed daily dose (PDD) was compared with the DDD. Differences in prescribing were assessed using multivariate logistic regression analyses. RESULTS: The majority of patients (19,549 [64% of 30,836]) were from Northern Europe and 13,830 (48%) belonged to the reference group. The largest proportion of patients was admitted through the hospital's medical specialty (55% of patients) [range: 49% in the reference group to 72% in the ≥85 years age group]. Penicillins were the most frequently used antimicrobials in all age groups (range: 32% in the reference group to 41% in the ≥85 years age group). Multivariate analyses showed three significant variations between the 65-74 years age group and the reference group (quinolones: odds ratio [OR] 1.17 [95% CI 1.05, 1.29]; tetracyclines: OR 1.58 [95% CI 1.26, 1.98]; aminoglycosides: OR 0.81 [95% CI 0.70, 0.93]). The number of significant variations increased to seven and eight in the 75-84 and ≥85 years age groups, respectively. A lower likelihood for PDD > DDD was observed in the 65-74 years age group for three parenteral antimicrobials (amoxicillin/clavulanic acid, gentamicin and vancomycin). This was reiterated in the older age groups (75-84 and ≥85 years), where piperacillin/tazobactam, meropenem and oral ciprofloxacin also showed a lower likelihood for PDD > DDD. CONCLUSIONS: Despite the methodology not being dedicated to elderly patients, the study identified elevated use of antimicrobial agents that are associated with serious adverse effects or a narrow therapeutic index as a target for quality of care improvement in elderly patients.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient penicillin use in Europe (1997-2009).

BACKGROUND: Data on 13 years (1997-2009) of outpatient penicillin use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project and analysed in detail. METHODS: For the period 1997-2009, data on outpatient use of systemic penicillins aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011) and expressed in DDD per 1000 inhabitants per day (DID). For detailed analysis of trends over time, seasonal variation and composition of outpatient penicillin use in 33 European countries, we distinguished between narrow-spectrum penicillins (NSP), broad-spectrum penicillins (BSP), penicillinase-resistant penicillins (PRP) and combinations with ß-lactamase inhibitors (COP). RESULTS: Total outpatient penicillin (ATC group J01C) use in 2009 varied by a factor of 3.8 between the countries with the highest (16.08 DID in France) and lowest (4.23 DID in the Russian Federation) use. COP represented 45.8%, BSP 40.7%, NSP 10.8% and PRP 2.6% of total European outpatient penicillin use. Total outpatient penicillin use significantly increased over time by 1.53 (SD 0.71) DID between 1997 and 2009. COP (mainly co-amoxiclav) increased by 2.17 (SD 0.40) DID, which was the result of its absolute increase as well as the observed shift from NSP and BSP towards COP. This increase exceeded 10% in 20 countries, where it coincided with a similar decrease in either BSP (15 countries) or NSP (5 countries). CONCLUSIONS: Penicillins represented the most widely used antibiotic subgroup in all 33 participating countries, albeit with considerable variation in their use patterns. For Europe, a continuous increase in overall penicillin use and of COP use was observed during the period 1997-2009.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient cephalosporin use in Europe (1997-2009).

BACKGROUND: Data on 13 years of outpatient cephalosporin use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC), and analysed in detail. METHODS: For the period 1997-2009, data on outpatient use of systemic cephalosporins aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011) and expressed in DDD per 1000 inhabitants per day (DID). For detailed analysis of trends over time, seasonal variation and composition of outpatient cephalosporin use in 33 European countries, we distinguished between first-generation (J01DB), second-generation (J01DC), third-generation (J01DD) and fourth-generation (J01DE) cephalosporins. RESULTS: Total outpatient cephalosporin use in 2009 varied from 8.7 DID in Greece to 0.03 DID in Denmark. In general, use was higher in Southern and Eastern European countries than in Northern European countries. Total outpatient cephalosporin use increased over time by 0.364 (SD 0.473) DID between 1997 and 2009. Cephalosporin use increased for half of the countries. Low-consuming Northern European countries and the UK further decreased their use. Second-generation cephalosporins increased by >20% in seven countries (mainly cefuroxime), coinciding with a decrease in first-generation cephalosporins. Substantial parenteral use of third-generation substances (mainly ceftriaxone) was observed in France, Italy and the Russian Federation. CONCLUSIONS: Since 1997, the use of the older (narrow-spectrum) cephalosporins decreased in favour of the newer (i.e. broad-spectrum) cephalosporins in most countries. Extreme variations between European countries in cephalosporin use over time suggest that they are to a large extent inappropriately used.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe (1997-2009).

OBJECTIVES: To describe total outpatient systemic antibiotic use in Europe from 1997 to 2009 and to analyse statistically trends of total use and composition of use over time. METHODS: For the period 1997-2009, data on outpatient use of systemic antibiotics aggregated at the level of the active substance were collected and expressed in defined daily doses (WHO, version 2011) and packages per 1000 inhabitants per day (DID and PID, respectively). Outpatient antibiotic (ATC J01) use in DID in the 33 European countries able to deliver valid data was analysed using longitudinal and compositional data analyses. RESULTS: Total outpatient antibiotic use in 2009 varied by a factor of 3.8 between the countries with the highest (38.6 DID in Greece) and lowest (10.2 DID in Romania) use. For Europe, a significant increase was found in total outpatient antibiotic use, as well as a significant seasonal variation, which decreased over time from 1997 to 2009. Relative use of penicillins and quinolones significantly increased over time with respect to sulphonamides and trimethoprim, and relative use of quinolones increased with respect to macrolide/lincosamide/streptogramin as well. More detailed analyses of these major antibiotic subgroups will be described in separate papers. CONCLUSIONS: Outpatient antibiotic use in Europe measured as DID has increased since 1997, whereas seasonal variation has decreased over time. European Surveillance of Antimicrobial Consumption (ESAC) data on outpatient antibiotic use in Europe enable countries to audit their antibiotic use. Complemented by longitudinal and compositional data analyses, these data provide a tool for assessing public health strategies aimed at reducing antibiotic resistance and optimizing antibiotic prescribing.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe (1997-2009).

BACKGROUND: Data on more than a decade of outpatient quinolone use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC). METHODS: For the period 1997-2009, data on outpatient use of systemic quinolones aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011), and expressed in DDD and packages per 1000 inhabitants per day (DID and PID, respectively). Using a classification based on pharmacokinetic and in vitro potency profiles, quinolone use was analysed with regard to trends over time, seasonal variation and composition. RESULTS: Total outpatient quinolone use in 2009 varied by a factor of 7.5 between the country with the highest (Italy, 3.61 DID) and the country with the lowest (the UK, 0.48 DID) quinolone use. The second-generation quinolones accounted for >50% of quinolone use (mainly ciprofloxacin), except for Croatia, where first-generation quinolones (mainly norfloxacin) were mostly used. A significant increase in outpatient quinolone use was found for Europe, as well as a large seasonal variation, which increased significantly over time from 1997 to 2009. Relative use of third-generation quinolones significantly increased over time with respect to the use of second-generation quinolones, while the relative use of both significantly increased with respect to the first-generation quinolones. Levofloxacin and moxifloxacin (respiratory quinolones) represented >10% of quinolone outpatient use in 17 countries, with extreme seasonal variation in all countries. CONCLUSIONS: There was a substantial increase and change in the pattern of quinolone use between 1997 and 2009, a period during which quinolones that are effective for the treatment of respiratory tract infections were introduced. These quinolones are not the first-line antibiotics for this indication and their use should generally be limited, and quinolones should ideally show no substantial seasonal variation in terms of their use.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe (1997-2009).

BACKGROUND: Data on more than a decade of outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe were collected from 33 countries as part of the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC). METHODS: For the period 1997-2009, data on outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials aggregated at the level of the active substance were collected and expressed in defined daily doses (DDD; WHO, version 2011) per 1000 inhabitants per day (DID). Using the Anatomical Therapeutic Chemical (ATC) classification, trends in the use of tetracyclines (J01A), sulphonamides and trimethoprim (J01E) and other antibacterials (J01X) over time, seasonal variation and composition of use were analysed. RESULTS: In 2009, the variations in outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials between countries, and also in the composition of use over time, were huge. For tetracyclines a significant and for sulphonamides and trimethoprim a non-significant decrease in use was observed between 1997 and 2009 in Europe. The seasonal variation in their use significantly decreased over time. For the other antibacterials, no significant changes in the volume of use or its seasonal variation were seen. CONCLUSIONS: As for all other major antibiotic subgroups, a striking variation in use and composition of use between countries in Europe was observed for outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials. In combination with the decreasing use, especially of recommended substances, this represents an opportunity not only to reduce antibiotic use but also to improve its quality.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe (1997-2009).

BACKGROUND: Data on more than a decade of outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 33 countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC), using the WHO Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) methodology. METHODS: For the period 1997-2009, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2011) per 1000 inhabitants per day (DID). Using a classification based on mean plasma elimination half-life, macrolide use was analysed for trends over time, seasonal variation and composition. RESULTS: Total outpatient MLS use in 2009 varied by a factor of 18 between the countries with highest (11.5 DID in Greece) and lowest (0.6 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were the most commonly used agents in 2, 25 and 5 countries, respectively (mainly erythromycin, clarithromycin and azithromycin, respectively). In Sweden, mainly lincosamides (clindamycin) were used. Lincosamide use was observed in all countries, while substantial use of a streptogramin was only seen in France (pristinamycin). For Europe, a significant increase in outpatient MLS use was found, as well as a significant seasonal variation, which increased over time from 1997 to 2009. Relative use of long-acting macrolides and lincosamides significantly increased over time with respect to intermediate-acting macrolides, and relative use of the latter increased with respect to short-acting macrolides. CONCLUSIONS: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this subgroup of antibiotics is still prescribed inappropriately in many countries.