In 2014, Public Health England (PHE) developed the behavioural change Antibiotic Guardian (AG) campaign to tackle antimicrobial resistance (AMR). This included an online pledge system aimed at healthcare professionals (HCP) and the public. Demographics of AGs were collected when pledging online and analysed by pledge group, type, geography, and source of hearing of the campaign between 24/07/2014–31/12/2017. Website visitors and acquisition routes were described using Google analytics data. From November 2016, five questions assessed AMR knowledge which was compared to published Eurobarometer AMR survey results for UK. Behaviour change of AGs was also assessed through an impact questionnaire, evaluating the effect of the campaign on self-reported behaviour around AMR. Overall there were 231,460 unique website visitors from 202 countries resulting in 57,627 English and 652 foreign language pledges. Website visitors increased each year with peaks during European Antibiotic Awareness Day and (EAAD) World Antibiotic Awareness Week (WAAW). Self-direction was the largest acquisition route (55%) with pledges more likely via this route than social media . AGs (including the public) were more likely to answer questions correctly than the Eurobarometer UK group . AG campaign engagement has increased over the four years with particular increases in the student group. AGs had greater knowledge compared to the Eurobarometer UK population. The latest impact evaluation of the online pledge scheme highlights that it continues to be an effective and inexpensive way to engage people with the problem of AMR especially among those with prior awareness of the topic. Antibiotic therapy has been one of the most important medical discoveries of the 20th century, preventing millions of deaths worldwide from infections and facilitating advancement in modern medicine . Antimicwww.antibioticguardian.com) with an online pledge system designed to improve knowledge and behaviours regarding antibiotic prescribing and use among healthcare professionals and the public.In 2014, Public Health England (PHE) developed the behaviour change and engagement campaign, Antibiotic Guardian (AG) in the UK with the aim of tackling AMR . This inA 2-min video which was aimed at the public, embedded at the top of the campaign website and hosted on YouTube.Active promotion of key messages through Social media in particular Twitter, actively promoting the use of hashtag #AntibioticGuardian.https://antibioticguardian.com/healthcare-professionals/).Development of a range of resources (leaflets/posters) and toolkits available for healthcare professionals to use in local campaigns/outreach (signposted to through the website http://antibioticguardian.com/Resources/playbuzz/).Development of an interactive quiz on the online publishing platform Playbuzz  to assess whether engagement had continued, describe the demographics and knowledge of AGs and to highlight any areas that could be addressed in future promotional activities.Since the start of the campaign, the website has been visited 291,431 times of which 79% were unique visitors . These visits have translated into 57,627 English language pledges, with an unadjusted conversion rate of 19.8% for the website as a whole. The number of visits to the site and pledges has increased each year . HoweverThe website received unique visits from 202 countries. The majority of these visits were from the UK (80.9%), but 19.1% of visits were from outside of the UK. The top five countries visiting the website outside of the UK were United States (n = 7391), Russia (n = 4675), Belgium (n = 3071), India (n = 1496) and Australia (n = 1420).p < 0.001). 8.7% (5019) of AGs had pledged more than once between 2014 and 2017.Overall, 44.6% of pledges were made from a unique IP address whereas 55.4% were from a repeated IP address. The median number of pledges made from a repeated IP address was 192 and ranged from 2–1647. The number of pledges from repeat IP addresses showed an increase from 64.2% in 2015 to 66.4% in 2017  pledges had been received from 149 different countries therefore antibiotic guardians were present in 57.7% of countries worldwide; 95.9%  from the UK, 1.4% (n = 618) from the rest of Europe and 2.6% (n = 1138) from the rest of the world. There was an increase in the number of countries with AGs from 63 countries in 2015 to 149 . There was some variation between UK countries with Wales having the highest rate at 206.6 per 100,000 population (95% CI 201.6–211.7), followed by England 81.1 (95% CI 80.3–81.9), Scotland 51.6 (95% CI 49.7–53.6) and Northern Ireland 35.2 (95% CI 32.6–38). A further breakdown by clinical commissioning groups (CCGs) and Health boards can be seen in The majority of unique visitors accessed the site through a desktop computer (58.8%) compared to a mobile device  (41.2%). Individuals were also more likely to pledge to become an Antibiotic Guardian if accessing the site via a desktop computer compared to a mobile device, OR 1.26 (95% CI 1.23–1.28).The most common acquisition route for unique visits to the site was self-directed, e.g., through a search engine or typing the website address directly into the browser which accounted for 55.2% of visits compared to 24.6% referred through social media, 15.3% referred through another website and 1.2% referred through links in emails. Other routes accounted for 3.7% of unique visits. Self-direction has remained the largest acquisition route across all four years. Compared to referrals via social media, individuals were more likely to pledge is they accessed the site through self-directed  or via email referrals  but showed no real difference of likelihood to pledge when referred through other websites .From 2014 to July 2016 there had been 136 publications, 108 bulletins/newsletters, 294 web articles and 40 international mentions of Antibiotic Guardian. The educational YouTube video entitled ‘Will you be an Antibiotic Guardian?’ accessible via the AG website and PHE YouTube channel was viewed 35,827 times with an average view time of 1.33 min out of 2.02 min (76% of the full video) and the ‘Antibiotic Resistance Playbuzz’ quiz launched on the website in November 2016 has been accessed 3900 times with 628 completions up until December 2016. Analysis of Twitter data over the first four years showed that #AntibioticGuardian had been tweeted 46,152 times by 15,307 people and 10,101 times during WAAW 2016. In 2017 WAAW 2333 individuals participated in Twitter’s social media with 5737 tweets posting the #AntibioticGuardian hashtag.The most common pledge group overall was health care professionals (54.3%) , which hp < 0.001). The highest proportion of students pledging were pharmacy students , the majority of which were adults (79.7%). The most common pledge chosen by the public was ‘for infections that our bodies are good at fighting off on their own, like coughs, colds, sore throats and flu, I pledge to try treating the symptoms for five days rather than going to the GP’. This was an adult sub group pledge and accounted for 32.3% of pledges (n = 5211). Where gender could be inferred , the majority of AGs were female (73%).There was a reduction in the proportion of pledgers who are members of the public (28% in 2014 vs. 23.8% in 2017) which was significant ; 94.4%  were answered correctly and 80% of AGs answered all five questions correctly. For individual questions, the percentage answered correctly ranged from 91.1% for ‘taking antibiotics often has side effects such as diarrhoea’ to 98% for ‘unnecessary use of antibiotics makes them become ineffective’ .p < 0.001) and the public  .There was some variation between pledge groups for the percentage of questions answered correctly as shown in The Eurobarometer survey on Antimicrobial resistance used questions 1 to 4 to survey the EU general population and publish results on AMR knowledge by country. For each of these questions, all AG groups (including the public) answered a higher proportion of these correctly when compared to the UK and EU published figures . AGs werWhere indicated , AGs  most commonly heard about the campaign from colleagues (23.9%), within the NHS (23.3%) or from professional organisations (14.8%) . These sThe source varied by group with the public mainly hearing about the campaign by NHS (31.1%) and the social media (20.9%), HCPs through colleagues (33.2%) and professional organisations (20.5%), whereas students heard from the university (47.6%). The public was more likely to hear about the campaign from social media than the health care professionals  and students .Overall, 1940 AGs (6.8% response rate) completed the online survey which self-reported behaviours following their pledges (outcomes). Of those with gender recorded, the majority (76.8%) were females and about half (56%) of the respondents pledged as health professionals with 30.8% (598) pledging as a member of the public. Of those respondents, where the year of the pledge was indicated (n = 1031), almost all (95.1%) had pledged within the previous 16 months of the survey. Characteristic of AGs that participated in the survey is shown in Prior to hearing about the AG campaign, 86% of respondents were aware of antibiotic resistance, 32.2% (537) of this group stated that they believed that antibiotic resistance is an important issue they can do something about as individuals. Where indicated (n = 1696), 28.1% believed Antibiotic Guardian website was an important source that impacted their knowledge on antibiotic resistance.p < 0.001).In selecting a pledge, 47.5% of respondents (922) chose a specific pledge because of their belief in successfully delivering on their commitment, of which 64.3% (593) were healthcare professionals. Of this group (n = 922), 60.6% self-reported to ‘always’ act in line with their pledge and 31.8% acted ‘most of the time.’ Overall, 61.8% of AGs ‘always’ acted in line with their pledge after the campaign. A higher proportion of AGs who were members of the public (84.9%), reported ‘always’ acting in line with their pledge compared to healthcare professionals (49.6%), with an odds ratio of 5.7  was the most common reason for pledging to become an Antibiotic Guardian, while professional experience with antibiotic resistance (37.6%) was the most commonly stated reason for healthcare professionals.The Antibiotic Guardian behavioural change campaign aimed at improving AMR related knowledge and behaviour amongst healthcare professionals and the general public has been shown to have sustained engagement with increases in AG pledges over the years. As a low-cost campaign reliant on local and individual engagement and promotion activities, this pledge based approach shows the impact of alternatives to traditional advice based interventions for effective public health intervention programmes . FindingThe number of pledges chosen yearly remains consistent with peaks in November during WAAW and EAAD due to the focused national, European and worldwide promotional activities. However, there has been a shift away from these profound peaks to an increase in year-round AG pledges and a decreasing trend in the number of pledges during WAAW compared to 2015.Health care professionals continued to be the main groups engaged with the campaign. This may be due to promotion of the campaign historically focused on changing healthcare professional’s behaviours especially prescribing. However, since 2016 promotional activities have been focused on actively engaging students and the public by encouraging students from universities to nominate themselves or be nominated as local Antibiotic Guardian champions to run campaigns within their universities. This change has led to increases in the number of pledges from students and the public compared to 2014. There was also an increase in nurses and dentists coinciding with the publication (November 2016) of the dental antimicrobial stewardship toolkit . It is eEngagement via social media was found to be particularly useful for the public with the majority of AGs from the public hearing about the campaign from this source. This highlights the need for continued social media promotion. A peak in pledges was also observed during March 2016 which corresponded with the use of paid for advertising used for the first time on Facebook to target mothers of young children and healthcare students aged 18–25 within England. This accentuated the potential of social media through dissemination of health campaign related information to the public in supporting behavioural change and engagement. Engagement through social media provides an opportunity to exchange on health matters and real-time learning .The majority of website visitors and pledges were from the UK, but there was variation by country within the UK and on a local level which requires further understanding of different engagement and promotional activities used. Antibiotic Guardian rates per local authority have been published in response to the NICE guidelines Antimicrobial stewardship: changing risk-related behaviours in the general population aimed at local authorities . AnalysiThe campaign has also gathered interest across Europe with WHO-Europe and Belgian Antibiotic Policy Coordination Committee (BAPCOC) requesting collaboration with PHE to translate the current UK Antibiotic Guardian campaign into Russian, Dutch and French languages during 2016 .Knowledge regarding AMR was found to be greater in AGs when compared to the Eurobarometer survey of the UK population and the EU. This also held true when focused only on the AGs who were members of the public. This is encouraging and could be an indicator of the knowledge acquired through the campaign due to the specific educational materials such as videos and quizzes available. However, it may also reflect a bias in the campaign towards those that already have an interest and are engaged in AMR. There were still some gaps in knowledge highlighted in all groups and in particular around knowing that antibiotics often have side-effects. Overall the general public had the least knowledge out of the AG groups, but this was still greater than the Eurobarometer comparison groups. This further illustrates the need for greater awareness regarding antibiotics and the continued efforts of such campaigns.This study did not make any direct comparisons with prescribing data; this is in part due to the known multifactorial influences on prescribing and other efforts that are ongoing to reduce prescribing making causality challenging to conclude. However, it was found that the CCG in England that has made the most substantial reduction in antibiotic prescribing over the last two years (Birmingham CrossCity CCG) also had the highest number of AGs during 2016 .Preliminary analysis also found a weak positive correlation between the rate of AG per 100,000 population (2014–2017) and the percentage reduction in the twelve-month rolling total number of prescribed antibiotic items per STAR-PU from December 2014 to December 2017 for Clinical Commissioning Groups within England  to the campaign website were analysed using Google analytics to compare numbers over time, geography, conversion rates, and acquisition routes . The keywww.antibioticguardian.com) (The primary outcome measure was pledging to become an Antibiotic Guardian in the English language on the website (ian.com) . A full From November 2016, Antibiotics Guardians were asked to answer true or false to five statements on AMR to assess their knowledge using pop up website box after pledging to become an AG. The first four statements were taken from the published 2016 Eurobarometer survey on antimicrobial resistance . The staBehaviour change of AGs was assessed through an impact questionnaire  , health boards and local authorities in the UK and using ONS 2017 mid-year population estimates [® Excel (2010) and STATA release 15 [Unless stated otherwise, Google analytics data was calculated using the number of unique visitors. Conversion rates were calculated as the proportion of visitors to the website that pledged to become an AG, and an adjusted conversion rate was calculated as the proportion of AG pledges from unique website visits. The decision to become an Antibiotic Guardian or not was calculated by the acquisition route using odds ratios and 95% confidence intervals. Significant differences between Antibiotic Guardian groups were identified using the Chi-squared test and a stimates . The proAfter four years the Antibiotic Guardian campaign has sustained year-round engagement within a wide range of individuals and countries, with particular increases in student and public groups. AGs (including public AGs) showed greater antimicrobial resistance knowledge when compared to the Eurobarometer UK group. Future work should focus on further promotion within the UK and Europe to sustain the engagement of the campaign and to understand and learn about differences in engagement between areas. Within England, a new media campaign for members of the public (Keep Antibiotic Working) was piloted in one region of England in 2016 and rolled out nationally in 2017. This campaign aligns with Antibiotic Guardian, and its aim will help fulfil the recommendation from the impact evaluation to reach those not previously engaged with AMR.


Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease characterized by exuberant deposition of extracellular matrix components, deterioration of lung architecture and impairment of lung functions. Its etiopathogenesis remains incompletely understood, as reflected in the lack of an appropriate therapy. Modeling the human disease in mice via the administration of bleomycin (BLM), despite the inherent limitations, has provided valuable insights into the underlying pathogenetic mechanisms, and has been instrumental for the development and validation of new pharmacologic interventions. Here we have directly compared the, most widely used, intratracheal (IT) route of administration with oropharyngeal aspiration (OA). Our results suggest that the OA route of BLM-administration can be used as a safe and effective alternative, minimizing peri-operative and experimental mortality, while preserving a solid fibrotic profile, as assessed with a plethora of standardized readout assays. Modelinghuman diseases in mice, despite the inherent limitations, has provided valuable insights into the underlying pathogenetic mechanisms, and has been instrumental for the development and validation of new pharmacologic interventions. In the context of Idiopathic Pulmonary Fibrosis (IPF), a fatal disease characterized by exuberant deposition of extracellular matrix components, deterioration of lung architecture and impairment of lung functions , the mosStreptomyces verticillus, is an anti-neoplastic/antibiotic drug for the treatment of some forms of cancer (Bleomycin (BLM), a mixture of glycopeptides isolated from f cancer . It actsf cancer . The lacf cancer , servingf cancer , 4. The f cancer .In order to mimic the human exposure, BLM was initially administered systemically, via intravenous or intraperitoneal injections, resulting, as in humans, to the subpleural development of fibrotic lesions . Howeverad libitum” (17). All experimentation in mice was in line with the ARRIVE guidelines and has been approved by the Veterinary service and Fishery Department of the local governmental prefecture, following the approval by the Institutional Animal Ethical Committee  of BSRC Alexander Fleming.Mice were bred under SPF conditions at the local animal facility at “20–22°C, 55 ± 5% humidity, and a 12-h light-dark cycle; water and food were given Pulmonary fibrosis was induced through the administration of BLM (Nippon Kayaku) to anesthetized  mice. The intratracheal (IT) route was applied essentially as previously published (17), and as described in the online Bronchoalveolar Lavage Fluid (BALF) collection and analysis, lung histopathological analysis and Quantitative RT-PCR analysis were performed with standardized protocols, as previously published  and as d(SCIREQ) following manufacturer instructions, as previously published . Data are presented as means (±SEM); p < 0.05 (*) was considered significant.Statistical significance was assessed with unpaired Student's Beyond the route of administration, the severity of BLM effects highly depends on the precise genetic background of mice , the local genetic drift of the colony and the health status of the corresponding animal house. As a result, a wide range of BLM concentrations have been employed to induce pulmonary fibrosis in mice , 4. As tPulmonary fibrosis was induced by IT or OA administration of BLM  in both male and female, 8–12 weeks old, C57Bl6/J mice. No sex effect was observed in any readout assays, so all following experimental results concern cumulative data, of randomly assigned, sex and age matched groups of littermate mice. No statistically significant difference on overall mouse survival was found between IT and OA BLM administrations Figures ; howeverCst), (2) respiratory system compliance (Crs), and (3) total lung capacity (A), as well as increases in: (4) respiratory system elastance (Ers), (5) tissue elastance (H), (6) curvature of the upper portion of the deflation limb of the PV curve (K),  administration mice were sedated, tracheotomized and connected to a mechanical ventilator to evaluate forced-oscillation lung mechanics Figure . OA admi, Figure . Both st, Figure , well co, Figure . TherefoThe route of BLM administration did not have an effect in BLM-induced vascular leak, as indicated by the total protein levels in the corresponding bronchoalveolar fluids (BALFs) Figure . SimilarIn line with the BALF assays, and as shown in representative images of H&E stained lung sections, BLM-challenge promoted extensive fibrotic changes and architectural distortion compared to saline-treated animals, irrespectively of the delivery method Figure ; no majoin vivo lung function measurements which are highly clinically relevant. Our results suggest that the OA route can be used as a safe and effective alternative route of BLM administration, allowing researchers to easily produce reproducible and robust kinetics of fibrotic lung injury combined with a beneficial safety profile sparing invasive surgical procedures of the IT administration, as well as the systemic effects of higher BLM doses. Moreover, the low BLM concentrations employed will allow drug testing in animals of a much better shape, without compromising a solid fibrotic profile.Overall, as prompted by the recent American Thoracic Society workshop report on the use of animal models , we haveVA designed the study; IB and IN performed all reported experiments; AT co-analyzed the data and wrote the paper, which was edited by VA and was critically commented by all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Health care-associated urinary tract infection (HAUTI) consists of unique conditions . These conditions could have different pathogen diversity and antibiotic resistance impacting on the empirical antibiotic choices. The aim of this study is to compare the estimated chances of coverage of empirical antibiotics between conditions  in urology departments from Europe.A mathematical modelling based on antibiotic susceptibility data from a point prevalence study was carried. Data were obtained for HAUTI patients from multiple urology departments in Europe from 2006 to 2017. The primary outcome of the study is the Bayesian weighted incidence syndromic antibiogram (WISCA) and Bayesian factor. Bayesian WISCA is the estimated chance of an antibiotic to cover the causative pathogens when used for first-line empirical treatment. Bayesian factor is used to compare if HAUTI conditions did or did not impact on empirical antibiotic choices.Bayesian WISCA of antibiotics in European urology departments from 2006 to 2017 ranged between 0.07  to 0.89 . Bayesian WISCA estimates were lowest in urosepsis. Clinical infective conditions had an impact on the Bayesian WISCA estimates (Bayesian factor > 3 in 81% of studied antibiotics). The main limitation of the study is the lack of local data.Our estimates illustrate that antibiotic choices can be different between HAUTI conditions. Findings can improve empirical antibiotic selection towards a personalized approach but should be validated in local surveillance studies.The online version of this article (10.1007/s00345-019-02963-9) contains supplementary material, which is available to authorized users. Health care-associated urinary tract infection (HAUTI) is a major concern with a prevalence of 7.7% 4.6–17.3%) in urology departments, which is higher compared to other departments 0.5–1.7%)  . The stuOn the study day, all patients in urology wards are screened for HAUTI and surgical site infections (SSI) as defined by the Center for Disease Control and Prevention (CDC) criteria (Supplement I) . ClinicaPrevalence of HAUTIs, pathogens and AMR of pathogens,Diversity of causative pathogens within conditions of HAUTIs using the Shannon diversity index ,Dissimilarity of causative pathogens between conditions of HAUTIs using the Bray–Curtis index ,Chances of an antibiotic to provide coverage for a condition using the Bayesian WISCA , 17,Differences of Bayesian WISCA estimates between conditions using the Bayesian factor .Outcomes of the study are:Geographical variability was accounted for by grouping countries based on the 2017 European Center for Disease Control (ECDC) AMR prevalence data . CountriData analysis was carried out in R version 3.5.1.Pathogen diversity within clinical conditions was illustrated with the Shannon diversity index . PathogeAMR rates were calculated for 11 single and 10 combination choices as recommended by international guidelines for HAUTIs (Supplement III) . AntibioBayesian WISCA represents the probability of an empirical antibiotic choice to cover the causative pathogens. Calculation involves two stages and two variables: (i) probability of etiological pathogens; and (ii) probability of each etiological pathogen to be susceptible towards the antibiotic. These probabilities are obtained from the GPIU prevalence data by applying the relevant functions (Supplement IV). After obtaining the two probabilities, they are multiplied and added.The Bayesian approach accounts for prior information of pathogens and their resistance to antibiotics . HierarcH0: Dissimilarity of pathogens and their respective AMR between conditions does not impact the chances of coverage of empirical antibiotic.H1: Dissimilarity of pathogens and their respective AMR between conditions impacts the chances of coverage of empirical antibiotic.The Bayesian factor was used to determine if the chances of coverage of an antibiotic will vary between HAUTI conditions. This was achieved by obtaining the likelihood of two competing hypothesis and calculating their ratio . The twoModel 1 (M1): Bayesian WISCA of antibiotic ~ study year (2006–2017) + regions of resistance (high vs low).Model 2 (M2): Bayesian WISCA of antibiotic ~ study year (2006–2017) + regions of resistance (high vs low) + HAUTI conditions .The Bayes factor quantifies the strength of evidence to support or refute the concept that HAUTI conditions impact the Bayesian WISCA. Analysis of variance (ANOVA) models were developed to account for geographic and time variability of Bayesian WISCA estimates. The likelihood probabilities for each hypothesis were calculated through the ANOVA models. Conceptually the models were as follows:M2vsM1). Interpretation of the Bayes factor was conducted using the classification proposed by Jeffreys  to 58.1% (AMX) for single antibiotic choices and 10.8% (TZP + GEN) to 28.9% (CIP + TMP) for combination choices (Supplement VII).AMR rates in the pooled sample of pathogens and years (2003–2017) ranged between 8.2% (imipenem) and 62.6% (amoxicillin) for single antibiotic choices and 16.3% [piperacillin/tazobactam (TZP) + GEN] to 32.3% [ciprofloxacin (CIP) + trimethoprim/sulfamethoxazole (TMP)] combination choices (Supplement VII). For Pooled data—all HAUTIs: Bayesian WISCA estimates ranged between 0.09  and 0.86 . Estimated median Bayesian WISCA per condition is illustrated in Fig. Cystitis: estimates for single agents ranged between 0.07  and 0.84 .Pyelonephritis: single agent median estimates were between 0.14  and 0.89 . Combination choice median estimates were lowest at 0.36  and highest at 0.89 .Urosepsis: single agent median estimates were between 0.11  and 0.83 . Combination choice median estimates were lowest at 0.29  and highest at 0.86 .A relationship between the clinical conditions and the chances of coverage of antibiotics was rejected in 19% of the antibiotics  Fig. b. For thIn this study, we hypothesized that distinct patterns of pathogen diversity and AMR between conditions would lead to differences in empirical antibiotic choices. Chances of coverage of 21 antibiotic choices were studied and condition-specific differences were supported in 81% of them. We achieved this by obtaining the Bayesian WISCA of antibiotics per year and compared each antibiotic choice between conditions using the Bayesian factor. We also accounted for geographical variation by separating the European countries into high and low resistance areas using the ECDC surveillance data.Frequencies of pathogens both in our previous and current Fig. a study wE. coli showed differences between conditions in 6 (28%) out of 21 studied antibiotics. These findings were similar to our previous published results in 2016 and illustrate that AMR can be different for pathogens between conditions but it does not explain the coverage of an empirical antibiotic [In our analysis, the AMR frequency of tibiotic . We, thetibiotic . Therefotibiotic . HoweverThe strength of the study is based on two main factors. First, the GPIU surveillance to our knowledge is the only study that has a sequential measure of HAUTIs in urology departments using validated definitions. This has generated data comparable over time. Second, analysis of the data utilizing the Bayesian WISCA approach has allowed us to unmask previously unknown findings. The WISCA measure has been used before , 24 and Although this study has demonstrated that condition-specific surveillance information in HAUTIs can improve the information obtained for the empirical antibiotic selection, there are several limitations. First, the data are derived from an annual surveillance study at a continental level and participation from each country was varied. Hence, the accuracy of the results is questionable but previous studies have identified that the inaccuracy is more likely to be gauged towards an underestimate of AMR , 26. SecOur estimates illustrate that antibiotic choices can be different between HAUTI conditions. The Bayesian WISCA approach was instrumental in highlighting these differences. The findings can improve empirical antibiotic selection towards a personalized approach but need to be validated in local surveillance studies.Supplementary material 1 (DOCX 2385 kb)Below is the link to the electronic supplementary material.


The aim of this paper was to highlight the most widely antibiotic protocols applied to the dental field, especially in the surgical treatment of impacted wisdom teeth. Once these protocols were screened, all the possible advantages or disadvantages for each drug and each posology were recorded in this review. In recent years, the need to use these protocols has been debated in the literature. The data obtained by this review underlined how antibiotic protocols applied to oral surgery treatments only included surgeries performed on patients who did not present other systemic pathologies. The first literature review obtained 140 results, and then after the application of the inclusion criteria, 12 papers were selected. The results showed that the most commonly used protocol involved the use of penicillin and clavulanate, obtaining safe clinical and prophylactic results in the management of infections. This widely used protocol seems to guarantee high predictability and safety. The presented review highlights the current possibility of antibiotic resistance affecting patients due to drug misuse. Further clinical studies are required to state specific guidelines; however, oral surgeons involved in third molar surgery should evaluate the local and general health conditions of the patients before suggesting any drug measures for patients. The surgical avulsion of wisdom teeth has now become a common surgical practice. However, it is a surgical practice that can expose patients to possible intra and post-operative infection . The antThe prescription of systemic antibiotics for the prevention of complications such as alveolitis and infection of the surgical site during the extraction of the third molar is a widespread practice among dentists, but this is also controversial and debated. The controversy arises because prophylactic antibiotic therapy is usually not indicated in healthy patients, and inappropriate use of antibiotics puts patients at risk of adverse reactions and contributes to the development of antibiotic resistance. Furthermore, considering the cost–benefit ratio, systematic reviews and published meta-analyses do not support the routine prophylactic use of antibiotics. In any case, patients undergoing this surgical therapy, in addition to antibiotic prophylaxis, are often forced to use other pharmacological therapies based on the duration and the complexity of the intervention for the management of the post-operative phase ,6,7,8,9.The purpose of this systematic review of the literature is therefore to highlight which antibiotic protocols are most used during wisdom tooth surgery, and to evaluate among these the best therapeutic, pharmacological, and posological routes for the patient, limiting the misuse of antibiotic drugs where possible.A literature search was conducted and gave a high number of results: 140. Subsequently, filters were applied to make the research and results more specific. Firstly, studies from the last 10 years were evaluated , then those that had accessible full texts , randomized clinical trials (RCTs), and then those in English. Only 12 studies were included in this review . The keyThe choice of keywords was intended to produce as many results as possible to support the review. A manual search was also conducted on textbooks to increase the scientific support and accuracy of the study. The textbook research did not produce sources in support of the review but provided information regarding the introduction and discussion sections.The results obtained subsequently were categorized based on the dosage, type of drug, and type of extraction surgery performed. The studies taken into consideration by this revision were all RCTs. Each article presents information about the use of antibiotic protocols during wisdom tooth extraction surgery. The information is shown in Evaluation on the total risk of bias for each selected paper, and the majority of the manuscripts were allocated as low risk  13,14,1,22,23,24Numerous limitations have arisen from the present revision. Current analysis of the data extracted from studies written in English only could introduce a possible publication bias. The main limitation of the revision is related to the oral surgery and to the third molar surgery. The use of antibiotics is still debated widely.The statistical analysis of the studies was singularly analyzed. The authors disagree on different parameters evaluated after surgery. Some studies take into consideration the duration of surgery, which was not evaluated in this study and is not presented in the tables; this seems to have a fundamental importance in the management of complications. On other topics the authors disagree, but most of them show that pain, swelling, fever, edema, reduced mouth opening, or postoperative surgical site infection do not show significant differences between study groups. Therefore, we have no significant statistical differences between the different types of antibiotics and between antibiotic and placebo, leading to the conclusion that performing surgery of wisdom teeth in the absence of antibiotic prophylaxis does not lead to more difficult management of complications.Surgical avulsion of third molars or wisdom teeth, as can be seen from the results, is a surgical procedure that often requires an antibiotic protocol by the clinician. However, some studies show that it is not always necessary ,22,23,24Regarding the topical use of drugs, we must not forget local anesthetics with and without adrenaline. Topical disinfection of the operating field often occurs with chlorhexidine-based mouthwashes or povidone iodide ,26. It iDuring these surgeries it is possible to use different topical hemostatic procedures or even medicated gauzes, especially in the case where annexed osteolytic lesions are present. Among the hemostatic practices it is possible to recognize the use of collagen sponges; it is certainly not necessary to proceed with bone regenerative maneuvers , but a rIn the article of Monaco et al. , they evA protocol including the investigation methods and the inclusion criteria for the current revision was submitted in the PROSPERO website, an international prospective register of systematic reviews. The parameters and the analytic structure of the present work can be visualized relating the CRD ID and code; this systematic review was submitted at the PROSPERO website platform, with PROSPERO acknowledgement of receipt number 131364.The data of this systematic investigation observed the Preferred Reporting Items for Systematic Review in accordance with the PRISMA statement.What are the most widely used antibiotic protocols during wisdom tooth extraction surgery?Are there any alternatives? Are these more beneficial for the patient?The questions processed the following guidelines, according to PICO :We conducted a search in five electronic databases, including Ovid MEDLINE, PubMed, and EMBASE. In addition a manual search on Dentistry and Pharmacological source was conducted, for relevant studies published.Digital and searches by hand were then performed in third molar extraction and antibiotic. In-depth research of the reference lists in the recorded manuscripts was performed in order to add significant studies and to increase the sensitivity of the revision.Medical Subject Headings (MeSH) were applied for finding the keywords used in the present revision. The selected key words: (“antibiotic prophylaxis” OR “antibiotic”) AND (“third molar” OR “wisdom teeth”) AND “extraction” were recorded for collecting the data. The date of last search with these results was 31 March 2019.Two independent reviewers of two different universities (Messina and Naples) singularly analyzed the obtained papers in order to select inclusion and exclusion criteria as follows. Reviewers correlated their evaluations and analyzed differences through comparing the manuscripts and consulting a third experienced senior independent reviewer  when a consensus could not be reached. For the stage of the full-text articles revision, a complete independent dual analysis was performed.The method of classification included all human prospective and retrospective clinical studies, split mouth cohort studies, case–control papers, case series manuscripts, animal investigations, and literature reviews published between February 2009 and March 2019, on antibiotics used for oral surgery and third molar extraction.Investigated pharmacological prophylaxis or third molar extractionClinical human randomized controlled trialsThe following exclusion criteria:Patients with other specific disease as osteoporosis, immunologic disorders, uncontrolled diabetes mellitus, or other surgical risk-related systemic conditionsNot enough information regarding the topicAnimal or in vitro studiesArticles published prior to 1 February 2009No access to the title and abstractThe full texts of all studies related to the main revision topics were obtained for comparing the inclusion parameters:After the first literature analysis, the entire manuscript titles list was highlighted to exclude irrelevant publications, case reports and the non-English language publications. Then, research was excluded based on data obtained from screening just the abstracts. The final selection was performed reading the full texts of the papers in order to approve each study’s eligibility, based on the inclusion and exclusion criteria.The results and conclusions of the selected full text papers were used for assembling the data, according to the aims and themes of the present revision, as listed onwards.“Author”—revealed the first author of publication“Year”—Year of publication“Type of study”—indicated the method of the research and some additional information“Sample size”—described the number of patients, animals or models examined“Protocols”—described types of groups or antibiotic protocols usedThe following parameters were used as a method for assembling the data and then organized following the schemes as seen in The grade of bias risk was independently considered, as reported in literature ,44,45,46Selection biasPerformance bias and detection biasAttrition biasReporting biasExaminer blinding, examiner calibration, standardized follow-up description, standardized residual graft measurement, standardized radiographic assessmentPotential causes of bias were investigated:Octaves, if they break out correctly, can contribute to chewing and do not cause any problems as long as proper oral hygiene is applied. However, the fact that growth is subject to variations and imperfections is also due to the evolutionary course of the human species: in the past man needed more molars to chew raw and difficult foods, which were abandoned during evolution, while the dimensions of the mandible and jaw were clearly reduced, leaving little space for the normal development of the eighth tooth. Therefore, wisdom teeth are a necessity of the past. It is only with age that the jaws can reach a sufficient size to allow them to develop. Nevertheless, according to some anthropologists, the appearance of the eighth teeth in later age would have the task of counteracting the excessive wear of the other teeth. The prehistoric diet and the non-existence of dental care caused early tooth loss. In this way, the third molar, having sufficient space to develop, performed a reserve function, preserving correct chewing ,53,54,55The use of antibiotics in dentistry, and more, is a fundamental clinical practice in eradicating bacterial infections. Therefore, the pathologies of dental expertise and, in particular, those of an endodontic nature are no exception. Typically, these are polymicrobial conditions involving Gram+ and Gram− bacteria, facultative anaerobes and narrow anaerobes. Antibiotics are actually the second most common pharmacological class prescribed by dentists, after painkillers. It is estimated that 10% of antibiotics are administered for dental needs . Even thThis study aimed to highlight the most widely used antibiotic protocols in dentistry, particularly during wisdom tooth surgery. The ultimate goal was to highlight any factors for or against one therapy over another. The population of clinicians is currently in favor of amoxicillin as evidenced in the results, although the real need to undertake an antibiotic protocol is still much debated in the literature. The use of antibiotics can involve some systemic adverse effects for patients and is not justified by literature. It is important to underline that performing an extraction of a third molar in the case of acute, chronic inflammation or in any case purulent infection without the use of antibiotics is not a topic often considered and taken into consideration. It must be considered that if wisdom teeth were extracted for orthodontic reasons and showed no inflammation, this could strongly influence the need for antibiotic therapy. Between the lines of the different articles taken into consideration, some assessed the surgeon’s experience and the speed or the duration of the intervention. Apparently, this factor is much more important and related to postoperative sequelae than the used drug therapy. Certainly, this study highlights and revises numerous articles, highlighting results in favor of antibiotic protocols. Still, there are few studies that support the non-use of antibiotic protocols during this surgery. Over time we will be able to evaluate these results by finding the most advantageous protocol for all the patients that need this kind of surgery.


The ability to fight bacterial infections with antibiotics has been a longstanding cornerstone of modern medicine. However, wide-spread overuse and misuse of antibiotics has led to unintended consequences, which in turn require large-scale changes of policy for mitigation. In this review, we address two broad classes of corollaries of antibiotics overuse and misuse. Firstly, we discuss the spread of antibiotic resistance from hotspots of resistance evolution to the environment, with special concerns given to potential vectors of resistance transmission. Secondly, we outline the effects of antibiotic pollution independent of resistance evolution on natural microbial populations, as well as invertebrates and vertebrates. We close with an overview of current regional policies tasked with curbing the effects of antibiotics pollution and outline areas in which such policies are still under development. Staphylococcus aureus, a leading cause of death in European hospitals at the time )While AFO- and CAFO-originating ARBs have to cross a species barrier, transmission of human-evolved ARBs, for example from hospitals and sewage, should be easily possible. As a consequence, humans in those settings may readily become vectors of ARB transmission and dissemination. Indeed, increased antibiotic resistance and thus a potentially increased ARB transmission risk have been associated with hospital workers ,115. ImpE. coli with ESBL genes than those staying in Central Africa, and establishment of ARB strains in the students’ microbiomes occurred without any antibiotic treatment [In addition to health care, farm, and WWTP workers, the dissemination of ARBs has been connected to international travellers. Several studies have demonstrated that commensals and pathogens carrying ARGs can establish themselves in the travellers’ microbiome, and that these ARBs can persist for a length of time after return to the country of origin ,108. Forreatment . The conApart from humans, other animals have been described as ARB-carrying vectors. Insects, and specifically houseflies and cockroaches, have been widely associated with transmissions of ARBs from AFOs and CAFOs , WWTPs , as wellE. coli carrying ESBL [A range of vertebrates have been shown to carry ARBs , but a ding ESBL , presumaing ESBL .While hotspots for the evolution and dissemination of ARBs such as hospitals AFOs and WWTPs have been thoroughly assessed, the importance and risk posed by vectors of transmission between environments has not been systematically studied. As vectors may aid in the multiplication of ARBs and recombination of ARGs and offer unique selective conditions, they are central to understanding the flow of antibiotic resistance between environments. Specifically, the risks of combining resistance genes from human and animal systems and the crossing of the species barrier need to be assessed. Ultimately, ARBs are deposited into the environment via vector transmission. Their possible fates there are outlined in Box 1ARBs:-Due to their adaptation to the gastrointestinal tract, fitness of many ARBs in soil and water environments is expected to be low, leading to persistence times in the order of weeks to months ,130,131.Acinetobacter, Pseudomonas, or Aeromonas may have wider niche breaths and may thus be equipped to survive longer or even thrive in soil and water [-Resistance-gene carrying opportunistic pathogens or commensals from hospital and AFO environments such as nd water .-ARBs could lose ARGs when the selective pressure of the antibiotic is no longer present (the cost of resistance hypothesis ), but thARGs:-The persistence of resistance genes in the soil environment is variable and depends on a range of environmental factors including temperature, moisture, pH, and the microbial community present ,136.Acinetobacter sp., Burkholderia sp., and Pseudomonas fluorescens with ARGs is possible [-The transformation of naturally competent soil bacteria such as possible ,138. -Human pathogens and soil bacteria have been shown to have overlapping resistomes, indicating a vast potential for HGT between the two groups .Even though research often focusses on antibiotics as means to treat or prevent bacterial infections, most clinical antibiotics are derived from biomolecules naturally produced by soil-dwelling microorganisms as secondary metabolites . As mentStaphylococcus spp. [In addition to favoring the evolution and spread of antibiotic resistance as discussed above, the selective pressures imposed by antibiotic pollution can impact on the evolutionary dynamics observed in microbial populations in different ways . Differecus spp. , a traitcus spp. ,151. In addition to changes in the population composition of bacteria, exposure to low levels of antibiotics has also been shown to increase genetic diversity in microbial population via the activation of the bacterial SOS response, resulting in an increased mutation rate throughout the genome , and viaBacteria and fungi inhabiting soil and water environments are not only the foundation of the most diverse and densely populated ecosystems on Earth ,161, butCyanobacteria species, causing eutrophication in freshwater environments and posing health risks to humans [For example, antibiotic pollution in aquatic environments was found to reduce overall microbial diversity, including taxa responsible for carbon cycling and primary productivity ,167,168.o humans .In addition to their impact on microbial populations, antibiotics can also affect higher organisms. Side effects associated with different antibiotics are well documented in human medicine thanks to standardized clinical trials and pharmacology reports . On the Daphnia magna [Artemia in laboratory conditions [While toxicity levels for humans are often a known quantity, there is comparatively little information regarding toxic concentration in wild animals, especially smaller and more susceptible organisms ,181. India magna  and Artenditions . Furthernditions , thus hiXenopus tropicalis [Antibiotic pollution has also been observed to have negative effects on vertebrates. The effect of antibiotic pollution is thought to be especially strong in aquatic environment where animals are chronically exposed to the pollutants . For exaopicalis . D. magna, mostly impacting the general stress response, as well as protein and carbohydrate metabolism [In addition to physiological effects, antibiotics can also interfere with development and behaviour, potentially resulting from changes in gene expression . In facttabolism . Moreovetabolism , thus poAntibiotics have also been shown to impact higher organisms by disrupting the microbial populations associated with animal hosts . Animal While the impact of antibiotic exposure on host microbiomes has been mostly studied in human or in the murine model at high concentration ,202, recThe sheer magnitude of the antibiotic pollution and resistance crisis, with the estimated deaths due to antibiotic resistance being 700,000 per year globally , makes mPolicies addressing antibiotic pollution and Antimicrobial Resistance (AMR) have been created in the Pan-American region addressing the misuse of antibiotics in the health and agriculture sectors, but much less attention has been devoted to other sources of exposure. Canada engaged in global efforts to fight antibiotic pollution and ABR and committed multi-sectoral support to the implementation of the WHO Global Action Plan on ABR with its own domestic plan “Tackling Antimicrobial Resistance and Antimicrobial Use: A Pan-Canadian Framework for Action” focusing on three main topics: (1) Surveillance, (2) Stewardship, and (3) Innovation .Inappropriate and rampant use of antibiotics is a major contributor to antibiotic resistance in the South-East Asian region, but comprehensive monitoring systems are absent . The incEurope has been at the forefront of tackling the antibiotic pollution and antibiotic resistance crisis and was quick to recognize the need to invest in research and policy starting in the early 2000s and implemented the “EU One Health Action Plan against AMR” in June 2017. The key objectives of this plan are: (1) making the EU a best practice region, (2) boosting research, development, and innovation, and (3) shaping the global agenda.In the following, we discuss antibiotic pollution and AMR policies by the main sources of contamination outlined above, which are agriculture, aquaculture, human medicine, wastewater treatment, and pharmaceutical industry  and theLikewise, as mentioned briefly above, current policies preventing the environmental release of antibiotics by drug manufacturing facilities are missing in all national action plans. Given the magnitude of localized antibiotic pollution by manufacturers, this omission may facilitate regional hotspots of resistance evolution from which ARBs and ARGs may subsequently spread world-wide.Lastly, currently no policies are in place in the three regions specifically addressing the problems of antibiotic and ARG pollution of WWTPs. As current WWTP design does not specifically consider the removal of antibiotics, ARBs and ARGs, policies need to be aimed at amending WWTP technologies establishing acceptable ARG load guidelines in WWTP effluents and biosolids. Large-scale antibiotic pollution and the resulting antibiotic resistance is a current major public health problem. While the environmental component of this issue  has received an increased research interest in recent years, many dimensions of environmental antibiotic pollution and resistance are still unknown and require further research.E. coli in coastal waters (~0.12%), certain activities, such as surfing, provided enough contact with the contaminated water to allow transmission. More of such benchmark studies are needed to accurately interpret the environmental resistome data collected and translate it into health risks. For example, current research of environmental dimensions of antibiotic resistance often tallies up resistance genes found within an environment but gives little indication of the associated risks of transmission, and thus the potential impact on human health. Technically, it is often difficult to infer absolute abundances of antibiotic-resistant pathogens from sequence data, which records relative abundances of resistance genes. Such technical issues aside, only little information exists linking the presence and abundance of ARGs directly to a human’s risk of becoming infected with an antibiotic resistant bacterium upon exposure . One notIn addition to contributing to the prevalence of antibiotic resistance, antibiotic pollution also has the potential to affect human and ecosystem health directly. On one hand, the effects of antibiotic pollution are expected to be especially disruptive in aquatic environments, where they can inhibit ecosystem functions and impact on organisms that are exposed throughout their life cycle. On the other hand, the presence of antibiotics in the environment and in animals could also impact on human health. While the effect of such exposure is unknown in humans, epidemiological surveys suggest that long-term exposure to antibiotics may lead to chronic conditions including obesity, diabetes, and asthma . For theMoving from data gathering to more interpretative studies will aid in developing efficient policies born out of the research. Current policy schemes are focussed on surveillance, but the scope of the crisis must eventually lead to forward-thinking policies. Understanding antibiotic pollution and antibiotic resistance as a “One Health Approach” may aid in creating more societal engagement and ultimately more efficient policies. Such policies need to evaluate direct risks of transmission posed by certain contaminated environments while at the same taking into account the complex patterns of inter-environmental transmissions that may exist. As antibiotic resistance and pollution is a global problem and especially rampant in the developing world, international cooperation, data-sharing and globally consistent policies are needed.


Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill patients have altered and fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic pharmacokinetics among these intensive care professionals.In May 2018, we carried out a cross-sectional study by sending out an online survey on antibiotic dosing to more than 20,000 intensive care professionals. Questions were designed to cover relevant topics in pharmacokinetics related to intensive care antibiotic dosing. The preliminary pass mark was set by members of the examination committee for the European Diploma of Intensive Care using a modified Angoff approach. The final pass mark was corrected for clinical relevance as assessed for each question by international experts on pharmacokinetics.A total of 1448 respondents completed the survey. Most of the respondents were intensivists  from 97 countries. Nearly all questions were considered clinically relevant by pharmacokinetic experts. The pass mark corrected for clinical relevance was 52.8 out of 93.7 points. Pass rates were 42.5% for intensivists, 36.1% for fellows, 24.8% for residents, and 5.8% for nurses. Scores without correction for clinical relevance were worse, indicating that respondents perform better on more relevant topics. Correct answers and concise clinical background are provided.Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient. This should be addressed given the importance of adequate antibiotic exposure in critically ill patients with sepsis. Solutions include improved education, intensified pharmacy support, therapeutic drug monitoring, or the use of real-time bedside dosing software. Questions may provide useful for teaching purposes.The online version of this article (10.1186/s13054-019-2438-1) contains supplementary material, which is available to authorized users. Sepsis and septic shock remain one of the deadliest diseases in intensive care units worldwide , 2 and aDespite the importance of antibiotic dosing, antibiotic exposure is well known to be frequently inadequate in intensive care patients –8. The DAdmittedly, adequate antibiotic dosing for critically ill patients is challenging. Intensive care patients have markedly altered and variable pharmacokinetic parameters for antibiotics as compared to healthy individuals or less severely ill patients. Organ dysfunction, abnormal fluid balances, altered hemodynamics, and organ replacement therapy can severely impact dosing requirements . HoweverTherapeutic drug monitoring may provide guidance, but is usually only provided for aminoglycosides  and the As a consequence, adequate pharmacokinetic knowledge remains pivotal to optimize antibiotic dosing at the bedside of the critically ill. It is currently not known whether the level of knowledge on pharmacometric principles among intensive care professionals is sufficient. Our hypothesis was that there is room for improvement given the signals of frequent inadequate antibiotic exposure in the critically ill. To test our hypothesis, we set out to assess the level of clinically relevant knowledge on pharmacokinetic principles governing antibiotic dosing in the setting of intensive care medicine using an expert-validated questionnaire. As a corollary, this questionnaire may serve as a validated educational tool. Therefore, we encourage readers to take the questionnaire themselves.In May 2018, we set up a cross-sectional study by sending out a questionnaire testing the level of knowledge on pharmacometric principles governing antibiotic dosing in the critically ill by electronic mail. Approximately 20,000 healthcare professionals in the field of intensive care medicine were approached using the professional networks of the authors and the database of the international fluid academy (iFAD) days meeting. iFAD comprises of an international collaboration group with the aim of improving outcomes in the critically ill through fluid management, organ support, and monitoring. Attendees include nurses and critical care specialists.Target populations for the questionnaires were intensivists, residents, fellows, and intensive care nurses. No patients were involved in this study. For the purpose of this study, intensivist was defined as a medical specialist in critical care medicine. Fellows were defined as physicians with a dedicated program towards national or international accreditation as an intensivist. Residents were defined as all other junior physicians working in intensive care medicine. As considerable differences in medical postgraduate programs exist among countries, respondents themselves were asked to select the category most appropriate to them –21.Only individuals who consented to receive electronic mail related to intensive care medicine were approached. Recipients were asked to further disseminate the questionnaire in their professional network at their own discretion to yield more responses. All intensive care professionals that chose to respond provided written informed consent for use of their data, in compliance with the General Data Protection Regulation . ParticiAll questions were specifically developed for this questionnaire and designed to cover the clinically relevant topics related to antibiotic pharmacokinetics in the setting of intensive care medicine. The core competencies defined by the Competency-Based Training in Intensive Care Medicine in Europe (CoBaTrICE) collaboration provided a reference standard for these topics . This yiQuestions answered correctly resulted in 10 points; subquestions yielded part of the points amounting to a total of 10. To set the pass mark for the designed questions, we used a modified Angoff approach . In thisAs an additional step, we asked pharmacokinetic experts to rate our questions on clinical relevance. A PubMed ReMiner-search was conducted to identify the top 10 publishing experts in intensive care pharmacokinetics . Titles n = 927, 64%); the majority of whom were between 40 and 50 years of age . Most of the fellows  were in their thirties, compared to 31% of intensivists. Experience in the practice of intensive care medicine varied widely, with nurses and intensivists having worked in their profession the longest. The largest group has worked in the ICU between 10 and 20 years (27% and 34% of nurses and intensivists respectively). Respondents from 97 different countries completed the survey, with the majority of those countries being located in Europe (74%). Even though completion of country of residence was not mandatory, it was provided in 1400 responses (97%).A total of 1448 respondents completed the survey. Characteristics of the respondents are shown in Table The Angoff pass mark was 70.8 out of 120 points (59.0% threshold). The final pass mark, adjusted for clinical relevancy, was 52.8 out of 93.7 points (56.4% threshold). Overall, 513 respondents (35.4%) passed with the final pass mark. Pass rates differed per job category; results are shown in Fig. All survey questions with their model answers are shown in Table This is the first study to show that clinically relevant pharmacokinetic knowledge on antibiotic dosing among international intensive care professionals is insufficient. More than half of intensivists failed the test, while fellows, resident, and nurses had even lower scores. Thus, we have identified a major knowledge gap. Given the pivotal importance of adequate antibiotic dosing, this should be addressed.The importance of pharmacokinetic principles to guide antibiotic dosing in critically ill patient is well recognized given the markedly altered and often changing pharmacokinetics in the critically ill , 8. In pEducation such as antimicrobial stewardship is a potential solution to improve pharmacokinetic expertise among intensive care professionals in order to optimize antibiotic dosing. However, large improvements in pharmacometric knowledge among intensive care professionals may not prove realistic. Causes include increasing workload in clinic  and the Automated pharmacokinetic modeling systems are another viable solution to tackle inadequate antibiotic exposure in the setting of intensive care medicine. The advent of electronic health record systems in most ICUs in resource-rich settings allows for continuous data feeds into integrated pharmacometric software, resulting in individual dosing recommendation at the bed side in real time , 34. OthThis study has several strengths. First, all questions were based on the Cobatrice framework, which ensures close adherence to validated training and examination goals for intensivists. Second, the number of respondents was high and their background was heterogeneous, which extends the results to an international audience of ICU professionals. Third, the pass mark and clinical relevance were assessed by members of the ESICM examination committee and world-renowned experts on pharmacokinetics, which assures test validity. Scores were adjusted for clinical relevance as an extra step after Angoff scoring. The two questions that were rated hard  concomitantly had lower clinical relevance scoring, which was therefore adjusted for in the final scores.intensivist is reserved globally for doctors taking care of patients threatened in their vital parameters, including sepsis and septic shock.This study also has some limitations. Firstly, although the number of responses is high, the response rate is low. We asked people to disperse the survey to colleagues to increase the number of respondents, which also clouds the response rate. We risk that only people who felt comfortable with the questions completed the survey. This would imply, however, that our score is an overestimation. Although we asked people to refrain from using other resources to answer the questions, 21% sought help, which would also contribute to the overestimation of their personal knowledge on the subject. Additionally, the number of respondents per country might not be a representative sample of that country. We therefore refrain from drawing conclusions on a per country basis. The sample from multiple countries, however, implies trends are similar in an international population. Lastly, definitions of intensive care units vary worldwide due to available resources and historical trends. Concomitantly, definitions of job titles in the ICU differ per region or even within countries , 21. We In conclusion, we showed that clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient. This should be addressed, as suboptimal dosing strategies are associated with poorer outcomes. Options include extended use of therapeutic drug monitoring and pharmacist support as well as automated pharmacokinetics systems that provide dosing advice at the bedside in real time.Box 1. Pharmacokinetic backgroundinto (absorption), within (distribution), and out of (metabolism and excretion) the body. All of these are subject to major alterations in critically ill patients, necessitating adaptations in antibiotic dosing. The following brief educational overview addresses relevant pharmacokinetic changes and provides explanations for the answers to our test questions. Changes in absorption are omitted here as antibiotics should always be given intravenously in critically ill patients (100% absorption).Pharmacokinetics (the ancient Greek kinetikos meaning “putting in motion”) deals with drug movement VD) of an antibiotic represents the necessary theoretical volume that contains the amount of administered drug to maintain the observed plasma concentration. VD is derived by the amount of drug in the body/concentration measured in plasma. Size of antibiotic molecules, protein binding, and preference for aqueous (hydrophilic) or lipid (lipophilic) environments are properties of an antibiotic and influence antibiotic distribution and thus VD  and phase II (conjugation) reactions. During sepsis, hepatic dysfunction, hypo- and hyperthermia, and altered hepatic blood flow, among others, may influence drug metabolism . The effVD and CL. Steady state is reached after 4 to 5 half-lives. This implies that for antibiotics with a long half-life, time to target concentration may be too long, necessitating a loading dose. This loading dose depends on VD only and not on CL or rate of elimination. Therefore, in the setting of decreased clearance, e.g., because of renal failure, the loading dose should still be given in full. This can be thought of as the full VD needed to be filled to quickly attain target concentration. An antibiotic with a low volume of distribution and short half-life such as meropenem will therefore quickly reach steady-state target concentration and requires no or low loading doses.Antibiotic elimination is mostly renal and to a lesser extent through hepatic routes, depending on antibiotic class. Hepatic elimination is generally related to cardiac output, which may be increased in sepsis. Likewise, augmented renal clearance may occur in the very early phase of critical illness, while impaired renal function is common at later stages , 39. RisT > MIC) dependent, or a combination of both (AUC0–24/MIC) [max—and T > MIC will remain unchanged. For AUC/MIC targets, the goal is to maintain AUC, possible through both a decrease in the maintenance dose and elongation of the interval. The smallest decrease in AUC is observed with a lowering of the dose and is therefore preferred. For some antibiotics, a decrease in renal clearance leads to an increase of hepatic clearance (ceftriaxone) in healthy subject, but this effect was not observed in a critically ill population [Pre-clinical and clinical studies have identified pharmacokinetic treatment goals for antibiotics Table . Dependi–24/MIC) . In casepulation .Additional file 1:Result per country for intensivists (percentages and absolute numbers). (DOC 434 kb)


Background: The management of prosthetic joint infections (PJI) with debridement and retention of the implant (DAIR) has its rules. Some authors claim that lacking the exchange of mobile prosthetic parts is doomed to failure, while others regard it as optional. Methods: Single-center retrospective cohort in PJIs treated with DAIR. Results: We included 112 PJIs  in 112 patients , 31 (28%) immune-suppressed) and performed a DAIR procedure in all cases—48 (43%) with exchange of mobile parts and 64 without. After a median follow-up of 3.3 years, 94 patients (84%) remained in remission. In multivariate Cox regression analysis, remission was unrelated to PJI localization, pathogens, number of surgical lavages, duration of total antibiotic treatment or intravenous therapy, choice of antibiotic agents, immune-suppression, or age. In contrast, the exchange of mobile parts was protective . Conclusions: In our retrospective single-center cohort, changing mobile parts of PJI during the DAIR approach almost doubled the probability for long-term remission. Prosthetic joint infection (PJI) management requires both surgery and antimicrobial therapy. The surgical options include one- or two-stage implant exchange, resection arthroplasty (with or without arthrodesis), or DAIR . DAIR itself can have two goals: cure ,2 or . We included the last patient on 10 October 2017 and continued the general follow-up until 31 December 2018. We also performed a literature review regarding mobile parts’ exchange in DAIR, by including all available reports of the last twenty years that provide original data with more than 10 own cases, and by excluding subsequent publications of the same database.2, the Wilcoxon rank-sum tests, and Kaplan–Meier curves for the entire study population, and repeated them for the subgroup of patients with at least two years of clinical active medical follow-up. Cox regression determined associations with remission. We introduced independent variables known to be associated with a poor DAIR prognosis into the multivariate analysis, except for surgical interventions and antibiotic treatment, which we automatically included into the final model. Likewise, we analyzed the number of surgical lavages and the duration of antibiotic therapy as continuous and as categorical variables. We included eight predictor variables per outcome and checked key variables for interaction. We used STATA software . P values ≤ 0.05 (two-tailed) were significant.We performed retrospective group comparisons using the Pearson-χn = 13), alcoholism (n = 7), cancer (n =5), cirrhosis CHILD C (n = 2), medications (n = 2), or mixed causes (n = 2). The median time delay between arthroplasty (implantation) and infection was 4.3 months . We detected 46 different microbiological PJI patterns. The most frequently identified pathogens were Staphylococcus aureus , skin commensals , streptococci (n = 22), Gram-negatives , enterococci (n = 6), and polymicrobial PJIs (n = 12). Six episodes were culture-negative.Among 154 DAIR episodes treated in our center, we excluded 42 for various reasons . We finan = 47), quinolones (n = 55), clindamycin (n = 27), amoxicillin/clavulanate (n = 20), and rifampicin (n = 55). The antibiotics provoked important side effects in 36 patients (32%), of which nine required the immediate stop of the medication: diarrhea (n = 14), nausea (n = 8), skin rash (n = 4), acute renal insufficiency (n = 3), or various other events such as transient hepatitis or mycosis. These adverse events occurred early in the course with a median delay of three weeks from the start.Overall, 108 DAIR cases (96%) were intended for cure. Suppressive DAIR was intended only in four cases. The median number of surgical interventions for infection was 2 , among which there was an exchange of mobile parts in 48 cases (43%). The median duration of total antibiotic treatment was 3 months , with a median of 12 first days intravenously . We used 62 different antibiotic regimens with the five most frequent drugs being vancomycin , a total of 94 patients  remained in remission. Eighteen episodes (16%) witnessed septic failures occurring after a median delay of 0.9 years  following the first infection. Among these 18 failures, 11 were true microbiological recurrences with the initial pathogens and 7 were new infections. We ignored non-infectious failures. In group comparison , remissiIn contrast, the exchange of mobile prosthetic parts was statistically protective. We saw this effect when analyzing all 18 failures  or when regarding only microbiological cure rates (excluding the 7 failures with new pathogens) . As expected, the Kaplan–Meier curve confirmed our significant findings only for the period of the first 400 days. Thereafter, the curves paralleled each other with almost no differences after 1000 days . We summAccording to our cohort, changing of mobile parts of PJI during the DAIR approach increases the probability of long-term remission, independently of if we had a follow-up of one year or beyond two years. This effect was seen in the multivariate analysis, whereas we failed to reveal it significantly in crude group comparisons with a huge case-mix. Surprisingly, despite worldwide expert recommendations and international consensus ,19, a scper se is not determinant in DAIR when surgery has been adequately performed. This is important, because every third patient in our cohort reported adverse events during the antibiotic course [We could not detect other variables associated with remission. The duration of antibiotic prescription did not influence long-term success. Several authors’ groups reported remissions with “short” prescriptions of 6 weeks in DAIR ,18,28,38c course .per se. Hence, we cannot pronounce on this latter group due to paucity of cases. Second, in our cohort, the median number of surgical interventions was two. This is higher than most author groups advocate [S. aureus [Pseudomonas aeruginosa [Besides the fact that our single-center study is retrospective, it has other limitations. First, the proportion of “curative” DAIR cases was very high (96%). These patients are foreseen to stop antibiotics after several weeks of treatment and should not be confounded with (life-long) suppressive therapy advocate ,28,31,33advocate . Third, advocate  or ciproadvocate , or spec. aureus ,16,23,31ruginosa ,32, wereruginosa , which wruginosa , and it ruginosa . Howeverruginosa  or femorIn conclusion, changing of mobile parts during DAIR likely increases the chance of long-term remission (doubling the hazard ratio in our study). As usual, we call for caution in the interpretation of our retrospective study data. For example, some relevant information to help clinical decision-making may be lacking, and our survivor analysis mainly highlights the first-year impact of the DAIR approach. We personally consider this exchange imperative and certainly more important than any antibiotic-related or demographic parameters. Nevertheless, because of the controversy in published literature, a well-designed meta-analysis (or “Cochrane review”) still remains warranted.


IgG4-related disease (IgG4-RD) is a systemic autoimmune disease that can affect multiple organs of the body. Pulmonary manifestations of IgG4-RD include pulmonary solid nodules, thickening of bronchovascular bundles, interstitial involvement, and ground glass opacities. Here we present a rare case of IgG4-RD with tracheobronchial nodules and review the relevant literature.A 52-year-old man was admitted to our hospital with a history of intermittent cough for 27 months and recurrent wheezing for 17 months. He had been diagnosed with asthma prior to admission and was responsive to oral prednisone . Bronchoscopy performed 2 years prior to admission showed tracheal and bronchial mucosal hyperemia, edema, and miliary nodules. Pathological tests showed chronic inflammation with focal lymphocytic infiltration in the bronchial mucosa. The patient had recurrent cough and wheezing after prednisone was stopped or the dose reduced. At the time of admission to our hospital, his serum immunoglobulin G4 (IgG4) level had increased to 7.35 g/L. Following bronchoscopy, the IgG4 expression in the bronchial mucosa was compared with that observed during the last two bronchoscopies. Bronchoscopy performed 7 months prior to admission revealed IgG4+ plasma cell infiltration in the bronchial tissue, with > 10 IgG4+ plasma cells per high power field and an IgG4+/IgG+ cell ratio of > 40%. The current bronchoscopy revealed a decrease in IgG4 expression in the bronchial tissue, probably because of the intermittent prednisone treatment. The case fulfilled the comprehensive clinical diagnostic criteria for IgG4-RD. He received prednisone and azathioprine, and he has never developed recurrence.Our case exhibited three important clinical indication: First, tracheobronchial miliary nodules could be the presentation of IgG4-related disease. Second, IgG4-related disease with pulmonary involvement has close connection with asthma. Last, IgG4-related disease can be very sensitive to prednisone, the infiltration of IgG4 positive plasma cells decreased after prednisone treatment and symptoms significantly improved in our case. In conclusion, we reported the first case of IgG4-RD presenting with miliary nodules on the tracheal and bronchial tube walls combined with asthma. The findings will further our understanding of the characteristics of IgG4-RD. IgG4-related disease (IgG4-RD) is a systemic autoimmune disease first described by Hamano H et al. in 2001 [9/l), with a serum IgE level of 4220 IU/ml. On admission to our hospital, his routine physical examination findings were unremarkable. His serum IgG4 level had increased to 7.35 g/L. Lung CT showed no abnormality. The pulmonary function test results were as follows: TLC %: 99.2%, RV %: 96.6%, RV/TLC: 93%, FVC%: 77.8%, VT%:154.1%, FEV1/FVC: 88.71%, FEV1%: 83.8%, DLCO-SB%: 67.8%, DLCO/VA:100.3%, and the bronchial dilation test was positive. His symptoms and pulmonary function test results were consistent with the diagnosis of asthma. However, the inhalation treatment  cannot improve his symptoms. We give him a repeated bronchoscopy which suggested scattered alleviated nodules under the tracheobronchial wall without obvious mucosal hyperemia and edema, which improved a lot compared with the bronchoscopy 7 months ago.  performed at the local hospital showed infiltration in the left lower lung  is an emerging immune-mediated disease that can affect any body organ. In 1961, Sarles et al.  first reThe widespread incomplete understanding of IgG4-RD has led to misdiagnosis of the disease. Because IgG4-RD can be controlled well by glucocorticoids, it is important to study its characteristics for correct diagnosis. In 2012, IgG4-RD study groups in Japan published the first comprehensive clinical diagnostic criteria . The criTo our knowledge, this is the first reported case of IgG4-RD presenting with miliary nodules on the tracheal and bronchial tube walls, which is a rare type of IgG4-RD. Two other cases of IgG4-RD with isolated tracheobronchial involvement presenting as mass-like lesions have been reported , 8, in aOur patient was diagnosed with asthma; he had a positive bronchodilator reversibility test. He suffered from recurrent cough and wheezing that aggravated at night and on exposure to cold air. Furthermore, he had increased eosinophils in the peripheral blood and bronchoalveolar lavage fluid smear. The asthma diagnosis was in line with previous studies reporting patients with a diagnosis of IgG4-RD and asthma , 10 (TabThe increased level of serum IgE in our patient was suggestive of an allergic immunological response in vivo. A previous study found that 44% patients with autoimmune pancreatitis had allergic diseases . SimilarIgG4-RD is a newly recognized systemic autoimmune disease. Our case exhibited three important clinical indication: First, tracheobronchial miliary nodules could be the presentation of IgG4-related disease. Second, IgG4-related disease with pulmonary involvement has close connection with asthma. Last, IgG4-related disease can be very sensitive to prednisone, the infiltration of IgG4 positive cells decreased after prednisone treatment and symptoms significantly improved in our case. In conclusion, we reported the first case of IgG4-RD presenting with miliary nodules on the tracheal and bronchial tube walls combined with the diagnosis of asthma. The findings from this case may advance our understanding of IgG4-RD and contribute to its diagnosis. Future studies are warranted to aid in early diagnosis and development of suitable therapies. Besides, the relationship between IgG4-related disease and asthma need further exploration.