Asynchronous virtual patient care is growing in popularity; however, the effectiveness of virtually delivering guideline-concordant care in conjunction with antibiotic stewardship initiatives remains uncertain. We developed a bundled stewardship intervention aimed at improving antibiotic use in E-visits for upper respiratory tract infections (URTIs).In this pre-post study, adult patients who completed an E-visit for “cough,” “flu,” or “sinus symptoms” at Michigan Medicine between 1/1/2018 and 9/30/2020 were included. Patient demographics, diagnoses, and antibiotic details were collected. The multi-faceted intervention occurred over 6 months .We performed segmented linear regression to estimate the effect of the intervention on the level and trend of appropriate antibiotic use for URTI diagnosis (defined as no antibiotic prescribed) and sinusitis (defined as guideline-concordant antibiotic selection and duration). Regression lines were fit to data before (March 2019) and after (May 2019) the physician championing period.Among 5151 E-visits, the mean age was 46 years old, and most patients were female . 3405/5151 E-visits were for URTI. Inappropriate antibiotic use for URTI was stable in trend prior to the audit and feedback intervention , followed by a 12%  decrease in inappropriate antibiotic use post-intervention. The trend in inappropriate antibiotic use continued to decrease after the intervention by 1.1%/month  .Of 2493/5151 E-visits specifically for sinus symptoms, guideline-concordant antibiotic use was low (intercept = 8%) pre-intervention . Post-intervention, there was an estimated 47% increase  in patients receiving guideline-concordant antibiotics.Solid line represents time of the webinar, dashed line represents time of modified questionnaire roll out and electronic medical record “nudges”, and shaded area is time of physician champion intervention. Guideline-concordant antibiotic prescribing for sinusitis included amoxicillin/clavulanate or doxycycline prescribed for a duration of 5-7 daysA multifaceted stewardship bundle for E-visits improved guideline-concordant antibiotic use for URTIs. Changes implemented in the EMR are most beneficial after a period of audit and feedback. This approach can aid stewardship efforts in the ambulatory care setting particularly with regards to telemedicine.Tejal N. Gandhi, MD, Blue Cross Blue Shield of Michigan  Involved: Self): Grant/Research Support Lindsay A. Petty, MD, Nothing to disclose


This work focuses on reviewing research works on antibiotic residues, evaluating antibiotics used in livestock production and their excretion in animal products and in environmental matrices such as water and soil worldwide, according to each of the variables used such as antibiotic family, name, concentration (% and mg/kg or ppm), country, and continent where the residue was found. The main antibiotics used worldwide and in animal production are sulfonamides, tetracyclines, quinolones, penicillin, and cephalosporins.The use of antibiotics in animal production are widely used for disease treatment, health protection, and as growth promoters. Common antibiotics used in veterinary medicine are excreted and eliminated through the sewage system, contaminating water and soil with negative effects on agricultural activities. This systematic review focuses on the trend of research works on antibiotic residues, evaluating antibiotics used in livestock production and their excretion in animal products and in environmental matrices such as water and soil. Our database was composed of 165 articles, reporting the concentration of antibiotic residues found in the environment, livestock , aquatic and terrestrial animal tissues, animal products (milk and eggs), wastewater, and soil. The documents were obtained from Asia, Africa, North America, South America, Europe, and Oceania. A descriptive analysis of antibiotic residues found worldwide was analyzed according to each of the variables used such as antibiotic family, name, concentration (% and mg/kg or ppm), and country and continent where the residue was found. The descriptive analysis was carried out using the “describe” function of psych package and pirate plots were drawn. According to our study, the main antibiotics used worldwide in animal production are sulfonamides, tetracyclines, quinolones, penicillin, and cephalosporins. At present, despite the trends of increased regulations on the use of antibiotics worldwide, antibiotics are still utilized in food animal production, and are present in water and soil, then, there is still the misuse of antibiotics in many countries. We need to become aware that antibiotic contamination is a global problem, and we are challenged to reduce and improve their use. The absorption of antibiotics in animals after administration is often poor and a significant proportion of 70–90% may be excreted unmetabolized , and theAntibiotic residues in food of animal origin also pose health risks such as bacterial resistance, toxicity, hypersensitivity reactions, cancer, and teratogenicity . In May Antibiotic use is estimated to increase by 67% by 2030, with China, Brazil, India, South Africa, and Russia being the main consuming countries . TherefoThe information search focused on studies reporting veterinary antibiotic residues found in the environment, wastewater, soil, and their bioaccumulation in animal tissues and products worldwide. For this purpose, a database of publications specifying antibiotic residues worldwide was created and the articles used covered the years 2000 to 2019. The publications were obtained from different databases such as ScienceDirect 2021, Scopus, Di-alnet, SciELO, Science Research, PubMEd, Redalyc, and Google Scholar.The search string with the particular topic was supported by Boolean operators . All search terms within a string were checked for a “title, abstract, and keyword”. The keywords used were antibiotic residues in the environment (wastewater and soil), traceability, animal husbandry, animal species , aquatic and terrestrial animal tissues, animal products (milk and eggs), bioaccumulation in animal tissues, and antibiotic concentrations (% and mg/kg). The search for information was carried out by continent.The Council Directive 96/23/EC, Annex 1 , classifThe ranking order of antibiotic families based on their occurrence (%) is shown in Our database was composed of 165 articles  reportinFrom all antibiotics produced worldwide in 2015, two-thirds  were used for animal husbandry. The highest consumption of antibiotics in livestock was in China , followed by the USA with 9000 tons, while France and Canada reported a consumption of approximately 2000 tons .According to the antibiotic management situation, the WHO has tried to create an observational and ecological database to define which antimicrobials are medically important. Recommendations and web pages have been derived for consultation as defined by the Guideline Development Group (GDG) .The residue levels of antibiotics based on continent showed a marked variability among antimicrobial families. The antimicrobial with the highest concentration in Asia was cephalosporins (450 ± 353.55 ppm), followed by fluroquinolone (129.44 ± 509.81 ppm). The tetracyclines were the antibiotic family with highest residual concentration in Africa (176.74 ± 930.75 ppm) and North America (106.11 ± 146.86 ppm). In South America, the family of antibiotics that depicted the highest level of residues was fluroquinolones (726.91 ± 1437.29 ppm), followed by macrolides (407 ± 574.17 ppm). In Europe, the largest concentration of residues was shown by ß-lactam (509.2 ± 1220.29 ppm), followed by nitroimidazole (250 ppm). The studies developed in Oceania only reported antimicrobial resistance of aminoglycoside (8.41 ± 15.74 ppm) and fluoroquinolones (1.9 ± 2.68 ppm) .According to the main animal products reported in the analyzed studies, the largest concentration of residues was found in chicken (341.44 ± 1025.76 ppm), shrimp (259.02 ± 691.38 ppm), and cow’s milk (100.65 ± 318.41 ppm) . Studiesn = 1), however, the largest number of studies focused on tetracyclines, which showed the second highest concentration of residues as well . Fluroquinolones (612.17 ± 1134.83 ppm) and sulfonamides (205.74 ± 409.83 ppm) were the antibiotics that showed the highest concentration of residues in shrimp (Tetracyclines were the antibiotics that had more information and showed the largest concentration of residues found in eggs (70.29 ± 139.84 ppm). Although the fluoroquinolones showed the highest average value of residues of antimicrobial in chicken (981.83 ± 1486.48 ppm), the tetracyclines showed the concentrations in this animal products, which were above 5000 ppm with an average of 438 ± 1441.29 ppm. Studies focusing on the evaluation of antimicrobial residues in fish reported the highest concentration of nitroimidazole  and water (325.0 ± 471.69 ppm) , fluoroqThe largest user of veterinary antibiotics worldwide are China (45%), Brazil (7.9%), USA (7.0%), Thailand (4.2%), India (2.2%), Iran (1.9%), Spain (1.9%), Russia (1.8%), Mexico (1.7%), and Argentina (1.5%) . It is iThe regulation of antibiotics in animal feed (for growth promotion or therapeutic use) is a priority for the Asian region, and policies for their prohibition have been developed, but few countries have the capacity to guarantee their application . The ChiIn India, in the last decade, changes in the population diet generated by the improved standards of living, has led to a demand for animal protein with consequent intensification of pig, poultry, and fish farming , which hIn Africa, the main antibiotics used for livestock farming are tetracyclines, fluoroquinolones, and β-lactams/aminoglycosides  . In our A study in 30 European countries found that the main antibiotics sold were tetracyclines (32.8%), penicillins (25.0%), and sulfonamides (11.8%) . TogetheWhen talking about meat producers, one must mention the world’s leading meat producers, North and South America, which are also among the main consumers of veterinary antibiotics ,46. For Although most countries have joined in the program of non-misuse of antibiotics in food animals, publication of reports, complex political, economic, and social barriers still limit the quality of data on this issue ,49. DataAntibiotics have been used for three main purposes in animals: therapeutic use against infectious diseases; prophylactic use for the prevention of these diseases; and as growth promoters to improve feed utilization and animal production . The groOveruse or lack of control in antibiotic stewardship results in high antibiotic deposition in the animal and excretion into the environment . OlatoyeIt has been mentioned that pigs are the main consumers of antimicrobials and are expected to use 45% of antimicrobials for animal production from 2017 to 2030, with cattle using 22% and chickens 33% of antimicrobials. On average, pigs consume 193 mg/PCU (stock correction unit), cattle consume 42 mg/PCU of antimicrobials, and chickens consume 68 mg/PCU of antimicrobials . HoweverIn pigs, depending on their production stage, the use of antibiotics changes, for example, oral antibiotics are used as routine prophylaxis for fattening and medicated feed as growth promoters for weaners. However, in all phases, the most widely used are aminopenicillin, tetracyclines, trimethoprim-sulfonamides, tylosin, and colistin . This waIn the present study, we found that the main antibiotic residues found in beef were sulfonamides (30%), which coincides with Ramatla et al.  and TreiAntibiotics used to combat mastitis-causing pathogens are the most common purpose of use in the dairy industry , HoweverE. coli isolated from pre-weaned dairy calves and found that isolates from calves treated with enrofloxacin were more likely to be resistant to fluoroquinolones. This example indicates an important concern, as these antimicrobial agents are essential in human medicine for treatment against Salmonella spp., Campylobacter spp. and Shigella spp. There are also other reports of antibiotic and anthelmintic residues in dairy products [Pereira et al.  evaluateproducts ,68 and tThe use of antibiotics as growth promoters in broilers is intended to modify the intestinal flora, thereby improving feed absorption to increase muscle mass by 15–20% in a short time. In addition, antibiotics are commonly used in high concentrations in overcrowded poultry . This caThe marketing of antibiotics for veterinary use is often not adequately restricted as there are cases of empirical supply without prescription. In addition, there is a lack of adequate registration in the control of medicines by the health authorities as well as periodic monitoring of infectious agents with zoonotic potential in backyard, semi-intensive, and intensive production sites. Good production practices are not considered by all producers from prevention, treatment, and slaughter due to the lack of maintenance of facilities . In the Most animal production focuses on poultry, pigs, and cattle, but aquaculture facilities, where there is a high use of antibiotics, must also be taken into account . OxytetrOpen water aquaculture also employs antibiotics to prevent disease and promote the growth of target species leading to evolution and a wide dispersal of resistance agents (ARBs and ARGs) in water and their possible deposition in sediments. This is of particular interest in systems where there is a connection of animal production and aquaculture as there is a closer relationship of resistance gene transfer between the systems involved . Salmonella spp, Campylobacter spp, Enterococcus faecalis, and others [As above-mentioned, there is evidence of some negative consequences of antibiotic use in animal production, especially in bacterial resistance, particularly zoonotic microorganisms such as d others . TherefoWith the aforementioned background such as the inappropriate use of antibiotics in animal production, antibiotic residues are excreted in feces or urine and present in environmental matrices such as soil, water, and vegetation, which may cause risks to human health , hence tMany of the antibiotics and hormones administered to animals cannot be fully absorbed or metabolized in the body and are excreted directly into the wastewater system ,82,83. CTriclosan, sulfonamides, and trimethoprim are the most frequently found antibiotics in soil , howeverIt has been shown through molecular markers that the main cause of antibiotic residues in the environment is due to livestock feces as doses much higher than those prescribed are applied to the human population, as demonstrated in animal excrement in the United States, where values exceeded 100 times more than those found in wastewater of anthropogenic origin . It is important to control the doses used in livestock production to avoid pathogen resistance to antibiotics and water contamination as wastewater in some areas is used as an alternative for the irrigation of agricultural fields ,46. Animal production systems have separate drains from the municipal ones, and in many cases, the waste is concentrated in waste lagoons where antibiotics accumulate. In these lagoons, sludge or water is obtained and applied to nearby land, so there is close contact with soil microbiota, or in rainy seasons, there is runoff or filtration of these compounds that reach aquatic bodies or groundwater . TherefoIn recent years, it has been demonstrated that antibiotic residues are present worldwide in wastewater, soil, and animal production, the most common being sulfonamides, tetracyclines, quinolones, penicillins, and cephalosporins. New international policies have limited their use as therapeutics, restricting their use as growth promoters in animal production. Intensive livestock production must change, as it would be impossible to sustain current market demands without the use of antimicrobials or friendlier alternatives, with a future decrease in antimicrobial resistance, so we are challenged to reduce their use.


What are the patterns of intraoperative antibiotic administration across US hospitals with respect to Infectious Diseases Society of America’s guidelines?In this multicenter cohort study comprising 414 851 surgical encounters across 31 institutions, more than one-third of the encounters did not adhere to guidelines. With the exception of timing of antibiotics, all measures of antibiotic administration  had marked nonadherence.These findings suggest that considerable nonadherence to intraoperative antibiotic administration best practices persists, which may be a contributory factor to stagnant rates of surgical site infections. This multicenter cohort study examines the patterns of adherence to the Infectious Disease Society of America’s guidelines for intraoperative antibiotic administration in US hospitals. Despite widespread adherence to Surgical Care Improvement Project antibiotic measures, prevention of surgical site infections (SSIs) remains a clinical challenge. Several components of perioperative antibiotic prophylaxis guidelines are incompletely monitored and reported within the Surgical Care Improvement Project program.To describe adherence to each component of perioperative antibiotic prophylaxis guidelines in regard to procedure-specific antibiotic choice, weight-adjusted dosing, and timing of first and subsequent administrations in a nationwide, multicenter cohort of patients undergoing noncardiac surgery.This cohort study included adult patients undergoing general, urological, orthopedic, and gynecological surgical procedures involving skin incision between January 1, 2014, and December 31, 2018, across 31 academic and community hospitals identified within the Multicenter Perioperative Outcomes Group registry. Data were analyzed between April 2 and April 21, 2021.The primary end point was overall adherence to Infectious Diseases Society of America guidelines, including (1) appropriateness of antibiotic choice, (2) weight-based dose adjustment, (3) timing of administration with respect to surgical incision, and (4) timing of redosing when indicated. Data were analyzed using mixed-effects regression to investigate patient, clinician, and institutional factors associated with guideline adherence.P < .001), surgery requiring blood transfusions , off-hours procedures , and procedures staffed by a certified registered nurse anesthetist . Overall adherence to guidelines for antibiotic administration improved over the study period from 53.1%  in 2014 to 70.2%  in 2018 (P < .001).In the final cohort of 414 851 encounters across 31 institutions, 51.8% of patients were women, the mean (SD) age was 57.5 (15.7) years, 1.2% of patients were of Hispanic ethnicity, and 10.2% were Black. In this cohort, 148 804 encounters (35.9%) did not adhere to guidelines: 19.7% for antibiotic choice, 17.1% for weight-adjusted dosing, 0.6% for timing of first dose, and 26.8% for redosing. In adjusted analyses, overall nonadherence was associated with emergency surgery (odds ratio [OR], 1.35; 95% CI, 1.29-1.41; In this cohort study, although adherence to perioperative antibiotic administration guidelines improved over the study period, more than one-third of surgical encounters remained discordant with Infectious Diseases Society of America recommendations. Future quality improvement efforts targeting gaps in practice in relation to guidelines may lead to improved adherence and possibly decreased SSIs. Whereas the SCIP antibiotic metrics have been a major focus of quality improvement efforts, little information has been reported regarding adherence to additional recommendations contained in the more extensive guidelines endorsed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), the Surgical Infection Society, and the Society for Healthcare Epidemiology of America.18 The salient features of these guidelines for perioperative antibiotic prophylaxis include choice of antibiotics tailored to type of surgery, weight-based antibiotic dose adjustment, completion of antibiotic administration prior to skin incision, and intraoperative redosing at specific intervals. The primary objective of this study was to describe the prevalence of guideline adherent practices for antibiotic prophylaxis during surgery among centers participating in the Multicenter Perioperative Outcomes Group (MPOG) consortium, a large research and quality improvement consortium based at the University of Michigan.The etiology of SSIs is multifactorial, and although not all risk factors are modifiable, the inappropriate administration of perioperative antibiotics has the potential to contribute to the problem. Importantly, antibiotic management represents a potentially modifiable risk factor. The critical role of appropriate perioperative antibiotics in preventing SSIs has been well established20 with a waiver of informed consent for the use of deidentified data. The MPOG database includes anesthetic encounters from a variety of academic and community hospitals across 21 states.21 Methods for data collection, validation, mapping to universal concepts interoperable across sites, and secure transfer to a coordinating center are previously described.22 Data validation includes both automated data quality monitoring by the coordinating center as well as case-by-case validation of a monthly sample of data by investigators at each contributing institution. The MPOG Perioperative Clinical Research Committee approved the analytic plan that was published prior to data analysis.23 The study was conducted in accordance with the Reporting of Studies Conducted Using Observational Routinely Collected Health Data (RECORD) statement, an extension of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.25This multicenter observational study was approved by the Yale University institutional review board in collaboration with the MPOG,Intraoperative records of patients aged 18 years or older who underwent general, orthopedic, gynecological, and urological surgical procedures involving a skin incision between January 1, 2014, and December 31, 2018, were eligible for inclusion. We excluded patients with the following characteristics: ongoing preoperative antibiotic therapy, missing intraoperative antibiotic documentation, missing American Society of Anesthesiologists score, or missing weight  appropriateness of procedure-specific antibiotic choice, (2) appropriateness of weight-based dose adjustment, (3) timing of antibiotic administration prior to surgical incision, and (4) timing of intraoperative redosing.The primary end point of this study was to determine the proportion of adherence to the recommendations for intraoperative antibiotic administration as stated in the IDSA, Surgical Infection Society, American Society of Health-System Pharmacists, and Society for Healthcare Epidemiology guidelines.Current Procedure Terminology (CPT) codes , doses that were at least 90% of the correct dose were considered as guideline adherent.For boluses, we used the documented time of antibiotic administration, and for infusions, we used the start of infusion administration as the qualifying administration time prior to incision. Adherence to this recommendation was considered successful if the antibiotic administration was documented within the time window established by the guidelines.Instances qualifying for redosing of antibiotics were identified when the duration of the surgery was longer than the minimum interval(s) for which redosing was recommended per guidelines. Adherence to this recommendation was considered successful if all required subsequent antibiotic administrations were documented prior to the end of surgery. Failure of any expected redosing event was adjudicated as failure of redosing.pm to 6:30 am), surgery start time, use of blood products, vasopressor infusions, and duration of surgery.For each surgical encounter, age at the time of surgery, gender, race, ethnicity, body mass index, and American Society of Anesthesiologists physical status classification were queried. Procedural characteristics that were examined included hospital setting , year when the surgery was performed, surgical specialty of the primary surgeon, anesthesist type , urgency of surgery (emergent vs nonemergent), regular vs off-hours .In the final cohort of 414 851 encounters across 31 institutions, 51.8% of participants were women, 48.2% were men, and the mean (SD) age was 57.5 (15.7) years. Overall, 1.2% of participants were of Hispanic ethnicity; 10.2% were Black, 71.2% were White, 14.2% were of unknown race, and 4.4% were of other race . In this cohort, 148 804 encounters (35.9%) were found to not be guideline adherent. Regarding adherence across the 4 individual metrics, adherence to timing of first dose administration—the one metric captured by SCIP public reporting—was 99.4%  , procedures starting during off-hour shifts  , and surgery requiring blood transfusions  were associated with guideline nonadherence. Among surgical specialties, orthopedic surgery , gynecology , and urology  were associated with higher guideline adherence compared with general surgery. Relative to solo anesthesiologists, cases performed with residents had lower odds of nonadherence , whereas cases performed with certified registered nurse anesthetists  had higher odds of guideline nonadherence. The unadjusted and adjusted analyses of factors associated with guideline nonadherence for the 4 individual metrics are shown in eTables 1 through 8 in the In adjusted analyses , we founP < .001). A post hoc test for trend further demonstrated a positive association of antibiotic adherence by center from 2014 to 2018 . Center-specific adjusted antibiotic nonadherence across the 31 centers ranged from a point estimate (SE) of 16.11% (0.05%) to 67.64% (0.05%) (The change by year in guideline adherence with respect to each metric and their composite is shown in  (0.05%) .P = .36). The association was also not statistically significant in the abdominal hysterectomy group . It should be noted that the above analysis to approach the question of potential associations among IDSA metrics and SSI rates does not include accounting for case-mix or numerous other important confounders.In a preliminary post hoc analysis  were nonadherent to IDSA guidelines for perioperative antibiotic administration. With the exception of the SCIP metric of antibiotic timing, substantial nonadherence to the guidelines for perioperative antibiotic administration was found across all examined domains, including appropriate procedure-specific antibiotic choice, weight-adjusted dosing, and timely redosing of antibiotics. Factors associated with overall guideline nonadherence were emergency cases, those requiring blood transfusions, and those performed during off hours. Additionally, although the overall adherence to guidelines improved across the study years from 53.1% in 2014 to 70.2% in 2018, it still remained suboptimal, with substantial room for improvement across the 3 domains not included in SCIP. Although further studies are needed to determine the association and relative importance of the various components of the guidelines and SSI outcomes, previous work reported associations between adequate presurgical antibiotic administration and lower rates of SSIs.31 Interestingly, the findings of our study show these factors to also be associated with antibiotic nonadherence. Although maximal prevention of SSIs is a multifactorial challenge, improved adherence to IDSA guidelines may be one critical step toward decreasing overall rates of SSIs.Emergency surgical procedures and increased blood transfusions have been reported to be associated with a higher rate of SSIs.38 Owing to near-universal adherence to SCIP metrics, some practitioners may incorrectly consider perioperative antibiotic prophylaxis to be a solved problem. To the contrary, the present study identifies key opportunities for further improvement regarding best practices for perioperative antibiotic administration. These findings are broadly consistent with those of other studies evaluating guideline-based intraoperative antibiotics administration that have also reported low to modest adherence depending on the type of surgery and the study population investigated.41In order to improve surgical outcomes, a number of quality improvement measures have been undertaken to promote guideline adherence practices with variable success.Staphylococcus aureus colonization,18 frequently seen in high-risk patients in health care settings. Using lower than recommended vancomycin doses may be especially deleterious owing to the potentially increased risk of SSIs in these patients.43 Moreover, nonadherence to guideline-based vancomycin administration has been linked to an increased rate of SSIs.44 Targeting efforts at optimizing vancomycin administration, especially related to its dose, may thus have an impact on reducing SSIs.In terms of specific antibiotics that may benefit from focused quality improvement initiatives, we identified certain medications that may warrant closer attention when administered. Our findings indicate that 50.5% of the patients administered vancomycin received a dose at least 10% lower than guidelines would dictate. Generally, vancomycin is the preferred antibiotic for patients with methicillin-resistant It is worth emphasizing that we found very high adherence to guidelines with respect to timing of initial antibiotic administration (99.4%) as compared with other metrics. Intense attention has been given to appropriate timing of antibiotics in the context of the SCIP initiative, which likely explains the excellent performance in this metric across institutions. The success in adherence to SCIP suggests that implementation of similar initiatives targeting a more comprehensive set of metrics relevant to appropriate antibiotic administration may similarly improve adherence.CPT of the surgical procedure. It is possible that additional CPT codes not included in the primary CPT would have led some apparently guideline-adherent surgical procedures to in fact be nonadherent. Any such errors would have led to greater levels of nonadherence than what we reported here. Moreover, we are unable to comment on inappropriate extension of antibiotics after surgery because the current registry does not record antibiotic administration data beyond the operating room.Despite its merits, our study has some limitations. First, this retrospective observational study has the pitfalls associated with this type of study design; however, the MPOG data have been extracted with several robust steps in place to enhance reliability and have been used in a variety of high-quality observational studies. Second, the link between nonadherent practices and increased rates of SSIs remains to be determined. In our post hoc exploratory analysis, we found no association between hospital SSI performance tertile and antibiotic adherence for colon operations and abdominal hysterectomy. However, as mentioned above, strong evidence from a number of prior studies have shaped the current antibiotic prophylaxis guidelines, and substantial evidence exists to show that nonstandard antibiotic administration practices are associated with increased SSIs. Third, we excluded patients who did not have any antibiotic documented in the anesthesia record. This exclusion was planned by design to avoid making assumptions about the reasons why documentation was missing. Finally, our procedure-specific antibiotic assessments were based on the primary A further limitation regards the issue of attribution. We did not attempt to elucidate the causes of nonadherence nor to attribute it to specific health care professionals. Although the IDSA guidelines were chosen as a reference for this study, it is possible that patients received antibiotics according to a subspecialty-specific guideline that differs from the standard IDSA guideline. However, these guidelines are based on similar evidence, share similar features, and are, we believe, the most widely used. Similarly, it is possible that health care professionals who were nonadherent to the guidelines were following institutional protocols that may not be reflective of the most current IDSA standards. Further exploration of institutional variation in antibiotic protocols would help clarify the issue of attribution and thus direct future quality improvement initiatives. Additionally, the underlying causes of these trends in antibiotic care cannot be determined from our data. Both individual- and hospital-based factors may be driving this change. Despite these limitations, we believe our study provides valuable data on large-scale patterns related to antibiotic nonadherence for various surgical procedures across a number of institutions in the US.Although adherence to perioperative antibiotic administration guidelines has improved over time, the findings of this cohort study suggest that substantial nonadherence persists. Our study highlights opportunities for intervention and suggests that a more comprehensive approach to evaluate guideline adherence beyond SCIP for the optimal management of perioperative antibiotic prophylaxis is needed. Future quality improvement efforts directed at improving antibiotic guideline adherence may lead to a decrease in SSIs and improved surgical outcomes. The effect of this nonadherence on SSIs needs to be further explored in future studies.


This paper presents an experimental investigation of the compressive behavior of high-strength self-compacting concrete exposed to temperatures up to 600 °C. Ten different concrete compositions were tested, in which part of the cement (by weight) was replaced by three different mineral additives . The stress–strain curves, compressive strength, modulus of elasticity and strain at peak stress were evaluated from uniaxial compression tests. Scanning electron microscope micrographs were also taken to evaluate the damage caused by the high temperatures. A sharp decrease in mechanical properties and an increase in peak strain were observed already after 200 °C for all mixes tested. The different mineral additives used in this study affected the variations of residual compressive strength by 24% and peak strain by 38%, while the variations of residual modulus elasticity were 14%. Comparing the obtained results with the recommendations for compressive strength given in regulatory code EN 1992-1-2 for high strength concrete, it can be concluded that the strength loss observed in EN 1992-1-2 at temperatures up to 400 °C is too conservative. The Popovics model for the relationship between stress and strain provided a good approximation for the experimentally determined stress–strain curves at different temperatures. Concrete provides the best fire resistance out of all building materials because it is a non-combustible material that does not produce smoke or burning droplets when exposed to fire. However, this does not mean that its properties will remain intact due to fire exposure. The properties that concrete retains after cooling from high temperatures are generally referred to as residual properties and are important in assessing the load-bearing capacity of the fire-affected member .The residual concrete’s properties of greatest interest include compressive strength, tensile strength, modulus of elasticity and stress–strain response . Each ofCompared to normal vibrated concrete, self-compacting concrete (SCC) contains a much higher amount/volume of fine particles ≤0.125 mm) needed to achieve mix stability or cohesion. A high percentage of fine particles in SCC is usually achieved by using mineral additives (pozzolanic and non-pozzolanic) such as fly ash, slag, silica fume, limestone, metakaolin, etc., since the use of cement alone as fines results in high production costs ,8,9. Whi5 mm needExtensive research has been carried out to study the effects of the different mineral additives on the mechanical properties of normal and high strength mortar and concrete at and after high temperature exposure ,13. In rData on the residual properties of SCC containing metakaolin are scarce in the available literature. Anand et al.  tested SAlthough SCC has been used in practice for more than 30 years , a liter–Portland cement CEM I 42.5R according to EN 197-1  and dolo–Mineral additives used  are available on the Croatian market. Binder materials:Natural, crushed dolomite aggregate  with a particle size distribution is shown in 3, and a viscosity modifying agent (VMA) based on high-molecular weight synthetic copolymer with a relative density of 1009 kg/m3, were added during concrete production to set the workability of the tested mixes.A superplasticizer based on modified polycarboxylic ether polymers, with a relative density of 1100 kg/mTap water was obtained from the general municipal drinking-water supply, which contained a negligible amount of chloride substances.The constituent materials for concrete production included the following:The dolomite aggregates and the dolomite powder used in the concrete mixes came from the same quarry. TG/DTA analyses were performed on the dolomite aggregate to determine the temperature at which the decomposition of the dolomite occurs. The results of the analysis, presented in The details of the studied concrete mixes are provided in An analysis of the fresh properties of the tested mixes can be found in Jelcic Rukavina et al. . All conHeat treatment was also performed according to the recommendations of RILEM TC 200 HTC ,31. The 5.First stage: heating at a rate ΔT/Δt of 2 °C/min (in the furnace) up to the target temperature;6.Second stage: keeping the target temperature constant until steady-state thermal conditions throughout the specimens were ensured, Δt;7.Third stage: slow natural cooling to ambient temperature in a closed furnace to avoid thermal shock.Each temperature cycle consisted of 3 stages a:5.FirstTemperature distribution in the specimens was monitored with 4 Ni-Cr thermocouples embedded in one specimen during each temperature cycle: three on the specimen surface at mid-height with equal spacing and one in the centre, all embedded during casting, After cooling, the specimens were stored under standard laboratory conditions until testing, which occurred 7 days after cooling to ambient temperature, when the lowest values of residual mechanical properties were expected . 2), from cement matrix at temperatures between 400 and 600 °C or, in this case, from the thermal decomposition of the dolomite aggregate and dolomite filler at a temperature of 763 °C. After the specimens cooled, moisture from the air was absorbed by the heated concrete and gradually penetrated deep into the exposed specimens. The absorbed moisture caused the rehydration of the lime, which was accompanied by a volume increase of 44% [The reference mix was heated to 800 °C to evaluate the effect of dolomite decomposition on post-cooling behaviour. In accordance with the TG/TDA analysis shown in e of 44% , resultiThe morphology and microstructure before and after heat treatments of the specimens were analyzed with an electron scanning microscope , type JEOL 5500 LV, connected to a spectrometer-Oxford energy dispersion spectrometer , using backscattered electrons and low vacuum. The parameters for the microscopic analyses were as follows: acceleration of 20 kV, working distance of 18–22 mm and working pressure of 17–28 Pa. The specimens were cut out from the central part of the specimen at a height of 5 cm. The specimens were further sawed to 1 cm and polished in the transverse direction. After sawing, the specimens were stored in isopropanol until analysis. The analysis was conducted on specimens taken from the reference mix and on one mix per group of mineral additives.The uniaxial compression tests were performed using a universal testing machine with a capacity of 3000 kN . The tesfc, corresponded to the peak stress (σmax) reached in the material during the test. The modulus of elasticity was calculated from the obtained stress–strain curves in the range from 10% to 1/3 of the peak stress.Three specimens of each concrete mix were tested per target temperature. Unheated specimens were also tested to determine the effect of heating temperature on the studied properties. The compressive strength, Although the present study referred to concrete with high strength and dense microstructure, of all the specimens that were subjected to thermal treatment, explosive spalling occurred only in two specimens during heating to 400 °C a and 600In heated concrete, the cement matrix expands slightly at temperatures between 80 °C and 100 °C, followed by significant shrinkage at higher temperatures. In contrast, the aggregate expands and forms large differential thermal stresses that can result in severe microcracking in the interfacial transition zone (ITZ) ,34. Sinc2/g) compared to other the binders used  resulted in the densest ITZ. This dense interface in the MK specimen resulted in more severe damage compared to specimens with FA and LF after temperature treatment at 400 °C. In addition to a wide crack in the ITZ, two cracks in the cement matrix can also be observed in the MK specimen. The specimen with FA, on the other hand, showed no visible cracks after treatment at 400 °C. After 600 °C, all specimens showed a similar appearance, with cracks appearing in both the cement matrix and the aggregate.The analysis of the microstructure of the unheated specimens (20 °C) showed that the ITZ of each specimen can be related to the particle size of a particular mineral additive in the mix, given as Blaine fineness in The curves shown include an ascending branch up to the peak stress. The descending portion of the σ-ε curve was not recorded during the test because the rate of displacement was controlled by the piston movement of the test machine.As observed from the curves given in Comparing the stress–strain curves shown in As mentioned above, the compressive strength (peak stress), static modulus of elasticity and strain at peak stress were determined from the stress–strain curves and analyzed in the next sections.It can be observed from the figure that all the mineral additives used (both pozzolanic and non-pozzolanic) had a positive effect on the compressive strength of the unheated specimens. The highest values after one year of curing were obtained for SCC concrete mixes in which cement was replaced by metakaolin (mixes M3–M5). Compared to the reference mix, the compressive strength of the mixes with MK increased with an increase in the content of MK up to 34%. The FA mixes increased the compressive strength of the reference mix by up to 9.3%, and the addition of limestone filler increased it up to 14%. The positive effect of MK and FA on the development of strength, especially at later ages, can be attributed to the effect of the filler in combination with the acceleration of cement hydration and the pozzolanic reaction with calcium hydroxide . To illustrate the effect of high temperatures on the change in compressive strength, The negative effect of the addition of MK is evident at all treatment temperatures. The higher the percentage of MK in the concrete mix, the lower the relative residual compressive strength. For the M5 mix, the strength loss after a temperature of 200 °C, 400 °C and 600 °C was about 21%, 51% and 66%, respectively. Compared to the reference mix, the decrease in compressive strength was higher by 13–15%. As mentioned above, the negative effect of MK addition on the residual strength is a result of the denser microstructure shown in The replacement of cement with FA in an amount of 20–40% had a positive effect on the residual compressive strength. After exposure to 200 °C, a slight increase (up to 4%) in compressive strength was observed in mixes with FA compared to their strength at 20 °C. In addition, the relative compressive strength of the mixes with FA was 13% higher compared to the reference mix. This can be explained by the subsequent hydration of the unhydrated cement particles due to internal steam curing due to the hot steam from the internal autoclave condition or the subsequent pozzolanic reaction of fly ash and calcium hydroxide due to the free movement of moisture in the material due to the high temperature . In addiMixes with limestone  showed comparable behaviour to the reference mix over the entire temperature range, with variations within 5%.In accordance with Abed et al. , the resThe recommended values provided in Eurocodes EC2  and EC4 EC2  recognizWith the exception of MK, the obtained results after 200 and 600 °C agree well with the results of Uysal et al.  but diffHigh temperatures have a negative effect on the elastic properties of concrete, mainly due to the decomposition of hydrated cement products and the breaking of bonds in the microstructure . Figure The initial values of modulus of elasticity ranged from 45.1 GPa for M8 to 51.7 GPa for the M2 mix  and decreased almost linearly with temperature.As expected, a greater effect of elevated temperatures was observed on the modulus of elasticity compared to the compressive strength, but in this case, the differences between the studied mixes were smaller. The highest difference in relative modulus of elasticity between the studied mixes is 14% after 200 °C and continues to decrease with increasing temperature. After 600 °C, the difference between mixes was 6%.Considering the different groups of studied mixes, a very similar pattern as for compressive strength was obtained—the lowest relative values after 400 °C and 600 °C were obtained within MK-based mixes, i.e., the initial modulus of elasticity of M5 mix decreased for 75% and 88%, respectively. After 200 °C, the reference mix had negligibly lower values compared to MK mixes—decrease was around 38%. FA and LF had a beneficial effect on the residual modulus of elasticity compared to reference mix. As with the compressive strength, there was a strong loss of the modulus of elasticity up to 400 °C in all tested mixes. In accordance with the observations of Bamonte et al.  and Chanσ is the compressive stress, σmax is the peak stress , ε is strain, εmax is the strain at peak stress and β is parameter describing the curvature of the stress–strain relationship [The prediction of the stress–strain relationship of concrete subjected to uniaxial compression at room temperature has been a topic of research papers for many decades ,42,43. Rtionship ,46. It wtionship ,45. To ptionship ,45,47.As said previously, increasing temperature changes curvature of the stress–strain relationship. An example of the influence of high temperature treatment on the shape of stress–strain relation in concrete is shown in σmax) yields the stress–strain relationship in absolute units. The differences between the values predicted by the model and the observed values were evaluated by the root mean square error (S). The range of S for samples from all mixes kept at 20 °C was 1.8–3.9 MPa. For specimens exposed 200 °C, 400 °C and 600 °C, the range of S was 0.9–1.9 MPa, 0.2–1.3 MPa and 0.2–1.2 MPa, respectively. As an example, a comparison between model and experimental values for specimens from mix M2 is presented in Nonlinear regression analysis using least squares method was applied to evaluate how well the model from Equation (1) represents experimentally determined stress–strain curves. Multiplying Equation (1) with peak stress (β), which is determined by regression analysis. Β represents the ratio E0/(E0 − Ep), where E0 is the initial tangent Youngs modulus and Ep is secant Youngs modulus at peak stress [E0 − Ep should decrease and consequently β increase. This was confirmed by analyzing β for specimens from mixes M2–M11. As temperature increases, parameter β increases, indicating that the stress–strain curve approaches linear dependence. β, and its standard deviations are compared between concrete mixes with different mineral additives. Increasing temperature also increased the dispersion of β.Equation (1) contains only one unknown parameter  represents relative stress (σ/σmax) expressed as a function of relative strain (ε/εmax). The area under relative stress vs. relative strain curve is proportional to the mechanical energy consumed by deforming the material. If β = 1, then Equation (1) produces σ/σmax = 1, which represents perfectly plastic material; on the other hand, if β proceeds to infinity, Equation (1) becomes σ/σmax = ε/εmax and represents linear elastic material. Integrating Equation (1) in the range of relative strain between 0 and 1 provides an area of 1 for β = 1 and 0.5 for β → ∞. The values of β for concrete start at 1.3 or 1.4 [A) under the relative stress–strain curve, the analysis shows that the area decreases with increasing β approximately according to A = 0.5 (−kβ + 1), where k ≈ 1.095. Using this equation for A, it can be shown that a change in β within the range of 2–4 would cause approximately the same change in the area as a variation in the range of 3–17. It is important to emphasize that the variation of 3 or 1.4 ,44. By aβ can be estimated from the compressive strength as 0.058fc + 1. In this work, for specimens stored at 20 °C, the relation between fc and β determined by linear regression is 0.044fc + 0.6. Both equations have a similar slope and are compared in For normal concrete cured at room temperature, Popovics proposed that fc and β for concrete exposed to elevated temperature does not follow the same trend as for concrete stored at room temperature. The correlation between fc and β was analyzed for each mix separately using linear regression. It was found that power law equation provided lower errors of estimation compared to the linear model. Due to the wide dispersion of data, no significant differences between models for mixes containing different mineral admixtures were found; thus, only overall regression models based on the results of all tested samples are provided in β increases with temperature, it can be shown that the effect of this variation on the area under the relative stress–strain curve is the greatest at low temperatures.The relationship between 8.By comparing the stress–strain curves within the mixes containing the same mineral additive, it can be observed that the different amounts of FA (20–40%) and limestone (5–15%) in the studied concrete mixes lead to a similar behaviour, while the mixes with different MK content (5–15%) show larger variations after all target temperatures.9.The different mineral additives used in this study  affected the development of different microstructures of the concrete, especially ITZ, which, in turn, affected the variations in the residual compressive strength by 24% and the peak strain by 38%, while the variation in the residual elastic modulus was 14%.10.Contrary to the findings in the literature, which show that concrete retains most of its strength up to 400 °C, in this study, a significant loss of mechanical properties (compressive strength and elastic modulus) and an increase in peak strain were observed up to a temperature of 400 °C.11.However, comparing the obtained results with the recommendations for compressive strength given in EC 2 for HSC, it can be concluded that the strength loss of EC 2 in the case of SCC with used mineral additives is too conservative in the lower temperature range (400 °C), especially for mixes containing fly ash.12.The Popovic model for the relationship between stress and strain, developed essentially for conventional concrete, provided a good approximation relative to the experimentally determined stress–strain curves at different temperatures.Previous studies on SCC have shown that the advantages of this type of concrete at room temperature over conventional concrete are its improved internal structure, which is achieved by more effective particle packing. Compared to normal vibrated types of concrete, a higher percentage of fines and, in most cases, mineral additives are used. In this study, new experimental results on mechanical properties were obtained by investigating the effects of elevated temperatures on the performance of high strength SCC with the common mineral additives, i.e., metakaolin, fly ash and limestone filler in different proportions. Based on the results obtained, the following conclusions can be drawn:In this study, one mineral additive was added to the mix. To increase the sustainability of the concrete, the tests should be extended to binary and ternary mixes of mineral additives and their mutual interaction should be evaluated after exposure to high temperature.


Overconsumption of antibiotics in hospitals has led to policy implementation, including the control of antibiotic prescriptions. The impact of these policies on the evolution of antimicrobial resistance remains uncertain. In this work, we review the possible limits of such policies and focus on the need for a more efficient approach. Establishing a causal relationship between the introduction of new antibiotics and the emergence of new resistance mechanisms is difficult. Several studies have demonstrated that many resistance mechanisms existed before the discovery of antibiotics. Overconsumption of antibiotics has worsened the phenomenon of resistance. Antibiotics are responsible for intestinal dysbiosis, which is suspected of being the source of bacterial resistance. The complexity of the intestinal microbiota composition, the impact of the pharmacokinetic properties of antibiotics, and the multiplicity of other factors involved in the acquisition and emergence of multidrug-resistant organisms, lead us to think that de-escalation, in the absence of studies proving its effectiveness, is not the solution to limiting the spread of multidrug-resistant organisms. More studies are needed to clarify the ecological risk caused by different antibiotic classes. In the meantime, we need to concentrate our efforts on limiting antibiotic prescriptions to patients who really need it, and work on reducing the duration of these treatments. The spread of antimicrobial resistance in hospital and community settings has raised awareness in the medical and scientific world of the need to fight this phenomenon. Although resistance is not exclusive to the human and hospital world, the overconsumption of antibiotics in hospitals and the observation of too many avoidable antibiotic prescriptions have led to the implementation of various control policies. These policies include the control of antibiotic prescriptions to limit or better still, to reduce antibiotic resistance.Enterobacterales (ESBL-PE), this policy has been intensified and it is characterized by a willingness to spare certain classes of antibiotics  in favor of other classes of antibiotics that have a narrower spectrum, and therefore less ecological consequences [These policies have been diverse, ranging from a detailed analysis of national, regional and rarely available local epidemiological data, the introduction of new microbiological diagnostic methods and the recruitment of antibiotic specialists, to policies to restrict the use of antibiotics supposed to have an important ecological impact. One of the essential and major measures introduced in the last two decades is the concept of de-escalation ,2,3. Thiequences ,5. Althoequences  as authoequences , authorsequences ,9,10. Moreover, despite the introduction of these policies in healthcare settings, their impact on the evolution of antimicrobial resistance remains uncertain. Therefore, it seems important to review the possible limits of such policies and to focus on adopting a better approach, which would consist of adjusting antibiotic prescriptions to be more efficient, and even more so, working on reducing these prescriptions. In this work, we review the literature to address the ecological effect of antibiotics, and attempt to explain why we believe that all antibiotic classes have the same impact on the spread of resistance. We also emphasize the importance of reducing antibiotic prescriptions in the context of limiting the spread of MDRO in healthcare settings.Many authors place the emergence of the first resistant bacteria as around the 1940s, right after the discovery of penicillin in 1928 and the onset of its human consumption. It is also common to describe a timeline suggesting a direct link between the discovery of new classes of antibiotics and the emergence of resistance to each of these antibiotics. If there is a temporal correlation between the introduction of new antibiotics and the emergence of new resistance mechanisms to these same antibiotics in clinical practice, it is important to highlight the fact that establishing such a causal relationship is difficult. In fact, if a causal relationship does exist, the cessation or reduction in the consumption of a given antibiotic should result in the disappearance of resistance to the same antibiotic. Moreover, it should enable the restoration of the dysbiosis observed in the affected bacterial populations. However, this idea remains exceptional in view of the observations made over more than a decade .The inability of a bacterial population to regain its normal state of sensitivity can be explained by the fact that antibiotics may not be the cause of resistance, but rather that resistance may have preceded their use. Indeed, it is now well demonstrated by studies conducted on permafrost ,13 that Actinomycetes or Paenibacillus [Streptomyces are resistant to an average of 7 to 8 antibiotics, including some that have been recently developed [Kluyvera sp, was responsible for the spread of ESBL-PE on a worldwide scale [The reservoir of resistance is in the environment. Indeed, it is important to remember that most antibiotics used in medicine or agriculture are derived from bacteria living in the soil such as bacillus . These abacillus ,19. Indeeveloped . Moreovede scale .Finally, it is important to note that one of the first bacterial strains collected in the United Kingdom in 1915, before any use of antibiotics, already harbored resistance genes to penicillin and erythromycin .It is obvious that the overconsumption of antibiotics at the human, animal and environmental level has worsened the phenomenon of resistance. Moreover, it is clear that antibiotic use is responsible for intestinal dysbiosis, which is alleged to be the source of the emergence of bacterial resistance ,24,25. AThis ability to resist colonization in the era of antibiotic resistance control has led researchers to focus on the gut microbiota and the impact of antibiotics on it. The effect of antibiotics on intestinal microbiota can be summarized as follows: (1) spatial liberation of the ecological niche; (2) they provide an additional quantity of nutrients; (3) destruction of sensitive bacterial species and emergence of resistant bacteria; and (4) modification of the microbiota’s diversity and richness ,30,31. TAlthough it has several functions, it is important to highlight the role of intestinal microbiota in limiting the acquisition of exogenous pathogenic bacteria and MDRO. While the pharmacokinetics and pharmacodynamics properties of an antibiotic can explain its effect on the intestinal microbiota, it is also important to note that the composition of the microbiota itself plays a role in the acquisition and/or clearance of MDRO. The intestinal microbiota is a complex organ composed not only of bacterial populations, but also of archaea, fungal, parasitic and viral populations. The functions of the microbiota are multiple including the fermentation of food, synthesis of vitamins and amino acids, regulation of the inflammatory/immune system, modulation of gastrointestinal hormone release, regulation of brain behavior, and finally, resistance to colonization by exogenous bacteria. There are many direct and indirect mechanisms involved in resistance to colonization ,44,47,48The administration of an antibiotic has an effect on different microbiota such as skin, vaginal, respiratory, urinary, and mainly, digestive microbiota. The latter seems to be the most “impacted” because of its richness and diversity (100 trillion bacteria per gram of stool). Numerous longitudinal studies, with varying methodologies, have shown large changes in the intestinal microbiota after the administration of antibiotics ,51. ThesThe subdivision of available antibiotics into two categories (narrow and broad-spectrum activities) began in the 1980s when cephalosporins were first marketed. Originally, this artificial categorization was used to highlight the “broader” activity of cephalosporins on Enterobacterales, including species that had acquired resistance mechanisms, mainly “penicillinases”. Subsequently, several studies focused on evaluating the impact of each antibiotic class on intestinal microbiota. However, these studies were methodologically questionable and did not compare the impact of one class to another and different molecules within the same class. For many years there seemed to be confusion in regard to the broad spectrum of an antibiotic and its ecological impact. In fact, many authors have attempted to define and classify the ecological effects linked to the administration of different antibiotics ,55. HoweThe antibiotic concentration in the intestinal microbiota seems to be a major factor associated with the risk of MDRO acquisition. The variable diffusion of an antibiotic at the different digestive levels, duodenum or colon, will probably have an impact on the total concentrations affecting the microbiota.For many years, the idea of digestive diffusion was the only factor associated with the risk of the emergence of resistance. Therefore, we could have wrongly supposed that molecules of the same antibiotic class could have a different impact on microbiota. Indeed, following the initial work of Hamzepour et al., we considered the difference in the impact of ceftriaxone (antibiotic with biliary elimination) and cefotaxime (antibiotic with urinary elimination) on intestinal microbiota .Klebsiella pneumoniae suggested that certain antibiotic classes, considered to have a high ecological effect, were able to inhibit colonization by Gram-negative pathogens. In this study, ertapenem suppressed the colonization by ESBL-producing K. pneumoniae strains, whereas imipenem-cilastatin did not promote or suppress colonization. These findings were explained by the high excreted concentrations of ertapenem in the intestinal tract, in contrast to the limited intestinal concentrations of imipenem-cilastatin that were incapable of altering the intestinal microflora [Moreover, animal studies carried out in mice, to evaluate the role of antibiotics in the acquisition and persistence of ESBL-producing croflora ,43.E. coli, before the antibiotic’s administration (70.6%), which remained stable despite imipenem-cilastatin administration. The authors suggested that the observed lack of impact could be explained by the known low biliary elimination of imipenem-cilastatin. Indeed, among carbapenems, there are significant differences in terms of biliary elimination [In parallel, antibiotic concentrations in the intestinal tract, as an important factor associated with dysbiosis and the emergence of MDRO, have been confirmed in clinical studies. In a recent study dealing with the effect of imipenem on the intestinal microbiota’s composition, authors were surprised by an unexpectedly, high colonization rate with imipenem-susceptible ESBL-producing mination ,44. ThusMore recently, two studies, the first conducted on healthy subjects and the other on hospitalized patients ,40, demon = 7) with recurrent urinary tract infections (UTIs) showed that nitrofurantoin did not affect Enterobacterales, Enterococci or yeast populations of intestinal microbiota during treatment. In this study, no resistant strains of Gram-negative aerobic bacteria were detected [However, certain broad-spectrum antibiotics with low intestinal concentrations, such as aminoglycosides and nitrofurantoin do not appear to have a significant impact on the intestinal microbiota. Thus, a study that included nine patients, colonized with ESBL-PE and treated with amikacin, showed no impact of amikacin on the intestinal microbiota . Moreovedetected . Bacteroides and an expansion of Enterobacterales, such as E. coli and K. pneumoniae [On the other hand, some antibiotic classes that have been identified as having little or no effect on intestinal microbiota compared to other classes, would have better results if we consider their pharmacokinetic characteristics. For example, orally administrated metronidazole is almost completely absorbed in the small intestine. Therefore, intestinal concentrations of metronidazole decrease significantly along the gastrointestinal tract, with minimal amounts reaching the colon. In contrast, poorly absorbed antibiotics, such as vancomycin, maintain high concentrations throughout the GI tract following oral administrations. This fact suggests that along the gastrointestinal tract, orally administrated metronidazole may have less effect on intestinal microbiota than oral vancomycin. Indeed, in a recent study, the authors demonstrated that oral vancomycin induces drastic and consistent changes in the human intestinal microbiota with a significant depletion of bacteria from the genus eumoniae .Moreover, while the concentration of antibiotics in the gut seems to play a major role in the emergence of resistance, several recent studies also suggest that the impact of an antibiotic on the intestinal microbiota seems to be fast and occurs within the first administered doses. Thus, a study evaluating the impact of dicloxacillin, clindamycin, cefuroxime, cefotaxime and ciprofloxacin on the intestinal microbiota of mice showed a significant impact for clindamycin and dicloxacillin, which was observed after the second day of administration .Additionally, there are many other factors involved in the concept of resistance to colonization . For morEnterococcus (VRE), highlighted the importance of certain bacterial protective species. All these findings can largely explain the variable behavior of different microbiotas regarding the emergence of MDRO. Surprisingly, Keith et al., used an experimental mouse model to demonstrate the role of certain commensal bacteria in harboring resistance genes, in the degradation of antibiotics in the gut and the protection of intestinal microbiota from dysbiosis [E. coli strains, significantly reduced the clearance of these pathogens and enhanced their systemic dissemination during ampicillin treatment. The authors concluded that commensal bacteria, by acquiring resistance genes, can provide protection to exogenous pathogens from the bactericidal effects of antibiotics. These findings help us to understand the effect of antibiotics, if they exist, on intestinal microbiota with regard to the emergence of antibiotic resistant bacteria. They also help us to understand the different impacts caused by different antibiotic classes on intestinal microbiota and to prioritize the use of those with less impact. Thus, human microbiota is diverse, dynamic and unequal when we consider the risk of resistance emergence. In a study evaluating the concentrations of ceftriaxone in the stool of five healthy volunteers, Leonard et al. highlighted the importance of endogenous beta-lactamase in the hydrolysis of ceftriaxone . Thus, wysbiosis . Indeed,Many authors have investigated the effect of different antibiotic classes on the emergence and acquisition of MDRO in hospitals. According to different studies, antibiotic therapy constitutes a necessary and crucial risk factor for MDRO acquisition; however, it is not the only factor. Indeed, published studies to date suggest that  if the oThere are many other factors that contribute to the emergence of resistance. The inefficiency of antibiotic de-escalation policies to reduce the emergence of MDRO could be the result of not considering these various other factors. Among these factors, we must highlight the possible antibiotic effect of non-antibiotic treatments ,75, the Most of the published studies suffer from methodological limitations related to the microbiological methods used, the populations involved, and the lack of comprehensive reviews.Besides the factors that have been forgotten and have not been considered in the various studies evaluating the ecological effects of antibiotics, the impact of other concomitant non-antibiotic treatments with antibiotic effects seems to be important. In fact, some commonly used non-antibiotic drugs have recently been associated with changes in the composition of the gut microbiota. In a study that analyzed more than 1000 marketed drugs and tested them on 40 intestinal bacterial strains, the authors found that 24% of the tested drugs, which belonged to different therapeutic classes, inhibited the growth of at least one bacterial strain in vitro . Some clWe have tried to demonstrate the complexity of the gut microbiota and its interaction with the administered antibiotics. Antibiotic prescription contributes to the emergence of resistance. Contrary to previously published theories, we believe that it is difficult to classify antibiotics according to their ecological effects.In the hospital environment, antibiotic therapy must be considered as a trigger for resistance at the individual and collective levels. Indeed, many recent studies have underlined the role of antibiotic therapy in the emergence of MDRO in hospitals. This emergence encompasses two distinct but complementary phenomena: the selection of MDRO and its acquisition by hand transmission.In fact, although many studies in intensive care units (ICU) ,79 and oIf we want to limit the spread of antibiotic resistance in the hospital environment, it seems important to reduce antibiotic consumption and to limit the transmission of MDRO by hand. Reducing antibiotic consumption requires a better definition of therapeutic indications, considering the need to introduce biomarkers into our clinical practice, and more importantly, a reduction in the duration of exposure to an antibiotic.For twenty years, we have promoted and debated the concept of de-escalation considering that the ecological effect of antibiotics is molecular and class dependent. Even if this is still the case, we have no data that allows us to differentiate between different antibiotic classes in clinical practice. The complexity of the intestinal microbiota’s composition, the impact of the pharmacokinetic properties of antibiotics and the multiplicity of other factors involved in the acquisition and emergence of MDRO, lead us to think that de-escalation, especially since no study so far has shown its effectiveness, is not the solution to limiting the spread of MDRO.More studies are needed to clarify the ecological risk caused by different antibiotic classes. In the meantime, it is important to concentrate our efforts on limiting antibiotic prescriptions to patients who really need it, and to work on reducing the duration of these treatments.


Immunoglobulin G4 (IgG4)‐related disease is established as a new clinical entity, characterized by high levels of plasma IgG4 and IgG4‐positive plasma cell infiltration. However, the elevation of plasma IgG4 and infiltration of IgG4‐positive cells have been observed in other diseases, including malignancy. We experienced a case of prominent IgG4‐positive lymphadenopathy, which was diagnosed as a reactive lesion in response to lung cancer. The cancerous lesion was so small in size that it was difficult to reveal the coexisting lung cancer. Surgical lymph node biopsy and endobronchial ultrasound‐guided transbronchial needle aspiration did not reveal lymph node metastasis of cancer. Mediastinal lymph node dissection finally revealed it. After the right upper lobectomy, the patient underwent postoperative chemotherapy and remains cancer‐free after 1 year. Our case suggests that close examination and careful follow‐up are necessary when IgG4‐positive lymphadenopathy is observed. This article discussed a case in which prominent lymphadenopathy with immunoglobulin G4‐positive cell infiltration was caused in response to microscopic lung cancer. Surgical lymph node biopsy, as well as endobronchial ultrasound‐guided transbronchial needle aspiration, could not reveal coexisting malignant cells in the mediastinal lymph node. Immunoglobulin G4 (IgG4) is a minor component that accounts for approximately 4% of IgG; however, its pathological significance has not been revealed. In 2001, a report was published of elevated plasma IgG4 levels and infiltration of IgG4‐positive cells to the lesion in patients with sclerosing cholangitis.We experienced a case in which prominent lymphadenopathy with IgG4‐positive cell infiltration occurred in response to lung cancer. The cancerous lesions were so small that the diagnosis of cancer was difficult with endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) or thoracoscopic lymph node biopsy.A 54‐year‐old man visited a nearby hospital because of a chronic cough. Chest computed tomography (CT) revealed mediastinal lymphadenopathy and a small subpleural nodule in the right upper lobe. He had a history of smoking 1.5 packs/day for 48 years and worked as a taxi driver. His medical history included childhood asthma, hyperlipidaemia and hypertension.He was afebrile, with no swelling of the superficial lymph nodes, and no other abnormalities were observed on physical examination. Laboratory findings revealed a normal blood count, normal hepatic function and normal renal function, except for an increase in C‐reactive protein 8.91 mg/dl). Tumour markers  were within the normal range. The antinuclear antibody level was not elevated (<40 times). The interferon‐γ release assay yielded negative results. Positron emission tomography (PET)‐CT showed a high accumulation of fluorodeoxyglucose (FDG) in the mediastinal lymph nodes and a low accumulation of FDG in the small nodule in the right upper lobe  and specificity (93%) in detecting IgG4‐RD.Plasma IgG4 level might be helpful to differentiate IgG4‐RD and cancer. Differential diagnosis between IgG4‐RD and cancer is sometimes difficult because IgG4‐RD can form tumour‐like lesions, and desmoplastic tissue around the malignant tumour is similar to the lesion of IgG4‐RD when IgG4‐positive plasma cells are abundant. Plasma IgG4 may be elevated in some patients with cancer, but plasma IgG4 tends to be higher in patients with IgG4‐RD. Oseini et al. reported that 17 (13.5%) of the 126 patients with cholangiocarcinoma had elevated IgG4 (>140 mg/dl) and four (2%) had more than two‐fold elevation (>280 mg/dl), whereas 39 (78.0%) of 50 patients with IgG4‐associated cholangitis had elevated IgG4 (>140 mg/dL) and 25 (50%) had more than two‐fold elevation.Our case showed marked IgG4‐positive lymphadenopathy in response to lung cancer. Surgical lymph node biopsy, as well as EBUS‐TBNA, could not reveal coexisting malignant lesions. Our case suggests that close examination and careful follow‐up are necessary when IgG4‐positive lesions are observed, especially if the lesion is limited to lymphadenopathy.None declared.Motoi Yuzawa and Hiromitsu Ohta designed this report and wrote the manuscript. Kentaro Minegishi performed thoracic surgery. Hisashi Oshiro made the pathological diagnosis. Motoi Yuzawa, Hiromistu Ohta and Motoko Nomura participated in the discussion. Yasuhiro Yamaguchi supervised this report. All authors were involved in drafting the manuscript and approved the final version of the manuscript.The authors declare that appropriate written informed consent was obtained for publication of this case report and accompanying images.


A 55-year-old woman presented to the medicine ward with an altered level of consciousness. She had been reviewed in an outpatient department three days earlier and prescribed 500 mg two times per day of metformin immediate-release (Met IR) for newly diagnosed type 2 diabetes mellitus (T2DM), to which she had been adherent; however, she had been experiencing intermittent episodes of hypoglycemia after taking the medication prescribed to treat her T2DM. On physical examination, she was diaphoretic and disoriented but responsive to sensory stimuli. In the ward, she received 25 ml of intravenous dextrose as the initial blood glucose reading was low at 54 mg/dl, and 4 ounces of apple juice additionally two hours later as her blood glucose level fell below 70 mg/dl again. She was no longer hypoglycemic a few hours later, and there was a significant neurological improvement. The remainder of the laboratory results, including serum renal and liver function tests, were normal. Met IR was discontinued, and metformin extended-release (Met XR) 500 mg/day was initiated at discharge. The patient's hypoglycemic episodes resolved within days after the initiation of Met XR. Hypoglycemia is rarely associated with accidental or suicidal overdose of metformin, metabolic dysfunction , exercise, missed meal, acute illness, or the initiation of additional antidiabetic medication. Albeit even uncommon, metformin-associated hypoglycemia may occur with no obvious trigger. In this context, we determine to what extent Met IR may contribute to the development of hypoglycemia in an individual case, but also that the risk could be mitigated by a switch to Met XR. In a preferred embodiment, the Met XR dosage form can be administered once a day, ideally with or after a meal, preferably with or after the evening meal, and it provides therapeutic levels of the drug throughout the day with peak plasma levels being obtained between four to eight hours after the administration (T The term antidiabetic or antihyperglycemic drugs refers to drugs that are useful in managing type 2 diabetes mellitus (T2DM). Preferably, a first-line antidiabetic drug is a biguanide such as metformin or its pharmaceutically acceptable salt such as metformin hydrochloride. Metformin is an oral antihyperglycemic drug that improves glucose tolerance in T2DM by lowering both basal and postprandial plasma glucose . Metform2. Of note, she had no history of renal insufficiency. When last checked at the outpatient, her urinary albumin-to-creatinine ratio had been 0.22 mg/mmol .On presentation, she was diaphoretic and somnolent, with normal vital signs. Pupils were equal, round, and reactive to light. Further neurologic examination revealed disorientation to time and place but normal deep tendon reflexes and no focal sensory or motor deficits. The cardiopulmonary examination was normal. Her bedside point-of-care capillary blood glucose was checked and it was low, a finding confirmed by a serum blood glucose of 54 mg/dl. The diagnosis prompted intravenous administration of 25 ml of 50% dextrose. Emergent laboratory test results were unremarkable except for low blood glucose and an above-optimal low-density lipoprotein level .A 55-year-old woman with newly diagnosed T2DM was found unresponsive by her family one morning. She had been seen in the outpatient setting three days ago and initiated on Met IR 500 mg twice daily in accordance with two consecutive fasting plasma glucose and hemoglobin A1c (HbA1c) readings of 126 and 155 mg/dl, and 6.3 and 6.8%, respectively, together with an insistence by the patient to "deliciously" control diabetes without an excessive cut-down on her favorite dessert. While in the ward, her daughter reported that the patient had experienced three episodes in the past two days characterized by headaches, nausea, sweating, and a feeling that she was going to pass out, despite adequate meals and adherence to Met IR as prescribed. During the most recent episode, her fingerstick glucose was 69 mg/dl and symptoms were relieved by oral fast-acting carbohydrates. Medical history included long-standing obesity only with a body mass index at present of 36 kg/mThe patient’s condition improved transiently after the administration of an intravenous bolus of dextrose. However, repeat blood glucose two hours later fell to 67 mg/dl and 4 ounces of apple juice were given at this stage. Subsequently, levels began trending towards the normal range without any recurrence of hypoglycemia, reflected also by her conscious and oriented mental status, till hospital discharge. Serial measurements of blood glucose are documented in Table Though not very familiar, the temporal association of hypoglycemia with the initiation of Met IR and the fact that there were no other factors to explore caused the medication to be withheld; her therapy was transitioned to Met XR 500 mg once a day. Over the next two weeks, a review of her self-monitored two-hour postprandial blood glucose showed levels of 125-165 mg/dl. Laboratory analysis at follow-up (day 14) revealed the following - fasting plasma glucose: 102 mg/dl, HbA1c: 5.9%. Met XR was now titrated up by 500 mg, i.e., 1000 mg once a day. After three weeks of therapy with Met XR (day 21), the patient is happy because of optimal glycemic control. She has experienced no more hypoglycemic attacks since the new therapy was started. A reasonable alternative is to reduce the dose of Met IR to 250 mg twice a day , but this was not experimented on in this particular case.max), as compared to the Tmax provided by Met IR. The delayed Tmax occurs from four to eight hours after administration [max would occur during the time when gluconeogenesis is expected to occur at its highest level [max) of Met XR was much lower than that of Met IR (p<0.05). Additionally, Met XR was generally well-tolerated [Metformin is the preferred initial medication for most patients with T2DM due to its overall efficacy and lack of hypoglycemia when used in monotherapy. Overall, the available case reports also suggest that clinically significant hypoglycemia is uncommon in metformin monotherapy and unlikely to occur abruptly in the absence of any predisposing conditions -11. Indest level . The extolerated .max minus minimum plasma concentration (Cmin)/average plasma concentration (Cavg) - is of particular interest when comparing drugs with varying release properties. The lower the fluctuation index, the more likely the Cmax is blunted while effectively extending the dosing interval, potentially allowing for up-titration to higher doses if needed for efficacy. This results in flatter concentration-time plots. There is even a benefit to having lower metformin levels in the blood during the afternoon in patients who are under concomitant therapy with at least one additional antidiabetic drug such as glyburide or its equivalents. In contrast to Met XR that does not increase endogenous insulin, a long-acting sulfonylurea, for instance, continues to stimulate pancreatic beta-cell insulin secretion even when blood glucose levels are normal (glucose-independent insulin release) and is therefore prone to causing hypoglycemia [The graph below Figure  shows thglycemia ,15.Some degree of research has been performed in the area of controlled-release compositions that employ antihyperglycemic drugs. The value of Met XR is further indicated by the results of a randomized, double-blind, active-controlled, six-month clinical trial among adult patients with drug-naive T2DM and HbA1c levels >7.0% and <8.5% . MetformIn accordance with the dosage forms of the present case, it has been determined that this patient suffering from T2DM achieved improved results  with Met XR than Met IR administered according to popular protocols, e.g., on a twice-a-day basis. Another clear advantage is a reduction in the frequency of administration with Met XR. All of these findings suggest that Met XR may improve the quality of therapy and the safety profile relative to a conventional dosage form in patients with T2DM.


Extensive use of antibiotics and the resulting emergence of antimicrobial resistance is a major health concern globally. In Norway, 82% of antibiotics is prescribed in primary care and one in four prescriptions are issued for the treatment of urinary tract infections (UTI). The aim of this study was to investigate time trends in antibiotic treatment following a consultation for UTI in primary care.For the period 2006–2015 we linked data from the Norwegian Registry for Control and Payment of Health Reimbursements on all patient consultations for cystitis and pyelonephritis in general practice and out-of-hours (OOH) services, and data from the Norwegian Prescription Database on all dispensed prescriptions of antibiotics.Altogether 2,426,643 consultations by attendance for UTI took place in the study period, of these 94.5% for cystitis and 5.5% for pyelonephritis. Of all UTI consultations, 79.4% were conducted in general practice and 20.6% in OOH services. From 2006 to 2015, annual numbers of cystitis and pyelonephritis consultations increased by 33.9 and 14.0%, respectively. The proportion of UTI consultations resulting in an antibiotic prescription increased from 36.6 to 65.7% for cystitis, and from 35.3 to 50.7% for pyelonephritis. These observed changes occurred gradually over the years. Cystitis was mainly treated with pivmecillinam (53.9%), followed by trimethoprim (20.8%). For pyelonephritis, pivmecillinam was most frequently used (43.0%), followed by ciprofloxacin (20.5%) and sulfamethoxazole-trimethoprim (16.3%). For cystitis, the use of pivmecillinam increased the most during the study period (from 46.1 to 56.6%), and for pyelonephritis, the use of sulfamethoxazole-trimethoprim (from 11.4 to 25.5%) followed by ciprofloxacin (from 18.2 to 23.1%).During the 10-year study period there was a considerable increase in the proportion of UTI consultations resulting in antibiotic treatment. Cystitis was most often treated with pivmecillinam, and this proportion increased during the study period. Treatment of pyelonephritis was characterized by more use of broader-spectrum antibiotics, use of both sulfamethoxazole-trimethoprim and ciprofloxacin increased during the study period. These trends, indicative of enduring changes in consultation and treatment patterns for UTIs, will have implications for future antibiotic stewardship measures and policy. Extensive use of antibiotics and the increasing emergence of antimicrobial resistance is a major health concern globally –3. In 20Urinary tract infections (UTIs) are the most common bacterial infections in females. Most women will experience an uncomplicated UTI during their lifetime, and one in five will have recurring infections . ConsequWhether to prescribe antibiotics is at the core of the clinical approach to cystitis. Withholding antibiotic therapy for cystitis has been associated with a small risk of progression to pyelonephritis –10, 17, Guidelines for antibiotic treatment differ between countries depending on the resistance patterns for the most common pathogens. In Norway, national guidelines for antibiotic treatment in primary care were introduced in 2000 and are updated regularly . TreatmeThe aim of this study was to investigate time trends in antibiotic treatment following consultations for UTI in primary care in Norway from 2006 to 2015.This is an observational study based on nationwide data from primary care in Norway. Norway has a patient-list system entitling all residents to a regular general practitioner (GP). Most consultations in primary care are carried out in GP practices during opening hours, including daytime emergency consultations . MunicipControl and Payment of Health Reimbursement (KUHR) Database contains data from all claims for fee-for-service from GPs and OOH services [Norwegian Prescription Database (NorPD) contains information on all prescription drugs dispensed from pharmacies to individual patients [Information from two national registries for the period 2006–2015 was linked at the individual level, using the unique personal identity number (encrypted) assigned to all residents of Norway. The services . For eacpatients . For eacWe identified all consultations by attendance (not by telephone or e-consultation) to general practice and OOH services from January 2006 until December 2015 registered in KUHR with the diagnoses U70 pyelonephritis and U71 cystitis.From NorPD we included all dispensed antibiotics for systemic use (ATC code J01). We considered antibiotics dispensed from pharmacies within 3 days following a UTI consultation to be linked to that consultation.We created binary outcome variables for type of service , and dispensing of antibiotic for the treatment of UTI . Type of antibiotics was categorized based on ATC codes.> 80 years.We recoded patient age into the following categories: 0–9, 10–14, 15–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and All descriptive analyses were conducted for cystitis and pyelonephritis separately. We investigate UTI consultations rather than UTI episodes. This implies that some consultations could possibly be for the same UTI episode, including scheduled follow-up visits after initiation of antibiotic treatment. We established the distribution of patient age and sex, and type of service for UTI consultations. We calculated the proportion of UTI consultations that were followed by antibiotic treatment and type of antibiotic dispensed. We explored time trends in the use of different antibiotics as treatment for UTI. Statistical significance was set at the 0.05 level. Analyses were performed using IBM SPSS Statistics for Windows, version 25.0 .During the 10-year study period, there were 2,426,643 consultations for UTI in primary care in Norway, out of a total of 140,199,637 consultations regardless of diagnosis (1.7%). Of all UTI consultations, 2,293,533 (94.5%) were for cystitis and 133,110 (5.5%) for pyelonephritis  and for pyelonephritis by 14.0%  (Table p < 0.001) and pyelonephritis   UTI consultations in primary care resulted in antibiotic treatment, and the proportion increased during the study period. Cystitis consultations resulting in antibiotic treatment increased from 36.6% in 2006 to 65.7% in 2015 in general practice, and from 47.0 to 69.7% in OOH services , respectively.Cystitis was predominantly treated with pivmecillinam (53.9%), followed by trimethoprim (20.8%). Young children (0–9) with cystitis were mostly treated with trimethoprim (45.0%), pivmecillinam (19.1%) or sulfamethoxazole-trimethoprim (16.8%). For pyelonephritis, pivmecillinam was most frequently used (43.0%), followed by ciprofloxacin (20.5%) and sulfamethoxazole-trimethoprim (18.1%). The youngest and oldest patients were more often treated with broad-spectrum antibiotics for pyelonephritis; sulfamethoxazole-trimethoprim accounted for 27.6% of prescriptions for children 0–9 years old, and ciprofloxacin accounted for 27.5 and 20.5% of prescriptions for patients 70–79 and > 80 years . We observed that proportionally more UTI consultations resulted in antibiotics during the study period. This could be due to more antibiotic prescribing per UTI-case, or it could indicate fewer consultations per UTI-case.We found that the proportion of cystitis consultations resulting in antibiotic treatment increased from 36.6% in 2006 to 65.7% in 2015. Paradoxically, overall use of antibiotics  typically associated with treatment of cystitis in Norwegian primary care  decreased from 2010 to 2015 according to the NORM/NORM-Vet report . Access We interpret these findings as indicative of a change in how cystitis is managed in primary care. A likely explanation is that short contacts for UTI most often resulted in antibiotic prescription, while the more unsure cases led to a face-to-face consultation without prescribing. As UTIs increasingly are managed by a consultation the proportion resulting in antibiotic prescription is higher for consultations, but lower for all sorts of contact combined. As coding of short contacts is less accurate than for consultations we conclude that reimbursement claims for short contacts will not provide data that can reliably answer this question .Compared to other European countries with comparable healthcare systems the percentage of cystitis consultations resulting in antibiotic treatment in Norwegian primary care is low, even towards the end of our study period. A cohort study of GP-practices in Belgium, the Netherlands and Sweden with data collected for the year 2012 found that 87, 67, and 84% of cystitis consultations resulted in antibiotic treatment, respectively . A SwediIn our study the proportion of pyelonephritis consultations resulting in antibiotic treatment was low, but increased during the study period from 35.3% in 2006 to 50.7% in 2015. This apparently low prescription rate is likely to reflect that pyelonephritis is a more severe infection with a higher proportion of consultations leading to hospital admittance for definitive treatment – thus decreasing the proportion of consultations in our dataset that led to antibiotic treatment. We do not have access to data on hospitalization. Other cases of pyelonephritis may have been followed up several times by the GP, with prescription only once. An increase in the number of pyelonephritis consultations resulting in ambulatory antibiotic treatment towards the end of the study period suggests that either proportionally fewer cases of pyelonephritis were admitted to the hospital or that fewer subsequent control-consultations (without prescribing) were performed. Trends in other European countries regarding the proportion of pyelonephritis consultations resulting in antibiotic treatment is difficult to assess, in part due to the scarcity of population-based studies on the condition and the age of those studies that do exist , 34.The proportion of UTI consultations resulting in antibiotic treatment was lower among male patients and the youngest and oldest age groups. Norwegian national guidelines define that cystitis in male is a “complicated infection” and recommend empirical antibiotic treatment . In this>70y) patients received more often broad-spectrum antibiotics for both cystitis and pyelonephritis. Contributing factors could be more vague symptoms [We found that pivmecillinam was most frequently used for both cystitis and pyelonephritis. The youngest (0-9y) and oldest (symptoms  or a higsymptoms .Ciprofloxacin use for UTIs in Norwegian primary care fell for cystitis (from 6.6% of antibiotics prescribed for the condition in 2006 to 5.9% in 2015) and increased for pyelonephritis (from 18.2% in 2006 to 23.1% in 2015). In a European context, there appears to be some variation in the use of fluoroquinolones for UTIs. Sweden, the Netherlands, and Switzerland have comparable low rates of fluoroquinolone use for cystitis at 3.0, 7.4 and 6.0% respectively , 32, wheThe management of cystitis remains a prime candidate for antibiotic stewardship measures; especially as the condition is prevalent and potentially self-limiting.A surprising finding in our study was that both the total number of UTI-consultations and the proportion of UTI-consultations leading to antibiotic treatment increased gradually during the study period. As discussed above, there are several factors that could contribute to this development; perhaps most important a possible enduring shift in consultation trends, where UTI increasingly is managed as face-to-face consultations. This introduces the possibility for individually targeted treatment for each patient with a potential of further reduction in antibiotic prescribing.To support this, more knowledge is needed about non-antibiotic management, the risk of complications and proper safety netting, both through clinical trials and epidemiological studies on the course of UTI episodes.