The relationship between antibiotic stewardship and population levels of antibiotic resistance remains unclear. In order to better understand shifts in selective pressure due to stewardship, we use publicly available data to estimate the effect of changes in prescribing on exposures to frequently used antibiotics experienced by potentially pathogenic bacteria that are asymptomatically colonizing the microbiome. We quantify this impact under four hypothetical stewardship strategies. In one scenario, we estimate that elimination of all unnecessary outpatient antibiotic use could avert 6% to 48% (IQR: 17% to 31%) of exposures across pairwise combinations of sixteen common antibiotics and nine bacterial pathogens. All scenarios demonstrate that stewardship interventions, facilitated by changes in clinician behavior and improved diagnostics, have the opportunity to broadly reduce antibiotic exposures across a range of potential pathogens. Concurrent approaches, such as vaccines aiming to reduce infection incidence, are needed to further decrease exposures occurring in ‘necessary’ contexts. Antibiotic consumption is a known driver of antibiotic resistance. In developed nations, over 80% of antibiotic consumption for human health occurs in the outpatient setting , and US-We use publicly available data to quantify potentially avertable exposures of bacterial species to commonly used antibiotics under hypothetical changes in prescribing practice. The set of scenarios included here are intended as thought experiments to explore the upper bounds of avertable antibiotic exposures. Reductions in antibiotic consumption have historically had variable impacts on resistance levels, likely dependent on setting, baseline consumption and resistance patterns, and fitness costs . In addiThis analysis includes sixteen antibiotics that are frequently prescribed in the outpatient setting and nine potentially pathogenic bacterial species that are commonly carried in the normal human microbiome. For each antibiotic-species pair, we estimate the proportion of antibiotic exposures experienced by that species that could be averted under four hypothetical scenarios. The scenarios range from broad elimination of unnecessary prescribing to focused modifications of antibiotic use for specific indications as follows:Eliminate unnecessary antibiotic use across all outpatient conditions.Eliminate all antibiotic use for outpatient respiratory conditions for which antibiotics are not indicated.Eliminate all antibiotic use for acute sinusitis.Prescribe nitrofurantoin for all cases of cystitis in women.We use the results reported by Fleming-Dutra and colleagues as estimates of unnecessary antibiotic use in ambulatory care settings . In thisAntibiotic treatment of acute bacterial sinusitis is currently guideline-recommended . Howeverhttps://www.cerner.com/solutions/drug-database).Extending our recent work on bystander selection , we useda represent antibiotic, s represent species, i represent ICD-9-CM diagnosis code, and g represent age group. Throughout the analysis we have weighted outpatient visits to be nationally representative using the sampling and nonresponse weights provided in NAMCS/NHAMCS. Let asX be the number of avertable exposures by antibiotic and species, asT be the total number of exposures by antibiotic and species, aigd be the number of prescriptions of antibiotic a associated with diagnosis code i in age group g, sigp be the carriage prevalence of species s among those with diagnosis code i in age group g, and aigq be the proportion of avertable exposures by diagnosis code and age group in the given scenario. For example, in the scenario assessing elimination of all unnecessary antibiotic use, aigq is the proportion of avertable antibiotic use by diagnosis and age group  are assumed to be constant within three age groups  (aigq) were reported for three different age groups  . For antibiotic prescriptions that occurred at visits without any ICD-9-CM diagnosis codes (i = 0), we applied the carriage prevalence among healthy individuals.The proportion of avertable antibiotic exposures for each species is defined by ge group . Alternaars old) , while pnd over) . G is thsigp is changed to s0gp as all eliminated exposures would have occurred during asymptomatic carriage. For cases where sige is 1, we assume zero avertable exposures. In addition, we make slight modifications to aigq when we estimate the proportion of bacterial cases to be larger than the proportion of necessary prescriptions (In scenarios where unnecessary use is eliminated (1 and 2), we assume that only bystander exposures are affected. This presumes that perfect discrimination between bacterial and non-bacterial etiologies is possible. This results in a slight modification to the numerator of riptions . As a seriptions . All anaS. pyogenes exposures to cefdinir and the largest with H. influenzae, E. coli, and P. aeruginosa exposures to azithromycin. If all unnecessary antibiotic use could be prevented, over 30% of exposures to amoxicillin-clavulanate, penicillin, azithromycin, clarithromycin, levofloxacin, and doxycycline across most potential pathogens of interest could be averted. Of particular interest, elimination of all unnecessary prescribing in the outpatient setting could reduce exposures of S. pneumoniae to penicillins and macrolides by 27% and 37%, respectively, and of S. aureus to penicillins and quinolones by 27% and 21%. For E. coli and K. pneumoniae, approximately one-quarter of exposures to cephalosporins and one-fifth of exposures to quinolones could be averted.We estimate that elimination of unnecessary antibiotic prescriptions across all outpatient conditions would prevent 6% to 48% (IQR: 17% to 31%) of antibiotic-species exposures . The smaS. pyogenes, M. catarrhalis, and S. agalactiae indicates that they have relatively frequent exposure to azithromycin during treatment of other conditions that are unaffected in this scenario, both as a bystander and causative pathogen.Scenario 2, elimination of all antibiotic use for outpatient respiratory conditions where antibiotics are not indicated, is a subset of Scenario 1 and accounts for a substantial portion of avertable exposures included in the first scenario. As in Scenario 1, the results are primarily driven by drug and depend on the amount of use of that drug for the affected conditions . Pathogen characteristics affecting the proportion of avertable exposures can be better understood by looking across all species for a single drug. For example, we focus on the row for azithromycin. Based on NAMCS/NHAMCS 2015, 32% of all azithromycin use is associated with the affected conditions. Since these conditions are never caused by our organisms of interest, the maximum proportion of avertable exposures for any species is 32%. However, the proportion of avertable exposures is modulated by the number of azithromycin exposures that occur for treatment of other conditions – for example, a lower proportion of avertable exposures for In Scenario 3, we explore elimination of all antibiotic use for acute sinusitis. Overall, acute sinusitis accounts for just 3% of prescriptions of our included antibiotic classes, resulting in the low proportions of avertable exposures across most bacteria-antibiotic combinations. However, proportions of avertable exposures are relatively high for amoxicillin-clavulanate and clarithromycin, antibiotics for which a large proportion of their use is due to acute sinusitis . In this scenario, we make the assumption that all use for acute sinusitis is unnecessary. In reality, a small number of cases are truly bacterial and antibiotics are indicated for patients with persistent, severe or worsening symptoms . We explE. coli and K. pneumoniae to cephalosporins could be reduced by 16% and 17%, respectively, and exposures to quinolones could decrease by 26% and 28%. Uniquely in this scenario among those we considered, several of our species of interest cause a large proportion of UTI cases . To explore the effects of being a causative pathogen on the proportion of avertable exposures, we focus on the results for ciprofloxacin. Overall, 27% of ciprofloxacin use is associated with acute cystitis in women. Organisms that are not causative pathogens of cystitis have proportions of avertable exposures close to or less than 27%, but a substantially higher proportion of exposures could be averted among causative pathogens - 33%, 36%, and 44% of ciprofloxacin exposures to E. coli, K. pneumoniae, and P. aeruginosa, respectively. Although E. coli is the most common cause of UTIs, its estimated proportion of avertable exposures in this scenario is lower than that of P. aeruginosa, likely due to the larger number of antibiotic exposures incurred by E. coli during asymptomatic carriage.In this scenario, we consider a program to prescribe only nitrofurantoin for all cases of acute cystitis in women, replacing all other antibiotics that are currently in use. As a result of this change, we estimate that exposures of M. catarrhalis is asymptomatically carried in children much more frequently than in adults. Since cystitis occurs primarily in adults, the proportion of avertable exposures is often lower for M. catarrhalis compared to other species due to bystander exposures in children that are largely unaffected by modified prescribing practices for cystitis. This age group effect can be substantial for antibiotics that are commonly given to children, especially when the antibiotic is also used to treat a condition caused by M. catarrhalis (e.g. cefdinir and otitis media), but is less influential for antibiotics that are infrequently prescribed to children, such as ciprofloxacin and levofloxacin.This scenario also allows us to observe the impact of differences in disease incidence, antibiotic use patterns, and carriage prevalence across age groups on the proportion of avertable exposures. For example, Overall, the proportion of avertable exposures is driven by pathogen, syndrome, and prescribing characteristics. Because our organisms of interest experience the vast majority of their antibiotic exposures as bystanders, the metric is largely dependent on the proportion of antibiotic use that is associated with the conditions affected in the given scenario. In a scenario where all antibiotic use for affected conditions is eliminated, this proportion would be equal to the proportion of avertable exposures for organisms exposed to antibiotics only during carriage (never pathogens). Being a causative pathogen for any of the affected conditions increases the proportion of avertable exposures. In contrast, being a causative pathogen for unaffected conditions increases unaffected antibiotic exposures and thus decreases the proportion of avertable exposures. For pathogens responsible for multiple syndromes, both factors may be at play. Finally, asymptomatic carriage prevalence is positively associated with both affected and unaffected antibiotic exposures, and, as a result, its overall effect on the proportion of avertable exposures is dependent on the antibiotic-species combination of interest.H. influenzae, E. coli, and P. aeruginosa to azithromycin) could be avoided. In addition, impact of the intervention across antibiotics and species is widespread, with half of antibiotic-species pairs expected to experience a reduction in exposures of over one-fifth (22%). For conditions which require antibiotic treatment, such as UTIs, switching to antibiotics with decreased collateral damage to the microbiome, such as nitrofurantoin, may be an effective strategy for reducing antibiotic exposures across species.We quantify the species-level impact of changes in antibiotic consumption as the proportion of antibiotic exposures experienced by common bacterial pathogens that could be averted under four hypothetical scenarios. In the scenario where unnecessary antibiotic use for all outpatient conditions is eliminated, we find that up to 48% of exposures  but did not report their estimates by condition . AlthougFinally, it is important to note that the reduction in antibiotic exposures estimated here does not translate to the same reduction in the prevalence of resistance or in the morbidity and mortality attributable to resistance. Although population-level antibiotic consumption has been positively correlated with levels of antibiotic resistance, the impact of changing consumption is not well-understood and is likely to vary widely by antibiotic-species combination (or even antibiotic-strain combination) based on resistance mechanisms, fitness costs, and co-selection, among other factors . AntibioReductions in antibiotic consumption are necessary to preserve the potency of these drugs. Quantifying changes in species-level exposures due to stewardship programs is one more step towards understanding how changes in antibiotic use correspond to antibiotic resistance. The methods presented here may be easily extended to incorporate other data sources, such as claims, or to assess more specific stewardship programs. We show that while improved prescribing practices have the potential to prevent antibiotic exposures experienced by bacterial species throughout the microbiome, complementary efforts to facilitate appropriate antibiotic consumption and decrease overall infection incidence are required to substantially avert exposures. In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.Acceptance summary:This manuscript provides a quantitative framework for assessing the impact of potential interventions to reduce unnecessary antibiotic use. It combines data on the prevalence of both infection-associated and colonizing bacterial populations with publicly available prescription data to assess the frequency of intentional vs. bystander antibiotic exposure in clinical practice. It then applies a modelling approach to understand how reduction in antibiotic prescriptions will affect overall antibiotic exposure across a variety of antibiotic-pathogen pairs. This extends previous work to provide further insights into the potential effectiveness of different antibiotic stewardship regimes.Decision letter after peer review:eLife. Your article has been reviewed by four peer reviewers, including Miles Davenport as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by a Reviewing Editor and Neil Ferguson as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Marc Bonten (Reviewer #3).Thank you for submitting your article "Potential impact of outpatient stewardship interventions on antibiotic exposures of bacterial pathogens" for consideration by The reviewers have discussed the reviews with one another, and the Reviewing Editor has drafted this decision to help you prepare a revised submission.Summary:This manuscript looks at strategies to reduce antibiotic prescribing, and the role of 'bystander' exposure of commensals. The authors present a theoretical framework and nice thought experiment to quantify the potential benefits of changing antibiotic prescription in the outpatient setting. They have used "publicly available data to quantify potentially avertable exposures of bacterial species to commonly used antibiotics under hypothetical changes in prescribing practice." The four scenarios are relevant and "All scenarios demonstrate that stewardship interventions, facilitated by changes in clinician behaviour and improved diagnostics, have the opportunity to broadly reduce antibiotic exposures across a range of potential pathogens." The methodology builds upon previous work of the authors on the effects of antibiotics in the open population and the methods are clearly described. The limitations of the data regarding to infection coding and true antibiotic exposure and the uncertainty that any of the four strategies can be realized in real life are addressed appropriately. And despite the – somewhat – obvious conclusions  this work presents a very thoughtful and interesting framework for future analyses.The take home message is that exposure is reduced but would remain substantial, so outpatient stewardship alone is not enough.Essential revisions:1) The impact of changes prescribing strategy is interesting, but actually only relevant to the particular circumstance of bacteria that are associated with infection and either treated or not treated appropriately (see (a) below). This does not discount the importance of the insights – but in fact it feels that the manuscript presented numbers more than insights (see (b) below). Thus, the manuscript would be greatly strengthened and appeal to a much broader audience if the current results could be supplemented by some more intuitive explanations and ways to think about the problem.a) While giving a percentage reduction is interesting, providing an intuition of how we might think about this and how it applies to different bacteria/drug pathogens combinations would be even more helpful. This is described to some extent in the Results section – but this was not an easy passage to follow unless you have a clear mental picture of pathogen/syndrome/antibiotic combinations, and could be explained much better in terms of 'classes' of pathogens. For example, if eliminating unnecessary use of penicillin for respiratory infection reduced overall penicillin prescriptions by 30%, then we can consider how this impact on three different classes of pathogen. (i) For unrelated pathogens , exposure is reduced by 30%. (ii) For pathogens that cause respiratory infection – but for which prescription is unnecessary and avoided by the strategy – they will have a >30% reduction ). (iii) For pathogens that cause respiratory infection and for which penicillin is indicated, then they will have a lower reduction than 30% (ie: 30% – correct prescription rate).This is not saying this issue is not described at all here  – just that it was not immediately clear that this fell out so easily, and the reader has to think about it. A flowchart-type figure of these classes and effects would make it very clear how the numbers in the tables were arrived at.b) One thing that is not considered here is pathogen population size/density. For example, one might expect that the number of bacteria present in the microbiome may be many orders of magnitude lower than that present in the context of infection caused by the bacterium. Since the probability of resistance (and transmission of resistance) no doubt scales with population size, this seems important to discuss. This could be simply summarised as a 'ratio' even if not known precisely. That is, if the results were presented in the intuitive way described in (a) above, the issue of ratio could be introduced even without actual numbers of bacteria in microbiome/infection being known. For example, discussion of the impact of 'density' on the different scenarios above (eg: in scenario (ii) above, exposure per bacterium is reduced more than expected (because the treatments avoided are high density ones), whereas for scenario (iii) the reduction would be lower than calculated. .2) An additional paragraph on the relationship between antibiotic exposure and antibiotic resistance would be valuable. I realize the authors are avoiding that because it is not at all straightforward, but I think worth stating that a 46% exposure does not mean a 46% reduction in the frequency of resistance . It might mean more or less; we have no idea. There is often a hidden assumption in the stewardship literature that if we can half exposure, we half the problem. The next important frontier is to figure out the relationship between the exposure and the resistance problem.3) The four scenarios chosen are interesting and clinically relevant. However, they are all fairly different for one another in terms of clinical behavior change and potential implications. Therefore, it could be helpful to the reader if results for each scenario were presented separately in the results and discussion, with additional section tying all findings together and evaluating impact of all four scenarios together.4) Additionally, for Scenario 1 it may be helpful to briefly define what is meant by unnecessary antibiotic use for readers unfamiliar with Fleming-Dutra et al. as it may be easy to confuse that with Scenario 2.5) There is an issue of assuming "20/20 hindsight": the 'incorrect prescription' rate is based upon post-hoc analysis of the proportion of infections caused by a given pathogen. This information is not known to the clinician in advance. Therefore, there is no way to reach 'optimal targeting' in real-time prescribing. This should be discussed in more detail.6) For acute sinusitis, it needs to be clarified that antibiotic treatment of acute bacterial sinusitis is currently guideline-recommended. Therefore, until guideline recommendations change, this scenario is unlikely to come to fruition. It may be helpful for the authors to consider a sensitivity analysis for acute sinusitis looking at (1) if only unnecessary use was eliminated  and (2) if all treatment was eliminated . Some of this already exists in the supplement  and main text, so little additional analysis would be needed.7) Consider being more explicit about codes/diagnoses are being considered in Scenarios 1, 2, and 4. Perhaps including a table in the supplement would be a nice way to summarize this.8) The incorporation of sensitivity analyses and discussion of outpatient departments is unnecessary and may be confusing to readers. Many outpatient settings are excluded from NAMCS/NHAMCS. Just mention that in the methods and limitations. Essential revisions:1) The impact of changes is prescribing strategy is interesting, but actually only relevant to the particular circumstance of bacteria that are associated with infection and either treated or not treated appropriately (see (a) below). This does not discount the importance of the insights – but in fact it feels that the manuscript presented numbers more than insights (see (b) below). Thus, the manuscript would be greatly strengthened and appeal to a much broader audience if the current results could be supplemented by some more intuitive explanations and ways to think about the problem.a) While giving a percentage reduction is interesting, providing an intuition of how we might think about this and how it applies to different bacteria/drug pathogens combinations would be even more helpful. This is described to some extent in the Results section – but this was not an easy passage to follow unless you have a clear mental picture of pathogen/syndrome/antibiotic combinations, and could be explained much better in terms of 'classes' of pathogens. For example, if eliminating unnecessary use of penicillin for respiratory infection reduced overall penicillin prescriptions by 30%, then we can consider how this impact on three different classes of pathogen. (i) For unrelated pathogens , exposure is reduced by 30%. (ii) For pathogens that cause respiratory infection – but for which prescription is unnecessary and avoided by the strategy – they will have a >30% reduction ). (iii) For pathogens that cause respiratory infection and for which penicillin is indicated, then they will have a lower reduction than 30% (ie: 30% – correct prescription rate).This is not saying this issue is not described at all here  – just that it was not immediately clear that this fell out so easily, and the reader has to think about it. A flowchart-type figure of these classes and effects would make it very clear how the numbers in the tables were arrived at.We thank the reviewers for their constructive feedback and agree that broader, more intuitive statements may be useful for a wider audience. Describing pathogen classes is slightly more complicated than outlined above because exposures depend not only on etiology for the condition of interest (e.g. respiratory infection) and carriage, but also on the propensity of an organism to cause other infections. In addition, whether antibiotics are or are not indicated does not depend entirely on the causative pathogen. These complexities make it difficult to put forth simple formulas for the proportion of avertable exposures by pathogen “class”, but we have included a set of more general statements at the end of the Results section. We hope that this approach will provide readers with the desired intuition.We have also added an additional source data file  including tables of minimally processed data inputs to help facilitate better understanding of the underlying calculations and enable further exploration/manipulation by readers.b) One thing that is not considered here is pathogen population size/density. For example, one might expect that the number of bacteria present in the microbiome may be many orders of magnitude lower than that present in the context of infection caused by the bacterium. Since the probability of resistance (and transmission of resistance) no doubt scales with population size, this seems important to discuss. This could be simply summarised as a 'ratio' even if not known precisely. That is, if the results were presented in the intuitive way described in (a) above, the issue of ratio could be introduced even without actual numbers of bacteria in microbiome/infection being known. For example, discussion of the impact of 'density' on the different scenarios above (eg: in scenario (ii) above, exposure per bacterium is reduced more than expected (because the treatments avoided are high density ones), whereas for scenario (iii) the reduction would be lower than calculated. .We thank the reviewers for their comment and acknowledge that bacterial density could play a role in propagation of resistance. However, we do not believe there is enough data to support the idea that an exposure during treatment is more important for resistance than an exposure experienced during colonization. There are also reasons to believe the opposite – for example, infections reflect bacteria that found their way into normally sterile sites, and resistant strains or their genes may find it harder to transmit from these sites . There is insufficient evidence to conclude whether infection is associated with higher loads of the causative pathogen throughout the body. In addition, many other variables beyond density may modulate the interaction between antibiotics and infecting and colonizing populations of bacteria. For example, pharmacokinetics, pharmacodynamics, the nature of the particular infection (e.g. abscess that is hard for antibiotics to penetrate) and the non-uniform distribution of bacteria across body sites may also play a role.We have added several lines to the Discussion section to acknowledge that population size/density, along with other factors mentioned above, may impact our findings.2) An additional paragraph on the relationship between antibiotic exposure and antibiotic resistance would be valuable. I realize the authors are avoiding that because it is not at all straightforward, but I think worth stating that a 46% exposure does not mean a 46% reduction in the frequency of resistance . It might mean more or less; we have no idea. There is often a hidden assumption in the stewardship literature that if we can half exposure, we half the problem. The next important frontier is to figure out the relationship between the exposure and the resistance problem.We thank the reviewers for raising this important point. We have added a paragraph on this issue to the Discussion section.3) The four scenarios chosen are interesting and clinically relevant. However, they are all fairly different for one another in terms of clinical behavior change and potential implications. Therefore, it could be helpful to the reader if results for each scenario were presented separately in the results and discussion, with additional section tying all findings together and evaluating impact of all four scenarios together.As recommended, the Results section has been separated by scenario. We hope this will help improve clarity for readers. Most of the Discussion section is broadly applicable and serves to tie the scenarios together.4) Additionally, for Scenario 1 it may be helpful to briefly define what is meant by unnecessary antibiotic use for readers unfamiliar with Fleming-Dutra et al. as it may be easy to confuse that with Scenario 2.We thank the reviewers for raising this potential point of confusion. A brief paragraph has been added to the Materials and methods section to define unnecessary antibiotic use as estimated by Fleming-Dutra et al.5) There is an issue of assuming "20/20 hindsight": the 'incorrect prescription' rate is based upon post-hoc analysis of the proportion of infections caused by a given pathogen. This information is not known to the clinician in advance. Therefore, there is no way to reach 'optimal targeting' in real-time prescribing. This should be discussed in more detail.We thank the reviewers for this important point. We have added “laboratory processing times that prevent identification of causative pathogens during outpatient visits” to the list of issues that preclude optimal prescribing (Discussion section); another related point that is already listed is “similar clinical presentation of viral and bacterial infections”. We also include rapid diagnostics as a key tool for reducing unnecessary antibiotic use (Discussion section).6) For acute sinusitis, it needs to be clarified that antibiotic treatment of acute bacterial sinusitis is currently guideline-recommended. Therefore, until guideline recommendations change, this scenario is unlikely to come to fruition. It may be helpful for the authors to consider a sensitivity analysis for acute sinusitis looking at (1) if only unnecessary use was eliminated  and (2) if all treatment was eliminated . Some of this already exists in the supplement  and main text, so little additional analysis would be needed.We have added this analysis as a third scenario in Figure 1—figure supplement 2 and clarified that antibiotic treatment of acute bacterial sinusitis is currently guideline-recommended in the text (subsection “Scenarios of interest”). Based on the Fleming-Dutra et al. paper, we estimate that 18% (0-19 years old), 100% (20-64 years old), and 34% (>64 years old) of antibiotic prescriptions given for acute sinusitis are unnecessary. Note that these estimates do not align directly with the numbers from the Fleming-Dutra paper  because the Fleming-Dutra paper groups together prescriptions for acute and chronic sinusitis. Although chronic sinusitis arises from multiple pathophysiologic processes, antibiotics may be indicated for chronic sinusitis patients with acute exacerbations and/or signs of infection. Thus, we back-calculate the modified proportions of unnecessary prescriptions for acute sinusitis alone under the simplifying assumption that all prescriptions for chronic sinusitis are necessary .7) Consider being more explicit about codes/diagnoses are being considered in scenarios 1, 2, and 4. Perhaps including a table in the supplement would be a nice way to summarize this.Explicit ICD-9-CM codes for each condition in Scenarios 1 and 2 can be found in eTable 2 of Fleming-Dutra et al., 2016. We describe in the text that we have directly applied their coding methodology: “We used methodology developed by Fleming-Dutra and colleagues, and applied in other studies, to group diagnosis codes into conditions…” (subsection “Data sources and methodology”). Codes for Scenario 4 are written out in the text in the Materials and methods section.8) The incorporation of sensitivity analyses and discussion of outpatient departments is unnecessary and may be confusing to readers. Many outpatient settings are excluded from NAMCS/NHAMCS. Just mention that in the methods and limitations.We apologize for any confusion this sensitivity analysis and discussion caused. The purpose of the sensitivity analysis in Figure 1—figure supplement 3 was not explicitly to explore the inclusion/exclusion of specific outpatient departments, but rather to explore validity of using the more recent 2015 data which is missing hospital outpatient department visits . Because we observed that the 2010-2011 results were similar with and without this segment of visits, we assumed the antibiotic use and diagnosis data from 2015 were representative of the entire NAMCS/NHAMCS population for the purposes of our metric.To simplify, we have maintained only Scenario 1 in the sensitivity analysis and have added more detail in the Discussion section to explain this Figure supplement. We have also briefly mentioned the limitation of missing outpatient settings in NAMCS/NHAMCS (Discussion section).


Steel bars embedded in reinforced concrete are vulnerable to corrosion in high chloride environments. Bidirectional electromigration rehabilitation (BIEM) is a novel method to enhance the durability of reinforced concrete by extracting chloride out of concrete and introducing an inhibitor to the surface of the steel bar under the action of an electric field. During the migration process, a higher ionization capacity of the inhibitor with a symmetrical molecular structure was introduced. A new imidazoline inhibitor was, therefore, employed in this study due to its great ionization capacity. The effect of imidazoline and triethylenetetramine inhibitor on chloride migration, corrosion potential, and strength of concrete were explored. The research results showed that the effect of chloride extraction and electrochemical chloride extraction made no significant difference on the surface of the concrete, where chloride extraction efficiency was more than 70%, and the chloride extraction efficiency was more than 90% around the location of the steel. while a dry-wet cycle test, the potential of concrete increased by about 200 mV by mixing imidazoline inhibitor. The imidazoline inhibitor was found to be effective at facilitating chloride migration and ameliorating corrosion, meanwhile, it had a negligible impact on the concrete’s strength. Reinforced concrete is considered as one of the most widely used engineering materials for constructions, and its durability is the major problem affecting the service life of the engineering structures. Corrosion induced by chloride ions ingress damages the passive film by penetration , which i- are produced on the surface of the reinforcement, which improves local basicity and is beneficial to the passivation of the steel bar [Various protective methods, including epoxy-coated steels, impregnation of inhibitor, are used to prevent corrosion in new structures. For old structures, a number of techniques have been studied and subsequently employed including cathodic protection, realkalisation and electrochemical chloride extraction (ECE). However, those methods cannot completely remove the chlorides in the structure and may therefore only be temporary solutions as chloride ions may remain available to attack the steel reinforcement once the treatment ends ,7,8. Bidteel bar ,15.The applicability of organic compounds as corrosion inhibitors for the metals in acidic medium has been recognized for a long time. Organic compounds employed as corrosion inhibitors can adsorb on the metal surface through heteroatoms such as nitrogen, oxygen, sulphur and phosphorus. But the alcamines inhibitor has weak electromigration ability and cannot migrate to the surface of steel effectively . Under h3, ether, ethylenediamine, triethylamine, 1,3-dibromopropane were purchased from chemical reagent factory . All of them were AR analytical reagent grade. The concrete materials include P∙O 52.5 grade cement, pebbles, medium coarse sand, and tap water.Sulfoxide chloride, lauric acid, NaHCOIn this study, a new imidazoline inhibitor with a symmetrical molecular structure and containing two imidazoline heterocycles and two alkyl long chains of lauric acid was synthesized. The synthetic route is presented in 3 and ether, and then ethylenediamine was dripped. Ethylenediamine bislauroyl amide was obtained by stirring for 6 h at 10–40 °C, filtering out the solid, washing and drying. Ethylenediamine bislauryl amide was mixed with phenoxyphosphatidyl diamide and reacted at 100–250 °C for 5–60 min. Then cooled and heated at 50–100 °C for 10–60 min. The insoluble substances were filtered and removed. Monocyclic imidazoline was obtained after cooling. Then monocyclic imidazoline lauric acid, 1,3-dibromopropane and triethylamine were dissolved in toluene and reacted for 10–25 h at 10–40 °C to obtain bicyclic imidazoline lauric acid. The synthesized imidazoline inhibitor was a light yellow solid. The solid product was easily soluble in water and had obvious surface activity, and the characterization with nuclear magnetic resonance (NMR) as shown in First, sulfoxide chloride dropping into lauric acid and stirring for 1–5 h at 40–80 °C. After the reaction is completed, the lauroyl chloride is obtained. Then lauroyl chloride was added to the mixed solution of water containing NaHCOA simulating pore solution of saturated calcium hydroxide and 0.01 mol/L sodium hydroxide was used to simulate the pore fluid of reinforced concrete in The steel bar used in this study was an HPB235 rounded steel bar with a 10 mm (diameter) × 100 mm (length). Before the experiment, 800# sandpaper was used to remove the rust on the surface of the steel bar, which was then washed with anhydrous alcohol to remove any potentially influencing factors, such as grease. After tests on the steel bar were completed, and vacuum drying was applied after each test to avoid the distorting of further oxidation when exposed to the air. The weight was determined using a high precision electronic balance and the quality of the steel bar specimen recorded. Double ring imidazoline and triethylenetetramine were used at a concentration of 1 mol/L as inhibitors. For controls, inhibitor was not added and the remaining conditions were unchanged. Each of the 6 rust-treated specimens was placed in the inhibitor solution. After soaking for 7 and 14 days, 3 steel samples were removed from each inhibitor solution. The surface corrosion products were washed away, the steel samples were weighed after vacuum drying, and the quality of the reinforcement samples was recorded after corrosion.In weight-loss experiments, the corrosion rate called V and corrosion inhibition rate called η calculated using Formulas (1) and (2).Corrosion rate:Corrosion inhibition rate:0 and m1-quality of steel bar before and after corrosion, respectively (g)m2)s-Exposure area (mt-Soaking time (h)0 and V1-corrosion rate in the absence and presence of inhibitor, respectively (g/m2 h)VType:The calculated corrosion inhibition rate results for the steel bar specimens are shown in From the above table, it can be seen that, in the simulated concrete pore solution, triethylenetetramine had relatively less effect on corrosion of the steel bar. After 14 days of immersion, the maximum corrosion inhibition rate was 26.5%, which was far lower than that of the self-made bicyclic imidazoline inhibitor. Bicycloimidazoline inhibitor incurred good resistance to rust after 7 days immersion, where the corrosion inhibition rate reached 40.3%. After 14 days immersion, the corrosion inhibition rate reached 38.8%. The steel corrosion rate first increased and then decreased with extensions in soaking time. Based on the weight-loss method, self-made bicyclic imidazoline inhibitor has been determined to be more effective than triethylenetetramine, which can protect for steel bar corroded by chloride salt. As shown in The bidirectional electromigration rehabilitation device is presented in The anode and cathode reactions were as follows:Anode reactions:Cathode reactions:Hydroxyl ions in the pore fluid can continue to be produced near the cathode steel bar and the steel near the original reinforced alkaline and passive corrosion can be stopped. The nitrogen ions in the inhibitor were stronger and smaller in size than the chloride ions. Therefore, the chloride ions can be isolated from the surface of the reinforcement.In this experiment, the strength grade of concrete is C30 which is according to engineering requirements. The dimensions of the concrete were 150 mm (length) × 150 mm (width) × 100 mm (height). Every concrete block contained two HPB235 round steel reinforcing bars with 10 mm diameters and the thickness of the concrete protection layer was 30 mm as shown in 2 for 14 days. The electrolytes used for bidirectional electromigration rehabilitation are listed in In order to investigate the effect of the new imidazoline inhibitor on concrete corrosion resistance, experiments comparing different inhibitors were carried out. In the experiments , steel wAfter 14 days, the concrete block was removed, and the surface was also cleaned and then soaked for 24 h in water. After the above step, the potentiodynamic polarization curve was directly measured. Following the polarization curve test, the concrete was ventilated and dried. Based on the size of the concrete blocks, the impact drill was selected, and the concrete powder sample was taken from every 5 mm in depth . The con2, 3% NaCl, charging time: 7 days, 15 days, and 30 days) using a mercury porosimeter. The Hg intrusion method was introduced to measure the porosity.After the concrete powder samples were retrieved from the C30, the test pieces were broken and cement hydration products near the surface of steel bar with diameters of no more than 10 mm were retrieved for analysis by scanning electron microscopy. After the concrete powder sample was collected from the concrete samples, the axial compressive strengths of the concrete blocks were determined. And the specimens were obtained near anode and cathode with different charging times  ions are successively removed along with the injection of inhibitors into the ordinary reinforced-concrete specimens [− ions were measured before and after the electrochemical process. According to the specification for inhibitors (GB/T 33803-2017), when the potential of steel is between −350 and −500 mV, the probability of steel corrosion is 95%, and if the potential of steel is higher than −200 mV, the probability of steel corrosion is less than 5%.In previous research, we have proposed the remedial technique of bidirectional electromigration rehabilitation (BIEM), through which chloride The effect of electrochemical treatment with different inhibitors on chlorine salt erosion of reinforced concrete corrosion potential and corrosion current were studied. It was found that imidazoline and triethylenetetramine inhibitors can increase the corrosion potential to some extent. The imidazoline corrosion potential shifted positively to the amplitude ratio of triethylenetetramine. The two inhibitors reduced the corrosion current, where the imidazoline corrosion current displayed a more significant reduction than triethylenetetramine.(2)Inhibitor from the external solution was found to discharge the majority of chloride ions in the concrete. The chloride extraction effect and electrochemical chloride extraction made no significant difference on the surface of the concrete, where chlorine removal efficiency and the efficiency of chlorine has reached the requirement around the location of steel, which revealing that the electromigration inhibitor did not affect the migration of chloride ions in the concrete.(3)The inhibitor content in the concrete specimens was evaluated after BIEM. After a dry-wet cycle test, the potential of the concrete increased by about 200 mV by mixing the imidazoline inhibitor, and the inhibitor content in the concrete specimens decreased along the thickness of the concrete protective layer. The imidazoline inhibitor content in the concrete was higher than that of triethylenetetramine, which indicates that the electric migration ability of the imidazoline inhibitor was stronger than the other compounds under an electric field.In the present study, the effectiveness of self-made imidazoline inhibitor on the durability of reinforced concrete was sysmetically investigated and compared with the conventional triethylenetetramine inhibitor. It can be concluded that:


Service-learning (SL) is the subject of a growing number of studies and is becoming increasingly popular in physical education teacher education (PETE) programs. The objective of this study was to conduct a systematic review of the implementation of SL programs with PETE students. The databases used were Web of Science, SPORTDiscus (EBSCO), and SCOPUS. Articles were selected on the basis of the following criteria: (a) published in a peer-reviewed journal; (b) covers the use of SL programs with PETE students; (c) relates to physical education or physical activity programs; (d) availability of a full-text version in English and/or Spanish. Thirty-two articles met the inclusion criteria. Two types of findings were observed: firstly, findings relating to the study characteristics and objectives and, secondly, recommendations for improvement of this type of intervention. The objectives of the different studies focused on (a) the impact of the SL methodology on PETE students’ professional, social, and personal skills; (b) its impact on the community; (c) analysis of the effectiveness and quality of the programs. All but two studies analyzed the impact of SL on PETE, while only four analyzed community participants and only three analyzed the quality of the SL program. Recommendations for improving SL programs used with PETE students included: all stakeholders, e.g., students and community participants, should be studied and coordinated; the quality of the programs should be assessed, as studying the effectiveness of SL programs could help to attain the objectives of both students and the community; mixed methods should be used; and intervention implementation periods should be extended to provide more objective, controlled measurements. Service-learning (SL) has been defined in multiple ways. The common thread running through these definitions is that SL is a methodological strategy that involves a program or a support service provided by students to the community. This methodology is widely used in university education, specifically in training physical education teacher education (PETE) students. Such programs are planned, coordinated, and integrated into university curricula to optimize learning and meet community needs . SL seekCarson and Raguse  state thA number of systematic reviews have focused on SL methodology across different disciplines, such as university social responsibility , nursingResearch on SL for PETE students has become increasingly prominent as a training resource for students in recent years. Due to its practical nature, there are numerous publications on the use of SL with this group, but only a few have centred around the implementation of PE programs, included scientific data, or been published in peer-reviewed journals.The results of the implementation of SL with PETE students tend to relate to three main elements: the students themselves, the community, and the SL program ,27. HoweStudies on SL for PETE students continue to be published, but there is no consensus as to their objectives. There is a need to determine whether SL really works and whether the results obtained from these interventions are positive. To this end, this review provides the levels of evidence of a selection of existing studies and analyses the duration of the interventions, the research methodology used, and the focus of the research: students, the community, or the SL program.The purpose of this systematic review is twofold. Firstly, it aims to analyze the characteristics of studies on the implementation of SL programs with PETE students that have been published in peer-reviewed journals and to identify their objectives: to assess the benefits for students and/or community participants, and/or to evaluate the effectiveness and/or quality of the SL programs themselves. Based on the literature reviewed, our second objective was to propose guidelines to help the scientific community to improve the implementation and quality of SL interventions in PETE.The search process was carried out following the protocol outlined in the PRISMA statement. A comprehensive search was conducted in the following databases: Web of Science (WOS), SPORTDiscus (EBSCO), and SCOPUS. Individual searches of all peer-reviewed studies published between 2013 and 2020 were performed. An 8-year window was applied to include only the most recent studies involving the implementation of SL with PETE students. The last search was conducted in November 2020. Search terms synonymous with “service learning” were used in combination with the search terms “physical activity” and “physical education”. Searches were conducted in English and Spanish. Only original articles were included in this study.Potentially relevant studies for this review were checked against the following selection criteria (PRISMA #6) : (a) theA flow chart was prepared based on the recommendations listed in the PRISMA statement. A total of 303 studies were retrieved from the literature search. Of these, 234 studies were discarded for failing to meet the inclusion criteria, leaving 38 potentially relevant studies. The full texts of these studies were examined in greater detail. A total of 26 of them failed to meet the inclusion criteria. As a result, a total of 31 articles were included in the systematic review. Data extraction was carried out independently and consistently by two reviewers (A.N. and R.P-O), who read all the titles and abstracts. Discrepancies were discussed until a consensus was reached. The studies were summarized, and the potentially relevant papers were screened for retrieval. Pilot test forms were used to extract data from the studies. A content analysis of the articles included in this review was also performed. Subsequently, the data were discussed and confirmed by the researchers. The following categories were defined a priori using the method suggested by Harris et al. : authorsThe criteria for assessing the quality of the studies included were adapted to the Consolidated Standards of Reporting Trials (CONSORT) Statement  as used The risk of bias is difficult to ascertain in qualitative, social science studies. Version 5.1.0 of the Cochrane handbook emphasizes that, in many situations, it is not practical or possible to blind participants or study staff in the intervention group.The duration of the interventions ranged from 2 weeks  to 4 yeaThe interventions included in this review followed three distinctive methodological approaches: qualitative (21/31), quantitative (2/31) and mixed (9/31). Studies analyzing the results from PETE students used all three types of methodology. Five studies used experimental and control groups: Chiva-Bartoll et al. , Chiva-BIn qualitative studies, both inductive and deductive study designs were found (21). Several data collection procedures, including interviews (10), self-reflection journals (13), reflective reports (5), focus groups (8), literature reviews (1), videos (3), life stories or biographical records (2), observations and field notes (6), and observation sheets (3), were used. Questionnaires intended for trainees were used in the only study adopting quantitative methods . Mixed mThe objectives of the different studies focused on: the benefits of SL programs for PETE students; the benefits of SL programs for the community and the effectiveness and quality of the SL programs.The most common objective in studies on SL for PETE students was to analyze how SL affected PETE students’ training. A total of 30 studies analyzed the influence of SL on PETE students (29/31); however, other studies had a twofold objective: they also analyzed the benefits of SL programs for community participants (4/31) or the quality of the SL program (3/31).The total number of PETE students in the SL interventions was 1872, ranging from 4 ,36 to 34Three types of benefits for PETE students’ skills were identified in the studies: 1. professional skills; 2. social and personal skills and 3. other.The studies focusing on the effects of SL for PETE students analyzed professional skills training (21/31), including generic, academic and professional skills. Lamoneda  observedWith regards to the pedagogical skill of reflective teaching, improvements in technical content and methodological strategies were also identified ,36. CapeSL contributed to the learning of participating students in general ,50,57. HCapella et al. ,39 compap = 0.473, = 0.021).Other studies assessed the acquisition of professional skills from SL with specific populations (17/31) such as cognitively impaired individuals ,55, chilChiva-Bartoll et al.  studied Other objectives were to assess the acquisition of social attitudes and skills and personal skills. The studies focusing on these objectives are shown in p < 0.05 for experimental group I and t(40) = 5.98; p < 0.05 for experimental group II. As expected, no significant differences between the pre-test and the post-test results for the control group were found: t(40) = 1.11; p > 0.05. Chiva-Bartoll et al. [p < 0.05) in the overall results of the experimental group in the Effective Personality Test for University Students . Heo et al. [According to Capella et al. , SL proml et al.  also fouo et al.  found tho et al.  analyzedo et al. , SL can o et al.  suggest o et al.  assumed o et al.  analyzedChiva-Bartoll et al. ,42 studiTwo studies analyzed changes in PETE students’ identities ,51. AccoM = 59.59; SD = 8.25) to follow-up  and were statistically significant (t(54) = −6.81; p < 0.001). Gil-Gómez et al. [Martínez et al. , Peraltaz et al.  found thz et al.  viewed tRuiz et al.  analyzedOnly four studies focused on community participants, but their objective was twofold: to analyze the benefits of SL programs for PETE students and the community ,50,54,56There are no studies exclusively assessing members of the community. The number of participants in the SL programs studied here could not be specified because most of the studies did not report or study them, or because they varied depending on the day or session ,56,60.There were different types of participants: people with special educational needs (15/31); people with other special characteristics  (8/31); primary and secondary school children (3/31); the school community as a whole  (1/31); elderly people (3/31); prisoners (1/31); and others (1/31).Regarding the implementation of an SL program at a school, Webster et al.  concludeThree studies analyzed the effectiveness of SL programs ,49,52. LThe purpose of this systematic review was twofold: to analyze the characteristics of studies on the implementation of SL programs with PETE students and, in view of the shortcomings identified, to propose future lines of research on SL in PETE. The results from the first study objective can be grouped into three categories: the benefits of SL programs for PETE students, the benefits of SL programs for the community, the effectiveness and quality of the SL programs. In this review, most studies (29 studies) focused on students, while four focused on community participants. Only three studies examined the effectiveness and quality of services provided in the SL program. These data are consistent with research in other areas, where the community is outside the scope of the study ,80,81. IIn this review, only four studies analyzed the benefits of SL programs for the community. SL interventions proved to be positive for the community subjects, and their objectives were achieved in all the cases studied. These data are consistent with those reported by Doolittle and Rukavina  and JoneIn this review, only three authors ,49,52 anRegarding the second objective of this research, analysis of the results of the studies has allowed us to identify several potential lines of work to ensure that SL programs in PETE produce better outcomes for all stakeholders, which may become possible lines of research. It is essential to analyze all the actors involved in SL programs in PETE. There is a lack of research assessing community participants, which is consistent with studies , who autThe quality of the program was only analyzed by three of the studies. We believe that focusing on program quality would benefit both students and community participants and that further research is required in this area. The quality of SL programs for PETE students should be assessed as a determinant of their effectiveness. In addition, Blouin and Perry  discuss We observed significant heterogeneity in terms of the research methods and techniques employed, as well as disadvantages in the use of exclusively quantitative methods. For this reason, we believe that mixed methods are more appropriate. These data are consistent with those observed in other systematic reviews , whose rThe limitations of this study are rather similar to those found in reviews of SL in other fields, such as nursing, medicine, and social work. It is possible that only papers with positive results were published. The strength of this study lies in its specific analysis of the implementation of SL programs with PETE students, which had not yet been studied. With regard to future lines of research, we propose the following: using mixed methods, coordinating the different stakeholders, and studying community participants and the quality of the programs themselves as well as students.This article sought to analyze the benefits of SL programs for PETE students and it is safe to say that, as a learning methodology, SL has excellent potential as a resource for developing professional, personal, and social skills in PETE students. SL also promotes participation in teaching by connecting future PE professionals to the realities and challenges of a diverse and constantly evolving educational environment. This produces benefits for the community and connects education to the real world. Teaching, research, and service objectives can be accomplished by including all stakeholders in the SL process. With respect to the guidelines to help the scientific community to improve the implementation and quality of SL interventions in PETE, we believe that further studies are needed to analyze all three factors: PETE students, community participants, and program quality. There is a need for a mixed research methodology that compiles contributions from all stakeholders. The effectiveness of the studies should also be assessed via longer implementation periods, as this could result in more objective, controlled measurements and more generalizable findings.


International Journal of Environmental Research and Public Health [Recently, a very interesting article on solastalgia was published in the c Health . In thisc Health .For this exploration, we conducted a social network analysis with coauthors  of publiThe main limitation of this analysis is related to the language of publications included. Galway et al. only included publications in English, thus any another language was excluded. However, it is possible that the inclusion of these publications does not greatly change the coauthors’ network. Results suggest that solastalgia is still a new concept in the scientific literature. Its main exponent is the person who coined the term , and the


A large majority of the pharmacists think that formal training in infectious disease should be a pre-requisite for pharmacists in ASP . In terms of antibiotic selection, the availability of antibiotics in hospital  and patient’s clinical condition  are more of a concern to the pharmacists. A total of 65% of the respondents (n = 192) demonstrated good levels of knowledge with a mean knowledge score of 10.1 out of 13 . Pharmacists from the managerial level, ward pharmacy, in-patient, and medication therapy adherence clinic (MTAC) unit had better knowledge of antibiotics compared to pharmacists from other units (p < 0.001). Antibiotic knowledge gap had been identified among pharmacists in different work settings, and longer years of service does not warrant good antibiotic knowledge.Antimicrobial Stewardship Program (ASP) has been implemented in major public hospitals in Malaysia, with pharmacists playing a key role in ensuring the appropriate use of antibiotics. This survey aimed to assess the practices, perceptions, and knowledge of public hospital pharmacists on antibiotic use and resistance. A cross-sectional survey involving pharmacists from six public hospitals in Penang was conducted using a self-administered validated questionnaire. The majority of pharmacists perceived that polypharmacy (92%,  The increased usage of antibiotics and inappropriate prescribing have exerted a selective pressure on clinically relevant bacteria, leading to the development of antimicrobial resistance (AMR). The AMR rate in Malaysia is reported to be on an increasing trend ,2. It wiThis was a multicenter cross-sectional survey using a self-administered printed questionnaire. All registered pharmacists and pre-registration pharmacists working at the public hospitals located in the state of Penang, Malaysia, were included in this survey. Based on the information given by the Penang Pharmaceutical Services Division, the total number of pharmacists practicing at the six public hospitals in Penang was 330. The six public hospitals were Penang General Hospital, Seberang Jaya Hospital, Balik Pulau Hospital, Bukit Mertajam Hospital, Kepala Batas Hospital, and Sungai Bakap Hospital. The pharmacists working in the private sectors , community pharmacy law enforcement unit, and academia were excluded from this survey. The pharmacists whom were on study leave or maternity leave were also excluded. The study respondents consisted of pharmacists from different pharmacy units, which included outpatient pharmacy, inpatient pharmacy, ward pharmacy, logistic, medication therapy adherence clinic (MTAC), Pharmacy Resources and Information Center (PRIC), management, and specialized units, i.e., therapeutic drug monitoring (TDM), clinical nutrition services, cytotoxic drug reconstitution (CDR), and pharmaceutical compounding/manufacturing. Printed questionnaires were distributed by one designated research coordinator from each hospital to the pharmacists that fulfilled the inclusion criteria. Questionnaires were recollected within the same day to discourage cross-referencing and discussion among respondents.The questionnaire was developed based on the study by Abbo et al.  ModificaA pilot study was done with a group of 47 pharmacists from the general hospital of the Kedah state in Malaysia. The final questionnaire consisted of 53 items. Based on data from the pilot study, the internal reliability coefficient was tested, and an average Cronbach’s alpha value of 0.7 was obtained for each domain, i.e., perceptions section and practices section. However, Cronbach’s alpha for dichotomous scores in the knowledge section calculated using KR-20 was relatively low at 0.6. This probably was due to the presence of several more technical questions on antibiotic knowledge whereby respondents chose the wrong answers. The validated questionnaire consisted of four sections (53 items), which included six questions on demographic data , 16 questions on “pharmacy practices”, 18 questions on “perceptions towards antibiotic use and resistance”, 13 questions on basic and specific “knowledge on antibiotic use and resistance”. The responses of the participants on the “perceptions towards antibiotic use and resistance” section were measured using a five-point Likert scale of agreement. A score of 1 was given to strongly agree, two to agree, three to neutral, four to disagree, and five to strongly disagree. In the “pharmacy practices” section, a five-point Likert scale of frequency was used with a score of one given to always, 2 to often, 3 to sometimes, 4 to rarely, and 5 to never. “Pharmacy practices” section consisted of seven basic general questions and six technical, clinical questions. Based on the finding from our pilot study, we categorized 13-item knowledge score into “Good” (≥ten correct answers), “Moderate” (six to nine correct answers), and “Poor” (<six correct answers).Data were analyzed by using SPSS v20. Descriptive analyses were employed to present the data as frequencies and percentages. The association between variables was analyzed using Pearson’s Chi-square (v2) test and the findings were reported with 95% confidence intervals (CIs). Items that were not answered by respondents were excluded from the analysis. The main outcomes measured were pharmacists’ antibiotic utilization knowledge, perceptions, and practices.Ethical approval for this study was obtained from the Medical Research and Ethics Committee (MREC), Ministry of Health Malaysia.The response rate was 90.6%, with 299 questionnaires collected (294 questionnaires with complete answer in the knowledge section one with incomplete answer in the knowledge section). Four incomplete questionnaires were excluded. Out of the 295 completed questionnaires, 79% were females, and 21% were males. Mean age was 29.1 (±Standard deviation 3.94) years old, median  year of practice in the hospital was 3  years, and 91% of them have bachelor pharmacy degree as their highest qualification. In term of involvement in antibiotic dispensing, the majority (93%) claimed that they performed antibiotic dispensing in the hospital whereby on average per week, 36% of these pharmacists estimated encountering more than 20 prescriptions containing antibiotics, 35% estimated handling 10–20 prescriptions with antibiotics, and 29% estimated handling less than 10 prescriptions with antibiotics. The distribution of pharmacists according to their respective work settings is presented in n = 57 out of 66) had better antibiotic knowledge compared to pharmacists from other units  (p < 0.001). The majority of the pharmacists answered the basic questions on antibiotic use and resistance correctly (p < 0.001) for a set of specific questions on clinical use of antibiotics. More than half of the pharmacists did not get the correct answer for the clinical use of antibiotics related to surgical prophylaxis, hospital-acquired pneumonia, and understanding of pharmacokinetic/pharmacodynamic properties of antibiotics. Besides, the percentage of correct answers for specific questions related to carbapenem usage was noted to be relatively low (64%) compared to questions relating to the treatment of Methicillin-resistant Staphylococcus aureus (MRSA) and bacterial meningitis.From the total of 294 respondents, 65.3% had a good level (score more than 10) of knowledge on antibiotic use and resistance with a mean knowledge score of 10.1 out of 13 , and only a small percentage (0.3%) scored below six. Pharmacists from the in-patient and ward pharmacy units , pharmacy management unit (100%), in-patient unit (73%), and MTAC units (73%) had significantly higher knowledge score (>10). It was followed by specialized units (67%), i.e., therapeutic drug monitoring, clinical nutrition services, cytotoxic drug reconstitution and manufacturing, out-patient unit (62%), pharmacy resources and information center (42%), logistic unit (37%), and pre-registered junior pharmacist  (55%) .The majority of the pharmacists perceived that polypharmacy of antibiotics could cause unnecessary adverse effects, and overuse of broad-spectrum antibiotics may potentially increase antibiotic resistance. The respondents had mixed responses concerning the overuse of antibiotics in the hospital; many of them remained optimistic that antibiotic resistance has yet to be a significant problem. The overall pharmacists’ perceptions were positive towards AMS as the majority agreed that ensuring the rational use of antibiotics is a shared responsibility between clinicians and pharmacists, as well as the patients. The summary of the findings is presented in More than 80% of hospital pharmacists agreed that the presence of the AMS program would affect antibiotic use and resistance in hospitals, whereby the ID team should be consulted at an early stage and pharmacist should be actively intervening inappropriate antibiotic use. The variability and availability of antibiotics in each hospital drug formulary was perceived to be one of the main factors affecting antibiotic use. Generally, the majority of hospital pharmacists also agreed that continual in-house audits on antibiotic use, the presence of National Antibiotic Guidelines, and the implementation of newer broad-spectrum antibiotic use restriction by pharmacists would impact antibiotic use and resistance. However, our findings indicated a mixed response concerning whether clinician’s preference for innovator antibiotics and pressure from the patients to prescribe antibiotics would have any influence on antibiotic use in the hospital .The variability in the types and availability of antibiotics in hospitals were the number one factors which influenced pharmacist’s recommendation to doctors on the choice of antibiotic . Public Before the release of the 3rd Malaysian National Antibiotic Guideline, the 2nd edition of the National Antibiotic Guideline 2014 was the primary source of information for public hospital pharmacists and the majority (>90%) of the respondents used the National Antibiotic Guideline as one of their sources of information during practice in the hospital. Second to it was the continuous medical education sessions provided by the hospital pharmacy colleagues or doctors, followed by the past clinical attachment to a ward pharmacy unit, antibiotic updates from medical journals, seminars provided by pharmaceutical companies, and international guidelines . In contrary to their positive perception towards ASP, only a small proportion (24%) of hospital pharmacists claimed that they obtained their source of information via consultation with the hospital ID team. Interestingly, pharmacists who claimed that they were exposed to the Infectious Disease Society of America and Sanford guidelines or consultations with the ID teams during practice were associated with a higher antibiotic knowledge score.This is the first documented study in Malaysia targeting only the pharmacists practicing in public hospitals, which include both tertiary hospitals and secondary hospitals. Overall, the current sample was appropriate to represent the hospital pharmacists who were directly or indirectly involved in antibiotic use.The majority of hospital pharmacists demonstrated good knowledge on antibiotic use and resistance. This should enable the pharmacist working in the public hospital to educate the general public in the region as more than half of the general public in Malaysia still have inadequate knowledge of antibiotic use ,20, espeThe number of years of pharmacy practice in the hospital, similar to other studies ,14,17,21Interestingly, the knowledge gap among hospital pharmacists from different work settings was identified with pharmacists from the in-patient and ward pharmacy units who had better antibiotic knowledge compared to pharmacists from other units. This probably due to the fact that ward pharmacists and in-patient department pharmacists had more exposure to complex antibiotic use in ward throughout their work routine. This particular group of pharmacist’s acts as a good point of reference on antibiotic use and resistance. Furthermore, selected pharmacists, especially those practicing in the ward and the in-patient department, could be trained as ID pharmacists in line with a recommendation by the Infectious Disease Society of America ASP Guidelines that suggested that ASP should be administered by either the ID physician or ID pharmacist . NeverthThe majority of the pharmacists agreed that polypharmacy of antibiotics increased patient’s risk of adverse drug effects. Local data reported that the incidence of the adverse drug reactions among patients prescribed with antibiotics was about 1.1%, with beta-lactam antibiotics, cephalosporins, vancomycin, and trimethoprim/sulfamethoxazole topped the list as the major contributors to such incidences . Most coAcinetobacter baumanii, emergence of ESBL among enterobacteriaceae, cases of carbapenem-resistant enterobacteriaceae, vancomycin resistant Enterococcus faecium, and erythromycin-resistant Streptococcus pneumoniae. Although the majority of pharmacists perceived that the overuse of broad-spectrum antibiotics may potentially increase antibiotic resistance, there was a mixed response concerning the overuse of antibiotics in the public hospitals. Many of the hospital pharmacists remained optimistic that antibiotic resistance has yet to be a significant problem in hospital. This false optimism could be due to a few possibilities. First of all, the hospital pharmacists may not be aware of the information of the increasing defined daily dose and resistance pattern published in the National Antibiotic Guideline 2014. It could also be possible that hospital pharmacists are not interested in taking note of these alarming statistics. On the other hand, many of the pharmacists agreed that an antibiogram should be made available in the hospital to ensure proper selection of antibiotics. However, the availability of an antibiogram for each hospital depends on the capacity of the microbiology lab of each hospital to produce it. It is worth mentioning that the antibiogram was not available in all public hospitals.Based on the National Surveillance of Antibiotic Resistance data , there wIn accordance with findings from other studies ,22,24,25The development of the AMS protocol by the Ministry of Health and implementation of AMS in public hospitals had successfully forced a downward trend in antibiotic utilization in 2016 .In terms of pharmacist perception towards factors affecting antibiotic use and resistance, a majority of the respondents agreed that variability and availability of antibiotics in each hospital drug formulary would affect antibiotic use. In contrast to perceptions of medical practitioners ,17, hospGenerally, the majority of hospital pharmacists also agreed that continual in-house audits on antibiotic use, presence of National Antibiotic Guideline, and implementation of broad-spectrum antibiotic use restriction by pharmacists will impact on antibiotic use and resistance. These findings were supported by other studies ,24,27,28A recent systematic review  identifiSince the first publication of the Malaysian National Antibiotic Guideline in 2008, it had gradually become the primary source of reference for many public hospital pharmacists. The second edition of the National Antibiotic Guideline published in 2014 had become more favorable among pharmacists in public hospitals. Both the National Antibiotic Guideline softcopies had been made available for free online download. It is not surprising to find that only a small proportion of public hospital pharmacists claimed that they obtained their source of information via consultation with the hospital ID team. This was because a well-established ID team was not readily available in certain hospitals in the state of Penang. At the time of discussion, ID consultant is only available at Penang General Hospital. In view of the high usage of Malaysian National Antibiotic Guideline 2014 among the hospital pharmacists, it is hoped that the latest Malaysian 3rd edition National Antibiotic Guideline 2019 would be adopted as a standard practice among all healthcare providers in the public hospitals.Generally, pharmacists’ perceptions were positive towards the AMS program as the majority agreed that ensuring rational use of antibiotics is a shared responsibility between clinicians and pharmacists. This study also reveals that pharmacists in public hospitals have good basic knowledge on antibiotic use and resistance. Longer years of service do not warrant good antibiotic knowledge, and the antibiotic knowledge gap had been identified among pharmacists in the different work settings. The AMS program, early ID referral, pharmacist intervention, audit on antibiotic use, restrictive policy by pharmacy departments, and timely updates of the National Antibiotic Guideline are perceived as the important factors that may affect antibiotic use and resistance in hospitals.


In addition, study has shown that compliance with environmental requirements is associated with heavy metal leaching.This article focuses on the impact of fly ash from the combustion of municipal sewage sludge (FAMSS) as a cement additive in the amounts of 5%, 10%, 15%, 20% and 25% (by mass) on selected concrete properties. In the course of the experimental work, water penetration depth and compressive strength measurements were made at various periods of curing (from 2 to 365 days). In addition, the potential impact of FAMSS on the natural environment was examined by determining the leachability of heavy metals. FAMSS-modified concretes showed small values of water penetration depth (lower than 50 mm), as well as good compressive strength (reaching minimum class C30/37 after 130 days of maturing)—similar to the compressive strength obtained for conventional concrete. In addition, the partial replacement of cement with FAMSS has environmental benefits, expressed as a reduction in CO However, it is impossible to produce clinker  without emissions caused by the decomposition of about 525 kg CO2 per ton of clinker [According to the Yearbook of International Statistics data , the proion tons , global ion tons , while P2), calcium phosphate (Ca3(PO4)2), and hematite (Fe2O3), while the main elements are Si, Ca, Fe, Al, P and O [In cement technology, and mainly in the concrete technology in Europe, siliceous and calcareous fly ashes from the combustion of black coal and brown coal are widely used ,11. Thei P and O . Additio P and O . Phospha P and O , which a P and O .Fontes et al  showed tTaking the variability of physical and chemical composition of fly ash from the combustion of municipal sewage sludge (FAMSS) into consideration, their application can affect the features of concretes manufactured with their addition. The results of the investigations presented in the current paper are a continuation and extension of previous investigations . The papThe main purpose of the research was to assess the properties of ordinary concretes with a modified composition. The modification consisted of the partial replacement of cement with fly ash from the combustion of municipal sewage sludge. For comparison, experiments were carried out for unmodified concretes and concretes, in which cement was replaced with FAMSS in the range of 5% to 25%. In addition to the technical properties of analyzed concretes, the leaching of selected substances , as well as the environmental impact of the produced composites, were determined.Concrete without admixtures—CON,Concrete mixed with fly ashes from combustion of municipal sewage sludge—FAMSS.Ordinary concrete samples were designed for testing in accordance with PN-EN 206 + A1: 2016-12 "Standard Concrete–Part 1: Requirements, properties, production and compliance" . To perfk value for CEM cement met the condition: fly ash FAMSS/cement C ≤ 0.33 (by mass). The concrete mix recipe per 1 m3 was established to comply with the assumption of ordinary concrete mix with use of the method of three equations. The proportions of concrete mix tested in the study are shown in In the individual samples mixed with fly ashes, 5% (FAMSS 5%), 10% (FAMSS 10%), 15% (FAMSS 15%), 20% (FAMSS 20%) or 25% (FAMSS 25%) of a defined cement mass were replaced by the ashes. The maximum amount of fly ash included in the CEM I 32.5R Portland cement was used in the tests, in all exposure classes excluding classes XA2 and XA3, for which HSR sulphate cements are commonly used. In order to characterize the physical-chemical properties and activity of FAMSS, and to investigate the possibility of the modification of concretes made with their participation, their chemical composition, mineral composition, grain size and pozzolanicity were examined.The chemical composition of fly ash was determined on an Epsilon 3  spectrometer using the X-ray energy dispersion fluorescence (XRF) method. The test was performed in the measuring range of Na-Am elements on an apparatus equipped with an Rh X-ray tube , a 4096-channel spectrum analyzer , 6 measuring filters  and a high resolution solid state SDD detector (50 µm thick Be window) cooled with a Peltier’s cell. The mineral composition of the fly ashes was determined using powdered X-ray diffraction (XRD) tests with a Panalytical X’pertPRO MPD X-ray diffractometer  with a PW 3020 goniometer . A Cu copper lamp (CuKa = 1.54178 Å) was used as the source of X-ray emission. X’Pert Highscore software was used to process diffraction data. The identification of mineral phases was based on the PDF-2 Release 2010 database, formalized by JCPDS-ICDD.The grain size analysis was based on laser diffraction using a Mastersizer 3000 analyzer . The measurement was carried out in a dispersing liquid  in the presence of an ultrasonic probe in order to break up larger aggregates of the tested samples. Grains with equivalent diameter sizes from 0.1 to 1000 µm were analyzed. The morphology and chemical composition in the micro area of the main components of the tested materials was determined using the SEM Quanta 250 FEG scanning electron microscope (FEI), equipped with a chemical composition analysis system based on X-ray energy dispersion—EDS  .The pozzolanic activity of fly ash was carried out according to PN-EN 450-1: 2012  and the In order to characterize the properties of the concrete mixes tested, the following tests were carried out: consistency of concrete mixes by the fall cone method , bulk deMoreover, concrete containing 5, 10, 15, 20 and 25% of fly ashes as well as the control sample were tested for heavy metals leaching using European standards . SamplesF) content, and reactive aluminum, calcium and silica oxides  of FAMSS are presented in 2), aluminum oxide (18.98% of Al2O3) and iron oxide (7.77% of Fe2O3) contents in FAMSS was lower than in conventional ashes, and did not meet the requirements of the PN-EN 450-1 + A1: 2012 standard  [2, Fe2O3 and Al2O3 contents in FAMSS from 2018 (52.29%) was higher than in FAMSS from 2017 (35.40%) tested by Rutkowska et al. [2 and CaO. In the ash applied in 2018, their percentage shear was higher than in that used in 2017. However, the strength results presented in this work do not correlate with the results of the chemical composition. In the previous work, the growth in the percentage share from 10 to 15% did not cause any significant changes in the mechanical strength of the obtained concrete. Nevertheless, the result was ca. 42 ÷ 46 MPa. In this work, the growth in the percentage share caused growth in the mechanical strength. However, the comparable result with the ash from 2017 (~45 MPa) was obtained only for the 15% addition. This is namely the visible difference between the ashes used in both works. This can be evoked by the fact that there is much more Al2O3 in the ash from 2018 than in that from 2017, which significantly changes the SiO2/Al2O3 ratio. In the previous work, this ratio amounted to 1.6 more than the value obtained in 2018 (1.35). The higher SiO2/Al2O3 ratio means more free loadings, which possibly positively affect the concrete hydration process. It is the result of replacement of trivalent elements (Al3+) by tetravalent ones (Si4+).The results of the composition analysis, with additional values of free calcium oxide  , which i% total) . Howevera et al. . Differe2 to be higher than 25%, reactive CaO lower than 10%, MgO lower than 4%, and Na2O lower than 5% by weight. For the tested FAMSS, the content was 13.33, 11.15, 2.33 and 0%, respectively. The set requirements were not met for reactive SiO2 and reactive CaO; the standard applies, however, to siliceous fly ashes obtained during the combustion of coal or co-combustion of coal and waste. In addition, compared to calcareous and siliceous fly ash, it has been noted that FAMSS contains significantly higher amounts of phosphate, which also exceed the required value of a maximum 100 mg/kg [Moreover, previously mentioned standards  require 00 mg/kg . This is00 mg/kg . Additio3/g, while the specific density was 1.826 kg/dm3. It should be emphasized that, according to Monzo et al. [The particle size distribution of FAMSS tested was monomodal . It can o et al. , the sizo et al. . Additio2 and Al2O3 content. According to the literature, the total content of SiO2 and Al2O3 above 20% indicates the pozzolanic character of the tested samples [2O/Al2O3 ratio, determine the activity of fly ashes. The content of K2O and Al2O3 in siliceous fly ash tested by Rutkowska et al. [2O/Al2O3·10), which, depending on the proportion of oxides, subdivides fly ashes into three classes. An index of 0.73 was obtained for the FAMSS tested, which classifies the material into medium reactive class (the second class of reactivity). The pozzolanic activity of fly ash according to ASTM C379-65T  is deter samples . Based o samples . However samples . The res samples , Monzo e samples  and Meri samples , that th samples , potassia et al.  was 0.2%a et al. , the poza et al.  introduc3 (CON) and was in the range characteristic for ordinary concrete (2000–2600 kg/m3).Based on consistency tests of the concrete mix using the fall cone method for the reference concrete and samples containing 10% and 15% of fly ash, a dense plastic consistency was obtained, while for the remaining samples a wet consistency was attained . The lowAccording to Monzo et al.  and Meri2 emissions  to 44% (FAMSS 25%)—and after 7 days from 58% (FAMSS 15%) to 71% (CON)—of the final strength determined after 365 days of maturation. After the next period of cement maturation (28 days), the reference concrete had 78% of the final  compressive strength, while in concretes made with FAMSS, the compressive strength accounted for 74–84% . After 5The results of the analysis of variance (ANOVA) carried out for data obtained for individual maturation periods are presented in Based on the conducted tests of the depth of water penetration under pressure, a decreasing depth was observed along with the increase in the percentage of FAMSS . AccordiThe chemical and physical characteristic of eluates from the crushed concrete samples is presented in 4 was higher for particle fractions smaller than 0.63 mm. It could be due to the larger contact surface of distilled water with the tested material. The concentration of sulfates in the eluate was only higher than the detection limit of the method for concrete samples with a grain size of 0.63–6.3 mm, containing 20% and 25% of FAMSS. The test results indicated an inverse relationship between the chloride leaching rate and the FAMSS content in concrete, but only in the range of 5% to 20% of FAMSS. Further increase in fly ash content caused a slight increase in chloride leaching. However, the addition of FAMSS increased the chloride concentration in the eluate in relation to the reference concrete. It should be emphasized that even the highest concentration of Cl in the eluate observed (34 mg/L) was lower than the values obtained by [Studies have confirmed the assumption that the addition of FAMSS increases the leaching of phosphorus compounds (orthophosphates) relative to reference concrete . It was ained by  for conc4, Cl and Ba and higher for Cu and Cr. Moreover, leachability tests confirmed the lack of stability of fly ash properties produced in the same municipal sewage sludge processing installation. According to Jiao et al. [For all analyzed samples, the concentration of As, Cd, Ni, Pb and Se in the eluates was lower than the detection limit . The baro et al. , the leaIn summary, it should be noted that the ashes studied are environmentally safe, because the sum of heavy metals washed out from concrete containing up to 25% FAMSS is less than 1.512 mg/L . The concentration of Mo, Hg and Sb was not included in this value; however, according to previous studies for FAMSS , their cThe addition of the analyzed fly ashes in amounts up to 25% by mass does not cause the deterioration of compressive strength of concrete in relation to reference concrete. The best strength parameters compared to the reference concrete were obtained for samples containing 10% to 20% FAMSS. The maturation time of the produced composites had a significant impact on the obtained results. The slow increase in the strength of concrete containing FAMSS could be caused by the presence of phosphorus delaying the cement hydration process. All concretes obtained the same class of C30/37 and higher C35/45 (FAMSS 20%) after 130 days of maturing, while the reference concrete (CON) and concretes with FAMSS in the amount of 10% (FAMSS 10%), 15% (FAMSS 15%) and 20% (FAMSS 20%) after 365 days of maturing achieved an even higher class of C35/45.The depth of water penetration under pressure for all samples was less than 30 mm, which met standard requirements.The pozzolanic activity of FAMSS did not meet the applicable requirements after 28 days (≥75%) and 90 days (≥85%) of curing. FAMSS reached the required values of pozzolanic activity (85%) after a longer period of curing, which allowed it to be classified as active mineral additives.Calcium, silica, phosphorus and aluminum oxide are the largest percentage of oxides in FAMSS samples. The sum of silica oxide, aluminum and iron oxides content does not meet the requirements contained in existing standards. However, there are no regulations regarding the physical and chemical properties of fly ashes from combustion of municipal sewage sludge.Based on the sum of heavy metals leached and the concentration of individual heavy metals concentration in the eluate it may be concluded that concrete containing FAMSS in the range of 5% to 25% is environmentally safe. However, studies of the physical and chemical properties of FAMSS have shown their variability in time. Therefore, further research on the impact of this variability on the technical parameters of concretes containing FAMSS seems necessary.Fly ashes are a very important additive modifying ordinary concrete and new generation concrete. However, when considering the use of fly ashes in concrete production, the physico-chemical composition, fineness and pozzolanic activity of the additives should be taken into account. Based on the presented research, the assessment of concrete modification with fly ash from the combustion of municipal sewage sludge was carried out and the following conclusions can be drawn: