Background: The utilization of antibiotic adjuvants presents a promising strategy for addressing bacterial resistance. Recently, the development of antibiotic adjuvants has attracted considerable attention from researchers in academia and industry. This study aimed to identify the most influential publications on antibiotic adjuvants and elucidate the hotspots and research trends in this field.Method: Original articles and reviews related to antibiotic adjuvants were retrieved from the Web of Science Core Collection database. The top 100 highly cited publications were selected and the visual analyses of publication outputs, countries, institutions, authors, journals, and keywords were conducted using Excel, VOSviewer, or CtieSpace software tools.Results: The top 100 cited publications concerning antibiotic adjuvants spanned the years 1977–2020, with citation counts ranging from 174 to 2,735. These publications encompassed 49 original articles and 51 reviews. The journal “Antimicrobial Agents and Chemotherapy” accounted for the highest number of publications (12%). The top 100 cited publications emanated from 39 countries, with the United States leading in production. Institutions in Canada and the United States exhibited the most substantial contributions to these highly cited publications. A total of 526 authors participated in these studies, with Robert E.W. Hancock, Laura J. V. Piddock, Xian-Zhi Li, Hiroshi Nikaido, and Olga Lomovskaya emerging as the most frequently nominated authors. The most common keywords included “E. coli”, “P. aeruginosa”, “S. aureus”, “in-vitro activity”, “antimicrobial peptide”, “efflux pump inhibitor” “efflux pump”, “MexAB-OprM” and “mechanism”. These keywords underscored the hotspots of bacterial resistance mechanisms and the development of novel antibiotic adjuvants.Conclusion: Through the bibliometric analysis, this study identified the top 100 highly cited publications on antibiotic adjuvants. Moreover, the findings offered a comprehensive understanding of the characteristics and frontiers in this field. Enterococcus faecium, Staphylococcus aureus (S. aureus), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (P. aeruginosa), and Enterobacter species) pose substantial threats due to their extensive resistance to the first line and last-resort antibiotics  sometimes manifest synergistic actions by acting on a variety of mechanisms, including targeting different steps in a common or related biochemical pathway . This geBibliometric analysis stands as a popular and powerful tool for both basic science researchers and clinical workers to obtain comprehensive overviews of certain research fields . CitatioThe publications for this study were sourced from the Web of Science Core Collection (WosCC) database from its inception up to 1 March 2023 (updated until 3 April 2023). The advanced search strategy was employed as follows: TS= NEAR/6 (adjuvant$ or potentiator$ or synerg*)) or chemosensitizer$ or membrane permeabilizer$ or (efflux Pump$ NEAR/5 inhibit*) or (quorum sensing NEAR/5 inhibit$) or (bate-Lactamase NEAR/5 inhibit*) or clavulanic acid or clavulanate or sulbactam or tazobactam or ((immun* NEAR/4 (stimulant$ or augment$ or activat$ or potentiat$ or modulat$)) NEAR/5 (bacter* or microbi* or antimicrobe* or antibacter*))). The asterisk (*) represents any group of characters, including no character. The dollar sign ($) represents zero or one character. The NEAR/5 or NEAR/4 finds records where the terms joined by the operator are within 5 or 4 words of each other, and the number 5 or 4 can specify the maximum number of 5 or 4 words that separate the terms. In total, 30,557 publications were retrieved, and subsequent refinement was performed to include only original articles or reviews. Additionally, the publications were ranked in descending order according to the citation counts. To ensure precision, two authors (Yu Zhang and Pingjing Yu) conducted a manual assessment. They reviewed the abstracts or full texts to exclude publications that were not relevant to antibiotic adjuvants. This process ultimately yielded the definitive selection of the top 100 highly cited publications and https://jcr.clarivate.com/) for the year 2022. Some regions of certain countries are presented separately in the publication, while they are generally regarded as one country internationally. Therefore, we performed a data refinement process to combine Scotland and England into the United Kingdom and combine Taiwan into China. In addition, merging keywords with similar meanings could help normalize different forms of text words, and then correctly calculate the occurrence frequency of keywords and generate the co-occurrence network of keywords. In addition, authors with the same name were authenticated through cross-referencing authors’ affiliations and collaborators.Full records of the top 100 highly cited publications were downloaded from the WoSCC database, including authors, title, journal, publication year, citation counts in all databases, addresses, affiliations, document type, keywords, and WoS Categories. The impact factors (IFs) and quartiles in category of journals were ascertained from the Journal Citation Reports  = 43.00, p = 0.462) was observed.The top 100 cited papers were published from 1977 to 2020, with an absence of highly cited articles between 1979 and 1995 . Among tThe list of the top 100 cited publications encompassed 49 original articles and 51 reviews. In the earlier stage (1977–2000), there were all original articles . These aAmerican Journal of Translational Research) to 120.1 (Nature Reviews Drug Discovery). Notably, 62 papers were from journals with 2022 IFs surpassing 5. Among them, 36 papers were from journals with 2022 IFs exceeding 10. It was noteworthy that Nanoscale Research Letters and Chemistry & Biology were not included in the 2022 edition of JCR. Dominantly, the top 100 cited publications were from journals encompassing domains of microbiology, pharmacology, and chemistry. The Spearman rank test indicated that the number of publications  and the total citation counts of journals  had positive correlations to the 2022 IFs of journals.The top 100 cited publications were from 64 journals and the 2022 IFs ranged from 2.2  emerged as a pivotal player with the largest number of publications . This journal mainly publishes original articles from areas of antibacterial, antiviral, antifungal, and antiparasitic agents. Earlier research on clavulanic acid was published in the Antimicrobial Agents and Chemotherapy, and this journal is also an important platform for antimicrobial research  and Drugs (2022 IF = 11.5) ranked second with 4 publications each, and the Clinical Microbiology Reviews outperformed in total citation counts . This might be because the reviews in the Clinical Microbiology Reviews covered a wide range of topics, including the novel strategy of phage-antibiotic combinations, the development of β-lactamase inhibitors, and the progress of EPIs  between countries was 0.34. Among them, Finland, Ireland, Palestine, Yugoslavia, and Poland independently contributed 1 or 2 papers, and they did not participate in international collaborations. P. aeruginosa ” (occurring 43 times), “P. aeruginosa” (occurring 35 times), and “S. aureus” (occurring 27 times). These strains have a high level of resistance to antibiotics and are classified as ESKAPE pathogens. Keywords related to anti-bacterial compounds appeared twice, including “antimicrobial peptide” (occurring 14 times) and “efflux pump inhibitor” (occurring 10 times). This revealed that these compounds were often used as antibiotic adjuvants against bacterial infections. Furthermore, subject “mechanism” occurred 14 times, and related targets “efflux pump” and “MexAB-OprM” also appeared over 10 times. Research methods, namely, “in-vitro activity” occurred 29 times. The co-occurrence network of keywords manifested for keywords appearing 3 or more times  made appearances ranging between 2 and 10 times, while the remaining top 14 keywords (4.22%) featured over 10 times. The top 14 keywords included three bacterial strains: “re times . AccordiCo-citation is defined as the simultaneous citation of two documents in a single publication . The mapRecent years have witnessed remarkable advancements in the field of antibiotic adjuvants. In this study, we identified the top 100 cited publications on antibiotic adjuvants. Bibliometric analysis of these influential publications provided focal domains and trajectories of the past research, which provided ideas and directions for further research .Streptomyces in 1976  surpassed that of countries (DC = 0.34). This revealed a phenomenon that cooperation and communication between institutions were predominantly confined to domestic spheres. It is imperative to transcend geographical boundaries and encourage global cooperation between academia, drug developers, and funding bodies. Further international research holds the potential to yield innovative combination strategies against antibiotic resistance.According to the results of the author analysis, Robert E.W. Hancock was the most productive author with 5 publications as a corresponding author. These publications have been cited over 1,386 times and focused on developing AMPs or host defense peptides to enhance antibiotic action . Laura JAntimicrobial Agents and Chemotherapy emerged as a prominent and influential journal with the largest number of publications (12) and total citation counts . This journal is also popular for researchers investigating topics related to bacterial infection, such as antibiotic-resistance of A. baumannii, P. aeruginosa biofilm, and bacterial persisters  Inactivation of antibiotics. Enzymes capable of modifying or degrading antibiotics’ key structural elements contribute to bacterial resistance. To date, tens of thousands of enzymes have been found to break down and alter various types of antibiotics, including β-lactams, aminoglycosides, chloramphenicol, and macrolides . A notabE. coli  family contribute to the most clinically relevant levels of antibiotic resistance. For instance, MexAB-OprM efflux pump of P. aeruginosacan export multiple different classes of antibiotics, like tetracycline, norfloxacin, and β-lactams ((2) Increased efflux. The active transfer of antibiotics out of the cells plays an important role in the resistance of bacterial pathogens. This mode of resistance is achieved through efflux pumps and the “multidrug resistance” (MDR) efflux pumps are capable of extruding a variety of structurally diverse compounds. Since the discovery of tetracycline efflux in E. coli , many ef-lactams .E. coli. Thus, alterations to the cell membrane, such as loss of porins, changes on the phospholipid and fatty acid content, as well as reduction of membrane fluidity, can prevent the entry of antibiotics into the cell and may lead to the emergence of antibiotic resistance ((3) Reduced permeability. Reduction of the membrane permeability can hinder the effective entrance of antibiotics, and it is the most common cause of bacterial resistance. Compared to Gram-positive bacteria, Gram-negative bacteria have a double-membrane structure and are intrinsically less permeable to several antibiotics. Many hydrophilic antibiotics cross the outer membrane by influx through outer membrane porin proteins, like the outer membrane protein F (OmpF) and outer membrane protein C (OmpC) channels of sistance .mecA gene mutations in methicillin-resistant S. aureus encode for a β-lactam insensitive PBP2a, allowing cell wall biosynthesis to proceed ((4) Modification of targets. Altering the structure of targets can lead to antibiotic resistance. Modification of the molecular targets usually occurs following a site mutation of selected genes or enzymatic catalysis, like methyltransferase. Mutations of target genes reduce susceptibility to inhibition while retaining the cellular functions of the target. For example,  proceed . In addi proceed . Drug re proceed .Resistance to antibiotics occurs through multiple molecular mechanisms, all of which can be inhibited by small molecules. Therefore, they are potential targets for antibiotic adjuvants. There are several main mechanisms of antibiotic resistance:(1) β-lactamase inhibitors. Currently, β-lactamase inhibitors are the only clinically approved adjuvants, and three main types of β-lactamase inhibitors have been developed. In 1976, clavulanic acid with β-lactam core was reported to inhibit serine β-lactamases . It becaS. aureus ((2) EPIs. A wide variety of synthetic or natural compounds have been identified as inhibitors of bacterial efflux pumps. For example, celecoxib derivatives and natural products like reserpine and flavonoid 5′-methoxyhydnocarpin D74 inhibit the major facilitator superfamily (MFS) NorA efflux pump in . aureus . There a. aureus . Some ef. aureus . This wain vitro and in vivo efficacy and safety profiles as new chemical entities, they will need to progress through clinical trials.(3) Outer membrane (OM) permeabilizers. OM permeabilizers are generally cationic and amphiphilic, including charged small molecules, cationic AMPs, cationic polymers, and chelators. pentamidine is the most promising OM permeabilizers because its clinical safety and pharmacology are well known . AMPs wi(4) Immunomodulatory peptides. Enhancing host defense provides alternative targets for antibiotic adjuvants. Immunomodulatory peptides are naturally occurring components of the innate immune system. they can regulate the immune response to infections. The natural cathelicidin peptide LL-37 shows weak antibacterial activity and has long been known to enhance the antimicrobial activity of the innate immune system . Several(5) Nanomaterials. Nanomaterials are considered as promising antibiotic adjuvants. They can enhance the activity of antibiotics through multiple mechanisms of action. Metal nanomaterials (including nano-silver and nano-copper), metal oxide nanomaterials (including copper oxide and zinc oxide nanoparticles), and non-metallic nanomaterials (including nano-selenium and nano-tellurium) have shown synergy with antibiotics in research settings . The appThere are various antibiotic adjuvants targeting the above resistance mechanisms: 1) β-lactamase inhibitors; 2) EPIs; and 3) outer membrane permeabilizers. Furthermore, several other antibiotic adjuvant strategies have also been developed, such as 4) immunomodulatory peptides and 5) nanomaterials.According to the results of the bibliometric analysis, antibiotic adjuvants mainly included direct resistance breaker, indirect resistance breaker, and host-modulating agents. Particularly, the direct resistance breakers, such as β-lactamase inhibitors and EPIs, are currently hotspots. This was because several β-lactamase inhibitors and EPIs have been approved for clinical application or are undergoing clinical trials. However, the emergence of extensively-drug resistant (XDR) bacteria might reduce the efficacy of these direct resistance breakers. Therefore, it is necessary to strengthen the development of indirect resistance breakers, such as OM permeabilizers. The OM permeabilizers could be used as broad-spectrum adjuvants to enhance multiple classes of antibiotics. However, the toxicity of OM permeabilizers should be taken into account, as they can also act on host cells. In addition, the low-toxicity host-modulating agents, like immunomodulatory peptides, have broad prospects for clinical application. Few studies have investigated the effect of antibiotic-adjuvant combinations on biofilm elimination. Complicated forms of infection, such as bacterial biofilms, persister bacteria, and intracellular infections, are closer to the real state of clinical infection. It is necessary to develop complicated infection models to evaluate the effects of different antibiotic adjuvants.It is essential to acknowledge the limitations in this study. First, our search strategy attempted to include as many textwords related to antibiotic adjuvants as possible. However, some relevant publications that did not use these words may have been excluded from this study. Meanwhile, we only searched the WoSCC database and this could not retrieve papers from different databases, like Scopus and Google Scholar. Second, filtering by citation counts and not excluding self-citations could inadvertently include contentious works. This might affect the objectivity of the analysis. Third, some early publications were omitted from keyword analysis due to missing author-provided keywords and keywords plus in the WoS database. Lastly, when an author was affiliated with multiple institutions/countries, this publication was counted as the work of each institution/country.Antimicrobial Agents and Chemotherapy emerged as a prominent journal for influential publications in this field. Currently, research focused on bacterial resistance mechanisms and the development of novel adjuvants. Future prospects included in-depth characterization of the known or unknown targets and exploration of more adjuvants for clinical use.In conclusion, this bibliometric analysis provided a comprehensive overview of the top 100 cited publications related to antibiotic adjuvants. These highly cited papers were published between 1977 and 2020. The analysis emphasized the prominence of the USA in the field, as the USA had the most number of highly cited publications and one-third of the highly productive institutions. Notably, several pharmaceutical companies have contributed to research on antibiotic adjuvants. Distinguished researchers like Robert E.W. Hancock, Laura J. V. Piddock, Xian-Zhi Li, Hiroshi Nikaido, and Olga Lomovskaya have made remarkable contributions. Enhancing international collaboration among institutions and authors in different countries held significance. Moreover,


Empiric Gram-negative antibiotics are frequently changed in response to new information. To inform antibiotic stewardship, we sought to identify predictors of antibiotic changes using information knowable before microbiological test results.We performed a retrospective cohort study. Survival-time models were used to evaluate clinical factors associated with antibiotic escalation and de-escalation . Spectrum was categorized as narrow, broad, extended or protected. Tjur’s D statistic was used to estimate the discriminatory power of groups of variables.In 2019, 2 751 969 patients received empiric Gram-negative antibiotics at 920 study hospitals. Antibiotic escalation occurred in 6.5%, and 49.2% underwent de-escalation; 8.8% were changed to an equivalent regimen. Escalation was more likely when empiric antibiotics were narrow-spectrum , broad-spectrum  or extended-spectrum . Patients with sepsis present on admission  and urinary tract infection present on admission  were more likely to undergo antibiotic escalation than patients without these syndromes. De-escalation was more likely with combination therapy  or narrow-spectrum empiric antibiotics . Choice of empiric regimen accounted for 51% and 74% of the explained variation in antibiotic escalation and de-escalation, respectively.Empiric Gram-negative antibiotics are frequently de-escalated early in hospitalization, whereas escalation is infrequent. Changes are primarily driven by choice of empiric therapy and presence of infectious syndromes. Theoretically, empiric antibiotics should represent an educated guess at appropriate coverage based on the patient’s condition, medical history, prior culture results and the facility’s antibiogram.4–8 Antibiotic stewardship programmes can support this reassessment to escalate, de-escalate or otherwise improve antibiotic therapy as needed.10 Because audit and feedback is labour intensive, antibiotic stewardship programmes employ rules and heuristics to guide which cases will be reviewed.11 Examples may include auditing all patients for whom IV antibiotics are prescribed, all patients receiving a fluoroquinolone, or all patients with a bug-drug mismatch.12As microbiological test results become available and the patient’s clinical course evolves, it is standard practice to reassess and adjust empiric antibiotics.In this study, we sought to facilitate the work of antibiotic stewardship programmes by identifying clinical factors that might predict when antibiotics require adjustment. Because it can be challenging to identify the appropriateness of antibiotic selection in retrospect, we examined instances in which empiric Gram-negative antibiotics were escalated or de-escalated shortly after initiation. To isolate clinical factors that might be ascertainable before microbiological test results become available, we focused on patient- and encounter-level characteristics from the first 2 days of hospitalization. The results of this analysis are intended to guide development, use, and implementation of antibiotic stewardship interventions to improve use of Gram-negative antibiotics in the hospital.13 The Premier database has been used frequently to evaluate patterns of antibiotic use across regions and hospitals.14–21 Hospitals contributing to the Premier database are diverse in geography, bed size and patient mix. This study did not include protected health information and was exempt from institutional review board review.We performed a retrospective cohort study of patient discharge data from 920 hospitals contributing to the Premier Healthcare Database (‘the Premier database’), an all-payer deidentified administrative dataset containing approximately 25% of US inpatient admissions.1 Hospital Day 0 was the day of presentation to or arrival at the hospital including time spent in the emergency department. Patients were excluded if discharged on the same day that empiric Gram-negative antibiotics were initiated.The study sample included all adult patients who were discharged from a Premier database hospital in calendar year 2019 and who were started on Gram-negative antibiotics during the ‘empiric window’, meaning within Days 0–2 of hospitalization.23 Overall spectrum of activity was ranked using four categories  and was determined by the broadest-spectrum Gram-negative antibiotic administered in a single day  and literature review (see Appendix JAC-AMR Online).23 For example, a patient receiving combination therapy with the broadest category of empiric antibiotics (protected) could still undergo antibiotic escalation if an additional Gram-negative antibiotic were added. A patient receiving narrow-spectrum empiric monotherapy could undergo de-escalation if antibiotics were discontinued altogether. Additional examples of de-escalation, escalation, and changes that do not count as either are provided in Table The primary outcome was antibiotic escalation, defined as an increase in the overall spectrum of Gram-negative antibiotic therapy or an increase in the number of Gram-negative antibiotics, within 5 days of antibiotic initiation.23 Antibiotic changes after 5 days may represent completion of treatment or treatment of a different infectious process. Models were constructed using shared frailty to account for clustering within each hospital.In the primary analysis, parametric regression survival-time models using a Weibull distribution were used to estimate HRs for the association between predictor variables and outcomes. The first day of antibiotic therapy, defined as Antibiotic Day 1, was used as the time of study entry. Thus, Hospital Day 0 may count as Antibiotic Day 1 if antibiotics were started in the emergency department. Observations were censored at the time of first escalation, de-escalation or neutral change, after five consecutive days of therapy without a change, or at hospital discharge. In the case of early hospital discharge, censoring was assumed to be non-informative, and patients who were discharged within 2–5 days of antibiotic initiation were nonetheless able to contribute days ‘at risk’ for use within the model. A follow-up period of 5 days was selected to capture antibiotic changes early in therapy or after an abbreviated course for the presenting syndrome.24 Relative importance of each category was represented by discriminatory power as measured using the coefficient of discrimination, D, of a model including only variables from that category as covariates.26 The D statistic is calculated as the difference in average predicted probabilities between observations with and without the outcome of interest. For instance, if the model including patient characteristics predicted an average probability of escalation of 70% among patients whose antibiotics were escalated and a probability of 40% among patients whose antibiotics were not escalated, the D statistic would be 0.70–0.40 = 0.30. The proportion of discrimination explained by each category of variables was estimated by dividing the D statistic for the model including only that category of variables by the D statistic for the model including all categories of variables. So, if the D statistic for patient characteristics was 0.30 and the D statistic for the full model was 0.60, patient characteristics would be estimated to provide a proportion of discrimination explained of 0.30/0.60 = 50%.24 The 95% CIs for proportion of discrimination explained were bootstrapped with 100 repetitions. The proportion of discrimination explained can be summarized as the extent to which a group of variables predict whether a patient will have the outcome. Because it is known that antibiotic prescribing varies substantially among hospitals,1 the full model including all covariates and the model only including hospital characteristics included a random intercept for hospital.In a secondary analysis, logistic regression models with binary outcomes representing antibiotic escalation or de-escalation within 5 days of initiation were used to estimate the relative importance of variables by category, including patient characteristics, infection characteristics, hospital characteristics and characteristics of the empiric antibiotic regimen.1 Covariates included patient demographics, baseline health represented by number of comorbidities from the Elixhauser comorbidity index, history of previous readmission to the same hospital within 90 days, severity of illness represented by requirement for ICU admission or organ support in the first 2 days of hospitalization, infectious syndrome present on admission, hospital characteristics, and characteristics of the empiric antibiotic regimen.28 Diagnosis code sets representing urinary tract infection present on admission and pneumonia present on admission were from the Healthcare Utilization Project’s Clinical Classification Software Refined.28 Explicit diagnosis codes were used to represent sepsis, septic shock and bacteraemia, which have a high positive predictive value and tend to select for more severely ill patients.29 Because Premier does not contain microbiological data from most hospitals, covariates related to microbiological testing or hospital-level antibiograms were not included. All statistical tests were 2-tailed with a threshold of ≤0.05 for significance of P values. Analyses were performed using Stata/IC version 14.2 .Covariates were selected for inclusion in multivariable modeling based on prior work studying variation in selection of empiric Gram-negative antibiotics, with an emphasis on data that would be available within the first 2 days of hospitalization.Data and code sets will be made available upon request.Discharge data were included from 920 US hospitals. Hospitals were located in the US South (47.6%), Midwest (21.7%), Northeast (16.3%) and West (14.3%). Teaching facilities accounted for 45.0% of hospitals, and 30.6% were 500 beds or larger. We identified 2 751 969 patients who received empiric Gram-negative antibiotics during an inpatient admission in 2019 , 34.6% were broad spectrum (e.g. ceftriaxone) and 7.4% were narrow spectrum (e.g. amoxicillin). A single Gram-negative antibiotic was included in 78.9% of the empiric antibiotic regimens, 18.3% included two, and 2.8% included three or more. The median total duration of Gram-negative antibiotics received was 4 days (IQR 2–6). Other characteristics of patients who received empiric Gram-negative antibiotics in this cohort have been reported previously.Patients who had their antibiotics changed within 5 days of initiation totalled 1 774 630 (64.5%), including 179 203 (6.51%) escalations, 1 354 290 (49.2%) de-escalations and 241 137 (8.76%) changes to a regimen with equivalent activity. The median time from initiation of empiric antibiotics to first antibiotic change was 2 days (IQR 2–4). Regarding escalations within 5 days, 71.1% involved an increase in the spectrum of antibiotic therapy, 28.9% involved an increase in the number of agents, and 12.6% involved both. As regards de-escalations within 5 days, 76.7% involved a decrease in the spectrum of antibiotic therapy, 23.3% involved a decrease in the number of agents, and 13.8% involved both. Characteristics of patients who had their antibiotics escalated or de-escalated within 5 days of initiation are provided in Table P < 0.001 by chi-square testing).Among the 1 774 630 patients whose antibiotics were escalated, de-escalated or changed within 5 days of antibiotic initiation, 168 874 (9.5% of 1.77 M) were started on antibiotics on Hospital Day 0, 1 371 516 (77.3% of 1.77 M) were started on antibiotics on Hospital Day 1, and 234 240 (13.2% of 1.77 M) were started on antibiotics on Hospital Day 2. As regards antibiotic changes, including escalations, de-escalations and neutral changes, 65.1% occurred the day after antibiotics were initiated. An escalation, de-escalation, or equivalent change occurred for 65.5% of antibiotics started on Hospital Day 0, 67.6% of antibiotics started on Hospital Day 1, and 50.6% of antibiotics started on Hospital Day 2 (Kaplan–Meier curves representing time to antibiotic escalation, de-escalation or first antibiotic change are provided in Figure Factors associated with time to de-escalation are also listed in Table A comparison of the relative importance of variables is included in Table 30When bacterial infection is suspected in a hospitalized patient, it is standard practice to start empiric antibiotics before the pathogen and site of infection are known. To our knowledge, this study is the largest to date that examines what happens next. For over 2.7 million patients admitted to 920 hospitals in a single year, about half of empiric antibiotics were de-escalated within 5 days. Escalation was much less frequent. These findings corroborate our clinical experience and the observations of others that clinicians would rather prescribe empiric antibiotics that are too broad than too narrow.31 When several options are available, selection of empiric antibiotics may not be perfectly rational and instead can be influenced by the prescriber’s emotional state or personal preference.33 To support better decision-making, antibiotic selection should utilize the expertise of an interdisciplinary team.35 In the negotiation between the prescribing clinician and antibiotic stewardship team, the empiric antibiotic regimen may be considered analogous to a starting offer.30 Though multiple changes can be perceived as lacking clinical ‘finesse’, clinicians should not be expected to predict the perfect regimen upfront based on incomplete data. Revisiting and adjusting antibiotic selections as needed supports safe, high-quality care.Changes to empiric therapy were most frequent on the day after Gram-negative antibiotics were initiated. In some cases, initial antibiotic selection may have been suboptimal, and antibiotic changes were driven by new data or evolution of the patient’s condition. However, in many cases, we suspect that these early antibiotic changes were driven primarily by hand-offs between care teams or within the same care team.37 By comparing D statistics, we were able to evaluate the relative importance of groups of variables in discriminating between patients who will or will not have their empiric antibiotics changed shortly after initiation. Based on this analysis, among patient, hospital and clinical factors that are knowable before microbiological test results become available, the primary determinants of antibiotic changes for both escalation and de-escalation were characteristics of the empiric regimen. From a stewardship perspective, this finding is reassuring in that it suggests suboptimal empiric therapy is frequently improved. At the same time, our results suggest potential opportunities to reduce the work of stewardship teams. For instance, a major driver of antibiotic de-escalation was use of combination empiric therapy. Implementation of protocols or policies that gently discourage clinicians from using multiple Gram-negative antibiotics in combination would likely pre-empt the need for streamlining later. Combination therapy is rarely indicated, except in the setting of pathogens with specific resistance patterns, such as carbapenem-resistant Acinetobacter baumanii.8Antibiotic de-escalation is known to be influenced by both the empiric regimen and the clinical syndrome.36–42 A strength of this study is that we leveraged a large dataset and addressed this gap in the literature by exploring factors associated with antibiotic escalation. Results of this analysis were both predictable and surprising. For instance, it was predictable that the infectious syndromes associated with severe illness in our model—sepsis and bacteraemia—were associated with increased likelihood of antibiotic escalation. On the other hand, it was surprising that urinary tract infection present on admission was associated with antibiotic escalation, whereas pneumonia present on admission was not. Instead, patients presenting with pneumonia were more likely to have their antibiotics de-escalated. The discrepancy in antibiotic changing behaviours between patients with urinary tract infection and patients with pneumonia suggests the potential role that positive cultures play in driving antibiotic use. Even when symptoms are absent or not consistent with an infection, positive cultures are a strong stimulus to prescribe antibiotics.43 Whereas urinary tract infection is frequently diagnosed based on a positive culture, no pathogen is identified for a large proportion of pneumonias.44 Further, though urinary tract infections are commonly perceived as being low risk, resistance is increasingly recognized.45–47 To address antibiotic use for urinary tract infections, stewardship teams likely need to emphasize appropriate culturing practices, including only obtaining cultures from symptomatic patients.48Studies examining antibiotic change behaviours tend to focus on de-escalation rather than escalation.49 However, protocols for early sepsis care prioritize reflexively broad antibiotic therapy with the understanding that the plan of care can be re-evaluated later.50 Given that one-third of patients presenting with sepsis will later be found to have non-infectious conditions or non-bacterial infection,51 decreased likelihood of antibiotic de-escalation in this patient population suggests that this re-evaluation is not occurring consistently. Instead, our findings may represent evidence of diagnostic inertia.52 Until practical guidance on how and when to re-evaluate ongoing need for antibiotics is built into formal protocols for sepsis care, such as the Centers for Medicare and Medicaid Services SEP-1 bundle, hospitals may encounter antibiotic overuse in this patient population.Though predictable, it is notable that empiric Gram-negative antibiotics were more likely to be escalated and less likely to be de-escalated among patients presenting with sepsis than among patients without sepsis present on admission. Increased likelihood of antibiotic escalation may be attributable to the inherent instability of septic patients and the diagnostic uncertainty that often accompanies their initial presentation.before results from microbiological testing predict antibiotic changes. Though we did not have access to hospital antibiograms, we used statistical techniques to account for clustering of data at the hospital level. Given the large size of the dataset, in this discussion we emphasized findings that may have clinical significance for antibiotic stewardship programmes, in addition to statistical significance.The major limitation of this study is that most hospitals do not contribute microbiological testing data to the Premier database. Though microbiological test results are a major driver of antibiotic changes, we specifically designed our study to examine how patient- and hospital-level factors that are knowable 53 Specifically, we did not have access to data related to symptoms, and thus patients with asymptomatic bacteriuria may have been misclassified as having urinary tract infections. Some instances of antibiotic de-escalation may have reflected perioperative antibiotics, though we controlled for number of surgeries during the first 2 days of hospitalization in multivariable analysis. Further, over half of the patients in our sample were discharged before Hospital Day 5 and thus were non-informatively censored. Based on the limitations of our dataset, we were unable to detect medications administered outside of the hospital encounter, including antibiotics prescribed prior to admission or after discharge, changes to antibiotic dosing during hospitalization, or specific antibiotic administration times. Finally, it was beyond the scope of this study to examine outcomes of care. Thus, we cannot assess whether antibiotic choices were appropriate or inappropriate.Additionally, our study is subject to the limitations of administrative data without chart review. Not all patients diagnosed with infection may truly have bacterial infection, and present-on-admission coding may only be accurate in about 70% of cases.De-escalation of empiric Gram-negative antibiotics is common among hospitalized patients. Antibiotic escalation and other antibiotic changes are much less common. Understanding predictors of escalation and de-escalation can help target stewardship efforts. For instance, stewardship programmes may consider re-examining protocols for combination therapy and empiric antibiotics for urinary tract infections. Combination therapy is more likely to be de-escalated than monotherapy, whereas empiric antibiotics targeting urinary tract infections are more likely to be escalated than antibiotics for other infectious syndromes.dlad054_Supplementary_DataClick here for additional data file.


Additionally, extending fibre measures become advantageous by enhancing the instance’s long-term shrinking performance. Compared to non-fibrous composites, adding more fibre to the composite often strengthens its mechanical properties. The outcome of this review study demonstrates the mechanical features of FRGPC, including density, compressive strength, split tensile strength, and flexural strength, as well as its microstructural properties.Alternative eco-friendly and sustainable construction methods are being developed to address growing infrastructure demands, which is a promising field of study. The development of substitute concrete binders is required to alleviate the environmental consequences of Portland cement. Geopolymers are very promising low-carbon, cement-free composite materials with superior mechanical and serviceability properties, compared to Ordinary Portland Cement (OPC) based construction materials. These quasi-brittle inorganic composites, which employ an “alkali activating solution” as a binder agent and industrial waste with greater alumina and silica content as its base material, can have their ductility enhanced by utilising the proper reinforcing elements, ideally “fibres”. By analysing prior investigations, this paper explains and shows that Fibre Reinforced Geopolymer Concrete (FRGPC) possesses excellent thermal stability, low weight, and decreased shrinking properties. Thus, it is strongly predicted that fibre-reinforced geopolymers will innovate quickly. This research also discusses the history of FRGPC and its fresh and hardened properties. Lightweight Geopolymer Concrete (GPC) absorption of moisture content and thermomechanical properties formed from Fly ash (FA), Sodium Hydroxide (NaOH), and Sodium Silicate (Na In this reaction, water is given, which normally burns through during disintegration and benefits the mixture throughout maintenance. This differs from how water reacts with Portland concrete during the hydration process, during which heat is created and water is absorbed [The aluminosilicate source’s mineralogical makeup, morphology, fineness, and glassy content all impact how reactive they are . To prodmonomers . A studymstances . Tetrahemstances : Si(OH)4absorbed . Metakaoabsorbed . The cheabsorbed .Even though many of the characteristics of geopolymers made from various aluminosilicate sources may seem to be the same, these polymers’ microstructures and material characteristics are very diverse ,45. TheyConcrete that has been reinforced with a fibrous material, or fibre-reinforced concrete (FRC), has higher structural stability. It has uniformly distributed, short discrete fibres that are randomly orientated. Steel, glass, synthetic, and natural fibres are all types of fibres. With variable concretes, fibre materials, geometries, distribution, orientation, and densities, fibre-reinforced concrete takes on distinct characteristics within these various fibres. Shotcrete uses fibre reinforcement the most, but regular concrete can also use it. In order to prevent plastic shrinkage cracking and drying shrinkage cracking, fibres are typically utilised in concrete. They also lessen the permeability of concrete, which lessens water bleeding through it. Greater impact, abrasion, and shatter resistance in concrete are produced by specific types of fibres ,47,48. TThe flexural strength and energy retention of geopolymer concrete have both been improved by the use of fibre in various forms, including steel, glass, hair, and nanoparticles. There are three essential criteria that must be taken into consideration when using fibre as a support in cementitious and geopolymer concretes as follows: (1) material qualities that are equivalent to those of the application; (2) fibre–framework cooperation to transfer stresses; and (3) appropriate perspective proportion to ensure strong post-breaking behaviour. Most importantly, the material’s schematic and mathematical characteristics of fibre are used in cement-containing material’s properties before looking at the concrete activity of fibres and geopolymers. Fibre-reinforced concrete may help in the resisting of more load ,51 and rSteel fibre is frequently utilised in cementitious concrete due to its high mechanical strength, flexibility, and availability. For specific uses, the American Standard’s Testing of Materials A820-16 lists five varieties of fibre i.e., steel, as follows: 1. twisted or smooth cold-drawn wire bits; 2. distorted or smooth sheets cut; 3. softened and separated; 4. factory cut; and 5. changed wire steel fibre. Due to the tiny size of these steel fibres, cement scatters them haphazardly ,57. SteeThe importance of inorganic fibres increases every day. Inorganic, as opposed to polymeric, fibres are made from substances found in, or are easily made from, substances naturally occurring in the earth’s crust. Glass, metals, carbon, asbestos, and ceramics are a few examples of materials that are now used or are being studied as sources of fibre. Asbestos is an example of an inorganic fibre that has been used since ancient times. These fibres are frequently employed in high-heat applications, such as refractories, because of their high melting points. They are composed of alumina and silica mixes. The key difficulties for these fibres include ease, high stiffness, material solidness, and wonderful protecting characteristics. Depending on the pre-existing material, various preparation techniques have been used to create inorganic fibres, including (1) bar drawing, which is used, for instance, in wire-making practices; (2) entry through an opening, which is used, for instance, in the creation of dissolve spun fibre; (3) fume statement, which is used for instance, to fume plate boron on a tungsten centre; and (4) gel formation from a soft arrangement or by the fume fluid strong strategy, for example, the amalgamation .Glass-fibre-reinforced polymer composites have been created using various assembly techniques and are typically used for multiple purposes. At first, the ancient Egyptians made holders out of glass strands that were pulled from glass and heated up. The 1930s saw the invention of glass-fibre-infused processes for high-temperature electrical applications. These days, it is used in electronics, avionics, automobile applications, and other things. Each glass strand has unique qualities and is used in various polymer composite applications. Different glass-fibre-reinforced polymer composite’s mechanical, tribological, thermal, water assimilation, and vibrational characteristics were taken into consideration. Glass is typically created by melting silica, the substance that makes up sand, at extremely high temperatures, adding substances , and then forcing the molten glass through a spinneret. Glass comes in a wide variety of types and is used for a variety of purposes. Energy bills are always higher when the temperature is high. When metal oxides are removed from the ores in which they are contained in the ground, concerns should be raised regarding energy usage, the need for large extraction or refining equipment, and the creation of considerable amounts of pollutants.2O5Si fibres refer to several types of M2O3 fibres that comprise around 45 to 60% Al2O3; the remaining material is silicate. They are often conveyed by the blown or spun cycle of liquid kaolin or related muds or precursors, including aluminium oxide and silicon dioxide [2O3 to SiO2 ratio of these materials greatly influences their mechanical properties. If the alumina % is increased, fibre with 52% Al2O3 content may resist temperatures as high as 1250 °C, whereas a fibre with greater silica content has lower rigidity and a lower flexible modulus [2O3 fibre that includes around 4% SiO2 are lowered from 18% to 0% and 1800 MPa to 500 MPa, respectively, when the crystal is enlarged from half to 100%.Al dioxide . The Al2 modulus . AdditioBasalt fibres are used as a substitute for glass because basalt is a rock created from volcanic lava that has hardened. Previously, they were only utilised as basalt “wool” for thermal insulation. They may be utilised in the temperature range of 200 to 800 °C and are more resistant to strong alkalis but are less resistant to strong acids than glass is ,68. It a4C, BN, zirconia, SiC, and Si3N4. Thought should be given to evaluating these fibres beyond this inquiry’s scope [Numerous inorganic fibres with high mechanical characteristics and warm obstruction were made for specific purposes, including boron, B’s scope ,71.Seeds , bast , straw . “First generation” steel fibres, which were created by shearing thin steel sheets, were ineffective because the matrix did not adhere to them well enough. The most crucial of the bonding methods, mechanical anchoring, was further improved using a variety of fibre shapes. Similar surface modifications have been used on synthetic fibres (mainly polypropylene) to strengthen the connection between the fibres and the matrix . When FRThe bending moment’s tensile stress changes into shear stress at the fibre–matrix interface in a fibre-reinforced composite, which is resisted by adhesion and friction at the surfaces where they make contact. Both at the interfaces of the two components and farther away from the interface, this contact force affects the geopolymer matrix. As a result, the matrix and fibres work in tandem to form an annular zone that encircles the fibres ,76. HoweContrarily, for hydrophobic fibres with minimal roughness, the transfer of stress between the fibre and matrix is reduced, and each operates independently . NumerouAs a fine aggregate, river sand from a nearby source is employed in many studies. As partial substitutes for fine aggregates, a variety of industrial waste products , includiIn stone quarries, coarse aggregates are often produced by blasting, breaking by hand, or using crushers. Stones that have been crushed by a machine come in several sizes, but aggregates that have been broken by hand only come in one size. To make graded aggregates for premium concrete, they are mixed once more in prescribed ratios. In order to utilise them in concrete, they must be well cleaned. Locally available coarse aggregates are used in many studies. Actual aggregate qualities were examined by method 49, supported by BIS 2386-1963. The findings should satisfy that the characteristics of totals meet the specifications recommended by BIS 383-1970. In structural concrete, coarse aggregates are employed as broken pieces of hard rock, such as granite and limestone (angular aggregates) or river gravels (rounded aggregates). For non-structural mass concrete of low strength, coarse particles such as cracked bricks, foamed slag, clinker, etc., may also be used. Coarse aggregates, including coal, lignite, soft bits, and clay lumps, should not include more than 5% foreign materials by weight. Aggregate size restrictions for different types of non-reinforced construction should range from 40 to 75 mm (1.5 to 3 inches).According to , when coClay kaolin is used to make metakaolin, which is then lit under carefully controlled circumstances to produce an aluminosilicate with no shape. The cleaned kaolin is placed in a revolving oven, compressed into a fine powder, and then stored to create metakaolin. When kaolinitic clay is calcined at a temperature ranging from 600 to 700 degrees Celsius, metakaolin is produced. Metakaolin is a very reactive and delicate substance. Thus, it provides a rich, non-tacky surface to make the delivery of final concrete easier. It may be used as a solid admixture and is cured similarly to regular concrete. You may use metakaolin as a partial or complete additional cementitious ingredient.2SiO3 solutions both are components of an alkaline liquid. Sodium silicate available in liquid form. NaOH is 97–98% pure and comes in flakes or pellets. These flakes or pellets might be dissolved in water to create a NaOH solution. The mass of NaOH solids in a solution is impacted by its molar or M concentration. The molecular weight of NaOH is 40. The solution prepared using flask with a capacity of 1 L, and a 1 L solution is made by gently adding NaOH flakes to distilled water. For instance, 320 g of NaOH flakes are weighed and may be dissolved in 1 L of distilled water to create an 8 M NaOH solution. To make fresh concrete more workable, a high-range, water-reducing, naphthalene-based super plasticiser can be used. More water and roughly 15% of the binder are added to make the concrete more workable.2SiO3 arrangement, NaoH arrangement, and fibre arrangement were used to lay out test instances. All of the sums were set up in a dry, surface-soaked condition. Before being added to the dry components, sodium hydroxide and sodium silicate arrangements were mixed over the course of one day. Dry materials were first blended in a blender of the drum type with a 1.5 concrete-filled tube (cft) (0.062 m3) limit. After being mixed with the soluble arrangement, the super plasticiser was applied to the dry materials. Steel fibres were introduced in the appropriate quantities throughout the mixing process. Freshly blended fibre-reinforced geopolymer concrete (FRGPC) was poured layer-by-layer into standard 3D shapes with dimensions of 150 × 150 × 150 mm to test concrete’s compressive strength; 150 mm and 300 mm cylinders for parting tensile testing and Poisson’s proportion; and into crystals with dimensions of 100 × 100 × 500 mm to find the modulus of rupture [Fly ash, FA, CA, Na rupture . There w rupture . In partIn any event, uniform fibre dispersion requires a request for fibre consolidation during mixing. Before exposing them to a salt activator, progressively mixing the dry precursors with monofibres (such as steel and carbon fibre) has often been suggested ,101,102.Specimens with nanosilica (NS) have lower compressive strength than those without NS, which is relevant . This ouGGBFS/CFR-M25 mortar mix has not achieved desired strength at the age of 28 days. Compressive strength improves initially before decreasing as NaOH concentration increases from 5% to 20%; the turning point was discovered at 10% . Higher Comparing the F3-AR80V0.75 concrete specimen to the GC specimen, the compressive strength improves by 33%. It should be mentioned, according to , that adSplitting tensile strengths for PC concrete were reduced by 26.4% and 12% with the inclusion of 1.0% basalt fibres. Compared to PSS concrete without fibres, all PSS concretes with fibres showed increases in splitting tensile strength. Even for modest fibre volume contents, the composite peak stress levels may be 25–30% greater than matrix tensile strengths . A brittAfter reaching its maximum strength, gradual strain softening takes place, with the softening stage governed by the presence of fibres, much like its tensile behaviour . Figure 3 fly ash had splitting tensile strengths similar to that of PC concrete. The optimal fibre content for all concrete is 0.45 kg/m3, according to the splitting tensile strengths of the concrete mixture. According to [Comparing ultra-high-performance fibre-reinforced concrete (UHPFRC) to UHPC, steel fibre content significantly improved tensile strength. It can be demonstrated that when compressive strength rises, splitting tensile strength climbs . The A1 rding to , strengtrding to . Hardenerding to ,44,56,95rding to ,89,115.According to , composiAccording to , SFRGPC’According to the analysis presented in  of the rSilica fume affects the flow characteristics of FA and slag-based geopolymer mortar in a number of different ways . Silica Numerous studies have demonstrated that the crucial value often declines as the fibre and filler content aspect ratio increases ,129,130.Furthermore, polypropylene and polyvinyl alcohol fibres significantly reduce drying shrinkage due to the same fibre type’s reducing shrinking scale and rising fibre dose. The shrinkage values for steel-reinforced composites fell from three 35 to two 81 micro strain on the 84th day of drying. According to , these cThe fact that geopolymer composites do not compress well when there are a lot of fibres present may help to explain this. The lower performance of PP fibres compared to steel fibre is also due to their decreased stiffness and weaker fibre–binder interaction. Because of PVA fibre’s hydrophilic qualities and higher stiffness, they exhibit comparable shrinkage performance to geopolymers reinforced with PP fibres. Shrinkage of geopolymer composites has also been observed to be (1) reduced , (2) inc3. The results shows poor binding results in reduced compressive strength and density of 1.60 and 1.62 g/cm3 respectively without reinforcement after twenty-eight days [3, and after 28 days, it decreased to 1.58 g/cm3. For various kinds of composition, density differences were not noteworthy. For this collection of samples, there is no evident link between density and mechanical properties. Density is measured under tension and compared to the yield strength of geopolymer composites and various fibres. Nearly all carbon and polymeric-based fibres are less dense than geopolymer composites, but steel and inorganic fibres have more densities. Where the composite’s lightness is a key characteristic, density variation should be considered. Regarding composite densities, the amount and specific gravity of fibres have a direct impact. When the geopolymer matrix is higher and the fibre-specific gravity is lower, the bulk density of associated geopolymer composites decreases [According to , the ligght days . There wecreases . Howeverecreases . As a reecreases .According to , better Consequently, surface waterproofing may reduce the thermal insulating capability of a material with considerable water absorption capabilities. The amount of polypropylene fibre present, which also has a negligible effect on the sample’s water absorption, directly proportionally affects how much water is absorbed by geopolymer concrete. However, a sample with a 2.5 monomer % and an increase in fibre from a little increase in the amount of water absorption is seen between 0.3 and 0.5, which may be the result of improper blending of the sample. As much as seventeen, thirteen, and fifteen vol less water is absorbed when an increase from 2 to 2.5 occurs in the sodium hydroxide to sodium silicate ratio. When more monomers were present, the amount of water absorbed was not altered considerably. Fresh concrete properties are described in Sodium, alumina, and silica make up the majority of the geopolymer. The geopolymer contains sodium alumina silicate as an extra product, according to SEM and EDAX analyses. On the 28th day, the geopolymer was devoid of microcracks . AccordiOn the other hand, samples with a high slag % (40%) revealed a geopolymer matrix covering the steel fibre surface. Furthermore, the observation that USF geopolymer blends result in higher degrees of hydration on the steel surface raises the possibility that the kind of SF included in the composite affects how well the fibre, i.e., steel, interacts with the matrix. In the case of the 10S mix, a large number of FA particles that were still present but only partially reacted, as well as clumped slag particles, were found. This is explained by FA’s low pozzalonic reactivity and low slag concentration when it is cured at room temperature. Higher magnification reveals distinct microstructures in the 40S combination geopolymer sample that produce a denser matrix than the 10S mixture. As a result of reactions on the surface of the particles, glassy crusts can be seen covering FA particles. A calcium alumino silicate hydrate (C-A-S-H) gel is produced as the percentage of GGBS is raised due to the mix’s higher calcium content. About 10% of the geopolymer mortar’s slag replacement is replaced in the SEM pictures shown in SEM micrographs of the basalt FRGP microstructure are shown in The performance of polypropylene fibre micrographs was inferior to that of the fibres above. The uniformity of cotton fibre dispersion in the matrix is a critical aspect in deciding how the properties of the composite behave, even though there is only a low 0.5 % cotton fibre present in the matrix. Hollow cellulose, cellulose, and hemicellulose make up around 82% of the total chemical components in lightweight concrete filler (LCF). Lignin, a chemical component also present in LCF, is thought to serve as a cellulose fibre binder and energy storage. SEM analysis indicates that more geopolymer gel is produced by the LF geopolymer composite. Coarser geopolymer gel particles and a denser microstructure are made possible by including the LF composite.According to , the amoBased on the discussions of various studies, geopolymer concrete has been identified as a good alternative to making sustainable concrete from industrial by-products. The main drawback of geopolymer concrete is the curing method, which requires heat curing or steam curing; however, in practice, for massive construction, it is quite difficult to adopt such curing and preparation of activator solution. Compared to non-fibrous composites, adding fibres to the composite often strengthens its mechanical properties. Various fibres, such as steel fibres, glass fibres, cotton fibres, polypropylene fibres, and flax fibres, can be added to geopolymer concrete to attain some desirable strength and durability properties. The density of geopolymer concrete can be achieved by adding flax fibres to it. Fibres also enhance the modulus of elasticity and impact strength to some extent. On the other hand, adding fibres to concrete resulted in reduced workability properties due to uneven dispersion of fibres. To some extent, polypropylene fibre added to geopolymer concrete resulted in reduced water absorption and moisture content. It has been noticed that there are no specified guidelines or standards available for the mix design of geopolymer concrete, such as the mix design procedure for OPC concrete. The industry has not completely accepted geopolymer concrete yet. This is mostly due to the inability to assess information at this time on the lifespan and endurance of geopolymer concrete applications or structures. Another issue is the significant degree of instability of geopolymer concrete’s financial and environmental costs. The price of geopolymer concrete is influenced by the location of the material supply, the source of the fuel, and the modes of transportation. Depending on these three factors, geopolymer cement may cost much more than OPC concrete. According to research data, researchers can focus on the following areas in the future: the development of geopolymer concrete through room temperature curing and a simplification of the preparation of activator solution for desired molarity; the formulation of specific guidelines for mix design of geopolymer concrete made by different industrial by-products; and the influence of fibres, which can be studied by blending different types and aspect ratios in geopolymer concrete.


We evaluated antibiotic use in a private health insurance network in Bolivia with two different healthcare plans. The Health Maintenance Organization plan had 29% lower antibiotic consumption and fewer broad-spectrum antibiotics prescribed than the Preferred Provider Organization. Furthermore, we identified potential targets for future antibiotic stewardship efforts. In the United States, approximately 50% of ambulatory prescriptions are inappropriate. Similar findings were observed in resource-limited settings, where >50% of antibiotic prescriptions in primary care were inappropriate, mostly due to treatment of viral illnesses. Understanding patterns and drivers of antibiotic use is important to inform effective antibiotic stewardship (AS) interventions. In high-income countries, several factors have been associated with higher antibiotic use including geographic region, provider specialty, health plan, and patient income. These data are lacking for Latin America, where most studies have focused on inpatient antibiotic use.It is estimated that 60%–90% of human antibiotic use occurs in the outpatient setting.We sought to investigate and describe ambulatory antibiotic use in a private health network in Bolivia with two different health plans, a Health Maintenance Organization (HMO) and a Preferred Provider Organization (PPO) plans.We conducted a retrospective observational study of ambulatory antibiotic use among all patients of a private healthcare insurance network in Santa Cruz de la Sierra, Bolivia (the country’s most populous city) between January 2017 and December 2018. The network includes two business plans, an HMO plan where care is coordinated by a general practitioner (GP) and a PPO plan in which patients can access specialists directly without a referral from a GP. While the PPO plan was slightly more expensive than the HMO plan; antibiotic co-pays were similar for both plans . Patients without a prescription are responsible for 100% of the medication cost. There were no incentives for physicians in either business plan to promote less or more antibiotic prescriptions during the study period.During the 24-month study period, there were 8,405 patients in the network, including 2,419 patients in the HMO plan and 5,986 patients in the PPO plan. were included in the study. Antibiotics were further grouped using WHO’s AWaRe  antibiotic classification.Access includes antibiotics such as amoxicillin, amoxicillin-clavulanic acid, first-generation cephalosporins, doxycycline, and trimethoprim-sulfamethoxazole. Watch antibiotics includes macrolides, second-, third-, and fourth-generation cephalosporins, fluoroquinolones, and aminoglycosides. We used descriptive statistics and the Byar test with 95% confidence intervals (CIs) for differences in DDD between different age, plan, and gender groups. A 2-sided P value < .05 was considered statistically significant for all tests. Statistical analysis was performed using Openepi.Data were extracted from pharmacy records (dispensed antibiotics), and antibiotic use was calculated as daily defined doses (DDD) per 1,000 patient-days. Antibiotics from the J01 group from the Anatomical Therapeutic Chemical (ATC)-World Health Organization (WHO) classification system which includes antibacterials used systemically The study was deemed exempt by the local Institutional Review Board.P < .01). Females represented 56.1%  and 52.9%  of HMO and PPO patients, respectively (P = .01). Thirty-six percent  and 33.6%  of HMO and PPO patients, respectively, were children (P = .08).The mean age of HMO and PPO patients was 23.8±standard deviation (SD) 15.5 and 26.3 ± SD 16.9, respectively (P < .001), for both female  and male patients , and for pediatric patients , Figure Antibiotic consumption was higher in the PPO plan compared to the HMO plan  compared to the HMO plan , Table Watch antibiotics in children versus adults , which was mostly driven by macrolides. GPs prescribed 27% of HMO and 7% of PPO antibiotics. Pulmonary, gastrointestinal, and ears/nose/throat physicians prescribed 3%, 5%, and 13% of PPO vs 0%, 2%, and 7% of HMO antibiotics.The two most prescribed antibiotics for both plans were macrolides and amoxicillin-clavulanic acid. Overall, 55% of antibiotics were in the  We speculate having care coordinated by a GP in the HMO plan may contribute to lower antibiotic use by HMO plan patients as GPs are more likely to provide longitudinal care increasing the chances of making more appropriate antibiotic decisions than specialists who are more likely to have occasional interactions with patients. While treatment guidelines which include recommendations for outpatients with common infectious syndromes were available to all physicians within the network, it remains unclear if lack of adherence was a major driver of the differences observed between the two plans. Female patients are more likely to receive antibiotics in their lifetime than male patients; however, sex alone would not explain antibiotic consumption differences as antibiotic consumption was also higher among PPO male patients.Evaluation of antibiotic use within a private healthcare network in Bolivia revealed disparities between health plans, with higher antibiotic consumption and more broad-spectrum antibiotic use in the PPO plan compared to a GP-coordinated HMO plan. Similar findings were reported in a study of antibiotic use in that included 360 health plans in the United States where HMO plans had lower prescription rates of antibiotics for acute bronchitis in adults, and more appropriate antibiotic use in children presenting with upper respiratory tract infections compared to PPO plans.AWaRe classification of antibiotics based on their impact on AMR as an AS tool. While all antibiotics increase the risk of colonization or infection with multidrug-resistant bacteria, patients exposed to Watch antibiotics have a higher risk of acquiring MDR bacteria than those exposed to Access antibiotics. WHO recommends Access antibiotics to represent at least 60% of all prescriptions at the country level. Bolivia has adopted the AWaRe classification in their essential national medication list and prohibits medication sales without a prescription; however, a national AMR action plan has not yet been implemented, and education campaigns about the risks of inappropriate antimicrobial use have been limited, according to recent WHO Tripartite AMR Country Self-Assessment Survey results. In our cohort, Access antibiotics did not reach the minimum target, with a larger gap for the PPO plan. We observed a higher proportion of Watch antibiotics among children compared to adults. This is in agreement with previous studies in resource-limited settings where increased use of Watch antibiotics was associated with patient characteristics  and non-patient factors such as pharmacy-drug availability. The later probably did not play a major role in our cohort since our patients would have had similar pharmacy access; however, patient demands for antibiotics could have differed between plan patients.WHO established the Limitations to this study include the lack of patient- and visit-level data including patient comorbidities and visit diagnoses which are not electronically available. Although our study did not explore a comprehensive list of drives of antibiotic prescribing, it highlights the need to strengthen AS efforts in ambulatory care, especially in the pediatric population, and to improve engagement of specialists in AS. Additional studies to better understand “antibiotic behavior” by physicians and patients in the different plans would be beneficial to refine AS initiatives at improving antibiotic use in the region.


Gram-negative bacterial bloodstream infections (GNB-BSI) are common and frequently lethal. Many patients experience recurrent GNB-BSI for unclear reasons. This study explores how antibiotic tolerance may lead to infection relapse.Approximately 63% of recurrent GNB-BSI are due to relapse  and 37% due to reinfection .BALB/c mice infected with paired initial or relapsed GNB-BSI isolate. 50 mg/kg ertapenem added at 3 hours post infection (hpi). Graph shows recovery of viable bacteria from liver tissue.Escherichia coli isolates. The biological relevance of antibiotic tolerance was tested using a murine bacteremia model.We used a prospective cohort of patients with GNB-BSI at Duke Hospital to identify patients with >1 episode of GNB-BSI due to the same bacterial species. We used whole genome sequencing (WGS) to distinguish reinfection (recurrent infection with different isolate) from relapse . Time-kill curves with meropenem were used to determine the development of antibiotic tolerance between the initial and relapsed E. coli pairs  using meropenem to identify increases in antibiotic tolerance. One isolate pair showed a 100-fold increase in multidrug antibiotic tolerance. We determined the decreased antibiotic killing was due to a loss-of-function mutation in the ptsI gene encoding Enzyme I of the phosphoenolpyruvate phosphotransferase system. To test if the in-vitro tolerance phenotype translated to decreased antibiotic efficacy in-vivo, we developed a murine model of E. coli bacteremia. In our murine bacteremia model, the ptsI mutant was equally virulent as the wild-type, but exhibited 10-fold less killing during antibiotic treatment.We determined that 63% (30/48) of recurrent GNB-BSI episodes were due to relapse and 37% (18/48) were due to reinfection. We screened 10 relapsed in-vivo by providing compelling data that not only do these mutations arise during bloodstream infection in humans, but the presence of antibiotic tolerance in-vitro likely leads to decreased antibiotic efficacy in-vivo. Further work is required to determine if early detection of antibiotic tolerance could lead to alterations in medical management and ultimately improve patient outcomes.Our work provides a unique insight into the molecular changes occurring during GNB-BSI and how the pathogen adapts to the host through acquisition of antibiotic tolerance. We address the controversy regarding the clinical relevance of antibiotic tolerance Vance G. Fowler, MD, MHS, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, Astra Zeneca: Advisor/Consultant|Genentech, Regeneron, Deep Blue, Basilea, Janssen;: Grant/Research Support|Infectious Diseases Society of America: Honoraria|MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius;: Grant/Research Support|Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny,: Advisor/Consultant|Sepsis diagnostic: Patent pending|UpToDate: Royalties|Valanbio and ArcBio: Stock Options Joshua T. Thaden, MD, PhD, Resonantia Diagnostics, Inc: Advisor/Consultant


The most valuable components of coal fly ash are cenospheres. Cenospheres are hollow spherical particles produced during the coal-burning processes. As a result of their excellent characteristics, such as high workability, high heat resistance, low bulk density, and high strength, cenospheres can be used in the manufacturing of lightweight cement concrete. The research efforts and outcomes are to produce long-lasting cement-based lightweight concrete (LWC) composites with good mechanical properties. The novelty of this investigation is to determine the cement concrete strength when silica fume (SF) and cenospheres (CS) were used as a replacement for cement. Throughout the experiments, a consistent substitution of 12% silica fume was incorporated into cement mass. Silica is used as a micro filler and pozzolanic reactant to strengthen concrete. The concrete mixtures were tested to ensure they met the requirements of the lightweight concrete in terms of their mechanical, physical, and durability qualities. According to the findings, lightweight concrete standards were met, and environmental sustainability was improved with the use of these mix proportions. Concrete specimen’s self-weight decreases by 35% with 30% cenosphere as a replacement. The micrograph shows the lack of portlandite is filled by mullite and other alumino silicates from the cenosphere. In order to achieve sustainability in concrete manufacturing, these mixtures can be suggested for the making of structural LWC that makes use of a large volume of industrial waste while conserving cement and natural resources. The usage of lightweight concrete (LWC) in structural applications has been around for a long time. In the past twenty years, there has been a significant amount of development in the field of lightweight concrete. Cenospheres, also known as CSs, are often produced as a byproduct of the burning of coal in thermal power plants. These cenospheres are hollow, lightweight spheres that are composed largely of silica and alumina and are filled with air or an inert gas. CS can be used as structural lightweight filler. CSs vary in appearance from grey to practically white, and their density is between 0.4 and 0.8 g per cubic centimeter. CS is a non-toxic, non-flammable, non-abrasive, light, waterproof, and insulating material, and so they can be used in a many applications and can be used as fillers ,3,4,5,6.The CS is used often in LWC intially, and it is later used in ultra-lightweight cement (ULWC), which is a type of innovative cementitious material that is now being researched. CS is a cementitious material, and concrete incorporated with CS has higher mechanical strength of at least 60 MPa and a low density of at least 1450 kg/m ,8,9. TheExperiments that were carried out on either LWC or ULWC employ other forms of lightweight aggregate (LWA), such as expanded polystyrene, thermal ash aggregate, leca, expanded glass aggregates, and natural fibers, which have been reported previously ,15,16,17Researchers have investigated CS mechanical qualities in concrete and in other materials. Little research has been conducted on adding CS to cement, so there is a need to study its high-performance effects by adding admixtures such as silica fume. The novelty of using cenospheres (CS) in concrete is that it provides a sustainable solution to the waste generated during the coal-burning process while also improving the mechanical and physical properties of the resulting lightweight concrete (LWC). This study also highlights the potential of combining CS with silica fume (SF) as a partial substitute for cement, which further enhances the strength and durability of the concrete. The micrograph analysis shows that the CS filling the lack of portlandite results in the formation of mullite and other alumino silicates, indicating that the CS can also contribute to the pozzolanic reaction and increase the cement hydration. Overall, this research offers a promising approach to producing high-quality LWC that meets the lightweight concrete standards, reduces the self-weight of the concrete, and promotes environmental sustainability by utilizing industrial waste materials.The key findings of the study were that the replacement of cement with CS in LWC reduced the self-weight of the specimens by up to 40%, and the lowest water absorption was observed in LWC with 30% CS replacement. However, the compressive and splitting tensile strength decreased with increasing percentages of CS replacement beyond 30%. Additionally, the flexural strength of LWC with 15% CS replacement was found to be good, but it decreased with higher percentages of CS replacement due to the formation of internal voids and capillary channels in LWC. The study also revealed that the microstructure of LWC with CS and SF as partial cement replacements was dense, and the bonding between the materials was maintained. Moreover, the addition of CS to LWC led to the formation of mullite and other alumino silicate substances that compensated for the voids formed by the absence of portlandite. However, the microstructure of LWC with 30% CS replacement was found to be fully degraded, with visible cracks. Overall, the study contributes to advancing the field of cenosphere concrete by providing insights into the use of CS as a partial cement replacement in LWC, the impact of varying percentages of CS on the properties of LWC, and the microstructural changes that occur with CS and SF as partial cement replacements. The findings of this study can aid in the development of more sustainable and lightweight concrete mixes for construction applications.Cenospheres are a crucial component in the development of high-strength concrete, and their effectiveness depends largely on their chemical and phase composition, as well as their physical characteristics, such as particle size and shell thickness. For applications that require maximum strength, particle thickness becomes particularly important, as particles with thicker shells provide greater strength compared with those with thinner shells ,38.Cenospheres derive their characteristic chemical makeup from the coal with which they are burned, as well as the coal itself ,41,42,43The cement used in this study was Type III  as stated in BS EN 197-1  Figure . StandarChemical composition of silica fume is shown in CS were obtained from Astra Chemicals, Chennai, India. Regarding particle size, CS grade 300 has the largest particles at 300 um . The cheCrushed stone sand was utilized in this investigation in accordance with BS EN 12,620  standard3) silica fume as a partial substitute for cement as a constant replacement in all specimens [The concrete cubes were made using a cement: coarse aggregate:fine aggregate ratio of 1:1:2 and a water/binder ratio of 0.45; the concretes were made using concrete mixing machines with this proportion. The CS was utilized to replace cement 30% by weight, and the replacement details are shown in pecimens . ASTM 30pecimens  was follpecimens , the speThe slump values of concrete mixes were prepared and tested. The results showed that when the percentage replacement of CS with continual replacement of silica fume increased, the workability was reduced. The value ranged from 100 mm to 65 mm, ensuring medium workability throughout all mix proportions. All of the mix proportions demonstrated true slump behavior. Slump values for CS5, CS10, CS15, CS20, CS25, and CS30 were 10 percent, 20 percent, 30 percent, and 35 percent lower, respectively. The lowest slump value in CS30 specimens was 65 mm, while the highest slump value in CS5 and control specimens was 100 mm. It was discovered that when the CS increased, the workability decreased. The capacity to carry weight is determined by compressive strength, which is an essential feature of CBM. The compression testing equipment was used to investigate the behavior of cement concrete substituted with SF and CS when subjected to compressive pressure. ASTM C109/C109M-20a  was usedThe method of evaluating the tensile strength of concrete specimens that split across the vertical cross-sectional area is known as splitting tensile strength. The effect of variable CS substitution as a cement replacement material and constant silica fume on splitting tensile strength was examined. The results revealed that, like compressive strength, the average splitting tensile strength of silica fume and CS admixed concrete specimens diminished. All CS specimens’ splitting tensile strength declined with age. The splitting tensile strength achieved on concrete cylinders after 7 days, 14 days, and 28 days was experimentally examined for three specimens at each age, and the average findings were taken. Findings are presented in The capacity of cementitious composites to withstand bending stresses is known as flexural strength. This test also determines the strength of the binding between the concrete elements. This test was carried out in compliance with ASTM C348-20  requiremWater absorption greatly influences the cementitious composite’s durability, and so water absorption is a crucial feature that needs to be assessed for composites based on cement, especially those that are immersed in water. The ASTM C1403-15  requiremThe specimens were also put through an acid impact test to see how resistant they were to sulfuric acid. Owing to the unavailability of an applicable standard from either the ASTM or the BS, this experiment was conducted using a mix of several standards, such as ASTM C1012 and C563-07 ,61, and Scanning electron microscopy and XRD patterns were also used to examine the specimens. A SEM study was performed at an analytical focus of 5000×, with a high resolution of 3.5 nm and an energy of 20 keV. For this study, specimens of 10 mm cubes were trimmed by a saw cutter on the 28th day. The XRD analysis was performed using a Bruker AXS with Cu K-beta radiation and two scans with a scale factor of 0.02 and analysis time of 10.00 Deg/minute. After 28 days of water curing, samples were taken from the cubes and ground on ball mills which need to pass through a filter of size 90 μ. The micrograph of the CS0 specimen in 2 did not grow along with the level of silica fume suggested that silica fume was largely engaged in the hydration process, which resulted in a substantial consumption of silica fume. XRD graph also revealed the presence of traces of ettrignite, aluminosilicate, mullite, portlandite, quartz, calcite, and Jaffeite. As observed in the micrograph, both the silica fume and the CS were successfully dispersed throughout the structure, and the bonding was not broken. A micrograph of the CS25 specimen can be appreciated in The research on the properties of concrete based on cenosphere and silica fume has important practical implications for the construction industry. The results could aid in the development of sustainable building materials that possess superior mechanical properties and reduced environmental impact. Cenosphere inclusion in lightweight concrete has generated significant interest due to its low density and high thermal conductivity. Integrating cenospheres in concrete can result in lighter structures, improved insulation, and increased durability. The resulting lightweight and strong structural elements could significantly lower the cost and environmental impact of construction projects. Ongoing studies on cenosphere concrete aim to enhance its mechanical properties, thermal conductivity, and durability to enable its practical implementation in various applications, such as building construction, transportation, and infrastructure. Consequently, this research carries significant implications for sustainable development and the construction industry. By replacing cement with industrial waste materials, such as cenospheres and silica fume, the demand for traditional raw materials could be reduced, resulting in lower production costs and a decreased carbon footprint. Moreover, the lightweight nature of cenosphere concrete can facilitate easier transportation and construction, lowering the weight of concrete structures. This study’s outcomes will help create high-performance structures with good strength and durability for concrete.The impact of using constant silica fume and varying CS as a partial replacement for cement in light weight concrete was investigated. The study found that up to 30% replacement of CS could be used in LWC without compromising the strength, but beyond this point, the strength decreased due to increased voids and capillary channels. Water absorption was reduced in all specimens, with the lowest value recorded in 30% CS replacement due to the denser structure of silica fume and admixed LWC from the CS. Further research could investigate ways to mitigate this decrease in strength and improve the durability of CS in hostile environments.The results of this study provide valuable insights into the use of industrial waste materials, such as CS and silica fume, as partial replacements for cement in lightweight concrete. These findings can be applied to the development of more sustainable building materials that offer superior mechanical properties and lower environmental impact.The replacement of cement with cenospheres and constant replacement of silica fume in lightweight concrete significantly reduces the self-weight of concrete without compromising its overall strength. The addition of up to 30% cenosphere reduces the compressive and splitting tensile strength of the concrete, but the strength remains within acceptable limits for the design mix. However, excessive replacement of cement with cenosphere (30%) results in a fully degraded microstructure with visible cracks. The use of cenosphere and silica fume as partial replacements for cement in lightweight concrete can have practical applications in the construction industry, particularly for structures where weight reduction is a critical factor.The results of this study also demonstrate the potential for using industrial waste materials, such as cenosphere and silica fume, to develop high-performance structures that offer good strength and durability to concrete. The use of these materials can reduce the demand for traditional raw materials, leading to lower production costs and reduced carbon footprint. The lightweight nature of cenosphere concrete can also lead to a reduction in the weight of concrete structures, resulting in easier transportation and reduced construction costs.In this study on lightweight concrete (LWC) using constant silica fume (SF) and changing cenosphere (CS) for partial cement replacement, there are limitations and potential improvements through future investigations. One limitation is the lack of certain investigations, such as the long-term durability, resistance to environmental factors (freeze–thaw cycles) and chemical exposure of cenosphere concrete. Additionally, exploring the potential use of CS in combination with other lightweight aggregates, such as expanded polystyrene or perlite, could further enhance the properties of LWC. Finally, assessing the environmental impact of using CS as a replacement material, including its carbon footprint and potential for recycling, would be valuable for future research.