Steel–concrete continuous composite beams are widely used in buildings and bridges and have many economic benefits. Slip has always existed in composite beams and will reduce the stiffness of composite beams. The effect of creep under a long-term load will also be harmful. Many scholars ignore the combined effects of slip and creep. In order to more accurately study the mechanical properties of steel–concrete continuous composite beams under long-term loads, this paper will consider the combined actions of slip and creep. By combining the elastic theory and the age-adjusted effective modulus method, the differential equation of the composite beam is derived via the energy variational method. The analytical solutions of axial force, deflection and slip under a uniform load are obtained by substituting the relevant boundary conditions. The creep equation is used to simulate the behavior of concrete with time in ANSYS. The analytical solution is verified by establishing a finite element model of continuous composite beams considering slip and creep. The results suggest the following: the analytical solution is consistent with the finite element simulation results, which verifies the correctness of the analytical solution. Considering the slip and creep effects will increase the deflection of the composite beam and the bending moment of the steel beam, reduce the bending moment of the concrete slab and have a significant impact on the structural performance of the continuous composite beam. The research results considering the coupling effect of slip and creep on continuous composite beams can provide a theoretical basis for related problems. The steel–concrete composite structure can not only give full play to the performances of the materials themselves  but also to the overall superiority of the materials after combination , so it is widely used in the construction industry and in bridge engineering ,2. In stMost of the studies on slip and creep effects were carried out in simply supported composite beams, and there are few studies on continuous composite beams. Dezi et al. proposed a viscoelastic analysis method and a parametric analysis of continuous composite beams with flexible shear connectors, considering the effects of creep in composite beams ,8. UsingBan et al. studied the time-dependent behaviors of simply supported composite beams with blind plate bolts under sustained loads. The results showed that the use of blind plate bolts in composite beams is beneficial to the time-dependent response . Nguyen Slip and creep have been considered in most composite beam research, but their combined effects can lead to inaccurate solutions under long-term loading. Compared with simply supported composite beams, the analytical problem of a continuous composite beam under the combined actions of slip and creep is difficult to solve. At present, there is no analytical solution in the literature for the internal force and deformation of a continuous composite beams under the coupling effect of slip and creep. This analytical solution is obtained in this paper. In order to accurately and conveniently calculate the coupling effect of slip and creep on steel–concrete continuous composite beams, this paper studies the mechanical properties of continuous composite beams under long-term uniform loads and establishes a governing differential equation for an axial force function for continuous composite beams via the energy variational principle. By introducing the relevant boundary conditions, the analytical solutions for the axial force, deflection and slip of a continuous composite beam under a uniform load are solved. Finally, the correctness and applicability of the obtained formulae are verified via ANSYS examples. At the same time, the effects of three kinds of shear stiffness on the slip and deflection of continuous composite beams are calculated. It is hoped that this research can provide a theoretical basis for the practical engineering calculation of continuous composite beams under the influence of a long-term load.In this section, based on the elastic theory and the age-adjusted effective modulus method, the basic assumptions of continuous composite beams are established, and the related theories of the slip and creep of continuous composite beams are described. Using the energy variational principle, the strain energy equation of the composite beam considering the effects of slip and creep is established, and the control differential equation and boundary conditions are obtained via the variational method and the partial integral method.Without considering the influence of transverse shear deformation in the composite beam, the curvatures of the steel beam and the concrete flange plate are completely consistent, and the vertical lifting phenomenon at the interface of the steel–concrete composite beam is ignored.The cross-sections of the concrete slab and the steel beam meet the plane section assumption, respectively, and the stud connector conforms to the elastic sandwich setting.The stress–strain relationship between the steel beam and the concrete is linear throughout the stressing phase, and the concrete is not cracked or spalled.The shear connectors are evenly distributed along the length direction of the composite beam, and the shear force of each shear connector is linearly related to the slip.In the coupled analysis of the slip and creep effects of continuous steel–concrete composite beams, the calculation is based on the following basic assumptions ,24:WithoV are the axial force, bending moment and shear force of the composite beam; The section and element force diagram of the composite beam is shown in From the diagram of the forces on the unit and the equilibrium relationship, it is known that:From the bending moment equilibrium condition, In Equation (2), The shear connector of the composite beam is similar to the assumption that the spring conforms to the elastic interlayer. The displacement diagram of the interlayer slip is shown in ectively .According to the relationship between the axial strain and the displacement of the composite beam, On the basis of considering the influence of the interface slip of the composite beam, the age-adjusted effective modulus method (AEMM) is used to consider the creep effect of the composite beam concrete. This method uses the integral mean value theorem to transform the integral equation into an algebraic equation. At the same time, the influence of the aging properties of the concrete is considered, which simplifies the calculation and meets the needs of calculation accuracy. It is suitable for finite element analysis. The algebraic constitutive relation is ,27:(6)εct; Through the effective modulus of age adjustment, considering the influence of the aging coefficient on the creep coefficient, we can rewrite Equation (6) as:The range of the aging coefficient H. Torst  recommenH. Torst  combinedH. Torst  considerThe standard loading age of concrete is 7~14 days, and most concrete creep is completed within 1~2 years. The creep coefficient curves of concrete are different under different initial loading times. When the loading time of concrete is the same, the earlier the initial loading age, the greater the creep coefficient of the concrete will be . The calAccording to the principle of minimum potential energy, the composite beam maintains an equilibrium state when subjected to external forces. Therefore, this paper will establish the strain energy equations of the flange and steel beam of the steel–concrete composite beam.The strain energy of the concrete slab:The strain energy of steel beam:The elastic interlayer slip’s strain energy:The external load potential energy:K is the single shear connector connection stiffness and e is the shear connector spacing.The total potential energy of the combined beam is According to the principle of minimum potential energy, the first-order variation of the total potential energy is divided into zero, that is, The governing differential equations and boundary conditions can be obtained by Equation (15):According to the internal force balance relationship of the composite beam, In Equation (18), According to the relationship between the bending moment and curvature:Substituting Equation (19) into Equation (18), we can obtain:Simplifying Equation (20) by After simplifying the first derivative of Equation (16), we obtain:After substituting Equation (20) into Equation (22) and calculating the first derivative, we obtain:Substituting the first term of Equation (16) into Equation (23), the slip differential equation is obtained:Simplifying Equation (20) by In the case of determining the structural form and load, arrange the integral using the boundary conditions and axial force control differential equations to obtain the expression of the deflection function:In this section, according to the differential equations of the axial force, slip and deflection solved above, an analytical calculation of continuous composite beams under the combined actions of slip and creep is carried out. By substituting different boundary conditions, the analytical solution for a continuous composite beam under a uniform load is obtained.A two-span continuous beam subjected to uniform load q is selected as the research object, as shown in The bending moment function of the continuous composite beam is shown in Equation (27):The bending moment function (27) of the composite beam is substituted into the differential Equation (21) of the axial force function. Then, with the boundary conditions The first derivative of the bending moment function (27) of the composite beam is substituted into the differential equation of the slip function (21). Then, through the boundary conditions According to the deflection function expression in Equation (32), the bending moment function in Equation (33) under the uniform load of the composite beam and the analytical solution of the axial force, shown in Equations (28) and (29), are introduced, and then through the boundary conditions There are two creep analysis methods in ANSYS: explicit and implicit time integration methods. At the same time, the equation of the creep strain rate, t in Equation (34), we obtain:After the first derivative of the variable Substituting the relationship Creep should have a linear relationship with the strain rate of concrete. Take t and the creep coefficient. The time at the ith moment is According to the expression, we can see the relationship between For the calculation of the creep coefficient 2, the Poisson’s ratio value is 2 and the Poisson’s ratio value is The section size of the steel–concrete continuous composite beam selected in this paper is shown in A sketch of the continuous composite beam model under a uniform load is shown in The ANSYS finite element composite beam model was built for structural analysis. The upper and lower flanges of both the concrete slab and the steel beam were simulated using the solid unit Solid45, and the web of the steel beam was simulated using the Plane42 unit; the studs between the concrete slab and the steel beam were simulated using the Combin39 spring element. Combin39 can define the load–slip curve with an axial or torsional function and can provide good simulations of studs in composite beams. By controlling the meshing and nodes of the steel beam and the concrete slab, the steel beam and the concrete node (two overlapping nodes) were selected at the position at which the studs were arranged, and the spring element Combine39 element was established. The spring element node, the concrete node and the steel beam node were connected by the degree of freedom coupling. The constraint arrangement was a fixed hinge support at the left end of the continuous beam and movable hinge supports at the mid-span and right end. The finite element model of the continuous composite beam is shown in The results of the comparison between the theoretical and FEM calculated axial forces at the mid-span position of the left span of the continuous composite beam are shown in As can be seen from As can be seen in The comparative results of deflection and slip at the mid-span position of the left span of the continuous composite beam are shown in As can be seen from As can be seen in The shear stiffness of the shear connector was taken as the research variable, and the remaining parameters were the same as in the previous example. Three kinds of shear stiffness, namely, The maximum axial forces of the composite beam at the initial time and the final time of creep under the three shear stiffnesses are compared, as shown in According to the data in In the case of different shear stiffnesses, the maximum deflection and slip values of the composite beam on the 14th and 728th days are compared, as shown in According to According to A comparison between the concrete bending moment of the composite beam and the bending moment of the steel beam at the initial moment and at the final moment of creep is shown in According to In this paper, the energy variational method is used to establish the control differential equation, considering the combined actions of slip and creep. The theoretical analytical solutions for the slip, deflection and axial forces of continuous composite beams under uniform loads are derived. The correctness of the analytical solution is verified by establishing a finite element composite beam model.For a composite beam under a long-term load, creep will increase the deflection of the composite beam and the steel beam bending moment, reducing the concrete bending moment. The deflection of the composite beam increases by 14% under the influence of creep, the bending moment of the steel beam increases by 12% and the bending moment of the concrete decreases by 49%. Creep has little effect on the slip and axial force of a composite beam, increasing by about 2%.The analytical solution obtained in this paper is suitable for the calculation and analysis of any equal-span continuous composite beam under a uniform load and can calculate any shear stiffness, which can quickly and intuitively reflect changes in the deflection, slip and axial force under a long-term load. The increase in the shear stiffnesses of shear connectors will increase the axial forces of composite beams and reduce slip, deflection and bending moments. The increase in shear stiffness will reduce the influence of creep on the axial forces and slip of composite beams and increase the influence of creep on deflection.In this paper, the slip, deflection and axial force of steel–concrete continuous composite beams under the coupling of slip and creep effects are analyzed and studied. The conclusions are as follows:In this paper, mechanical properties under the coupling actions of slip and creep are studied. Future work will carry out experimental research on continuous composite beams. The changes in the internal forces in the negative moment zones of composite beams under coupling and the stress caused by concrete cracking affected by creep must be further studied.


Results showed that the use of recycled concrete aggregate (8/31.5 mm) with replacement ratio of 50% (by weight of aggregate) improved the mechanical properties of pervious concrete in all analyzed cases. Whereas the replacement of 10% rubber waste aggregate (2/5 mm) by volume of aggregate reduced the compressive strength by a maximum of 11.4%. Addition of 2 kg/m3 of polymer fibers proved the strengthening effect of concrete structure, enhancing the compressive and tensile strengths by a maximum of 23.4% and 25.0%, respectively. The obtained test results demonstrate the possibility of using the recycled waste aggregates in decarbonization process of pervious concrete production, but further laboratory and field performance tests are needed.The aim of the study was to check the possibility of reusing aggregate from recycled concrete waste and rubber granules from car tires as partial substitution of natural aggregate. The main objective was to investigate the effects of recycled waste aggregate modified with polymer fibers on the compressive and flexural strength, modulus of elasticity and permeability of pervious concrete. Fibers with a multifilament structure and length of 54 mm were deliberately used to strengthen the joints among grains (max size 31.5 mm). Eight batches of designed mixes were used in the production of pervious concrete at fixed water/binder ratio of 0.34 with cement content of 350 kg/m Pervious concrete (PC) is a form of concrete with a special structure and is made from strictly controlled amounts of water and cementitious materials (binders) used to create a paste that forms a coating around coarse aggregate. Unlike conventional concrete, the mixture has little or no fine aggregate, creating substantial void ratio. Using sufficient paste to coat and bind the aggregate particles together creates a system of highly permeable, open, and interconnected voids, allowing water and gases to permeate through its structure rapidly. Both the low binder content and high porosity reduce strength compared to conventional concrete, but sufficient strength is readily achieved for many applications. Therefore, PC is an effective stormwater management tool to reduce the volume of stormwater runoff and the concentration of pollutants . PerviouThe storage of massive quantities of waste rubber tires or construction materials coming from demolition activities, especially in urban areas, is one of the global largest sustainability challenges and environmental concerns ,10,11,12Addition of recycled waste tire rubbers as fine aggregate in PC had a negative impact on mechanical properties , which i3, which is already close to the upper limit of lightweight concrete. The air void content of the hardened PC can range from 15 to 35% allowing a drainage rate of 81 to 730 L/min∙m2 , with typical compressive strengths of 2.8 to 28 MPa , F—load applied [kN], l—length of the sample (l = 3d) [m], d—width, height of the sample [m].According to code EN 12390-3 , a compr 12390-6  . Each slice surface was scanned and transferred to AutoCAD software (Autodesk Autocad 2022 version S.51.0.0) see . Then, ua—cross sectional area of a graduated cylinder [cm2], A—cylindrical sample cross section [cm2], L—length of a sample [cm], h1—initial water level, h2—final water level [cm], t—time required for water to fall from level h1 to h2 [s]. The test was performed for at least 3 times per sample to obtain an average value of permeability.The permeability coefficient test was measured using the falling head method . Permeabcm). The modulus of elasticity was figured out using the following formula:cm—modulus of elasticity [GPa], cm) [MPa], According to EN 12390-13 , the modHerein, the study presented investigated the effects of natural vs. recycled aggregate modified with polymer fibers on characteristics of PC. Eight batches of mixes (J1–J8) were used in the production of pervious concrete see .3, the void content was between 11.6% and 21.1%, and the permeability was in the range of 0.71–1.24 cm/s  is a measure of tensile strength in bending, calculated on Formula (1). Flexural strength is typically used in Portland Cement Concrete mix design for pavements because it best simulates slab flexural stresses, as they are subjected to loading. Because the flexural test involves bending a beam specimen, there is some compression involved, and thus flexural strength shall generally be slightly higher than tensile strength measured using a split tension test. This phenomenon was observed within the natural aggregate component in the PC mixes J1–J2, but no longer noticed in the recycled aggregate composition of mixes J4 and J6 see .The results of the 7, 28 and 56 days compressive strength tests, summarized in 3. In all mixtures, the addition of fiber produced an increase of 28 days compressive strength from 14.2 to 23.4%  had compressive strength in the range of 17.6 to 21.1 MPa, whereas the rubberized mixes (J5-J8) were from 15.6 to 21.6 MPa. In the mixes containing natural coarse aggregate, the compressive strength was decreasing with dosing the rubber waste by a maximum of 11.4% . For all PC mixes (J1–J8), the obtained value of permeability was high, ranging from 0.71–1.24 cm/s. The obtained test results are promising and demonstrate the possibility of using the recycled aggregates in the decarbonization process of pervious concrete production.The study aimed to evaluate the effects of recycled concrete and rubber waste aggregate addition modified with polymer fibers on characteristics of pervious concrete. Results showed that the use of recycled concrete aggregate (8/31.5 mm) with a replacement ratio of 50% (by weight of aggregate) increased the mechanical properties of pervious concrete in all analyzed cases, whereas the rubber waste aggregate (2/5 mm) with a replacement of 10% (by volume of aggregate) reduced the compressive strength by a maximum of 11.4%. The most satisfactory results were registered by adding 2 kg/mIn fact, pervious concrete cannot be designed with the only purpose of achieving the greater mechanical performances. To guarantee appropriate drainage and environmental qualities of the material, the optimal balance between strength and permeability is to be targeted. Further laboratory and field performance tests are needed to better understand porosity and its relationship to the mechanistic response variability due to the heterogeneous nature of PC containing recycled aggregate being modified with polymer fibers. Potential research directions may follow, i.e., the clogging potential of pervious concrete, fiber adhesion to the cement paste and influence of dosing and length of fibers, and the possibility of modifying rubber granules to increase adhesion to the cement paste and influence granulate size and its content in the mixture. As mechanical properties of PC are strongly affected by the mixture composition and placement method, further research on different application methods  affecting void content, permeability and strengths is recommended. Therefore, within the next steps of the present study, it is planned to investigate and report on vibrated specimens simulating the potential method of application, with respect to compaction time influencing the strength and porosity of pervious concrete that contains recycled materials.


A man in his 70s presented to the emergency department with painless obstructive jaundice. Initial blood test results show a predominantly cholestatic picture with elevated tumour markers, and imaging findings are concerning for a pancreatic head neoplasm or cholangiocarcinoma with involvement of the entire common bile duct. The patient underwent staging laparoscopy and biopsies including peritoneal washing, but did not identify any features of malignancy. Immunoglobulin G and immunoglobulin G4 testing were subsequently tested and shown to be elevated. The provisional diagnosis of immunoglobulin G4-related sclerosing cholangitis was made, and steroid treatment was empirically started. Treatment with steroids was successful, with complete resolution of symptoms and abnormal imaging findings and near complete resolution of liver function test results after 1 month. This case report aims to highlight the classical presentation of immunoglobulin G4 (IgG4)-related sclerosing cholangitis mimicking as cholangiocarcinoma. We discussed the latest literature regarding the disease, the diagnostic criteria, the treatment options, and the common pitfalls of an incorrect diagnosis.A man in his 70s presented to the emergency department with painless obstructive jaundice with dark urine and pale stools. The patient denied having any fever, nausea, vomiting, or weight loss. Liver function test progressively worsened during the admission peaking at a bilirubin of 287 umol/L , alkaline phosphatase 694 U/L , and alanine aminotransferase 160 U/L . Initial assessment on computed tomography and ultrasound raised concerns for primary pancreatic head neoplasm or cholangiocarcinoma . He subsThe patient underwent a staging laparoscopy, which found a distended gallbladder with bulky portal lymph nodes but no evidence of liver, peritoneal, or omental metastasis. Liver biopsy showed portal tract-based granulomatous cholangitis and IgG4 immunohistochemistry testing was negative on the liver biopsy. Portal lymph node biopsy was benign, and no malignant cells were identified in peritoneal washing. Serum immunoglobulin G (IgG) testing revealed an elevated total of 30.53 g/L  and IgG4 of 3.03 g/L . He remained well with no evidence of cholangitis despite no antibiotics being administered.A presumptive diagnosis of IgG4-related sclerosing cholangitis was made, and he was started empirically on 40 mg of oral Prednisolone for 4 weeks.Repeat liver function test 1 month later showed dramatic improvement, with bilirubin level at 25 umol/L , total IgG 13.23 g/L , IgG4 1.45 g/L , and CA19-9 44 . The steroids were gradually tapered and ceased. Repeat MRI 4 months later showed a normal biliary system with complete resolution of the common bile duct pathology .IgG4-related sclerosing cholangitis is a subtype of a multiorgan IgG4-related sclerosing disease, which responds well to steroid therapy. It is characterized by the presence of a biliary stricture, frequently associated with other fibrosing diseases such as autoimmune pancreatitis, and by the presence of IgG4-positive plasma cells and T-lymphocyte in various organs , 2. IgG4et al., this could be because of a patchy distribution of the disease process, insufficient tissue sampling from the biopsy, and fibrotic phenotype [et al. [Diagnosis is challenging as primary sclerosing cholangitis, IgG4-related sclerosing cholangitis and cholangiocarcinoma can mimic each other with each requiring a different treatment plan. An intraductal ultrasonography and transpapillary biopsy may be useful in diagnosing IgG4-related sclerosing cholangitis with IgG4 immunostaining . Cytologhenotype . A diagn [et al.  based onet al. Their patient was a 59-year-old man with features of autoimmune pancreatitis, but histology showed carcinomatous change with abundant IgG4-positive cells in the common bile duct [et al. In their study, they have highlighted the importance of follow-up tumour marker tests and repeat imaging after immunosuppressive therapy was started [It is also worth noting, however, that there is a possibility of carcinomatous change in a patient with autoimmune disease, as reported by Oh ile duct . It is a started . The poset al. reported in their study that 139 out of 924 patients with IgG4-related sclerosing cholangitis subsequently developed malignancy, with relapses being an independent risk factor, highlighting the importance of surveillance. The study acknowledges that whilst there is ongoing debate in regards to the ideal duration of therapy to prevent relapses, a maintenance steroid treatment period of 3–5 years has been suggested to yield a longer relapse-free period [Kubota e period .


After six months of mandatory antibiotic prescription-indication, all units achieved the target set. The study suggests that a simple, bundled ASP intervention can be rapidly effective obtaining the objectives of PNCAR on the reduction of overall antibiotics and FQs consumption.Fluoroquinolones (FQs) represent an class of antibiotics of medical importance, but their use has been restricted due to their ecologic impact and associated side effects. The reduction of FQs use is an important goal of antimicrobial stewardship programs (ASP). This work describes an ASP focused on overall antibiotics and FQs consumption reduction. From January 2021, an ASP was implemented in a 700-bed teaching hospital. The ASP was based on: (i) antibiotics consumption monitoring system (DDD/100 bed days); (ii) mandatory antibiotic prescription-motivation (using a dedicated informatic format) with the goal of >75% of motivated prescriptions; and (iii) data feedback and training on FQs use indications. We evaluated the impact of the intervention on overall systemic antibiotics and FQs consumption according to the objectives posed by Italian PNCAR . A decrease of 6.6% in antibiotic use was observed (2019 vs. 2021). Notably, the FQs consumption fell by 48.3% from 7.1 DDD/100 bd in 2019 to 3.7 DDD/100 bd in 2021 ( Antimicrobial resistance, recently defined as a “silent pandemic”, remains one of the most urgent and serious global health challenges that can compromise the effectiveness of key medical interventions, such as cancer treatment and organ transplantation . AntibioAntimicrobial stewardship programs (ASPs) play a critical role in improving the quality of antimicrobial use while optimizing patient outcome and minimizing the unintended consequences of antimicrobial misuse, including toxicity and resistance selection . The terItaly is among the European countries with high dissemination and consequent public health burdens of antibiotic-resistant bacteria . The repIn order to face the increasing resistance and spread of antibiotic-resistant microorganisms, the PNCAR provides specific objectives and the clearly stated roles of institutions for national coordination, both in the human medicine and the veterinary fields.The Italian strategies in the hospital setting involve two objectives: (i) the reduction of systemic antibiotics consumption by more than 5% and (ii) the reduction of fluoroquinolones (FQs) consumption by more than 10%, in the 2016–2021 period.Quinolones and FQs are synthetic antimicrobials that are highly effective in treating a wide range of infections and are among the most commonly prescribed antibiotics worldwide ,11. AlthIn this work, we described the implementation of a bundled antibiotic stewardship intervention with rapid effect on overall antibiotic use and, especially, FQs consumption. The intervention allowed us to achieve both objectives posed by the Italian PNCAR.From 2019, at the Siena University Hospital, a large 700-bed tertiary-care teaching hospital, a multidisciplinary team, including medical doctors, specialists in infectious diseases, intensivists, clinical microbiologists, pharmacists, nurses, and statistics, was instituted. The team defines the policy for an appropriate use of antibiotics, meets several times a year, organizes an annual professional practices assessment, and suggests updates to local guidelines referring to hospital health management. The team coordinates an annual hospital point prevalence survey (PPS) of healthcare-associated infections and antimicrobial use according to the protocol proposed by ECDC (European Centre for Disease Prevention and Control) . The teaFrom January 2021, we implemented a bundled antibiotic stewardship program as a part of the AID Team activities, based on an (i) antibiotics consumption monitoring system; (ii) mandatory antibiotic prescription-indication; and (iii) feedback, audit, and educational interventions. The organizational structure of the hospital remained unchanged for the study period.InterventionsAs a first step, an antibiotic consumption monitoring system was implemented with a retrospective data analysis on antimicrobial use for the years 2019 and 2020.Antibiotics classification was carried out according to the Anatomical Therapeutic Chemical Classification code, ATC J01, and antibiotic usage data were obtained from the computerized database of the Pharmacy Unit after data analyst processing. The antimicrobial consumption was expressed as the defined daily dose (DDD), according to the World Health Organization’s definition as the assumed mean maintenance adult daily dose of an antimicrobial for 1 day of treatment .We analysed systemic antibiotics consumption both cumulative and by antimicrobial class, expressed as DDD/bed days (DDD/100 bd). The number of bed days in 2019, 2020, and 2021 was 173.674, 145.823, and 161.505, respectively.For consumption data visualization, we used a dedicated “heat map”, showing the magnitude of phenomena as colour intensities in two dimensions. The variation in colour by intensity gives obvious visual cues to the reader regarding how a phenomenon is clustered or varies over time, setting, and drugs.The wards were grouped into five patient-care areas: medical, surgical, intensive care, COVID-19 (for 2020 and 2021 only), and maternity–paediatric areas. Stratified consumptions were calculated for each ward and referred “patient-care areas”.The following indicators were selected according to PNCAR goals: total consumption of antibiotics (ATC code J01) and of FQs expressed in defined daily doses (DDD) per 100 bed days. Variations in consumptions were calculated using the formula [(2021 consumption/2019 consumption) − 1] × 100.According to the hospital 2020 PPS data of healthcare-associated infections and antimicrobial use (data not shown), slightly more than half of antibiotic prescriptions were motivated in the medical records only.Therefore, as a second step, in February 2021, the hospital management decided to set, as a 2021 outcomes-based incentive, at least 75% of the motivated antimicrobial prescriptions for certain critical wards. The targeted units were chosen among those with lower percentages of motivated prescriptions, as determined by 2020 PPS (Units A–G).To facilitate the achievement of the objective, mandatory motivation registration for antimicrobial prescription in hospital electronic medical records by using a standardized prescription-format was introduced from June 2021. The format encourages physicians to select the motivation for the prescription from a predefined list whenever they prescribe an antimicrobial agent to be administered systemically (J01). The list of possible indications was taken from the Diagnosis website’s antimicrobial use list for empiric or targeted therapies of the European Protocol for Point prevalence survey. The list was amended to include medical and surgical prophylaxis .As a third step, during the first semester 2021, the health management conducted the systematic feedback on antimicrobial consumption to team AID and clinicians through audits, interviews, and trainings. The objective of these audits was to provide an update for healthcare workers on the advancements and preliminary results of the intervention.During the audits, antibiotic consumptions were reviewed in order to compare antimicrobial use with other regional and national settings.The interviews were conducted on the units with critical levels of FQs consumption (Units 1–3) and focused on indications for FQs use, the perception of the relationship between fluoroquinolone use and relevant side effects, and barriers to an intervention successfully restricting fluoroquinolone use. Interviews were conducted by the team AID manager, an infectious diseases specialist and a pharmacist, together with the hospital health director. The interviews were conducted via teleconferences or meetings.We also provided educational session on antimicrobial stewardship within the institutional hospital annual training plan. In the first semester of 2021, a total of three editions focused on the rational use of antibiotics and aimed at medical doctor personnel were carried out.Simple linear regression analysis was used to assess the effect of the ASP on the trend of total antibiotics consumption and FQs consumption. Semi-annual trend changes in FQs consumption were tested using the semi-annual consumption data from 2019, 2020, and 2021 as time points.A more detailed report with the analysis of consumption per month from 2019, 2020, and 2021 can be found in p value of <0.05 was considered statistically significant. Statistical analyses were performed with the 9.3.1 version GraphPad Prism statistical package.A p = 0.644), the reduction exceeded the target of a 5% decrease set by PNCAR. As shown in the heat map  in 2019 to 79.1 DDD/100 bd in 2021 . Althougheat map , the mosp < 0.001) in the linear regression analysis. The target of a 10% reduction set by PNCAR was reached. The consumption of glycopeptides remained almost stable (from 6.4 DDD/100 bd to 7.5 DDD/100 bd). An increasing trend in the consumption of carbapenems was observed from 5.2 DDD/100 bd in 2019 to 7.1 DDD/100 bd in 2021 (37.8%). The antimicrobial use of the single antimicrobials is shown in Analysing the data by antibiotic classes, we observed a reduction trend for 3rd and 4th generation cephalosporins (from 15.0 to 11.9 DDD/100 bd) and macrolides/lincosamides (from 7.2 to 4.4 DDD/100 bd). Notably, FQs consumption globally fell by 48.3% from 7.1 DDD/100 bd in 2019 to 3.7 DDD/100 bd in 2021  and one to a medical area (Unit 2). The observed consumption ranged from 81.6 DDD/100 bd (Unit 3) to 32.0 DDD/100 bd (Unit 2) .After the intervention, the FQs consumption decreased in all three units, respectively, by 80.0%, (from 67.1 DDD/100 bd to 13.4 DDD/100 bd), 50.3% (from 32.0 DDD/100 bd to 15.9 DDD/100 bd), and 92.8% (from 81.6 DDD/100 bd to 5.9 DDD/100 bd), as shown in After six months of mandatory antibiotic prescription-motivation system training, we performed the first evaluation (referring to the period June–December 2021).The data analysis showed that the percentage of antibiotics prescriptions for which the motivation was documented in electronic medical records was over target  in all of seven targeted units , with a Analysing the data for selected indications by antibiotic class, it emerged that over the total amount of prescribed FQs (n. 234), 20.9% (49/234) was for surgical prophylaxis > 1 day (SP3), 14.5% (34/234) for symptomatic lower urinary tract infection (CYS), 13.7% (32/234) for pneumonia (PNEU) infections, and 9.8% (23/234) for gastrointestinal infections (GI) .Continuous antibiotic consumption monitoring is the cornerstone of all AS strategies.In our institution, in 2019 and 2020 before the intervention, the overall antimicrobial consumption was stable, with 84.7 and 84 daily doses of antibiotics per 100 bed days, respectively. In 2020, the most frequently prescribed antibiotics were the β-lactam antibacterials and penicillins (J01C), followed by the 3rd and 4rd generation cephalosporins, glycopeptides, and FQs, in line with the national data. In fact, in 2020, the penicillin combinations category (including beta-lactamase inhibitors) was the most prescribed in Italy (22.5 DDD/100 bd), accounting for a quarter of the total hospital consumption at the national level .In 2020, the overall and FQs consumption in our hospital were already below the national data of 92.1 and 9.9 DDD/100 bd, respectively, but higher than those of the regional average for the same period  ,19. In 2Recently, quinolones have been subject to control by regulatory agencies for reasons of safety of use. The press release (12 April 2019) issued by the Italian Medicines Agency (AIFA) ended a lengthy process of reviewing safety data for quinolones and FQs at the EU level, announcing the withdrawal of some quinolones from the market and the implementation of use restrictions for all FQs. The procedure was initiated by the European Medicines Agency (EMA) in 2017, and based on the available evidence, the EMA concluded that the drugs under investigation were associated with serious, known, debilitating, long-term (months to years), and potentially irreversible side effects on one or more organs/systems ,21.In the EU/EEA hospital sector, there were statistically significant decreases in the mean 10-year trends for the consumption of quinolones (ATC group J01M) . In ItalKlebsiella pneumoniae shows an increasing trend in Europe, rising from 25.3% in 2012 to 33.8% in 2020. In Italy, the situation is even more complicated, with an increase from 20% in 2009 to 52.4% in 2020. A similar trend was reported for E. coli [In fact, fluoroquinolone-resistance among clinically relevant pathogens continue rising. For example, the prevalence of FQs resistance in  E. coli .For these reasons, we targeted our interventions to two indicators in order to achieve the objectives set by the PNCAR: (i) the reduction of the consumption of systemic antibiotics by more than 5% and (ii) the reduction of the FQs consumption by more than 10% in the 2016–2021 period.In our institution, the decrease in FQ use was not balanced by an increased use of other antibiotic classes (with the exception of carbapenems), and during the study period, the overall antibiotic consumption in the whole hospital also decreased globally.This project has allowed us to achieve the national objectives set by the PNCAR with a 48.3% reduction in the consumption of FQs (target 10%) and a 6.6% reduction in global consumption (target 5%).During the interviews, it emerged that in some cases, professionals were not aware of the restrictions on FQs prescriptions. The core components of our ASP were the feedback of antimicrobial consumption data to providers and training on FQs-use indications as a persuasive approach, which made it possible to increase the level of awareness in prescribing physicians in conjunction with the mandatory documentation of the indication at the moment of antibiotic prescription. Through the documented indications system, we achieved a global rate of motivated antibiotic prescriptions of 83.7% compared to 51.1% in the 2020, as emerged from the Point Prevalence Survey of healthcare-associated infections and antimicrobial use.A mandatory indication for antimicrobial agents is recommended by a number of organizations as a key element for implementing policies and interventions to improve antibiotic use . This waSeveral studies have shown that the COVID-19 pandemic caused significant perturbations on antimicrobial consumption data, especially in the early periods of the pandemic . For thihttps://www.who.int/publications/i/item/2021-aware-classification, accessed on 25 January 2023) but the COVID-19 pandemic made it difficult to achieve this target [Carbapenems and FQs are classified as reserve and watch groups, according to the World Health Organization (WHO) antimicrobial classification. The WHO target is that by 2023, at least 60% of all antimicrobial consumption should come from the access group  the systematic quantification of antibiotics consumption, global, and stratified per ward on a semi-annual basis; (ii) providing audits and feedback to healthcare workers; and (iii) the implementation of a system for mandatory antibiotic prescription-indication in medical records. At the same time, the aim is to increase the knowledge and the level of awareness of the appropriate use of antibiotics in all healthcare settings and for all healthcare staff, adopting both persuasive and restrictive interventions .In conclusion, we demonstrate that a short-term antimicrobial stewardship bundle aiming at reducing the overall antibiotic consumption, with its main target being FQs prescription, can be effective in only a few months. Several other works have focused on this topic, but they were all based on long-term interventions ,33.


This study provides the results of an experiment on the possibility of using high-volume ground granulated blast furnace slag (HVGGBFS)-based concrete as mass concrete. In addition to the control concrete, the total weight of the binder was 75% ground granulated blast furnace slag (GGBFS) and 25% ordinary Portland cement (OPC). For the aggregates, both natural and recycled aggregates were used. Three specimens with dimensions of 800 mm × 800 mm × 800 mm were prepared to simulate mass concrete. The workability, temperature aging and strength of the mass concrete were tested. The test results showed that utilizing HVGGBFS concrete as mass concrete can significantly reduce the heat of hydration due to the low heat of hydration of GGBFS, while the heat of hydration of GGBFS and recycled aggregate combination is 11.2% higher than normal concrete, with a slump that is 31.3% lower than that of plain concrete. The results also showed that the use of recycled aggregates in HVGGBFS concrete can significantly reduce workability. However, the compressive strength is higher than when natural aggregates are used due to the alkali activation effect caused by the recycled aggregates. The compressive strength at 7 and 28 days increased by 33.7% and 16.3%, respectively. Racturing ,10,11,12acturing ,16,17,18acturing ,20,21,22acturing ,24,25,26acturing ,28. Sincacturing ,30,31,32acturing ,34,35,366 tons of solid waste generated in Europe is due to demolition activities, which is approximately 31% of the total waste generated, out of which only 3% of them are being used as aggregate originating from recycled aggregates (RA) [Also, the demand for construction aggregates globally in the construction industry is rising at a rate of approximately 5.2%, which reached 51.79 billion metric tons in 2019 ,39,40,41tes (RA) ,43,44. Htes (RA) ,46.Recycled concrete aggregates are one kind of building material obtained by crushing abolished construction waste ,48,49. NBecause of the high alkaline level of the impurities, using recycled concrete aggregates as alkali activators is a possible way to activate the potential hydraulicity of the GGBFS . AccordiMass concrete used in many structural and non-structural applications, such as raft foundations, large size columns, concrete blocks for quay walls, suffers from cracking at early ages from the heat generated due to the hydration reaction of the binder (cement) . The hea2O3 ratios, but with similar Ca/SiO2 ratios. Their results showed that a low MgO/Al2O3 ratio can result in high autogenous shrinkage and therefore promote the EAC risk. However, these studies have not deeply explored the contribution of GGBFS to the heat of hydration in mass concrete. In addition, besides GGBFS, a variety of inexpensive wastes are needed to enter the concrete system. Recycled aggregates are a good alternative. The old mortar on its surface can assist the hydration of GGBFS to occur.Malhorta and Mehta studied the effects of high-volume fly ash (HVFA) concrete, with fly ash making up more than 50% of the total mass of the binder, and obtained even better durability performances than OPC-based concrete ,72,73,74To summarize, it is very necessary to go for introducing high-volume GGBFS and recycled aggregates into the concrete system for economic and ecological benefits. The alkaline nature of the waste mortar on the surface of recycled aggregate and the potential hydration properties of GGBFS is utilized to alleviate the problem of exothermic cracking inside the mass concrete and to expand new ideas for the development of concrete.This study focuses on the possibility of mass concrete with HVGGBFS and the alkali activation after RCA incorporation. Based on this, mock-up tests of mass concrete with HVGGBFS as a binder are provided. Workability, compressive strength and temperature age are tested to compare the different binders. To examine the effect of recycled aggregates as an alkali activator, both recycled and natural aggregates are used in HVGGBFS concrete. This study also developed a strategy for producing mass concrete with lower internal temperature.3 and 2.90 g/cm3, respectively. The chemical composition of OPC and GGBFS is given in In this study, P·O42.5 ordinary Portland cement (OPC) from Yatai Group Harbin Cement Company  and the S95 grade ground granulated blast furnace slag (GGBFS) from a local processing plant  were used as binders, and the density was 3.15 g/cmA total of four types of aggregates were selected for use: natural coarse aggregate (NCA), natural fine aggregate (NFA), recycled coarse aggregate (RCA), and recycled fine aggregate (RFA), respectively. The natural aggregates are gravel and river sand, which come from the local quarries in Harbin. The recycled aggregates came from a local construction site in Harbin, where the waste concrete was crushed by a jaw crusher, as shown in The proportions of the mass concrete are given in Three days before the preparation of concrete, the coarse and fine aggregates are dried in a natural environment to a dry condition (moisture content approximated to 0). One hour before preparation, the RCA and RFA were pre-absorbed and the amount of water absorbed was calculated based on the water absorption of the recycled aggregate over the natural aggregate. Four 150-L capacity concrete mixers were used to prepare the mass concrete together (one mass concrete specimen was approximately 520 L). The solid components, including OPC, GGBFS, and coarse and fine aggregates, were first mixed for 2 min. Water was then added to the mixer and mixing continued for 2 min. All the fresh concrete mixture was poured into the mould (800 mm × 800 mm × 800 mm) as shown in The slump, air content and chloride contents of fresh concrete were tested immediately in compliance with test methods regulated in ASTM C143/143M , C231 88 and JGJThe authors conducted detailed field monitoring of temperature rise in mass concrete blocks. As shown in The compressive strengths of concrete mixes were determined at 3, 7 and 28 days of age. Concrete cylinders of 300 mm × 150 mm were used for the compressive strength tests as per ASTM C39 . The loaThe rebound number test of hardened concrete was conducted according to the methods specified in ASTM C805/805M . All tesSamples at the age of 7 and 28 days were immersed into isopropanol for one week to stop the reaction and dried in a 40 °C oven for 1 h for the SEM studies. The surface of the samples was coated by carbon and subsequently dried in a low vacuum desiccator before analysis. Afterwards, the fractured and polished samples were observed by SEM with the secondary electron (SE) mode at an acceleration voltage of 20.0 kV under a low vacuum, respectively.The air content ranges from 3.4% to 5.1%, which satisfied the target range. The high water absorption of RCA leads to a decrease in the effective water–cement ratio, which in turn introduces more air pockets and increases the air content of the material. Moreover, there are micro-cracks and voids in the paste attached to the surface of RCA, which also leads to an increase in the air content.3 chloride content, which satisfies the standard range [The three types show a lower than 0.30 kg/mrd range . When a Previous studies have shown that the risk of thermal cracking in large concrete infrastructure is highly dependent on the temperature development and the maximum temperature . The resThe temperature change is closely related to the performance of the material in terms of the heat of hydration. Gao et al.  tested t2 and released heat. It is considered the reason that a higher peak is observed in RFA-based specimens. Similarly, the old mortar attached to the surface of the RCA had a large amount of residual cement. These cement particles with a high quantity of CaO increase the alkali concentration and further activate the hydraulicity of GGBFS.Considering the limitations of the heat of hydration test, we could not measure the effect of RCA on the heat of hydration of HVGGBFS concrete. Given this, since recycled fine aggregate (RFA) and RCA have similar compositions, we tested the effect of RFA on the heat of hydration, details of which can be found in . RFA incONN has 54.7%, 22.4% and 12% higher strength than BRR at 3, 7, 28 days as expected. According to the literature, the use of 100% RFA in OPC-based concrete leads to a loss of compressive strength ranging from 39% to 60% ,95. In c(1)3.For fresh concrete, slump decreases with increasing GGBFS content and aggregate dosage; 75% GGBFS and recycled aggregate combination gives a 31.3% lower slump than BNN with natural aggregates. The chloride content of all specimens was less than 0.3 kg/m(2)The higher volume level of GGBFS replacement resulted in a significant reduction in heat of hydration compared to OPC. The combination of GGBFS and recycled aggregate showed 11.2% higher heat of hydration than BNN of natural aggregate.(3)At 28 days of age, high-volume GGBFS reduces compressive strength compared to ONN. The compressive strength at 7 days and 28 days with recycled aggregate was 33.7% and 16.3% higher than with natural aggregate when high-volume GGBFS was used as a binder.In this study, the potential for the incorporation of high volumes of GGBFS and recycled aggregate into a mass concrete system at the same time was emphasized. Slump, air content and chloride content of fresh concrete were tested. And three 800 mm × 800 mm × 800 mm mass cube specimens were tested for monitoring the internal heat of hydration and rebound number. Also, the compressive strength of concrete was tested at 3, 7, and 28 days. The main conclusions obtained are as follows:


The emergence of carbapenem-resistant organisms (CROs) is a significant global threat. Reduction of carbapenem consumption can decrease CROs. In the global endemic era of ESBL-producing bacteria, carbapenems are considered the treatment of choice, leading to challenge in limiting carbapenem use. This review describes the role of precision prescribing for prevention of CROs. This involves improving antibiotic selection, dosing and shortening duration. The effect of different antibiotics, dosing and duration on CRO development are explored. Available options for precision prescribing, gaps in the scientific evidence, and areas for future research are also presented. Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA), are increasing in incidence globally.1 CRE can be categorized into carbapenemase-producing CRE (CP-CRE) and non-carbapenemase-producing CRE (non-CP-CRE).2 CP-CRE is the most problematic among CROs due to plasmid localization allowing for horizontal gene transfer in both environmental and clinical Enterobacterales.3Carbapenem-resistant organisms (CROs), including carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant 1 Mortality following CRO infection is up to 50%, largely due to the limited treatment options.4 Consequently, they have been categorized by the WHO as critical priority pathogens for discovery, research and development of new antibiotics.5The emergence of CROs is a significant global threat.7 especially CRPA and CRAB.9 CRO outbreaks incur a high cost for the hospital.10 Cost associated with CROs is not only from direct cost such as antibiotics, contact precautions or decontamination, but also indirect cost from bed closure and missed opportunities for patient care.10 Several hospital infection prevention and control interventions are deployed to tackle the problem.11–15 These interventions include surveillance, hand hygiene, standard and transmission-based precautions, isolation, antibiotic stewardship, decolonization and environmental hygiene.CRO transmission frequently occurs in hospital,16 Interventions focusing on reducing antibiotic consumption are effective in reducing CROs.17 For example, reduction of carbapenem consumption can decrease incidence of CRE,18 CRPA18–20 and CRAB.21Core strategies of antibiotic stewardship include interventions to reduce inappropriate antibiotic use, antibiotic optimization, diagnostic approaches and programme measurement.22 The global endemic nature of ESBL-E in recent decades has led to an inevitable rise in carbapenem use.23In the era of resistance, it is becoming difficult to restrict broad-spectrum antibiotic use. Carbapenems are considered the treatment of choice for ESBL-producing Enterobacterales (ESBL-E).24 Optimizing antibiotics involves precision prescribing, allergy assessment and timely use of oral antibiotics.16 This review will focus on the role of precision prescribing for prevention of CROs, which is a key aspect of antibiotic stewardship. This involves improving antibiotic selection, dosing and shortening duration through the application of more individualized interventions. First, the effect of different antibiotics, dosing and duration on resistance development will be explored. We will then explore available options for antibiotic selection, dosing and duration, with an aim to prevent CROs.If carbapenem use is now unavoidable in many circumstances, the optimizing of antibiotic use, including careful selection of agents in these contexts, may be considered as an important intervention in local infection prevention and control strategies to minimize the development of antimicrobial resistance, particularly carbapenem resistance, and drug-resistant hospital-acquired infections.There is emerging evidence describing the effects of different antibiotics, doses and treatment durations on resistance development. CRO emergence in this section is defined as isolation of CRO in any specimen obtained from the same individual during or after exposure to antibiotics. This does not include treatment failure caused by antibiotic resistance developing during the treatment with the specific antibiotic for the same organism, as shown in Figure 25 Notably, the WHO classifies antibiotics in the essential medicines list (EML) into three groups based on risk of toxicity and resistance selection: Access, Watch and Reserve (AWaRe).26 For CRO, a recent meta-analysis of 349 studies by Sulis et al.27 demonstrated that carbapenem use at both individual and population levels is the strongest risk factor for CRO colonization/infection. CRPA colonization/infection is most strongly associated with carbapenem use , followed by CRE  and CRAB , respectively.Numerous efforts have been made to find and characterize the effect that individual antimicrobials exert on selection of resistance.et al.27 defined that other significant antibiotics associated with CRO include lincosamides (OR 2.4 for CRE), polymyxin (OR 2.4 for CRE), tigecycline (OR 2.4 for CRE), linezolid (OR 2.1 for CRE), fourth-generation cephalosporins (OR 1.7–2.0 for CRO), glycopeptides (OR 1.5–1.9 for CRO), daptomycin (OR 1.8 for CRE), macrolides (OR 1.6 for CRE), fluoroquinolones (OR 1.4–1.9 for CRO) and piperacillin/tazobactam (OR 1.3–1.5 for CRO). It should be noted that polymyxin and tigecycline, reserved for the treatment of CRO, are also amongst the strongest risk factors of CRE colonization/infection. However, these associations should be interpreted with caution as it is difficult to control all the confounding factors influencing antibiotic selection.25 For example, glycopeptides do not have activity against most Gram-negative pathogens, but are often used in combination with broad spectrum β-lactams, such as carbapenems, as empirical treatment in hospitalized patients.28 Moreover, these associations are usually derived from population-level instead of patient-level data, disregarding the complexity of clinical parameters, epidemiological factors and antibiotic exposure in each patient.30 Because this complexity may be too difficult for classical statistical analysis, machine learning is expected to be used in the future to define antibiotic pressure in individual patients.31 Machine learning was successful in estimating antibiotic exposure and ESBL-E colonization in a recent study.32 The random forest model derived from machine learning could rank antibiotics, whether used as monotherapy, used in combination or used sequentially, based on the measurement of error in predicting ESBL-E colonization. However, there is currently no machine learning model to estimate the impact of antibiotic exposure on CRO colonization/infection. This model may be needed to understand the complex interaction between antibiotic utilization and development of CRO from patient-level data.Identification of antibiotics with the least selective pressure for CRO is important as it can help guide alternative, carbapenem-sparing regimens. The meta-analysis by Sulis Mechanisms of carbapenem resistance are different amongst CROs. For CRE, the selection of carbapenemase is the most important mechanism, whereas for CRPA, permeability changes (e.g. OprD) and multidrug efflux pumps (e.g. MexA-MexB-OprM) are usually the determining factors.33 Any carbapenem use can aggravate the occurrence of CRE, with ertapenem the least selective within the group.33 On the contrary, ertapenem use, unlike other carbapenems, is not associated with the emergence of CRPA and CRAB.34–37 However, it should be noted that a strategy of replacing group 2 carbapenems with ertapenem failed in reducing CROs in three studies of carbapenem stewardship.38 The mandatory use of ertapenem for ESBL-E infections did not lead to a post-intervention reduction in CRAB and CRPA.38Carbapenem agents consist of imipenem, meropenem, ertapenem, doripenem, panipenem, biapenem, razupenem, tebipenem and faropenem. Individual carbapenems exert variable selection pressure on CRO. Selecting a carbapenem with least resistance pressure has been proposed as a potential method to reduce the occurrence of CROs.39 These slow-growing bacteria are capable of producing subpopulations of non-replicating or slowly growing cells in response to antimicrobials, also called persister subpopulations, resulting in drug tolerance.40 Therefore, treatment of mycobacteria consists of exceptionally long courses of antimycobacterial combinations. The mechanism of combination antimycobacterial therapy is thought to occur by resistance suppression, i.e. the first drug kills mutants resistant to the second drug, while the second drug kills those resistant to the first drug.39Antibiotic combination therapy has also been proposed as a strategy to suppress the emergence of resistance. Combination therapy is an effective strategy to suppress the emergence of resistance in mycobacterial infections such as tuberculosis and leprosy.P. aeruginosa.41–44 Various preclinical studies in P. aeruginosa infection found benefit in preventing resistance emergence in antibiotic combinations of β-lactams with aminoglycosides or fluoroquinolones.41–44 Early clinical studies suggested that a β-lactam in combination with an aminoglycoside could delay resistance development compared with monotherapy.45 However, several subsequent clinical studies and meta-analyses in P. aeruginosa infection have failed to demonstrate any benefit of combination treatment to the emergence of resistance.42 Because of the increased toxicity, continuous aminoglycoside combination therapy is not recommended for suppressing resistance.46 There are no clinical data evaluating fluoroquinolones in combination with β-lactams for this specific purpose.For pyogenic bacteria that have more rapid growth, the possible benefits of antibiotic combination to prevent resistance emergence are found in In vitro experiments demonstrate low resistance selective pressure occurs when drug exposure is at relatively low or high concentrations, forming an ‘inverted U’ relationship.47 Antibiotic concentrations achieved in vivo using recommended doses for clinical cure are associated with greater selective pressure for resistance.48 For carbapenems, this phenomenon is found in experiments of P. aeruginosa and may explain resistance development during therapy.49–52 A meta-analysis of 28 studies found that CRPA developed in 35% of patients with P. aeruginosa infections during carbapenem treatment without resulting in treatment failure.53 Therefore, increased target concentration of carbapenems may arguably be justified in P. aeruginosa infection to suppress resistance, but not to improve clinical outcomes.54Drug exposure can have a significant impact on resistance development. 55 A study found that the percentage of the dosing interval for drug concentration to remain above MIC (fT>MIC) for the maximal killing effect of razupenem for Enterobacterales was 63%–92%, but CRE rarely occurred at >70%.55 In clinical practice, CRE and CRAB rarely emerged during carbapenem treatment (<1%).53 Therefore, increased target concentration may not be needed in general cases of Enterobacterales and Acinetobacter spp. infection.On the other hand, for Enterobacterales, the concentration for maximal killing is the same as for suppression of carbapenem resistance.56 Intestinal carriage is an important source of transmission.58 Resistance can occur even with antibiotics with minimal bile excretion into the intestine, such as cefotaxime.60 A recent study found that increasing ciprofloxacin pharmacokinetic/pharmacodynamic (PK/PD) target attainment did not reduce the chance of resistance emergence.61 Moreover, higher ceftriaxone PK/PD indices were associated with increased amplification of resistant genes.62 In clinical practice, resistance commonly emerges away from the site of the primary infection.64 Therefore, serum antibiotic concentrations should be aimed at maximal treatment efficacy and minimal toxicity. For most infections, using current PK/PD approaches, it is difficult to include resistance suppression in the treatment plan.65Although optimizing antimicrobial dosing to suppress resistance may seem plausible, it has potential consequences. Antibiotics can transform intestinal flora into a reservoir of antibiotic-resistant organisms, also called the gut resistome.67 Evidence from experimental models and subsequent clinical studies has demonstrated that shortening duration can reduce resistance emergence.68–70 Regarding CROs, prolonged duration of many antibiotics is associated with resistance acquisition. Prolonged duration of piperacillin/tazobactam and aminoglycosides was associated with subsequent CRO acquisition .71 Prolonged duration of β-lactams with β-lactamase inhibitors (BL-BI), or carbapenems and fluoroquinolones was associated with subsequent CRE infection .72 Prolonged duration of fluoroquinolones, broad-spectrum cephalosporins and carbapenems was associated with CRAB infection .73Historically, the misconception that shortening antibiotic duration can lead to resistance emergence was held by clinicians and the general population.74 However, another study showed that early carbapenem de-escalation was associated with a shorter duration of carbapenem usage by 2 days and lower incidence of CRAB acquisition.75 A reduction in CRE and CRPA was also observed in this study, although this was not statistically significant.Although optimizing the duration of antibiotic is one of the strategies of antibiotic stewardship, not many studies specifically evaluate its effectiveness in reducing CRO acquisition. A resistome study nested in a clinical trial found that shortening antibiotic duration from 14 to 7 days did not result in a decreased quantity of carbapenem resistance genes in gut microbiota.In conclusion, the current evidence suggests that the best option for minimizing CRO emergence is selecting alternative agents in place of carbapenems. If carbapenem usage is unavoidable, options to reduce antibiotic resistance are dosing carbapenem therapy to achieve defined PK/PD targets for efficacy and prescribing the shortest effective duration.76 Because carbapenem use is amongst the strongest risk factors for CROs, research has focused on carbapenem-sparing strategies for the treatment of ESBL-E.77–83 These strategies include combination antibiotic regimens, evaluation of other potential antibiotics, and selecting ertapenem as a carbapenem agent with the narrowest spectrum.Optimal antibiotic selection involves choosing the most appropriate antibiotic to achieve efficacy in managing infections whilst minimizing adverse events associated with antibiotic use, including development of antibiotic resistance.The main benefit of combination therapy for ESBL-E is likely to be promoting antibiotic synergy and broadening the spectrum of coverage.in vitro results. Apart from the standard combination of BL-BIs, the most frequently described combination antibiotics for ESBL-E are aminoglycosides, in combination with β-lactams, such as cefepime or piperacillin/tazobactam.84–86 Several studies have been unable to demonstrate evidence of improved clinical outcomes of combination therapy compared with β-lactam monotherapy for ESBL-E.88 Instead, increased toxicity may be observed in the combination group.87 Moreover, a recent study found that some Escherichia coli strains can exhibit in vitro antagonistic effects between aminoglycosides and β-lactam combinations.89For targeted therapy, combination antimicrobial therapy was investigated clinically for synergistic effects based on organism 90 Another study reported clinical cure in 10 patients with ESBL-E urinary tract infection treated with ceftibuten and clavulanate.91 Several clinical trials are evaluating cephalosporins in combination with β-lactamase inhibitors. It should be noted that all ongoing trials are being conducted in patients with mild infections without bacteraemia.92Another proposed combination option is between β-lactams, mostly between a cephalosporin and a BL-BI. A study found that an oral third-generation cephalosporin, cefixime, in combination with clavulanate can effectively treat patients with ESBL-E urinary tract infection.P = 0.04).93 As combination therapy has been found to broaden the spectrum of coverage, a study also confirmed that empirical combination therapy could improve appropriateness for ESBL-E and was associated with survival.94For empirical treatment, evidence from meta-analysis of six studies found that appropriate empirical antibiotic therapy, i.e. given within 24 h of initial culture, is associated with improved survival in patients with ESBL-E bacteraemia  genes, which caused a major error in piperacillin/tazobactam susceptibility interpretation used in the trial.104 Therefore, many patients allocated to the piperacillin/tazobactam arm actually had bacteraemia resistant to piperacillin/tazobactam. The question still remains whether the extended infusion of piperacillin/tazobactam is comparable to carbapenems.79 There is an ongoing trial in Israel, Canada, and Italy evaluating this issue.105The most extensively studied antibiotic as a carbapenem-sparing option is piperacillin/tazobactam,106 They may be an alternative to carbapenems only for non-severe infections and should be used at high dose and continuous infusion.107Cephamycins, such as cefoxitin or cefotetan, may be used against ESBL-E; however, AmpC producers have unfavourable susceptibility to these.108 However, renal toxicity was common.108 Another retrospective study in patients with bacteraemia from urinary tract infection found that aminoglycosides were non-inferior to carbapenem or piperacillin/tazobactam in mortality, without difference in acute kidney injury.109 However, the subgroup analysis comparing aminoglycosides and carbapenems was not reported.Aminoglycosides may be used against ESBL-E bacteraemia. In a retrospective cohort, INCREMENT, differences of 30 day mortality between patients treated with meropenem and aminoglycosides were not observed.110 It was again relaunched in the 2010s in the UK and some European countries to combat drug-resistant organisms.111 A retrospective study found that the clinical cure rate was 93%, 83% and 100% in patients with ESBL-E urinary tract infection, bloodstream infection and hospital-acquired pneumonia, respectively.112 Currently, there is an ongoing clinical trial evaluating the efficacy of temocillin for ESBL-E bacteraemia.113Temocillin is a β-lactamase-resistant penicillin, which was marketed in the UK in the 1980s.Pseudomonas and Acinetobacter spp.114 It is marketed for use in severe community-acquired infections, where Pseudomonas and Acinetobacter spp. are unlikely, such as intra-abdominal infections, community-acquired pneumonia, acute pelvic infection, skin and soft tissue infections and complicated urinary infections. Because of the limited data on ertapenem efficacy as empirical treatment of severe ESBL-E infections, it is not recommended for patients with bacteraemia and severe infection, especially septic shock.99 A recent retrospective propensity score matching study in patients with ESBL-E bacteraemia reported no difference between ertapenem and other carbapenems in mortality, even in a subgroup of patients with septic shock.115Ertapenem is an carbapenem with activity against ESBL-E but has only weak activity against 116–118 On the other hand, supratherapeutic levels may lead to toxicity. Therefore, maintaining serum concentrations within therapeutic range is crucial.The aim of antibiotic dosing is to keep antibiotic levels within the therapeutic window. Suboptimal levels of antibiotics are not only associated with treatment failure, but also with the emergence of resistance.24There are many approaches for antibiotic optimization to maintain antibiotic concentrations within the therapeutic window. The most frequently described methods are the antibiotic nomogram and therapeutic drug monitoring (TDM).a priori dosing method, was introduced shortly after the discovery of antibiotics.120 This method usually relies on simple clinical parameters such as renal function and body weight.121–123 Some software can take more variables into account, such as gender, height, weight, age and serum creatinine.124 Compared with clinician-guided dosing, this method can improve target attainment of antibiotics such as vancomycin.126The concept of a nomogram, sometimes called a population model or CR) of patients.128 All studies found that a standard daily dose of 3 g meropenem is sufficient for target attainment in patients with normal renal function and susceptible organisms. However, it remains unclear whether nomogram-based dosing would increase the frequency of achieving β-lactam target concentrations.123 Moreover, this method is aimed at achieving a predefined PK target, which may be different between patients.129Regarding carbapenems, three studies developed a dosing nomogram for continuously infused meropenem based on creatinine clearance  were used to detect antimicrobials in clinical specimens. These assays are less expensive and can be a point-of-care test. Traditional LFAs are used for qualitative analysis. Recently, there has been improvements in affordable and compact detection devices, such as smartphone cameras, to support analysis and quantification of immunochromatographic results.144 However, detection of smaller molecules such as antibiotics is more challenging because of the lack of immunogenicity. Therefore, LFAs for antibiotics often use a competitive technique instead of the common sandwich technique. The competitive technique has a major advantage in its low lower limit of quantitation (LLOQ). Therefore, the competitive technique is commonly used for detection of residual antibiotics in animal products.146 The major limitation of this technique is that it usually has a low upper limit of quantitation (ULOQ), making quantification of drug concentration within a clinically relevant range difficult. Newer techniques may increase the ULOQ. For example, a recently tested LFA for tenofovir TDM in clinical specimens has the ULOQ of as high as 100 mg/L.148Quantitative LFAs have been evaluated as a tool for TDM for large molecules such as immunosuppressive drugs in serum.149 TDM for β-lactams is usually conducted in plasma.150–153 Because of the unreliability of immunoassay, chromatographic methods are frequently used. The mostly commonly used method is liquid chromatography (LC).154 Detectors for chromatography also vary between laboratories, ranging from simple detectors such as ultraviolet (UV) to mass spectrometry (MS).131 MS has the highest specificity, although it is more expensive and requires time-consuming optimization.For antibiotics such as β-lactams, commercial TDM assays are not available.155 Although chromatography-based methods have a relatively short run time at 3–30 min,156 the typical laboratory workflows increase the average turnaround time to 18–24 h.157 In a study in real-world practice, this number was as high as 4 days,158 making prompt dose adjustment for critically ill patients challenging.Because of the sophistication, the adoption of β-lactam TDM is limited to large medical centres. Moreover, the turnaround time is usually prolonged.131 Biosensors can measure serum levels from collected blood specimens or directly from patients. They can be minimally invasive and wearable, supporting the measurement of other biological fluids, which can be linked to the sites of infections. Biosensors can be classified according to their detection method, sensing mechanism, functionality or degree of invasiveness.131 Common antibiotic detection methods include optical and electrochemical sensors.159A biosensor is a device that transforms the interaction between antibiotics and bioreceptors into a quantifiable signal.160–162 Their main limitations are the lower specificity from the background signal and the inability to be used as a wearable biosensor.Optical sensors are the most common method. These devices can measure the levels directly from the blood without using chromatography. They can be portable, offer high sensitivity and fast turnaround time.159 Bioreceptors for this type of sensor include antibodies,163 enzymes164 and aptamers.165 Their limitations are the lower specificity from non-specific binding and the low ULOQ for some methods and high LLOQ for others.Electrochemical sensors can work with small sample volume and can be miniaturized to allow on-site monitoring.166After receiving the results of serum drug levels, several different dose-adjustment strategies are being implemented. These strategies include dose adjustment made specific to the intervention, dosing nomograms and software for dose optimization.168 Some studies increased the dose based on the degree of the differences. For example, one study suggested increasing antibiotic dose by one step if the levels were within 50%–100% of the target, or two steps if the levels were within 10%–50% of the target.169Specific intervention is the least sophisticated method. Dosing adaptation is usually simplified according to the difference between the targets and the levels measured. For example, some studies increased the frequency of the same dose by 25%–50% when the concentration was below the target and reduced the dose by 50% when the concentration was above 10 times the expected dose.170 this may be the most feasible method for adoption in general practice. However, it is the least reliable method to attain the target levels.Because some studies found that physicians may not adhere to consulting pharmacy service advice for dose adjustment,171 Nomograms are also available for β-lactams but they have not been validated.127Dosing nomograms are well described and validated for aminoglycosides and vancomycin. However, they cannot be used in critically ill patients as most PK data are derived from non-critically ill patients.129Software for dose optimization is designed for more accurate dose adjustment. It can be categorized into two methods: linear regression models; and models that incorporate Bayesian forecasting or artificial intelligence.172Linear regression (one-compartment model) is the least complicated method, which uses an algorithm to calculate a drug clearance rate from antibiotic levels derived from two different times. This method performs better than using a nomogram but still does not include other variables from the patients.a priori) with the current PK information (a posteriori) to suggest the dose and the expected PK results after the adjustment.120 Many validated software programmes are available, both commercially and for free.173–175 This method can suggest the dose adjustment even from a single measured drug level. Moreover, it can calculate even after the first few doses before the steady-state concentration. These programmes demonstrated higher PK/PD target attainment for meropenem dosing.176 However, it failed to achieve target attainment for dose adjustment based on the concentration in a recent study.177Because of the limitations of the linear regression model, most software now uses real-time Bayesian forecasting. This method combines the population model , regardless of antibiotic class, resulted in higher clinical cure rate with no significant difference in clinical failure.185 ESBL-E was responsible for about half of isolated pathogens. Another randomized controlled trial in patients with intra-abdominal infection and adequate source control found that 4 day duration was comparable to antibiotic discontinuation after clinical resolution in term of mortality, recurrent infection or surgical site infection.186For intra-abdominal infections, a randomized controlled trial in patients with post-operative intra-abdominal infection found that 8 day duration was equivalent to 15 day duration in terms of mortality and length of stay.70 Another randomized controlled trial also found that 8 day duration was non-inferior to 15 day duration in terms of clinical cure and mortality, but also found a significantly higher rate of infection in the 8 day arm.187For ventilator-associated pneumonia, which is commonly caused by Gram-negative pathogens, a randomized controlled trial found that 8 day duration was non-inferior to 15 day duration in terms of mortality or recurrent infection. However, subgroup analysis found that patients with non-fermenting Gram-negative infection had a significantly higher rate of recurrent infection in the 8 day arm.In the era of resistance, it is becoming difficult to restrict broad-spectrum antibiotic use. Precision prescribing, involving selection, dosing and duration of antibiotic, may help prevent CROs and associated hospital-acquired infections, and play a key role in infection prevention and control strategies. Future work must focus on improving precision antibiotic prescribing, not only to improve patient outcomes and reduce toxicity, but also to prevent resistance.Current evidence suggests that the best option is selecting alternative agents to carbapenem with comparable efficacy. More work is required to investigate the effect of different carbapenem-sparing treatment options on CRO emergence, and their efficacy against ESBL-E as empirical and targeted treatment.If carbapenems are unavoidable, the options include the improved dosing of the carbapenems, aiming to achieve defined PK/PD targets for efficacy, and prescribing shortest effective duration. However, to achieve target levels for minimal resistance development and maximal treatment outcome, innovation and new technological solutions are needed to provide rapid antibiotic concentrations for prompt dose adjustment.


To characterize opportunities to postprescriptively modify antibiotic prescriptions initiated for treatment of suspected urinary tract infection (UTI) in nursing homes.Cross-sectional cohort study.Data from the health records of residents treated for UTI between 2013 and 2014 in 5 Wisconsin nursing homes were abstracted using a structured approach. Explicit definitions were used to identify whether the prescribed antibiotic could have been stopped, shortened, or changed to a nonfluoroquinolone alternative. Antibiotic treatments appropriately modified by study nursing home providers in real time were not considered modifiable. Identification of >1 potential modification opportunity  per antibiotic treatment event was permitted.In total, 356 eligible antibiotic treatment courses among 249 unique residents were identified. Only 59 antibiotic courses prescribed for treatment of suspected UTI (16.6%) were not amenable to any modification. Discontinuation of treatment due to lack of signs or symptoms of infection was the most frequently identified potential modification opportunity (66.2%). Although less common, substantial numbers of antibiotic treatment courses were potentially amenable to shortening (34%) or agent change (19%) modifications. If applied in concert at 72 hours after antibiotic initiation, stop and shorten modifications could eradicate up to 1,326 avoidable antibiotic days, and change modifications could remove a 32 remaining avoidable fluoroquinolone days.Substantial opportunity exists to enhance the quality of antibiotic prescribing for treatment of suspected UTI in nursing homes through postprescriptive review interventions. Additional studies examining how to best design and implement postprescriptive review interventions in nursing homes are needed. A resident living in a nursing home for at least 6 months has a >50% risk of being prescribed at least 1 antibiotic course. Urinary tract infection (UTI) is the most frequent indication for antibiotics in nursing homes, and fluoroquinolones are the most commonly prescribed antibiotic class for UTIs. Antibiotic treatment is associated with several possible harms, such as adverse drug reactions, Clostridioides difficile infection (CDI), and risk of colonization with and spread of multidrug-resistant organisms. Fluoroquinolone use is associated with additional risk of tendinopathy, confusion, and QT prolongation. Many of these harmful events are potentially avoidable; it has been estimated that 25%–75% of antibiotic use in nursing homes is inappropriate.Antibiotic overuse and misuse are common problems in nursing homes. Between 8% and 11% of the 1.4 million individuals who reside in nursing homes are treated with an antibiotic each day. Many of the efforts to improve antibiotic prescribing practices in nursing homes employ preprescriptive interventions focused on avoiding initiation of unnecessary treatments. The use and effects of postprescriptive interventions, such as prospective audit and feedback as well as antibiotic timeouts, have been less well studied in this setting. Achieving a better understanding of how much opportunity there is to modify antibiotics after their initiation is needed to support the development and successful implementation of effective postprescriptive stewardship interventions in the nursing home setting.Adoption of programs and interventions aimed at improving the quality of antibiotic prescribing is increasingly common in nursing homes.The objective of this study was to characterize the frequency and types of potential postprescriptive modifications of antibiotics initiated for treatment of suspected UTI in nursing homes, specifically opportunities to stop, shorten, and/or change to nonfluoroquinolone alternatives.Data for this study were collected during a retrospective cross-sectional chart review study conducted in 5 Wisconsin nursing homes between January 2013 and September 2014. Participating nursing homes were purposively sampled for their geographic proximity to the University of Wisconsin–Madison. Trained research staff collected and managed study data using REDCap electronic capture tools hosted by the Department of Medicine at the University of Wisconsin School of Medicine and Public Health. Resident identifiers were not recorded as part of this study, and the Human Subjects Institutional Review Board at the University of Wisconsin School of Medicine and Public Health approved this study protocol.An antibiotic course was included in the study if it was (1) prescribed for treatment of a UTI, (2) administered systematically, and (3) initiated in the nursing home or following a clinic or emergency department (ED) encounter without an intercurrent hospital admission. Antibiotic treatment courses prescribed for an indication other than UTI or initiated during hospitalization and continued after transfer to the nursing home were excluded from the analysis. Research staff reviewed resident medication administration records, nursing staff and provider records, provider orders, and results of laboratory and imaging studies documented or collected 72 hours before and through the second day of eligible antibiotic treatment courses. Information on the antibiotic agent prescribed, duration of treatment, and culture results or susceptibilities, as well as pertinent patient factors , were recorded. The appropriateness of each antibiotic treatment course was assessed using prevailing explicit criteria.Each antibiotic treatment course was evaluated for 3 potential modification opportunities (PMOs): stop, shorten, or change to a nonfluoroquinolone alternative (described below). Opportunities to change to an active therapy when then initial agent was inactive was not specifically reviewed. Modification opportunities were not considered mutually exclusive, and identification of >1 PMO per antibiotic treatment course was possible.The antibiotic treatment course was considered potentially amenable to discontinuation in the absence of supportive clinical and microbiological findings. A “stop PMO” was identified when McGeer or Loeb clinical criteria were not satisfied or when urine cultures were negative even if Loeb clinical criteria were met. Cases were excluded from review if there was not enough information in the medical record, if the antibiotic was started in error, if the patient was transferred to the hospital prior to completion of therapy, if urine culture data became available within 48 hours of discharge, or if the culture data became available after resident discharge.Microbiologically active antibiotic duration was calculated based on days of antibiotic treatment that targeted the urinary pathogen(s) recovered from culture. Antibiotic courses were excluded from review if there was not enough information in the medical record, if the antibiotic was started in error, if the patient was transferred to the hospital prior to completion of therapy, if the provider stopped therapy due to negative culture results, or if effective antibiotic duration could not be calculated due to either lack culture data or prescription of an effective antibiotic agent. Antibiotics with an effective antibiotic duration of >7 days were considered amenable to potential shortening.Fluoroquinolone antibiotic courses for which urine culture data were available and results had been acquired at least 48 hours before the resident was discharged from the facility were considered for review. Cases were excluded if there was not enough information in the medical record, the antibiotic was started in error, the patient was transferred to the hospital prior to completion of therapy, or if a nonfluoroquinolone antibiotic was prescribed. If the available urine culture data indicated an organism susceptible to at least 1 oral nonfluoroquinolone alternative , the antibiotic was considered potentially amenable to modification.t tests. A 2-tailed P value of <.05 was considered statistically significant. Data and statistical analyses were conducted in R version 1.3.1073 software .The proportions of antibiotic courses amenable to each PMO and days of microbiologically active antibiotic duration were calculated. Comparisons of microbiologically active antibiotic durations between nursing home resident groups were performed using In total, 1,451 antibiotic treatment courses were identified during the cross-sectional study. Antibiotic treatment courses initiated in the hospital (n = 599), including 185 courses for treatment of UTI, were excluded from further analysis. Antibiotic courses initiated in the nursing home or clinic or ED for reasons other than the treatment of UTI (n = 485) were also excluded. Of the 367 antibiotic courses initiated for treatment of suspected UTI, 11 were excluded from the study due to insufficient data to assess any of the 3 treatment modification opportunities (n = 10) and a treatment course that was started in error (n = 1). The final study sample of 356 antibiotic treatments were prescribed to 249 unique residents, with a mean of 1.43  antibiotic courses per resident. The average age of the residents included in this study was 84.3 . Participants were predominately female  and one-fifth had an indwelling urinary catheter . Moreover, 8 different antibiotic classes were prescribed for initial treatment of suspected UTI in this study  was justified based on the presence of suggestive resident symptoms and positive urine culture data. Another 28 treatment courses (8.0%) were stopped appropriately by the treating provider either due to negative urine culture results or lack of suggestive symptoms within 48 hours. The remaining 233treatment courses  were continued despite not meeting McGeer criteria or Loeb criteria with positive urine culture. Figure P = .03). We detected no difference in average microbiologically active antibiotic duration between residents with or without an indwelling urinary catheter (P = .93). Of the 286 microbiologically active antibiotic treatments, 121 (42.3%) were prescribed for 7 days or fewer. The remaining 165 microbiologically active antibiotic treatment events (57.7%) were prescribed for >7 days and could have potentially been shortened, resulting in a total of 442 potentially avoidable days of antibiotic therapy, with a mean of 2.68 avoidable days per patient.In total, 286 antibiotic courses were evaluated for a “shorten PMO.” The average microbiologically active antibiotic duration was 7.9 days (SD 2.8) with slightly longer courses prescribed for male compared to female residents  of the eligible antibiotic courses. The 117 cases in which a fluoroquinolone was prescribed, and urine culture data were available for review were assessed for a nonfluoroquinolone alternative PMO. In 28 antibiotic courses (23.9%), fluoroquinolones were appropriately prescribed for an organism that was resistant to other oral antibiotic options. Providers changed to a nonfluoroquinolone alternative in a further 22 antibiotic courses (18.8%) after the urine culture data became available. Despite the availability of a nonfluoroquinolone alternative, 67 (57.3%) of the initially prescribed fluoroquinolone antibiotic courses were continued. Implementation of nonfluoroquinolone alternative PMO at 72 hours could remove up to 374 fluoroquinolone days of therapy.After examining the eligible antibiotic treatment courses for each potential modification opportunity, only 59 (16.6%) were deemed to be not amenable to any modification. The remaining antibiotic courses  were eligible for at least 1 PMO: 154 (43.3%) were eligible for 1 PMO, 118 (33.1%) were eligible for 2 PMOs, and 25 (7.0%) were eligible for all 3 PMOs  is the most employed and effective form of postprescriptive stewardship intervention in hospitals. are imperfect, which could have contributed to the overestimation of modification opportunities. Third, the current study was conducted using data on nursing home antibiotics that were prescribed in 2013 and 2014. Although national nursing home antibiotic prescribing patterns were stable from 2012 through 2016, i the 2016 release of regulations requiring nursing homes to implement antibiotic stewardship programs may have altered prescribing practices in ways that may limit the generalizability of our findings. Finally, our study is based on sample of only 5 nursing homes in Wisconsin, which may further limit the generalizability of our findings.This study had several limitations. First, the data used in the current study were collected using information available in resident health records. Important aspects of resident health status may have been omitted from these records, which could have led to overestimation of the number of modification opportunities identified in this study. Second, the explicit criteria employed during the assessment of the clinical appropriateness of antibiotic treatmentsIn summary, we identified a high frequency of postprescribing modification opportunities among antibiotic courses prescribed for the treatment of suspected UTI in a sample of Wisconsin nursing homes. Our study identified opportunities to discontinue, shorten, and modify these treatments, and only a minority of antibiotic prescriptions were not amenable to at least 1 modification opportunity. Although these results likely represent a best-case estimate of the amount of antibiotic modification achievable through postprescriptive interventions, even a moderate to large attenuation of findings would support a potential role for this stewardship approach in nursing homes. Additionally, our study excluded review of hospital-initiated UTI treatment courses, which may provide additional opportunities to enhance the quality of UTI antibiotic prescribing at the transition between hospitals and nursing homes. The actual returns achievable with postprescriptive interventions in the real world , their cost-effectiveness and issues related to their implementation in nursing homes require further study.