Reinforced concrete (RC) columns typical of existing structures often exhibit premature failures during seismic events  due to the poor quality concrete and the absence of proper seismic details in the potential plastic hinge region. The Fiber Reinforced Polymers (FRP) externally bonded reinforcement is known to be a valid technique to improve the shear capacity or the ductility of existing RC columns. However, few experimental tests have proven its effectiveness in the case of columns affected by shear interaction mechanisms. In this work, the behavior of existing RC columns with border line behavior between flexure and shear have been investigated in the case of poor quality concrete and light FRP strengthening with local jacketing and medium quality concrete and strong FRP strengthening with local jacketing, in order to highlight the effect of concrete strength on the effectiveness of the retrofit intervention. As an alternative to FRP jacketing; the effectiveness of the Fiber Reinforced Cementitious Composite (FRCC) jacketing for the seismic strengthening of columns with highly deteriorated concrete cover or columns already damaged by an earthquake is also evaluated. Six full-scale RC columns have been tested under cyclic loading: one was used as a control specimen; four were strengthened in the potential plastic hinge region with carbon FRP (CFRP); and one was fully jacketed with FRCC. The comparison between poor and medium quality concrete columns showed that the CFRP local jacketing is more effective in the case of poor quality concrete. The FRCC jacketing appears to be a sound repair strategy and a suitable alternative to the FRP jacketing in case of poor quality; however, more experimental research is needed for improving this retrofit technique. Post-earthquakes reconnaissance ,2,3,4 anTo prevent the shear interaction mechanism and improve the performance of existing RC members, the use of two strengthening techniques has been herein investigated and compared: the partial jacketing of the plastic hinge region with Carbon Fiber Reinforced Polymers (CFRP) and the full-length jacketing with Fiber Reinforced Cementitious Composite (FRCC).It is well known that the seismic performance of RC members can be improved significantly by providing an FRP external jacketing, especially in the potential plastic hinge region. A large number of experimental tests conducted on FRP jacketed RC columns under cyclic actions can be found in the literature ,17,18, bHowever, in the case of poor quality concrete columns with heavily deteriorated concrete cover or columns already damaged by a seismic event, the original cover should be totally removed and replaced with a new one before the application of the FRP jacketing. Thus, an alternative strengthening technique could be the replacement of the original cover with a Fiber Reinforced Cementitious Composite (FRCC) jacket. This strengthening solution reduces time and costs of intervention if compared with the externally bonded FRP technique . HoweverIn the present work, an experimental program on six full-scale RC columns representative of existing structures and strengthened with two different jacketing techniques (CFRP and FRCC) is presented.In the first part of the work, the effectiveness of CFRP jacketing in the potential plastic hinge region of existing RC columns, which exhibit a borderline behavior between flexure and shear, is investigated on four columns. The effect of different concrete compressive strength  and FRP reinforcement ratio on the jacketing effectiveness have been investigated. A detailed analysis of the strain distribution along the external jacketing is also reported. The last part of the present work investigates the use of the FRCC jacketing for the repair/strengthening of poor quality concrete RC columns already damaged by a seismic event, as an alternative to the externally bonded FRP technique. One column with poor quality concrete was pre-damaged and then repaired/strengthened with FRCC jacketing. The performance of jacketed specimens was compared in terms of failure mode, lateral capacity and ductility, stiffness degradation, energy dissipation and damage evolution.s > d/3, where d is the cross-section effective depth, and shear contribution provided by the reinforcement (sV) lower than 3/4 of the total shear capacity. A borderline behavior between flexure and shear was expected at failure, according to refined shear capacity models [Full-scale experimental tests on six square RC columns were performed under constant compressive axial load and cyclic lateral loading. The columns were designed accordingly to past Italian codes’ minimum requirements and old construction practice, in order to be representative of real existing structures. No longitudinal reinforcement along the cross-section secondary direction have been included, according to what was found in heavily damaged columns after the L’Aquila earthquake (2009) . Transvey models ,14. fc = 15 MPa), was used as the control specimen to confirm the predicted failure mode. Four columns were locally strengthened in the potential plastic hinge region with a CFRP jacketing for investigating the effectiveness of this strengthening intervention in case of columns with borderline behavior between flexure and shear. The effect of concrete strength on the CFRP jacketing effectiveness was evaluated for two classes of concrete: two columns with poor quality concrete (fc = 15 MPa) and two with medium quality concrete (fc = 30 MPa) were tested. Poor quality concrete columns were strengthened with a light CFRP jacketing  whereas medium quality concrete columns were jacketed with a strong reinforcement . Two types of CFRP composite material (named FRPa and FRPb) were adopted, to analyse the influence of elastic stiffness and ultimate strain of the strengthening system on the specimen behavior.One column, characterized by poor quality concrete . The foundation block and the column of each specimen were cast in two different phases in order to reproduce the discontinuity of concrete at the column-foundation interface, as is common practice in concrete casting procedures.The specimens were cantilevers , made by a column and a foundation block . No additional longitudinal reinforcement, which could help in shear resisting mechanism, was provided in the column secondary direction. The concrete clear cover thickness was 20 mm on each specimen.Specimens had a square cross-section 300 × 300 mmw = 0.2%). A reduced spacing was adopted in the zone of load application to avoid localized damages.Transverse reinforcement was made of 8 mm diameter ties, spaced at 150 mm apart . The specimens’ geometry along with the strengthening intervention details are reported in The columns total height was 1800 mm, but the lateral load was applied at a distance of 1500 mm from the foundation block, in order to simulate the behavior of a typical 3000 mm height column, assuming that shear length R = 20 mm, in order to avoid premature rupture of the fibers. Then the concrete surface was treated with the primer and the carbon sheets were applied and impregnated with epoxy-resin, as depicted in CFRP strengthened specimens were locally jacketed at the plastic hinge region with continuous uniaxial CFRP sheets with fibres perpendicular to the column longitudinal axis, for a length of 500 mm from the foundation block. Before applying the external reinforcement, the columns corners were rounded with radius The FRCC jacketed specimen (CL_FRCC) was pre-damaged up to a residual drift ratio equal of slightly greater than 1.5%, in order to be representative of columns with poor quality concrete heavily damaged by a seismic event . After tfc, derived for each specimen is reported in fyl = 531 MPa for longitudinal reinforcement and fyw = 525 MPa for transverse reinforcement were derived from tensile tests on coupon bars. The main mechanical properties of the materials are summarized in 2 but different ultimate strain and elastic modulus were used. The mechanical properties of the dry fiber material types declared by the manufacturers  are also reported in As aforementioned, two types of CFRP composite material, FRPa and FRPb, with the same unit weight of 600 g/mThe FRCC material is characterized by a high-strength cement-based mortar with very small aggregates (maximum size 2.5 mm) and plain short steel fibres , see fc,FRCC, elastic modulus Ec,FRCC, ultimate compressive strain εcu and tensile strength ft,FRCC. Stress-strain curves for the FRCC material in both compression and tension are depicted in To characterize the mechanical properties of the adopted FRCC material, compression tests on cylindrical specimens  and direct tension tests on dog-bone coupon tests  were performed under displacement control. The average mechanical properties derived from experimental tests on FRCC materials are summarized in The full-scale columns were subjected to constant compressive axial load and horizontal cyclic displacements. The lateral displacements were applied at a distance of 1500 mm from the base cross-section by using an electrohydraulic actuator  integrated in a steel reaction wall and a 500 kN load cell was used to measure lateral loads. A detailed description of the test setup and relevant instrumentation is reported in  and showν = N/Acfc, where N is the compressive axial load, Ac is the concrete gross area and fc is the mean cylindrical concrete strength) equal to 0.1 and a lateral cyclic loading under drift control , see All the specimens were subjected to an axial load ratio , to monitor the distribution of axial strains along the height of confined region and for checking strain concentration at corners. The SGs scheme for CFRP strengthened specimens is depicted in Strain gauges  were placed at the mid-height and mid-span (termed M) of each CFRP jacketed column side, with the aim of monitoring axial strains in the external reinforcement. Additional SGs were installed on the flexural sides (side A and side C), at 50 mm from the top and bottom of the sheet (named T at top and B at bottom) and at corners along the mid-height  and transverse reinforcement (on shear sides B and D) before the FRCC jacket casting. The strain field on the shear side of the FRCC jacket was monitored by means of the Digital Imagine Correlation (DIC), see The main outcomes derived from the experimental program are described in the following sections in terms of the global behavior of columns and relevant failure mode as well as the effectiveness of the strengthening solutions.Fmax and ΔFmax, drift ratios at apparent yielding Δy, drift ratios at conventional failure, Δ0.8Fmax, defined as the values corresponding to 80% of the peak force on the envelope curve, and ductility factor, μΔ, defined as the ratio between ultimate and apparent yielding drift, and percentage of increased ductility due to the strengthening with respect to the control specimen in the positive and negative load direction, respectively, ΔμΔ. The apparent yielding drift used for the ductility factor evaluation is assumed as the intersection point between the secant at the 70% of the peak strength and the horizontal at the peak strength on the experimental load-drift curve.The experimental lateral load-drift relationships for the control specimen, CL, and the four columns strengthened with CFRP jacketing, CL_FRPa, CL_FRPb, CM_FRPa, CM_FRPb, are depicted in In terms of strength capacity, the CFRP jacketing of plastic hinge region has no significant influence on the peak force of columns under combined axial load and bending moment. Indeed, control column CL achieved peak strength of 86.1 (−85.4) kN and CFRP strengthened specimen, CL_FRPa and CL_FRPb, reached values of 86.0 (−86.5) kN and 88.2 (−87.2) kN, respectively. Specimens characterized by medium quality concrete, CM_FRPa and CM_FRPb, achieved similar values of flexural capacity: 101.3 (−107.1) kN and 114.1 (−105.5) kN for CM_FRPa and CM_FRPb, respectively. The FRCC jacketing produced a slight increase in flexural capacity with respect to that achieved during the pre-damage phase: the peak strength increased from 81.6 (−84.0) kN to 94.8 (−104.7) kN, as reported in In terms of ductility, poor quality concrete specimens CL_FRPa and CL_FRPb achieved a ductility factor of 7.2 (6.7) and 7.8 (6.5), respectively. Thus, specimen strengthened with FRPb type, characterized by higher axial rigidity, achieved a greater ductility factor with respect to specimen strengthend with FRPa type. This is due to a lower apparent yielding drift ratio experienced by CL_FRPb with respect to specimen CL_FRPa. In comparison with the control column, the CFRP local jacketing increased the ductility by 67%–60% and 81%–55% for specimens CL_FRPa and CL_FRPb, respectively. Medium quality concrete strengthened specimens achieved ductility factors comparable with those of poor quality concrete strengthened specimens: CM_FRPa and CM_FRPb reached ductility factors of 8.2 (7.5) and 6.2 (6.7), respectively. Thus, the strong CFRP strengthening combined with a medium quality concrete did not significantly improve the deformation capacity of members. Conversely, the CFRP local jacketing is more effective in the case of poor quality concrete columns.The poor quality concrete FRCC jacketed specimen ductility factor was 6.8 (7.1). Thus, an improvement of 58%–69% with respect to control column was observed. Also in this case, this improvement in ductility factor is related to the lower apparent yielding drift ratio experienced from specimen CL_FRCC with respect to the control column.A deep analysis of the specimens’ failure mode and of the strengthening systems behavior is discussed in the following.In the control specimen, slight horizontal flexural cracks appeared at the time of the first cycles of loading in correspondence to steel transverse reinforcement. Starting from a drift ratio of 1.2%, one small diagonal cracks appeared on both shear sides of the control column. As the displacement demand increased (3.2%) the diagonal cracks expanded and extended on the shear sides of the specimen. At a drift ratio of 4.8%, the buckling of a corner longitudinal bar caused the spalling of the concrete cover. After the imposed drift ratio of 6.4%, the concrete in the plastic hinge region was highly deteriorated and a large shear crack crossing the core was opened. The control column damage evolution is depicted in Thus, the specimen exhibited a flexural behavior up to the imposed drift ratio of 6.4%, when a sudden drop of lateral capacity and stiffness caused by the shear interaction in the plastic hinge region was observed see a and theThe control specimen confirmed the expected failure mode of the column that was influenced by the shear interaction mechanism. Theoretical predictions for the shear capacity of the control column, according to degrading capacity models proposed by Biskinis et al. 2004  and SezeThe CFRP local jacketing of the potential plastic hinge region avoided the sudden drop of lateral capacity observed in the control specimen and, consequently, the shear interaction mechanism, as observed from the comparison of load-drift capacity curves in In particular, poor quality concrete specimen CL_FRPa achieved the conventional flexural failure caused by the strength degradation. No FRP tensile rupture or debonding phenomena were recognized on the external CFRP jacketing. However, longitudinal cracks between fibers, caused by the high lateral pressure exerted by the deteriorated concrete inside the jacket, were observed at a distance of 50 mm from the base see a.Specimen CL_FRPb, also characterized by poor quality concrete but strengthened with a composite material with higher axial rigidity with respect to CL_FRPa, experienced a flexural behavior up to a drift ratio of 9.6%, when the tensile rupture of one longitudinal rebar caused a drop of the lateral capacity and the test was arrested. Thus, in this case, the conventional failure was not achieved. Longitudinal crack between fibers was observed on the jacket, but in a lower ratio with respect to specimen CL_FRPa see b. The reThe medium quality concrete specimen CM_FRPa experienced the flexural conventional failure in the positive load action direction, whereas in the negative one the tensile rupture of a longitudinal rebar was achieved for a drift ratio of −9.6% see d. The coConversely, specimen CM_FRPb did not achieve the conventional failure due to a local rupture of a longitudinal steel bar during the second repetition of the last cycle, which caused a degradation of lateral strength, and the test was arrested. A few small diagonal cracks were detected on the shear sides in the unconfined region, but no significant strength degradation due to shear was recorded. In this case, no longitudinal cracks between fibers were observed, see To compare the effectiveness of the strengthening systems for different concrete strength and CFRP axial rigidities, the effective strains on the CFRP jacket due to combined shear action and concrete lateral dilatation were investigated. The CFRP strains were measured by means of strain gauges located at mid-span and mid-height of each side of the specimens. Additional strain gauges were also installed at the top and bottom and near corners on flexural sides.εf, and ultimate composite material strain, εfu, are depicted in Hconf . It should be noted that carbon fibers in the plastic hinge region work simultaneously for shear action and for confinement, contrasting the concrete lateral dilatation caused by a non-uniform distribution of compressive stresses given by the combined action of axial load and bending moment. Thus, in the positive load action direction, column side C is subjected to compression whereas side A is in compression for very small imposed drift ratios, otherwise it is in tension.Firstly, the vertical strain profiles on CFRP sheets were analyzed, to monitor the effectiveness of the strengthening system along the height of the jacketed region. In particular, the ratios between CFRP experimental strains recorded at positive peak drift ratios of each cycle, εfu and 25.6%εfu were recorded at the bottom of specimens CL_FRPa and CL_FRPb, strengthened with one ply of CFRP. Conversely, peak strain of 31.9%εfu and 14.0%εfu were recorded for specimens CM_FRPa and CM_FRPb, strengthened with two plies of CFRP, respectively.The carbon fibers effective strains recorded on CFRP sheets are linearly distributed along the confined region height. Strain concentrations are observed at the bottom of all specimens, where the longitudinal cracks between fibers were developed. These stress/strain concentrations are mainly caused by the high damage of concrete inside the CFRP jacket, which is disaggregated and exerts a high lateral pressure at the column base. Peak strains ratios of 34.9%The distribution of fibers axial strains along the perimeter of the specimens was also investigated. The horizontal strain ratio profiles recorded at the mid-height of each columns side are reported in The horizontal strain ratios were not perfectly symmetric for the positive and negative load action directions for almost all the CFRP strengthened specimens. The axial strains were not uniformly distributed along the columns perimeter of all specimens, as visible in εfu, expect for a peak of 16.6% εfu recorded on the corner of side A for specimen CL_FRPa.The axial strains ratios recorded at the mid-height were usually smaller than 10%It should be also observed that strain ratios recorded on specimen CM_FRPb d are parNo significant differences in terms of fibers effective strains can be observed among specimens with different concrete compressive strength or composite axial rigidity.As aforementioned, the specimen was first pre-damaged, according to the load protocol depicted in The repaired and strengthened specimen exhibited a flexural behavior up to a drift ratio of 6.4%, see The longitudinal strain fields derived from the digital imagine correlation (DIC) for specimen CL_FRCC before and after the jacketing at a drift ratio of 3.2% in both positive and negative load action directions are depicted in To better compare the performance of CFRP or FRCC jacketed specimens with respect to the control specimen, the envelope curves for both positive and negative drift ratios are reported in From the comparison of the envelope curves in Both specimens, characterized by medium quality concrete and strengthened with two plies of CFRP, had a larger initial lateral stiffness if compared with all the poor quality concrete specimens. Specimen CM_FRPa exhibited a performance very similar to poor quality concrete strengthened specimens but with a faster strength degradation in the post-peak phase. Conversely, specimen CM_FRPb had a poor performance if compared with companion specimen CM_FRPa, with a strong post-peak strength degradation in the positive direction caused by the premature rupture of the longitudinal bar.Specimen CL_FRCC exhibited a very similar response of control column during the pre-damage phase b. After In the following, the cyclic performance of specimen retrofitted with FRCC jacketing is compared with those of CFRP strengthened specimens in terms of stiffness degradation, energy dissipation and damage index. This clearly show that the system was able to repair the column but the effectiveness in terms of strengthening was limited due to the attainment of a premature failure mode at the column base.K, and the theoretical elastic stiffness, Kflex = 3EIg/SL3 (where E is the concrete elastic modulus and Ig is the gross section inertia), is plotted for the six RC columns as a function of the drift ratio in K/Kflex for tested specimens are also summarized in To investigate the effects of the strengthening techniques on the columns stiffness degradation caused by the damaging under cyclic loading, the experimental stiffness was computed as the peak-to-peak secant stiffness of the first cycle of each imposed drift ratio. The ratio between the experimental secant stiffness, K/Kflex is 33% in the case of the control column, 34% for specimen CL_FRPa and 41% for specimen CL_FRPb. Specimens with medium quality concrete, CM_FRPa and CM_FRPb, achieved initial ratios of 43% and 53%, respectively. However, after a drift ratio of 1.6%, the stiffness degradation followed the same parabolic trend up to failure for all specimens.At first cycle, the ratio The FRCC jacketed specimen achieved a greater lateral stiffness (53%) with respect to the control specimen for first cycles up to a drift ratio of 2.4%. Compared with CFRP strengthened specimens, specimen FL_FRCC experienced a very similar stiffness degradation as specimen CM_FRPb, characterized by a medium quality concrete and strengthened with two plies of CFRP.The cumulative dissipation energy due to the cyclic loading, evaluated at the end of each cycle as the area below the force-drift hysteretic curve, is reported as a function of the drift ratio for the six specimens in A slight difference in the cumulative dissipation energy trend is observed for the control specimen, CL, and the specimens strengthened with one ply of CFRP, CL_FRPa and CL_FRPb. Conversely, specimens CM_FRPa and CM_FRPb, characterized by medium quality concrete and strengthened with two plies of composite system, dissipated more energy with respect to other specimens, since from the first cycles. Thus, the combination of higher confinement effect and better quality concrete reduced the pinching phenomenon. The FRCC jacketed specimen CL_FRCC dissipated more energy with respect to the undamaged control specimen and the other two poor quality concrete strengthened specimens, since the first cycles. This is mainly related to the reduced pinching effect observed in the force-drift relation in The damage evolution is investigated by means of a cumulative damage index, which give a numerical indication of the damage for the RC member. This cumulative index is obtained by cumulating the damage achieved during each loading cycle.d is the peak displacement achieved at each cycle, du is the specimen ultimate displacement, Fy is the yielding strength and dE is the increment in absorbed hysteretic energy. The constant parameter β gives the ratio of the incremental damage caused by an increase of the maximum response to the normalized incremental hysteretic energy and it is taken equal to 0.25 for slightly reinforced structures [Recent research showed that the RC members damage is dependent on the residual deformation and on the energy dissipated at the end of each cycle ,30,31,32The damage index, DI, calculated at each cycle for all specimens is reported in Six full scale RC columns, representative of existing members with a borderline behavior between flexure and shear, were tested under constant axial load and cyclic lateral displacements. Four specimens were jacketed in the potential plastic hinge region with CFRP sheets and the influence of concrete quality (poor and medium) and composite system axial rigidity were investigated. The use of a FRCC jacketing as a valid alternative to FRP strengthening has been also investigated for poor quality concrete columns. The comparison between strengthening techniques has been developed.The control specimen, non-conforming to current standards, was not able to fully develop its ductility capacity, due to the buckling of longitudinal bars and the shear interaction mechanism, as typically observed in damaged structures after recent earthquakes.Specimens jacketed with CFRP in the potential plastic hinge region experienced a flexural behavior avoiding the shear interaction mechanism, with significant ductility improvement with respect to the control specimen. The CFRP jacketing were more effective in the case of poor quality concrete columns. The axial rigidity of composite system influenced the columns initial lateral stiffness and the post-peak strength degradation.FRCC jacketing can be seen as a viable alternative to FRP external reinforcement, since the jacket avoided failure phenomena like bars bucking and shear interaction mechanism and significantly reduced the concrete deterioration. Furthermore, an increase in lateral capacity and energy dissipation was observed.More research is needed to avoid the rocking behavior, by providing a proper anchorage with the foundation able to better increase the flexural capacity and the ductility.Based on experimental evidence, the following conclusions can be drawn:


Gliomas represent the most common type of malignant brain tumor, among which, glioblastoma remains a clinical challenge with limited treatment options and dismal prognosis. It has been shown that the dysregulated receptor tyrosine kinase  signaling pathways have pivotal roles in the progression of gliomas, especially glioblastoma. Increasing evidence suggests that expression levels of the RTK MET and its specific stimulatory factors are significantly increased in glioblastomas compared to those in normal brain tissues, whereas some negative regulators are found to be downregulated. Mutations in MET, as well as the dysregulation of other regulators of cross-talk with MET signaling pathways, have also been identified. MET and its ligand hepatocyte growth factor (HGF) play a critical role in the proliferation, survival, migration, invasion, angiogenesis, stem cell characteristics, and therapeutic resistance and recurrence of glioblastomas. Therefore, combined targeted therapy for this pathway and associated molecules could be a novel and attractive strategy for the treatment of human glioblastoma. In this review, we highlight progress made in the understanding of MET signaling in glioma and advances in therapies targeting HGF/MET molecules for glioma patients in recent years, in addition to studies on the expression and mutation status of MET. Gliomas comprise the most common type of primary malignant brain tumor, and except for pilocytic astrocytoma and subependymal giant cell astrocytoma, nearly all are characterized by a high recurrence rate, a lack of effective treatment strategies, high rates of mortality, and short survival times. According to the CBTRUS statistical report of the central nervous system tumors in the United States in 2010–2014, gliomas account for approximately 26.6% of all brain tumors, and glioblastoma represents the majority of gliomas (56.1%) and 47.1% of all malignant brain tumors [According to the World Health Organization (WHO) classification of tumors of the central nervous system, gliomas can be categorized into four grades (grade I to IV), among which grade IV is also called glioblastoma or glioblastoma multiforme (GBM) . MoreoveIDH1/2) mutation, telomerase reverse transcriptase (TERT) promoter mutation, 1p/19q co-deletion, BRAF mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, which can help to estimate the prognosis and direct treatment options [Genetic alterations in glioma occur frequently. Apart from histological classification, genetic diagnoses are recommended to identify the status of isocitrate dehydrogenase 1/2 (Gene amplifications or mutations are most common among receptor tyrosine kinase (RTK)/RAS/PI3K, p53, and RB signaling pathways, and approximately 86% of glioblastoma samples harbor at least one genetic event in the core RTK/PI3K pathway . RTKs arGliomas are the most lethal primary brain tumors, among which glioblastoma is characterized by a high rate of angiogenesis and aggressive invasiveness, and is resistant to all current therapeutic options. A mechanistic understanding of glioma initiation and progression is complicated by the complexity of genetic and environmental initiating events and the lack of clarity regarding the original cell or tissue. Gene mutations seem to be the most important and well-studied mechanism underlying the formation of gliomas.MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation results in its transcriptional silencing and increases chemosensitivity to temozolomide (TMZ) [MGMT promoter methylation still has not changed with current therapies. Moreover, TERT promoter mutations  were found to be associated with significantly shorter progression-free survival (PFS) and overall survival (OS) time in grade III and IV glioma patients [The tumor suppressor gene TP53, p16, and phosphatase and tensin homolog (PTEN) phosphatase control cell cycle progression and proliferation, the mutations in or loss of these tumor suppressor genes contribute to the initiation or formation of gliomas , and havde (TMZ) , the dispatients . Anotherations C2T, C250T Although receptor tyrosine kinases (RTKs) possess the roles as key regulators of normal cellular processes, the dysregulation of growth factor signaling pathways via amplification and the mutational activation of receptor tyrosine kinase (RTK)-encoding genes has been identified as important events in human glioblastomas, and approximately 86% harbor at least one genetic event in the core RTK/PI3K pathway . The ampMET proto-oncogene is located on chromosome 7q31 and HGF is located on chromosome 7q21.1 [The human e 7q21.1 –19. Earle 7q21.1 . Moreovee 7q21.1 –35.MET gene at 7q31.2 showed that gain occurred in 47% of primary and 44% of secondary glioblastomas [p = 0.004) [One study searched for genetic alterations in glioblastomas occurring with or without IDH1 mutations  using data from The Cancer Genome Atlas (TCGA) and identified 25 genes, of which 21 were located at 7q31–34 . Furtherlastomas , suggestlastomas . Further= 0.004) . However= 0.004) . In glio= 0.004) , which mApart from autocrine HGF secretion, paracrine HGF secretion from neurons and the vasculature facilitates glioma invasion and augments the chemotactic invasion and proliferation of cells that are MET-positive , 39. FurMET gene comprise another activating mutation. These include PTPRZ1-MET (ZM), which was revealed in an RNA-seq study of 272 gliomas conducted by Bao et al. [To delineate the functions of MET in glioma, it is of primary importance to understand mutations in the MET signaling pathway. One animal study showed that MET amplification is one of the most significant oncogenic events in transgenic mouse models of glioblastoma formation . Moreoveo et al. , and theo et al. . These Mo et al. , 44.MET overexpression, amplification, and mutation events, based on recent studies, are summarized in Table MET is a high affinity tyrosine kinase receptor for HGF and consists of α and β subunits. The α-subunit and the amino-terminal region of the β-subunit form the extracellular domain. The remainder of the β-chain spans the plasma membrane and contains a cytoplasmic region with tyrosine kinase activity . The intSPINT2 gene has been extensively studied in gliomas. It encodes hepatocyte growth factor activator inhibitor type 2 (HAI-2), which is a membrane-anchored protein and a serine proteinase inhibitor that hinders proteases involved in the activation of HGF [Regarding dysregulation of the HGF/MET signaling pathway, the n of HGF . In human of HGF . Moreoven of HGF . Basic en of HGF , 49. TheMicroRNAs (miRNAs) are small non-coding RNAs (containing approximately 22 nucleotides) that function in RNA silencing and the post-transcriptional regulation of gene expression; they can thus regulate oncogenes/tumor suppressors and their associated signal transduction pathways at the cellular level . Long noMET 3′-untranslated region and inhibit its expression, thus potently repressing glioblastoma cell proliferation and invasion in vitro and in vivo [MiR-34a, miR-182, and miR-144-3p levels are inversely correlated with MET levels in human gliomas and mechanistic studies have illustrated that they can specifically bind the  in vivo –54. In c in vivo . Thus, tIn addition to activating mutations in MET and the dysregulation of modulators of this RTK, the activation of downstream signaling and cross-talk between MET and other molecules have also been demonstrated in gliomas.The downstream signal transduction mediators of HGF/MET signaling in gliomas include Ras/MAPK, PI3K/Akt, and STAT pathways, which mediate a variety of cellular behaviors including proliferation, survival, cell cycle progression, angiogenesis, invasion, migration, stemness, and therapeutic resistance and recurrence in glioblastomas –20. In rSOX2 encodes a core transcription factor essential for maintenance of the self-renewal capacity of neural stem cells [Several other molecules and axes associated with HGF/MET signaling have been found to contribute to the stem cell phenotype and aberrant vascularization of glioblastomas. em cells . In miceem cells . Ganglioem cells . One stuem cells . Recentlem cells .Heat shock protein 90 (HSP90) plays a key role in processes related to protein folding, stabilization, and degradation. In cancer cells, HSP90 is present entirely in multichaperone complexes with high ATPase activity, which are involved in the processing of oncoproteins critical to cancer progression. A study by Miekus et al. demonstrated that the expression of MET receptor is dependent on the presence of HSP90 protein, and thus the HSP90 inhibitor was found to block glioma cell growth and migration through the inhibition of MET receptor expression . In searHGF/MET signaling also involves cross-talk with EGFR, HER3, and EGFRvIII. EGFRvIII induces the transactivation of JNK2 in glioblastoma cells, and then promotes increased cellular invasion through the stimulation of an HGF/MET signaling circuit –74. MoreIn human cancers, transforming growth factor-β (TGF-β) signaling can induce tumor-suppressive or tumor-promoting functions depending on the tumor type and the stage of tumor progression . NeverthThe intricacies of downstream signaling pathways and the cross-talk between MET and other molecules presented in this section indicate the complexity of gliomas; thus, drugs that inhibit single targets could be combined to achieve multiple target inhibition and obtain better treatment results.The dysregulation of MET signaling is associated with WHO grades, therapy resistance, recurrence, and poor outcomes for glioma patients –35, makiThe humanized monoclonal anti-HGF antibody, YYB-101, suppresses tumor growth in vitro and in an orthotopic mouse model of human glioblastoma; it also downregulates important cellular molecular effectors including p-MET, p-Gab1, p-FAK, MMP2, uPA/plasminogen, and Ki-67 , 80. ComRilotumumab (AMG102), a neutralizing antibody against HGF, has shown antitumor activity in vitro and in U-87 MG tumor xenograft models as a single agent . NeverthOnartuzumab, a humanized monovalent monoclonal anti-MET antibody, resulted in the inhibition of glioblastoma growth in preclinical testing . HoweverCrizotinib, an available ATP competitive selective inhibitor, was originally developed as an inhibitor of MET, but it also inhibits structurally-related tyrosine kinases such as ALK and the ROS proto-oncogene 1 (ROS1) . It effeVolitinib is a highly selective small molecule, ATP competitive MET kinase inhibitor that is being investigated as a monotherapy for MET-amplified cancers such as gastric and lung cancer. However, for glioblastoma, there has only been one preclinical study that has demonstrated good anti-tumor activities using a human xenograft model in athymic nude mice . No furtThe small molecule inhibitor, SGX523, potently inhibits MET activation and MET-dependent signaling in glioma cells and inhibits proliferation, cell cycle progression, migration, invasion, and in vivo tumor growth . HoweverINCB28060 is a potent and selective inhibitor of MET kinase and shows strong anti-tumor activity in MET-dependent mouse tumor models . HoweverCabozantinib (XL184), a potent inhibitor targeting MET and VEGFR2, exerts anti-angiogenic, anti-proliferative, and anti-invasive effects in animal xenograft models , 91. A pAltiratinib is a novel inhibitor of MET, TIE2, VEGFR2, and tropomyosin receptor family kinases. A study conducted by Piao et al. demonstrated that in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume and prolonged OS compared to those with bevacizumab alone . HoweverCM-118 is a novel lead compound against both ALK and MET with high specificity, as compared to that for 90 human kinases. It selectively inhibits the proliferation of MET-addicted U87MG cells in vitro and was found to elicit the tumor regression of U87MG xenografts in mice after oral administration at a dose of 60 mg/kg . AlthougDictyostelium cellular slime molds. It was found to inhibit the growth of human astrocytoma cells through the reduced expression and activation of MET and reduced the secretion of HGF [Brefelamide is an aromatic amide that was originally isolated from n of HGF . NeverthPLB-1001 is a highly selective, efficient, and blood-brain-barrier (BBB)-permeable MET kinase inhibitor. It was previously characterized and demonstrated effective suppression of MET-induced glioma progression in cell lines and xenografts; further, in an open-label phase I clinical trial, the safety and efficacy of PLB-1001 for the treatment of patients with a ZM fusion and/or METex14 was shown .Since there have been no phase III clinical trials for these therapies with respect to gliomas, it is of great importance to identify the patient subgroups most likely to benefit from these targeted therapies and conduct further studies to assess the penetration of these agents through the BBB. Moreover, with respect to the heterogeneity of gliomas, combination therapies should be mainly considered.As is known, aberrant RTK signaling is a key driver of tumorigenesis and resistance to treatment in glioblastoma . AlthougIn 2009, the U.S. Food and Drug Administration accelerated the approval of bevacizumab, a humanized monoclonal antibody against VEGF, as a single agent, based on its therapeutic benefit in recurrent glioblastoma patients . SubsequCollectively, EGFR- and VEGF-targeted therapies seem to contribute little to the treatment of gliomas in current situations. Further, one paper reported that the majority of targeted molecular drugs evaluated for malignant gliomas result in response rates of only 10 to 15% or less and no prolongation of survival . Thus, tAmong all gliomas, glioblastomas, regardless of whether they are primary or secondary, are the most devastating and intractable disease and are associated with dismal outcomes. Standard treatment for glioblastoma involves maximum surgical resection followed by the Stupp regimen consisting of fractionated radiotherapy plus concomitant TMZ chemotherapy, as well as 6–12 cycles of adjuvant TMZ chemotherapy. Despite this aggressive therapy, the median OS is 14.5–16.6 months, and the 2-year and 5-year OS rates are 27.2 and 5.5%, respectively . As suchMET gene, and HSP90 is essential for the translation and modification of the MET protein  play a critical role in the proliferation, survival, migration, invasion, angiogenesis, stem cell characteristics, and therapeutic resistance and recurrence of glioblastomas. The progress made in understanding of MET signaling in glioma and advances in therapies targeting HGF/MET molecules for glioma patients in recent 30 years were highlighted, in addition to studies on the expression and mutation status of MET. Our review makes a significant contribution to the latest concepts related to MET signaling and targeted therapies for glioma, as combined targeted therapy for this pathway and associated molecules remains an attractive strategy for the treatment of this disease.


Inclusion of rubber into concrete changes its behavior and the established shape of its stress-strain curve. Existing constitutive stress-strain models for concrete are not valid in case of rubberized concrete, and currently available modified models require additional validation on a larger database of experimental results, with a wider set of influential parameters. By executing uniaxial compressive tests on concrete with rubber substituting 10%, 20%, 30%, and 40% of aggregate, it was possible to study and evaluate the influence of rubber content on its mechanical behavior. The stress-strain curve was investigated in its entirety, including compressive strength, elastic modulus, strains at significant levels of stress, and failure patterns. Experimental results indicated that increase of rubber content linearly decreases compressive strength and elastic modulus, but increases ductility. By comparing experimental stress-strain curves with those plotted using available constitutive stress-strain models it was concluded that they are inadequate for rubberized concrete with high rubber content. Based on determined deviations an improvement of an existing model was proposed, which provides better agreement with experimental curves. Obtained research results enabled important insights into correlations between rubber content and changes of the stress-strain curve required when utilizing nonlinear material properties. Structural concrete is a non-linear material both at ultimate strength limit states and service loads, as well as for certain design situations and analysis of complex problems, which implies that linear analysis may not be sufficient . Being tIn order to improve ductility of reinforced concrete elements, the concrete’s core is usually confined with steel hoops . Nowadays there are additional ways to improve the ductility of concrete, which take into consideration sustainability and environmental pollution. One such method is the substitution of natural aggregates with recycled tire rubber in various forms: powder, crumb or chipped rubber particles ,4,5. TheUntil today, stress-strain curves were obtained mostly for normal, lightweight , high-stInclusion of rubber into concrete to replace a certain percentage of aggregate can change its mechanical properties and consequently influence the shape of the stress-strain curve, compared to commonly used concrete. Due to induced changes, available constitutive stress-strain models for concrete are not valid in case of rubberized concrete, and available modified models need to be experimentally verified on more compositions. Considering specific aspects of rubberized concrete, this paper will present previous studies of rubberized concrete’s behavior, new and literary available experimental investigations, and stress-strain curve analytical models. The main contribution of this paper is based on the applicable constitutive compressive axial model and direct guidelines of utilization of rubberized concrete in structural concrete elements based on values of compressive strength and deformations.Previous investigations of rubberized concrete were mostly focused on durability and mechanical properties of rubberized concrete. It was concluded that with the increase of rubber content in concrete mixes, compressive strength and elastic modulus decrease, and strain at fracture increases ,28,29. HCompressive stress-strain behavior of rubberized concrete with 12.5%, 25.0%, 37.5%, and 50.0% was investigated by Khaloo et al. , to deteL. Li et al.  performeXie et al.  substituNoaman et al.  conducteD.V. Bompa et al.  investigAslani et al.’s ,22 studyD. Li et al.  investigA summary of described previous research is presented in To mathematically simulate concrete’s behavior under uniaxial load, constitutive uniaxial models were developed. It should be noted that there are also other constitutive models which describe the behavior of concrete under various stress states, and for various purposes , but dueL. Li et al.  presente. Aslani  develope. Aslani  model ani et al.  later moi et al.  presente3) and 60 cylindrical (∅150 mm × 300 mm) concrete specimens were casted out of 10 different concrete mixes and tested after 28 days.To investigate compressive strength, elastic modulus and compressive stress-strain behavior of rubberized concrete compared to normal concrete (NC), in total 30 cubic  and recycled aggregates (RA). Mineral aggregates were sand of 0–2 mm and 2–4 mm fraction, and coarse aggregates which included gravel of 4–8 mm and 8–16 mm fraction. Recycled aggregate crumb rubber (CR) with particles of 0.5–4 mm size and density of 1050 kg/mx-y where R represents rubber, x refers to the percentage of crumb rubber in mix (0–40%), and y to the amount of cement in mix (400 or 500 kg/m3).Concrete mixes are labeled with NC-R3 of cement and Series II with 500 kg/m3 of cement. In each concrete mix, water to cement (w/c) factor was constant. In Series I, normal concrete had a composition of 323.6 kg/m3 sand, total of 1473.4 kg/m3 gravel of different fractions, 180 kg/m3 of tap water, and 2 kg/m3 of super-plasticizer Glenium (GL) ACE 430 to obtain better workability. Additional water was necessary due to the dry surface of natural aggregates. Other rubberized concrete mixes in this group contained rubber which replaced 10–40% of volume of sand. Quantities of rubber used were 66.8 kg/m3, 133.6 kg/m3, 200.6 kg/m3, and 266.2 kg/m3 for ratio of 10%, 20%, 30%, and 40% of crumb rubber, respectively. In mix NC-40-400, 4 kg/m3 of super-plasticizes Glenium ACE 430 was needed and 0.8 kg/m3 of RheoMATRIX (RM) to enable the right balance between fluidity, passing ability, and resistance to segregation. In Series II, normal concrete mix without rubber was composed of 281 kg/m3 sand, 1277 kg/m3 gravel of different fractions, 198.1 kg/m3 tap water, and 2.6 kg/m3 Glenium ACE 430. Mixtures with rubber differentiated as 26.9 kg/m3 of water was added and the amount of CR, sand and gravel of 0–4 mm fraction was varied. Quantities of CR used were 58.4 kg/m3, 116.8 kg/m3, 175.2 kg/m3, and 233.8 kg/m3 for ratio of 10%, 20%, 30%, and 40% of CR, respectively.Two series of concrete mixes were made with a principal differentiation in the amount of used cement —Series IFresh properties of concrete were investigated according to EN 12350-2:2009 , to EN 13) and cylindrical (∅150 mm × 300 mm) specimens were casted for each mix of both series. The cylinders and cubes were demolded 24 h after casting and then continuously moist-cured for 28 days. After this period, test specimens were measured and prepared for testing.According to HRN EN 12390-1:2012  guidelinCompressive strength, modulus of elasticity, and stress-strain curves were tested under uniaxial compression in a four-column high stiffness welded frame Controls Automatic Compression machine which conforms to HRN EN 12390-4:2000 , with a 3) in Series II resulted in lower reductions of strength and general in higher strength. Results obtained from tests that include mean values (mean), standard deviation (SD) and coefficient of variation (CoV) are given in In The compressive stress-strain behavior of cylindrical test specimens is presented with curves in Stress-strain curves were divided in the pre-peak and post-peak behavior as shown in When comparing stress-strain curves for both series, in terms of ductility and predictability better results were obtained for Series II. Namely, with the increase in rubber content, peak stress reduction was gradual, and similar can be observed for increase in ultimate strain. Curves obtained for Series I mixes with 20% and 30% of CR content showed no difference in peak stress, with ultimate strain being greater for mix with 20% rubber than that of mix with 30% rubber. Taking into account all obtained results it can be concluded that rubber greatly influences the behavior of concrete.An additional intention of performed compression tests was to observe failure patterns of cylinder specimens during loading and failure, as that can help to understand the overall behavior of specimens. Figures illustrate that reference NC mixes fail in a more brittle manner, suddenly and without any indications after reaching peak stress. Specimens were separated into large pieces and cracks were wide. However, mixes with rubber fail with less pronounced cracks, in more uniform manner, which is in accordance with previously analyzed strain-strain curves, i.e., post peak behavior. Namely, after reaching peak stress test specimens could withstand further increase of strain without sudden loss of force, similar to observations made by Khaloo et al. . SpecimeConstitutive models for rubberized concrete presented in As Bompa’s expression for peak compressive stress To take into consideration some of the influential parameters –(9).L. Li et al.’s  model prInput parameters are compressive strength t 0.4 fc  obtainedPeak compressive stress for rubberized concrete:Tangent elastic modulus for rubberized concrete:Coefficient for calculating strain at peak stress:Strain at peak stress for rubberized concrete:Secant modulus of elasticity:Coefficients of linear equation:Modified material parameter:Stress factor to obtain the constitutive curve:From the The accuracy of improved constitutive model is analyzed with statistical performance measures presented in According to the results presented in In order to verify that a given constitutive model can be suitable for reliable results, a completely new experimental data ,18 that In order to present the most important highlights that can be concluded from current study, parametric analysis is performed. The parameters that were varied are initial compressive strength of normal non-rubberized concrete  and percentage of rubber replacement  as it is presented in According to the presented results it is evident that larger deformability of rubberized concrete is more obvious with concrete with smaller compressive strength (corresponding deformation of maximum stress is higher) with higher percentage of rubber replacement .Change of rubber replacement is directly related to modulus of elasticity, with consequence of decrease up to 60% for highest rubber replacement.The deficiency of any specific directions about mix design of rubberized concrete is generally absent. Therefore, from parametric analysis with large number of increments in terms of normal concrete compressive strength and rubber replacement resulted in the initial Model for mix design of rubberized concrete . The comPrevious studies of rubberized concrete have shown that mechanical properties of concrete change with the addition of rubber aggregate, i.e., elastic modulus and compressive strength are lowered. However, obtained stress-strain curves reveal benefits, such as the reduction of softening stiffness in the post-peak area and thus improvement of ductility and energy absorption.From experimental results regarding compressive strength, it is determined that the addition of rubber aggregate reduces compressive strength, with a linear relation.Experimental stress-strain curves of rubberized concrete reveal that increase of rubber content decreases elastic modulus. However, strain at peak stress and ultimate strain increase, which support the premise that rubberized concrete is more ductile than normal concrete.Observation of specimens after executed experiments confirms the conclusion that rubberized concrete is more ductile, due to cracks being narrower and aligned in a mesh, without separation of large parts. There is no unexpected failure of specimens, as they stay compact even after peak stress.Available constitutive stress-strain models were not able to adequately represent experimentally obtained stress-strain curves. One of the models was modified to encompass important parameters, so an improved constitutive model is proposed which can be used for estimation of rubberized concrete behavior. However, due to the limited number of test specimens, validation of the proposed analytical model by results from different studies is done in order to approve its accuracy.New model for evaluation of compressive strength of rubberized concrete, based on compressive strength of normal concrete and percentage of rubber replacement is provided.The primary aim of the current investigation presented in this paper was to determine correlations between rubber content and compressive strength, modulus of elasticity, complete stress-strain behavior, and specimen’s failure pattern. From obtained results the following should be emphasized:


Escherichia coli CFT073 in immunocompetent Balb/c mice was used as a model of human UTI. The value of the model in investigating antibiotic exposure on in vivo emergence of antibiotic resistance was examined. Experimentally infected mice were treated with 20 or 200 mg/kg ampicillin, 5 or 50 mg/kg ciprofloxacin, or 100 or 1000 mg/kg of fosfomycin. Ampicillin and ciprofloxacin were given twice daily at 8 h intervals, and fosfomycin was given once daily. Antibiotic treatment began 24 h after bacterial inoculation and ended after 72 h following the initial treatment. Although minimum inhibitory concentrations (MIC) for the experimental strain of E. coli were exceeded at peak concentrations in tissues and consistently in urine, low levels of bacteria persisted in tissues in all experiments. E. coli from bladder tissue, kidney, and urine grew on plates containing 1× MIC of antibiotic, but none grew at 3× MIC. This model is not suitable for studying emergent resistance but might serve to examine bacterial persistence.Urinary tract infections (UTI) are common worldwide and are becoming increasingly difficult to treat because of the development of antibiotic resistance. Immunocompetent murine models of human UTI have been used to study pathogenesis and treatment but not for investigating resistance development after treatment with antibiotics. In this study, intravesical inoculation of uropathogenic  Urinary tract infections (UTIs) are one of the most common bacterial infections in humans and a major burden to healthcare systems. UTIs cause an estimated 11 million doctor visits in the US annually and over 150 million doctor visits globally, with an annual cost upward of 6 billion dollars (USD) .E. coli isolates among US outpatients from 2000 to 2010 showed greatest resistance increases for ciprofloxacin (3% to 17.1%), TMP-SMX (17.9% to 24.2%), and ampicillin (38.2% to 43.4%) [The most commonly used antibiotics for the treatment of UTIs are ampicillin, ciprofloxacin, trimethoprim-sulfamethoxazole (TMP-SMX), fosfomycin, nitrofurantoin, cephalexin, and ceftriaxone. Although antibiotics have been used to treat UTIs for many years, the management of UTIs has become complicated by increasing rates of antimicrobial resistance. An in vitro study of antimicrobial resistance in urinary o 43.4%) ,6. Fortun 3% to 1.1%, TMP-E. coli have led to the use of broad spectrum agents, combination antibiotic treatment, decreases in clinical cure rates, and higher risk of recurrence [Increases in antimicrobial resistance in uropathogenic currence . Measurecurrence ,9,10,11.currence ,13. The currence ,15,16,17Animal models, especially mouse models, are commonly utilized to assess the efficacy and pharmacokinetic/pharmacodynamic (PK/PD) relationships of antibiotics in urinary tract infections and to optimize the efficacy and minimize the cost and duration of clinical trials . Limited8 cfu of UPEC, organisms persisted in the urinary bladder, kidneys, and urine samples 10 days after initial infection in the absence of antimicrobial treatment. The median bacterial counts at 24 h post-infection were 106, 105, and 105.5 cfu/mL for urinary bladder, kidneys, and urine, respectively. The bacterial counts gradually declined over the course of infection and, at 10 days post-infection, stood at 103 cfu/mL for urinary bladder and 102 cfu/mL for kidney and urine samples.  studies were conducted for all three antibiotics . AmpicilMice treated with low dose ampicillin had consistently higher median bacterial counts in the urinary bladder, kidneys, and urine compared to high dose mice, although this difference was only significant at 48 h after treatment initiation in bladder tissue . Median There were no differences in median bacterial counts in urinary bladder, kidneys, and urine between mice treated with high- or low-dose ciprofloxacin except in the 48 h group. Urinary bladder tissue UPEC were eliminated completely from the urine after 48 h in mice treated with high-dose ciprofloxacin and after 72 h in most mice treated with low-dose ciprofloxacin . The 72 For mice treated with fosfomycin for three days, significant differences in the median bacterial counts of the urinary bladder tissues were observed between high and low dose–treated groups. Although significant count differences were not seen in the kidney, the majority of the high-dose fosfomycin-treated mice had sterile kidneys, and none were sterile in the low-dose groups. In high-dose urine samples, UPEC were largely eliminated at all time points (sterile urine), while this was observed with less frequency in low-dose group urine . As obseIn the long term study, mice treated with fosfomycin showed persistence of UPEC in the bladder and kidneys even after three weeks of treatment. The median bacterial count in the urinary bladder and kidneys at the end of each of the three week treatments were similar, but the number of sterile mice increased in the second and third weeks whether in treated or control groups. Urine samples showed the presence of UPEC in the first week of fosfomycin treatment but bacteria in the urine were not detected after the second and third weeks of fosfomycin treatment. Control group urine samples showed the presence of UPEC after week one and in a few animals after week two, but UPEC were completely eliminated following the third week with no treatment .E. coli against antibiotics were screened on respective 1× MIC antibiotic media  inside the epithelial cells of urinary bladder D. HigherTreatment was more efficacious in urine where each of the these antibiotics is concentrated. Antibiotic concentrations in the urine of antibiotic-treated mice far exceeded the minimal inhibitory concentrations with all antibiotics at all time points. Urine samples were in most cases cleared of all bacteria, presumably due to much higher antibiotic concentrations in the urine than those achieved in bladder (1000× for ampicillin and fosfomycin) or kidney tissue . Other studies have shown the presence of higher antibiotic concentration in the mouse urine after administration of ampicillin, ciprofloxacin, and fosfomycin ,27,28.Campylobacter jejuni. None of the C. jejuni isolates recovered from mice after subcutaneous or oral administration of enrofloxacin developed resistance to enrofloxacin and only modest shifts in the MIC of the isolates were observed [Antibiotic pressure on UPEC at very different concentrations and over different time periods did not reveal any emergent resistance or significant difference in bacterial persistence in urinary bladder and kidneys, which often did not differ much from persistence in control mice. Longer-term intermitant treatment of fosfomycin did not completely eliminate the bacteria from urinary bladder and kidneys of treated mice but also did not result in increased prevalence of antibiotic resistance. Investigation of resistance development in the laboratory or clinical isolates following treatment with different antibiotics have been examined by antimicrobial susceptibility testing and genotypic characterization ,10,11. Sobserved . SimilarIn the present study, occasional growth was seen in a 1× MIC environment after intermittent or suboptimal duration of clinical or subclinical exposures to ampicillin, ciprofloxacin or fosfomycin. Due to the sporadic and infrequent nature of this growth and that growth was not duplicated at 3× MIC, these were not considered truly “resistant” and were not explored for genotypic changes in the bacteria. The inability to exacerbate emergent resistance suggests that resistance may be evolving similarly in this mouse model as it does clinically but that, as is the case clinically, this would be too infrequent and unpredictable to serve as a good model for studying emergent resistance. The protective effect of the immune competent urinary tract was demonstrated in the present study as the infected mice treated with excipients alone eliminated most of the UPEC at 72 h post-infection, similar to the antibiotic treated groups. This suggests that in most situations immune factors are responsible for resistance suppression in immune competent mice. The few colonies observed in the present study may have been mildly “resistant” due to genetic or physiological adaptations to antibiotic pressure in the micro-environment of urinary tract tissues or may not have been truly resistant if more rigorously tested. It is critical to note that non-resistant bacteria consistently persisted in urinary tract tissues, becoming a previously exposed reservoir of bacteria with a potential for emergent resistance.Escherichia coli (UPEC) isolate CFT073 purchased from ATCC  was used for experimental infection in a UTI mouse model for antibiotic resistance development studies. Luria-Bertani (LB) broth and agar plates were used for the growth and selection of UPEC isolates. Ampicillin trihydrate , Cipro 5% suspension , or Monurol (Fosfomycin tromethamine)  were used for the treatment of infected animals. Ampicillin was dissolved in 0.1 M HCl, ciprofloxacin  was dissolved in cipro excipient , and Monurol was dissolved in water to create oral dosing solutions. Ampicillin sodium salt, ciprofloxacin HCl and phosphomycin disodium salt  were purchased for creation of antibiotic containing LB agar plates. The laboratory specific MIC of ampicillin (4 μg/mL), ciprofloxacin (0.03 µg/mL), and fosfomycin (64 μg/mL) for the experimental strain were determined in-house by the in vitro broth dilution method following Clinical and Laboratory Standards Institute guidelines [The clinical uropathogenic idelines .Female Balb/c mice 8–10 weeks old were purchased from Taconic Biosciences  and were housed and maintained according to the Guide for the Care and Use of Laboratory Animals, 8th Edition, under an Institutional Animal Care and Use Committee approved protocol in the AAALAC accredited Animal Program of the White Oak Federal Research Center. Mice were provided with autoclaved feed  and were permitted food and water ad libitum. Animals were acclimated to the facility for six days before commencement of experiments. Individual mice were randomly assigned to treatment groups. At the initiation of each experiment, animals were socially housed according to facility standards in an animal cage with a wire mesh grid placed at the bottom, to avoid drug carry-over by coprophagic behavior.A pilot study was conducted to determine the UPEC persistence in the urinary bladder, kidneys and urine for 10 days post-infection  in a Balb/c mouse without any treatment. The single dose pharmacokinetics of ampicillin (200 mg/kg), ciprofloxacin (50 mg/kg) and fosfomycin (500 mg/kg) antibiotics in the mouse model were determined in pharmacokinetic studies . Based on these pilot studies, time points post-infection for UPEC estimation and dose and dosing interval for the antibiotics were selected for the main studies. High and low (10× lower than high dose) antibiotic doses were selected to study the resistance evolution under high and low antibiotic pressure environments. Antibiotic treatment duration was selected as a short-term treatment of three days for all three antibiotics  and a long-term treatment of three weeks (short-term treatment protocol followed for three weeks) for fosfomycin only. The long-term fosfomycin treatment study was done to compare the long-term treatment pressure on the evolution of antibiotic resistance compared to short-term treatment pressure.Based on these pilot and other prior studies, six mice per group were deemed minimally sufficient to demonstrate a difference in plasma concentrations between treatment groups. This difference was a factor in applying variable antibiotic pressure to the bacteria. Each experiment was limited to a total of 64 mice due to practical limitations to the number of mice that could be infected and the desired dosing time and sample collection schedules maintained. Mice were assigned to groups on the time point groups selected based on pharmacokinetics for each antibiotic experiment. This made the number of animals per group either six for an antibiotic requiring more time points or nine for an antibiotic with a longer half-life. Based on pharmacokinetics, the study included 2 and 4 h groups for all post ampicillin administration days and 2, 4, and 8 h groups on only the first day of post ciprofloxacin and Fosfomycin administration. To keep the animal numbers constant, the follow-on low dose antibiotic experiments included six animals per group.n = 4) group was included in each experiment to assess the sterility of the urinary tract tissues. To roughly compare multi-dose versus single dose pharmacokinetic parameters during high dose treatment experiments, groups were sampled at 2 h and 4 h following each day’s initial treatment with ampicillin and 2 h, 4 h, and 8 h following the second day’s initial treatment with ciprofloxacin and fosfomycin.For short-term high-dose studies (three days) with ampicillin, ciprofloxacin or fosfomycin, either six or nine female Balb/c mice were randomly assigned to the treatment groups. The low dose studies (3 days) included six mice to the treatment groups. Groups with 24, 48, and 72 h of antibiotic treatment were included in low and high dose treatment studies. As the focus of these studies was on resistance development of UPEC in vivo after antibiotic treatment, only one group of infected mice treated with excipient (solvent used for creating dosing solutions) was included as a control in each experiment. This control group was assessed 72 h after initial excipient exposure. Mice from antibiotic treatment and excipient control groups were given either antibiotics or excipient at the same dosing frequency for 1, 2, or 3 days beginning 24 h after infection. Groups of mice were sacrificed, and samples were collected either 24 h, 48 h, or 72 h after initiation of antibiotic treatment. High and low dosing concentration for experiments were ampicillin (200 and 20 mg/kg), ciprofloxacin (50 and 5 mg/kg), and fosfomycin (1000 and 100 mg/kg). A naïve  or excipient that was repeated each week for three weeks. To avoid complete elimination of bacteria from the urinary tract and to provide longer antibiotic exposure for resistance development, a 500 mg/kg fosfomycin dose was selected for the long-term study. Urine and tissues from bladder and kidneys were sampled from groups 24 and 96 h after the last treatment each week. The infection, treatment, and sample collection schedules for the long-term study are shown below .600 of 1 to 1.1. This optical density corresponded to a cell density of between 8 × 108 to 2 × 109 colony forming units (CFU)/mL. Bacterial suspensions were aliquoted and maintained on ice until used. Urinary bacterial cystitis was induced by injecting 50 µL (approximately 4 × 107 to 108 CFU) of inoculum into the bladder by trans-urethral catheterization under isoflurane anesthesia. To confirm densities of viable E. coli cells, the inoculum was diluted 10-fold serially (10−1 to 10−5 dilutions), 100 μL of each dilution was spread in triplicate onto LB agar, incubated at 37 °C, and the number of E. coli colonies were counted after 16–18 h. of incubation.Eight- to 10-week-old immunocompetent female Balb/c mice were used to create a previously described  unobstruAntibiotics and excipients were administered via oral gavage 24 h after UTI infection using 18G stainless-steel gavage needles attached to 1 mL tuberculin syringes. Antibiotics were administered for three consecutive days in a total volume of 150 to 220 µL twice daily for ampicillin and ciprofloxacin and once daily for fosfomycin. Twice a day dosing was separated by an 8 h interval. Correspondingly the infected control mice were given 0.1 M HCl, cipro excipient or water in similar volumes as the ampicillin, ciprofloxacin, and fosfomycin treatment groups, respectively.Mice were anesthetized by isoflurane general anesthesia, and a midline incision was made after spraying the skin with 70% ethanol. The urinary bladder was located and grasped by the neck with curved forceps. Urine samples were collected with a 27ga needle attached to a 1 mL syringe. Blood samples were collected by cardiac puncture and placed in 1 mL EDTA tubes. Death was assured by cervical dislocation followed by placement of aseptically collected urinary bladder and kidney samples in sample tubes containing 1.0 and 0.8 mL PBS, respectively. Urinary bladder and kidney samples were weighed upon collection, and all samples were kept on ice until processed. Blood samples were spun at 10,000 rpm for 15 min. at 4 °C, and resultant plasma samples were stored at–20 °C until analyzed for antibiotic concentration. The urinary bladder and kidney samples were homogenized with tungsten carbide beads in a Tissue Lyser apparatus  and kept at 4 °C until estimation of susceptible and resistant UPEC and measurement of antibiotic concentration. The samples were first analyzed for the total and resistant UPEC population and then analyzed for the antibiotic concentration. If the samples were not analyzed for antibiotic concentration immediately after bacterial estimation, the samples were stored at −20 °C until analysis.10 CFU/mL. For preliminary assessment for antibiotic resistant UPEC, the samples were spotted onto LB agar plates containing 1× MIC of antibiotic incubated at 37 °C for 16–24 h. Samples with no growth were incubated for an additional 24 hr to check for slow growing resistant phenotypes. Colonies observed in the 1× MIC antibiotic plates were re-streaked on 1× MIC antibiotic plates to confirm the 1× MIC resistant phenotype and on 3× MIC plates to further evaluate resistance. In parallel, the 1× MIC plate was streaked with wildtype CFT073 E. coli to show no growth.The bacterial count in urinary bladder, kidney, and urine samples was quantified by spotting 50 µL of a series of 10-fold dilutions in LB broth or undiluted samples in triplicate on LB agar plates. The plates were incubated at 37 °C for 16–18 h, and the total UPEC population estimated and expressed as logUrinary bladder, kidney tissues, and urine samples not used for estimating UPEC populations were stored either at 4 °C or −20 °C and used for measuring antibiotic concentrations. Blood samples collected in EDTA tubes were spun at 10,000 rpm for 15 min. at 4 °C, and the resulting plasma samples were stored at −20 °C until analyzed for antibiotic concentration. Ciprofloxacin was quantified in urine and urinary tissues by LC-MS/MS as previously described . FosfomyOne half of bladder tissues from UTI infected and excipient control mice were collected for histopathological analysis. Gross observations were made, and subsequently tissues were fixed in 10% neutral buffered formalin for 48–72 h. Tissues were processed through graded alcohols, xylene and paraffin on an ASP300S tissue processor  and embedded into paraffin blocks. Then, 4 µm tissue sections were cut, mounted on glass slides, and stained with hematoxylin and eosin (H&E) . The slides were examined by a veterinary pathologist.p < 0.05 and p < 0.01.All data collected were in triplicates of each experiment, and the results are presented as median bacterial counts, range of bacterial counts, and number of sterile animals out of total number of animals. The statistical analysis between treatments as well as treatment and control groups were carried out using student’s t-test (two tailed) in GraphPad Prism 6 software. Statistically significant results were indicated as E. coli in a 1× MIC environment that could not be duplicated at 3× MIC, which was considered the minimal threshold for resistance in this study. The immunocompetent murine model’s inability to demonstrate emergent resistance suggests that resistance may be evolving similarly in this mouse model as it does clinically, which would be too infrequent and unpredictable to serve as a good model for studying emergent resistance. However, this model could be used to study bacterial persistence in urinary tract tissues, which was observed consistently throughout the study with each of the antibiotics.The present study assessed the feasibility of an immunocompetent Balb/c mouse model for investigating mechanisms of resistance development in UTI infection after treatment with antibiotics. After intermittent or suboptimal duration of clinical or subclinical exposures to ampicillin, ciprofloxacin, or fosfomycin, the study yielded sporadic and infrequent growth of


The evaluation of antibiotic use among hospitalized patients is a primary step required to design antibiotic stewardship intervention. There is paucity of data describing antibiotic use in hospitals across Northern Nigeria. This study evaluates the prevalence and indications for antibiotic use among inpatients in three acute care hospitals.A point-prevalence survey was conducted among patients in the wards before or at 8.00 a.m. on the day of the survey, using the point-prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals protocol. The survey was conducted between April and May 2019. The medical records of the patients were reviewed by a clinical pharmacist with the support of physicians and nurses.Overall, 80.1% (257/321) of the patients used at least one antibiotic on the day of the survey. The prevalence of antibiotic use ranged from 72.9% in obstetrics and gynecology to 94.6% in pediatric medical specialty. Community acquired infections (38.7%) and surgical antibiotic prophylaxis (22.5%) were the most common indications. Surgical antibiotic prophylaxis was used or scheduled to be used for more than a day in all the cases. Metronidazole (30.5%), ciprofloxacin (17.1%), ceftriaxone (16.8%), amoxicillin-clavulanate (12.5%) and gentamicin (11.8%) were the most commonly prescribed antibiotics. Overall, broad spectrum antibiotics represented one-third of all the prescriptions. The change of initial antibiotic prescription was reported in one-third of the patients and the reasons include a switch to oral antibiotic (28.5%), escalation (4.5%) and de-escalation (3.6%). Of the 257 patients with an antibiotic prescription, 6.2% had redundant antibiotic combinations.The prevalence of antibiotic use was high with one in three prescriptions having a broad spectrum antibiotic. Prolonged use of surgical antibiotic prophylaxis and redundant antibiotic combination were observed. Antimicrobial stewardship interventions are recommended in order to reduce the use of antibiotics and promote appropriate antibiotics prescribing. Globally, antimicrobial resistance has become a threat to public health security . AntimicPoint-prevalence survey is increasingly been used to monitor antibiotic prescribing patterns in acute and long-term healthcare facilities. This design has been found to be a valid and reliable method to measure and monitor antibiotic use in healthcare facilities . It is oIn Nigeria, studies showed that the prevalence of antibiotic use among hospitalized patients ranged from 62.4 to 78.2% –11. CommThe point-prevalence survey was conducted in three acute care hospitals across two states in Northern Nigeria, between April and May 2019 using the point-prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals protocol version 5.3 . The surHospitalized patients in all the wards including pediatric emergency (where patients were often admitted for more than 24 h) and neonatal wards of the participating hospitals were considered for inclusion. However, those admitted to psychiatric, adult accident and emergency, and outpatient units were excluded. All hospitalized patients in the ward before or at 8.00 a.m. on the day of the survey were included, and those who were discharged from the wards before the time of the survey and daycare patients were excluded.The data was collected using the European protocol for point-prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals version 5.3 . In addiThe data collected includes: hospital type, ward specialty, patient’s demographic information and the presence of antibiotic prescription on the day or at the time of the survey. For those with at least one antibiotic prescription, the following information was collected for each antibiotic: name of drug, number of doses per day, strength of one dose, route of administration , indication for prescription , diagnosis, documentation of reason for antibiotic prescription, date antibiotic was started, and whether antibiotic was changed during the current infection episode. For patients receiving surgical antibiotic prophylaxis, their medical records were reviewed to 24 h before the time of the survey to ascertain whether it was prescribed as a single dose, for less than 24 h or for more than 24 h. Medical records of those with potential redundant antibiotic combinations on the day of the survey were reviewed to 48 h prior to the time of the survey. All the patients in a single ward were surveyed on the same day. The data collection process lasted for 2 weeks in one of the participating hospitals. Ethics approval was obtained from the Human Research and Ethics Committee at the three hospitals with a request for waiver of patient informed consent .Clostridium difficile infection or biliary tract infection were not classified as redundant [Redundant antibiotic therapy was defined as the prescription of two or more antibiotics with overlapping spectra of activity for 48 h or more , 15. Duaedundant . Human iedundant . The WorP < 0.05) in the bivariate analysis were included in the multivariate model. P value less than 0.05 was considered as statistical significance.The data was analyzed using Statistical Package for the Social Sciences (SPSS) version 23. The data was de-identified before analysis. Categorical data was reported as frequency with percentage while continuous data was presented as mean (with standard deviation) or median. Bivariate and multivariate regression analyses were used to determine the factors associated with redundant antibiotic therapy. Only variables that demonstrated statistical significance , obstetrics and gynecology , surgical  and pediatric medical unit . Others were admitted to pediatric surgical  and neonatal  units. About one-third of the surveyed patients had surgery during the current admission.A total of 321 inpatients were surveyed and the median age of the patients was 27 years with females representing approximately 58%. The majority of the surveyed patients were admitted to the medical unit  followed by neonatal (92.9%) and pediatric surgical (90.0%) specialties. Obstetrics and gynecology had the lowest prevalence (72.9%) (Table The most common indication for antibiotic prescription was community acquired infection (38.7%) followed by surgical antibiotic prophylaxis (22.5%) and hospital acquired infection (16.3%). Medical prophylaxis and unknown indication represented 14.9 and 7.6% of all the indications, respectively. Bloodstream infection (22.8), pneumonia (17.3%), skin and soft tissue infections (13.4%) and surgical site infections (11.0%) were the most common diagnoses with antibiotic prescription. Other diagnoses included gastro-intestinal infections (9.4%), intra-abdominal sepsis (7.9%), pyelonephritis (7.1%), obstetric or gynecological infection (3.9%) and central nervous system infection (3.1%). All the prescriptions for surgical antibiotic prophylaxis were prolonged beyond a day.Overall, the most prescribed classes of antibiotic were nitroimidazoles 28.5%), third generation cephalosporins (18.9%), fluoroquinolones (13.6%), combinations of penicillins beta-lactamase inhibitors (10.5%) and aminoglycosides (8.5%). The proportion of broad spectrum antibiotics prescribed on the day of the survey was 32.9%. Broad spectrum antibiotic prescriptions constituted 33.9, 43.8, and 41.6% of antibiotics prescribed for community acquired infections, hospital acquired infections, and surgical antibiotic prophylaxis, respectively. Table 8.5%, thiThe classes of antibiotic prescribed on the day of the survey varied according to the indications. The five most commonly prescribed classes of antibiotic for community acquired infections include nitroimidazoles (26.4%), fluoroquinolones (19.0%), third generation cephalosporins (14.9%), combinations of penicillins beta-lactamase inhibitors (10.3%) and aminoglycosides (7.5%). In the case of hospital acquired infections, nitroimidazoles (31.5%), third generation cephalosporins (20.5%), aminoglycosides (13.7%), fluoroquinolones (11.0%) and combinations of penicillins beta-lactamase inhibitors (11.0%) were the most prescribed antibiotics. Of the 101 antibiotic prescriptions for surgical antibiotic prophylaxis, nitroimidazoles, third generation cephalosporins, combinations of penicillins beta-lactamase inhibitors, second generation cephalosporins and fluoroquinolones were the most prescribed and represented 33.7, 20.8, 10.9, 8.9 and 7.9% of all the prescriptions, respectively.Antibiotic prescription varied among the specialties; ceftriaxone (28.8%), gentamicin (16.9) and metronidazole 13.6%) were the most commonly prescribed antibiotics in pediatric medical specialty. Among neonates, gentamicin (40.0%), ceftazidime (15.6%) and ampicillin-sulbactam (15.6%) were the most prescribed antibiotics. The three most common prescriptions in adult medical specialty were metronidazole (28.9%), ciprofloxacin (18.4%) and ceftriaxone (15.8%). In the surgical specialty, metronidazole (29.4%), ciprofloxacin (21.2%) and amoxicillin-clavulanate (15.3) were the most frequent antibiotic prescriptions while tinidazole (25.8%), cefixime (20.2%) and metronidazole (13.5%) were the most commonly prescribed antibiotics in the obstetrics and gynecology ward/specialty. Metronidazole, amoxicillin and gentamicin had the highest prescriptions and represented 36.8, 21.1 and 12.3%, of antibiotics prescribed in the pediatric surgical specialty, respectively. Table .6% were Metronidazole was the most commonly prescribed antibiotic for community acquired infections (23.6%), hospital acquired infections (20.5%), surgical antibiotic prophylaxis (20.8%) and unknown indication 32.4%). Other common antibiotic prescriptions include: ciprofloxacin (16.7%) and ceftriaxone (12.1%) for community acquired infections; gentamicin (13.7%) and ciprofloxacin (11.0%) for hospital acquired infection; and cefixime (12.9%) and amoxicillin-clavulanate (10.9%) for surgical antibiotic prophylaxis. Table %. Other n = 127, 28.5%), escalation , de-escalation  and unknown reason . The initial antibiotic was not changed during the infection episode in 61.9% of the patients.Of the 446 prescriptions with data regarding change of an initial antibiotic, 170 (38.1%) were changed during the infection episode. The reasons for change of an initial antibiotic include switch from parenteral to oral therapy  and dual anti-streptococcal (4.5%). Redundancy was higher in oral (54.5%) compared to parenteral route (36.4%). Of the 22 redundant antibiotic therapy, 40.9% were prescribed for community acquired infections while 27.3 and 22.7% were used for hospital acquired infections and surgical antibiotic prophylaxis, respectively. Overall, the combination of amoxicillin-clavulanate with nitro-imidazoles (59%) was the highest type of redundant antibiotic therapy. Multivariate regression analysis showed that the number of antibiotics prescribed  and oral antibiotics  were independent predictors of redundant antibiotic therapy.Twenty two cases of redundant antibiotic therapy were identified in 20 patients corresponding to a point-prevalence of 6.2% in all patients (and 11.7% among patients who received two or more antibiotics). The most common types of redundancy were dual anaerobic (77.3%) and dual beta-lactam (13.6%) therapy. Other types of redundancy include dual anti-The study found that four in every five hospitalized patients received at least one antibiotic each day and approximately two-third of the antibiotics were used for treatment of community acquired infections and surgical prophylaxis. The prevalence of antibiotic use in the current study was consistent with a similar study conducted in South East Nigeria 78.6%) . The pre.6% . TheApproximately one-quarter of the antibiotics were prescribed for surgical antibiotic prophylaxis. Several studies have demonstrated that single dose antibiotic prophylaxis is as effective as multiple doses , 18. ThuThe study also found that majority about 67%) of the patients who used antibiotic on the day of the survey had two or more prescriptions, similar to the result in Ghana . However7% of theClostridium difficile infection [Overall, nitroimidazoles, third generation cephalosporins and fluoroquinolones were the most commonly prescribed antibiotic groups. This was similar to previous findings in Southern Nigeria , 11. In nfection  and the nfection . The excnfection . TherefoThe review of initial antibiotic prescription is an important antimicrobial stewardship strategy used to reduce overuse of antibiotics, particularly broad spectrum antibiotics. The current study found that review of initial antibiotic prescription was common as demonstrated by the change of about 40% of all the prescriptions. This confirmed the result of a previous study in Nigeria . In the Another important finding of the current study was the relatively high rate of redundant antibiotic combination, approximately 12% of patients with two or more antibiotics had redundant antibiotic prescription with redundant anaerobic combinations, particularly the combination of amoxicillin-clavulanate with nitro-imidazoles, been the most common. These observations were consistent with previous studies conducted in the United States for prevalence  and typeOverall, the current study highlights the need for the establishment of antimicrobial stewardship program in Nigerian hospitals considering the high rate of antibiotic use, prolonged use of surgical prophylaxis, considerably high proportion of broad spectrum antibiotic, and use of redundant antibiotic combinations. A recent study revealed that only few hospitals had a formal antimicrobial stewardship team . Lack ofThe current study has a number of limitations and thus, should be interpreted with caution. First, this is a 1 day cross sectional survey  and it is not the gold standard for assessing antibiotic use. However, point-prevalence survey design is considered as a valid method for measuring antibiotic use in healthcare facilities. Secondly, the survey was conducted in only three hospitals, thus, the findings are not generalizable. However, the findings were comparable with previous studies conducted in the southern parts of Nigeria. Thirdly, the current study did not evaluate the appropriateness of antibiotic prescription among the patients. And fourthly, the sample size of the study was small. There is a need for a more elaborate study that will encapsulate the concerns highlighted above.The prevalence of antibiotic use among hospitalized patients was relatively high with broad spectrum antibiotics constituting about one-third of all antibiotic prescriptions. Antibiotics were commonly used for community acquired infections and surgical antibiotic prophylaxis in which the duration was prolonged beyond 1 day in all cases. Metronidazole, ciprofloxacin and ceftriaxone were the most commonly prescribed antibiotics. Approximately, one in 15 antibiotic prescriptions had redundant antibiotic combination. Antimicrobial stewardship interventions are strongly recommended to reduce the high rate of antibiotic prescription and promote appropriate use of antibiotics in Nigerian hospitals.