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Purpose: To analyze the process of early oral osseointegration of titanium (Ti) implants in diabetic 129/Sv mice through microCT and histologic and immunohistochemical analysis. Materials and Methods: A group of 30 male 129/Sv mice was equally subdivided into two groups: (1) nondiabetic (ND), in which mice did not undergo systemic alterations and received a standard diet, and (2) diabetic (D), in which mice were provided a high-fat diet from the age of 6 weeks until the conclusion of the study and received two intraperitoneal (IP) injections of streptozotocin (STZ) at a concentration of 100 mg/Kg each. Each mouse underwent extraction of a maxillary first molar, and customized Ti screws (0.50 mm diameter, 1.5 mm length) were placed in the residual alveolar sockets of the palatal roots. At 7 and 21 days after implant placement, the animals were euthanized for maxilla and pancreas collection. Maxillae containing Ti implants were analyzed with microCT, histology, and immunohistochemistry for cells that were positive for F4/80, CD146, runt-related transcription factor 2 (Runx2), and proliferating cell nuclear antigen (PCNA). Pancreata were histologically analyzed. Quantitative data were statistically analyzed with a significance level at 5% (P < .05). Results: ND mice presented successful healing and osseointegration, with a significantly higher fraction of bone volume compared to D mice, both at the alveolar sockets (53.39 ± 5.93 and 46.08 ± 3.18, respectively) and at the implant sites (68.88 ± 7.07 and 44.40 ± 6.98, respectively) 21 days after implant placement. Histologic evaluation revealed that the ND mice showed a significant decrease in inflammatory infiltrate and a significant increase in newly formed bone matrix at 21 days, whereas peri-implant sites in the D mice were predominantly encapsulated by fibrous tissue and chronic inflammatory infiltrate. Immunohistochemical characterization revealed higher Runx2 osteoblast differentiation and higher cell proliferation activity in the ND mice at 7 days, while higher amounts of macrophages were present in D mice at 7 and 21 days. Interestingly, no differences were found in CD146-positive cells when comparing ND and D mice. Conclusions: This study evaluated the effects of immediate dental implant placement in 129/Sv diabetic mice by using specific healing markers to identify changes in cellular events involved in early oral osseointegration. This approach may serve as tool to evaluate new materials and surface coatings to improve osseointegration in diabetic patients. [ABSTRACT FROM AUTHOR]

Simple Summary: PTEN is an essential tumor suppressor gene whose alterations are causative of cancer and neurodevelopmental disorders, grouped as PTEN hamartoma tumor syndrome (PHTS). Here, we present translational readthrough as a potential therapeutic approach to restore the function of PTEN isoforms in patients harboring nonsense mutations at PTEN that cause aberrant PTEN biosynthesis. We have found that aminoglycosides and protein synthesis inducers reconstitute PTEN isoform expression and the function of PTEN variants containing nonsense mutations. Our results provide insights with which to optimize readthrough-based therapies for patients with cancer and PHTS. The PTEN tumor suppressor is frequently targeted in tumors and patients with PTEN hamartoma tumor syndrome (PHTS) through nonsense mutations generating premature termination codons (PTC) that may cause the translation of truncated non-functional PTEN proteins. We have previously described a global analysis of the readthrough reconstitution of the protein translation and function of the human canonical PTEN isoform by aminoglycosides. Here, we report the efficient functional readthrough reconstitution of the PTEN translational isoform PTEN-L, which displays a minimal number of PTC in its specific N-terminal extension in association with disease. We illustrate the importance of the specific PTC and its nucleotide proximal sequence for optimal readthrough and show that the more frequent human PTEN PTC variants and their mouse PTEN PTC equivalents display similar patterns of readthrough efficiency. The heterogeneous readthrough response of the different PTEN PTC variants was independent of the length of the PTEN protein being reconstituted, and we found a correlation between the amount of PTEN protein being synthesized and the PTEN readthrough efficiency. Furthermore, combination of aminoglycosides and protein synthesis inducers increased the readthrough response of specific PTEN PTC. Our results provide insights with which to improve the functional reconstitution of human-disease-related PTC pathogenic variants from PTEN isoforms by increasing protein synthesis coupled to translational readthrough. [ABSTRACT FROM AUTHOR]

In recent years, bacterial resistance to conventional antibiotics has become a major concern in the medical field. The global misuse of antibiotics in clinics, personal use, and agriculture has accelerated this resistance, making infections increasingly difficult to treat and rendering new antibiotics ineffective more quickly. Finding new antibiotics is challenging due to the complexity of bacterial mechanisms, high costs and low financial incentives for the development of new molecular scaffolds, and stringent regulatory requirements. Additionally, innovation has slowed, with many new antibiotics being modifications of existing drugs rather than entirely new classes. Antimicrobial peptides (AMPs) are a valid alternative to small-molecule antibiotics offering several advantages, including broad-spectrum activity and a lower likelihood of inducing resistance due to their multifaceted mechanisms of action. However, AMPs face challenges such as stability issues in physiological conditions, potential toxicity to human cells, high production costs, and difficulties in large-scale manufacturing. A reliable strategy to overcome the drawbacks associated with the use of small-molecule antibiotics and AMPs is combination therapy, namely the simultaneous co-administration of two or more antibiotics or the synthesis of covalently linked conjugates. This review aims to provide a comprehensive overview of the literature on the development of antibiotic–AMP conjugates, with a particular emphasis on critically analyzing the design and synthetic strategies employed in their creation. In addition to the synthesis, the review will also explore the reported antibacterial activity of these conjugates and, where available, examine any data concerning their cytotoxicity. [ABSTRACT FROM AUTHOR]

Background: The study aims to investigate the effect of combining silver nanoparticles (AGNPs) with different antibiotics on multi-drug resistant (MDR) and extensively drug resistant (XDR) isolates of Pseudomonas aeruginosa (P. aeruginosa) and to investigate the mechanism of action of AGNPs. Methods: AGNPs were prepared by reduction of silver nitrate using trisodium citrate and were characterized by transmission electron microscope (TEM) in addition to an assessment of cytotoxicity. Clinical isolates of P. aeruginosa were collected, and antimicrobial susceptibility was conducted. Multiple Antibiotic Resistance (MAR) index was calculated, and bacteria were categorized as MDR or XDR. Minimum inhibitory concentration (MIC) of gentamicin, ciprofloxacin, ceftazidime, and AGNPs were determined. The mechanism of action of AGNPs was researched by evaluating their effect on biofilm formation, swarming motility, protease, gelatinase, and pyocyanin production. Real-time PCR was performed to investigate the effect on the expression of genes encoding various virulence factors. Results: TEM revealed the spherical shape of AGNPs with an average particle size of 10.84 ± 4.64 nm. AGNPS were safe, as indicated by IC50 (42.5 µg /ml). The greatest incidence of resistance was shown against ciprofloxacin which accounted for 43% of the bacterial isolates. Heterogonous resistance patterns were shown in 63 isolates out of the tested 107. The MAR indices ranged from 0.077 to 0.84. Out of 63 P. aeruginosa isolates, 12 and 13 were MDR and XDR, respectively. The MIC values of AGNPs ranged from 2.65 to 21.25 µg /ml. Combination of AGNPs with antibiotics reduced their MIC by 5–9, 2–9, and 3-10Fold in the case of gentamicin, ceftazidime, and ciprofloxacin, respectively, with synergism being evident. AGNPs produced significant inhibition of biofilm formation and decreased swarming motility, protease, gelatinase and pyocyanin production. PCR confirmed the finding, as shown by decreased expression of genes encoding various virulence factors. Conclusion: AGNPs augment gentamicin, ceftazidime, and ciprofloxacin against MDR and XDR Pseudomonas isolates. The efficacy of AGNPs can be attributed to their effect on the virulence factors of P. aeruginosa. The combination of AGNPs with antibiotics is a promising strategy to attack resistant isolates of P. aeruginosa. [ABSTRACT FROM AUTHOR]

Bacteria employ small regulatory RNAs (sRNA) and/or RNA binding proteins (RBPs) to respond to environmental cues. In Enterobacteriaceae, the FinOdomain containing RBP ProQ associates with numerous sRNAs and mRNAs, impacts sRNA-mediated riboregulation or mRNA stability by binding to 5'- or 3'-untranslated regions as well as to internal stem loop structures. Global RNAprotein interaction studies and sequence comparisons identified a ProQ-like homolog (PA2582/ProQPae) in Pseudomonas aeruginosa (Pae). To address the function of ProQPae, at first a comparative transcriptome analysis of the Pae strains PAO1 and PAO1ΔproQ was performed. This study revealed more than 100 differentially abundant transcripts, affecting a variety of cellular functions. Among these transcripts were pprA and pprB, encoding the PprA/PprB two component system, psrA, encoding a transcriptional activator of pprB, and oprI, encoding the outer membrane protein OprI. RNA co-purification experiments with Strep-tagged Pae ProQ protein corroborated an association of ProQPae with these transcripts. In accordance with the up-regulation of the psrA, pprA, and pprB genes in strain PAO1ΔproQ a phenotypic analysis revealed an increased susceptibility toward the aminoglycosides tobramycin and gentamicin in biofilms. Conversely, the observed down-regulation of the oprI gene in PAO1ΔproQ could be reconciled with a decreased susceptibility toward the synthetic cationic antimicrobial peptide GW-Q6. Taken together, these studies revealed that ProQPae is an RBP that impacts antimicrobial resistance in Pae. [ABSTRACT FROM AUTHOR]

Background: Aminoglycosides, such as Streptomycin, are cheap, potent antibiotics widely used Sub-Saharan Africa. However, aminoglycosides are the commonest cause of ototoxicity. The limited prospective epidemiological studies on aminoglycoside ototoxicity from Sub-Saharan Africa motivated this study to provide epidemiological information on Streptomycin-induced ototoxicity, identify risk factors and predictors of ototoxicity. Method: A longitudinal study of 153 adults receiving Streptomycin-based antituberculous drugs was done. All participants underwent extended frequency audiometry and had normal hearing thresholds at baseline. Hearing thresholds were assessed weekly for 2months, then monthly for the subsequent 6months. Ototoxicity was determined using the ASHA criteria. Descriptive statistics were used to analyze socio-demographic variables. Ototoxicity incidence rate was calculated, and Kaplan-Meier estimate used to determine cumulative probability of ototoxicity. Chi-square test was done to determine parameters associated with ototoxicity and Cox regression models were used to choose the predictors of ototoxicity. Results: Age of participants was 41.43 ± 12.66 years, with a male-to-female ratio of 1:0.6. Ototoxicity was found in 34.6% of the participants, giving an incidence of 17.26 per 1,000-person-week. The mean onset time to ototoxicity was 28.0 ± 0.47 weeks. By 28th week, risk of developing ototoxicity for respondents below 40 years of age was 0.29, and for those above 40 years was 0.77. At the end of the follow-up period, the overall probability of developing ototoxicity in the study population was 0.74. A significant difference in onset of ototoxicity was found between the age groups: the longest onset was seen in <40 years, followed by 40-49 years, and shortest onset in ≥50 years. Hazard of ototoxicity was significantly higher in participants aged ≥50 years compared to participants aged ≤40 years (HR = 3.76, 95% CI = 1.84-7.65). The probability of ototoxicity at 40 g, 60 g and 80 g cumulative dose of Streptomycin was 0.08, 0.43 and 2.34, respectively. Age and cumulative dose were significant predictors of ototoxicity. Conclusion: The mean onset time to Streptomycin-induced ototoxicity was 28 weeks after commencement of therapy. Age and cumulative dose can reliably predict the onset of Streptomycin-induced ototoxicity. Medium to long term monitoring of hearing is advised for patients on aminoglycoside therapy. [ABSTRACT FROM AUTHOR]

Exploring new methodologies for simple and on-demand methods of manipulating the emission and sensing ability of fluorescence sensor devices with solid-state emission molecular systems is important for realizing on-site sensing platforms. In this regard, although conjugated polymers (CPs) are some of the best candidates for preparing molecular sensor devices owing to their luminescent and molecular recognition properties, the development of CP-based sensor devices is still in its early stages. In this study, we herein propose a novel strategy for preparing a chemical stimuli-responsive solid-state emission system based on supramacromolecular assembly-induced emission enhancement (SmAIEE). The system was spontaneously developed by mixing only the component polymers (i.e., polythiophene and a transient cross-linking polymer). The proposed strategy can be applied to the facile preparation of molecular sensor devices. The analyte-induced fluorescent response of polythiophene originated from the dynamic displacement of the transient cross-linker in the polythiophene ensemble and the generation of the polythiophene–analyte complex. Our successful demonstration of the spontaneous preparation of the fluorescence sensor system by mixing two component polymers could lead to the development of on-site molecular analyzers including the determination of multiple analytes. [ABSTRACT FROM AUTHOR]

Aims This study was conducted to evaluate the in vitro activity of clinically relevant aminoglycosides and to determine the prevalence of genes encoding aminoglycoside modifying enzymes (AMEs) and 16S ribosomal RNA (rRNA) methyltransferases among aminoglycoside - resistant E. coli (n  = 61) and K. pneumoniae (n  = 44) clinical isolates. Associated resistances to beta–lactams and their bla genes as well as the genetic relatedness of isolates were also investigated. Materials and methods A total of 105 aminoglycoside-resistant E. coli (n  = 61) and K. pneumonia e (n  = 44) isolates recovered between March and May 2017 from 100 patients hospitalized in different wards of Charles Nicolle Hospital of Tunis, Tunisia, were studied. Minimal inhibitory concentrations of aminoglycoside compounds were determined by broth microdilution method. Aminoglycosides resistance encoding genes [ aph(3´)-Ia, aph(3′) IIa, aph(3´)-VIa, ant(2″)-Ia, aac(3)-IIa, aac(3)-IVa, aac(6′)-Ib, rmtA, rmtB, rmtC, armA , and npmA ] and bla genes were investigated by PCR and sequencing. Genetic relatedness was examined by multilocus sequence typing (MLST) for representative isolates. Results High rates of aminoglycoside resistance were found: gentamicin (85.7%), tobramycin (87.6%), kanamycin (78.0%), netilmincin (74.3%), and amikcin (18.0%). Most common AME gene was aac(3)-IIa (42%), followed by aac(6′)-Ib (36.2%) and aph(3′)-VIa (32.4%). The majority of isolates were resistant to beta–lactams and bla CTX-M-15 was the most common ESBL. The bla NDM-1 and bla OXA-48 were also produced by 1 and 23 isolates, respectively. Novel sequence types have been reported among our isolates and high-risk clonal lineages have been detected, such as E. coli ST43 (ST131 in Achtman MLST scheme) and K. pneumoniae (ST11/ST13). Conclusions The high prevalence of aminoglycoside resistance rates and the diversity of corresponding genes, with diverse β-lactamase enzymes among genetically heterogeneous clinical isolates present a matter of concern. [ABSTRACT FROM AUTHOR]

Aminoglycosides (AGs) represent a prominent class of antibiotics widely employed for the treatment of various bacterial infections. Their widespread use has led to the emergence of antibiotic-resistant strains of bacteria, highlighting the need for analytical methods that allow the simple and reliable determination of these drugs in pharmaceutical formulations and biological samples. In this study, a simple, robust and easy-to-use analytical method for the simultaneous determination of five common aminoglycosides was developed with the aim to be widely applicable in routine laboratories. With this purpose, different approaches based on liquid chromatography with direct UV spectrophotometric detection methods were investigated: on the one hand, the use of stationary phases based on hydrophilic interactions (HILIC); on the other hand, the use of reversed-phases in the presence of an ion-pairing reagent (IP-LC). The results obtained by HILIC did not allow for an effective separation of aminoglycosides suitable for subsequent spectrophotometric UV detection. However, the use of IP-LC with a C18 stationary phase and a mobile phase based on tetraborate buffer at pH 9.0 in the presence of octanesulfonate, as an ion-pair reagent, provided adequate separation for all five aminoglycosides while facilitating the use of UV spectrophotometric detection. The method thus developed, IP-LC-UV, was optimized and applied to the quality control of pharmaceutical formulations with two or more aminoglycosides. Furthermore, it is demonstrated here that this methodology is also suitable for more complex matrices, such as serum, which expands its field of application to therapeutic drug monitoring, which is crucial for aminoglycosides, with a therapeutic index ca. 50%. [ABSTRACT FROM AUTHOR]

Aminoglycosides are crucial antibiotics facing challenges from bacterial resistance. This study addresses the importance of aminoglycoside modifying enzymes in the context of escalating resistance. Drawing upon over two decades of structural data in the Protein Data Bank, we focused on two key antibiotics, neomycin B and kanamycin A, to explore how the aminoglycoside structure is exploited by this family of enzymes. A systematic comparison across diverse enzymes and the RNA A‐site target identified common characteristics in the recognition mode, while assessing the adaptability of neomycin B and kanamycin A in various environments. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance among Enterobacterales continues to be a growing problem, particularly in those with urinary infections. Previous studies have demonstrated safety and efficacy with the use of single‐dose aminoglycosides in uncomplicated cystitis. However, data in complicated infections are limited. Single‐dose aminoglycosides may provide a convenient alternative for those with or at risk for resistant pathogens causing complicated urinary infections, especially when oral options are unavailable due to resistance, allergy, intolerance, or interactions with other medications. This study evaluated the safety and effectiveness of single‐dose aminoglycosides in treatment of complicated cystitis in the emergency department (ED). Methods: This was a multicenter, prospective study performed between July 2022 and March 2023 of patients who met criteria for complicated cystitis and were otherwise stable for discharge at an academic ED. Primary outcomes were clinical or microbiologic failure within 14 days of treatment. Safety was assessed by review of adverse events. Descriptive statistics were used. Results: Thirteen patients were included. Complicating factors were male sex (n = 4), kidney stone (n = 2), urinary catheter (n = 6), recent urologic procedure (n = 1), urinary hardware (n = 1), antibiotic allergy precluding use of alternate oral options (n = 4), immunocompromised status (n = 2), and <1‐year history of multidrug‐resistant organisms on urine culture (n = 8). Eleven patients (85%) had positive urine cultures in the preceding 12 months with no oral antimicrobial option. Eight patients (62%) received amikacin (median dose 15 mg/kg), four patients (31%) received gentamicin (median dose 5 mg/kg), and one patient (8%) received tobramycin (5 mg/kg) for treatment. Ten patients (77%) reported resolved urinary symptoms after treatment and 11 patients (85%) reported no new urinary symptoms since discharge. No patient required hospital admission for treatment failure, and no adverse events were noted. Conclusions: Single‐dose aminoglycosides appear to be a reasonably effective and safe treatment for complicated cystitis, which avoided hospital admission in this cohort. [ABSTRACT FROM AUTHOR]

Background: Ventilator-associated pneumonia (VAP) in acute respiratory distress syndrome patients is expected in the setting of prolonged mechanical ventilation due to abridged immunity and dysregulation of the microorganisms inhabiting the oral cavity. We conducted this study to identify the spectrum of microorganisms causing VAP in patients admitted to the medicine intensive care unit (MICU) and their antibiotic susceptibility patterns. Materials and Methods: We conducted a retrospective cross-sectional laboratory-based study from January 2021 to April 2021. Our cohort included patients with respiratory distress who were admitted to the MICU. We observed the incidence of VAP and the risk factors responsible for multidrug resistance (MDR) microorganisms in the MICU, along with 250-day survival in the existence of specific comorbidities along with VAP. Results: Clinical charts of patients (n = 366) admitted to the MICU between January 2021 and April 2021 were used. The mean age of patients admitted to MICU was 57.3 ± 18.7 years with a male predominance (n = 252, 68.8%). VAP was diagnosed in 69.1% (n = 253) of patients, and the most common microorganism in our cohort was Klebsiella pneumoniae (n = 78, 30.8%), followed by Acinetobacter spp. (n = 77, 30.4%). None of the K. pneumoniae isolates (n = 0/78) and only a minority of Acinetobacter spp. (n = 4/77, 5.2%) and Pseudomonas aeruginosa isolates (n = 8/54, 14.8%) were susceptible to fluoroquinolones. A higher proportion of K. pneumoniae (n = 1/78, 1.3%), Acinetobacter spp. (n = 2/77, 2.6%), and P. aeruginosa isolates (n = 9/54, 16.7%) were susceptible to aminoglycosides. The incidence rate of MDR microorganisms among the 253 patients diagnosed with VAP was 92.8% (n = 219/253). Conclusion: There is a high prevalence of multidrug resistance (MDR) isolates among those causing VAP in the MICU setting. Knowing the broad spectrum of causative pathogens and their susceptibility to various antibiotics may guide the physician in judicious and appropriate use of antibiotics for treatment.

Introduction: Chronic osteomyelitis in the paediatric age group is a frequent complication of improperly treated acute haematogenous osteomyelitis, leading to devastating complications such as pathological fractures and deformities in affected children. There is a growing need to comprehend the disease process and develop improved treatment strategies. Aim: To evaluate bacterial culture and antibiotic sensitivity patterns in children and adolescents with chronic haematogenous osteomyelitis in North India and to explore associations between radiological patterns and antibiotic sensitivity. Materials and Methods: The present retrospective study was conducted in the Department of Orthopaedics of tertiary care centre, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, North India, from July 2018 to June 2020. Total 100 children and young adolescents with chronic osteomyelitis who reported to OPD of hospital with pus discharge from an extremity persisting for more than six weeks, along with radiological features indicative of chronic osteomyelitis. Parameters such as site of infection, illness duration, blood parameters, bacteriological culture reports, etc., were examined. Radiological evaluation was performed using the Beit CURE (BC) classification. Data were analysed and represented in the form of frequencies and percentages. The Chi-square test was used to compare proportions, with significance set at p-value

Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multi ligand receptors megalin and cubilin play pivotal roles in the endocytic uptake of normally filtered proteins in PT cells but also contribute to the uptake of nephrotoxic drugs, including aminoglycosides. We previously demonstrated that opossum kidney (OK) cells cultured under continuous fluid shear stress (FSS) are superior to cells cultured under static conditions in recapitulating essential functional properties of PT cells in vivo. To identify drivers of the highcapacity, efficient endocytic pathway in the PT, we compared FSS-cultured OK cells with less endocytically active static-cultured OK cells. Megalin and cubilin expression are increased, and endocytic uptake of albumin in FSScultured cells is > 5-fold higher compared with cells cultured under static conditions. To understand how differences in receptor expression, distribution, and trafficking rates contribute to increased uptake, we used biochemical, morphological, and mathematical modeling approaches to compare megalin traffic in FSS- versus static-cultured OK cells. Our model predicts that culturing cells under FSS increases the rates of all steps in megalin trafficking. Importantly, the model explains why, despite seemingly counterintuitive observations (a reduced fraction of megalin at the cell surface, higher colocalization with lysosomes, and a shorter half-life of surface-tagged megalin in FSS-cultured cells), uptake of albumin is dramatically increased compared with static-grown cells. We also show that FSS-cultured OK cells more accurately exhibit the mechanisms that mediate uptake of nephrotoxic drugs in vivo compared with static-grown cells. This culture model thus provides a useful platform to understand drug uptake mechanisms, with implications for developing interventions in nephrotoxic injury prevention. [ABSTRACT FROM AUTHOR]

Two distinct spherical gold nanoparticles (AuNPs) were compared for the spectrophotometric determination of neomycin in saliva. The AuNPs were produced using AuCl3 and monobasic sodium citrate (in water bath at 100 °C) under magnetic stirring (AuNPs-citrate) and using HAuCl4 and NaBH4, at room-temperature under mechanical agitation in a commercial reactor (AuNPs-H). Both AuNPs were spherical with diameters of 7.7 nm (AuNPs-H) and 26.1 nm (AuNPs-citrate) and the maximum wavelength of the localized surface plasmon resonance (LSPR) bands were at 511 nm (AuNPs-H) and 529 nm (AuNPs-citrate). Equivalent spectral extinctions were found despite the fact the large difference in concentrations of AuNPs in dispersions: 4.2 × 10−9 mol L−1 for the AuNPs-H and 8.7 × 10−11 mol L−1 for the AuNPs-citrate. Both AuNPs interacted with aminoglycosides (AMG), affecting intensity of the LSPR band as the concentration of AMG increased. The response of the AuNPs-H was more sensitive toward AMG covering the following ranges: 0.6–600 µg L−1 (gentamicin), 7.3–550 µg L−1 (neomycin) and 14–520 µg L−1 (kanamycin). AuNPs-H optical response was more robust in function of the pH with AuNPs-citrate response only observed in acid solution, favoring electrostatic interaction with AMG. Catalytic activity of AuNPs-H, in reducing the 4-phenolate ion, presented a higher rate constant (4.3 × 10−3 s−1) and was used as analytical probe to determine neomycin in saliva after solid phase extraction with a commercially available AMG imprinted polymer enabling quantification to 0.36 μg of the analyte. [ABSTRACT FROM AUTHOR]

This study ventures into unexplored realms by investigating the combined efficacy of aminoglycosides (amikacin (AMI), gentamicin (GEN), kanamycin (KAN), streptomycin (STR), and tobramycin (TOB)) and silver nanoparticles (AgNPs) against pathogenic E. coli, offering a novel approach to combating antibiotic resistance. A noticeable transformation in color from a soft yellow to a rich brown marked the transition of silver ions to AgNPs, a process visually captured over 42 h. Morphological investigations showcased untreated E. coli cells retaining their natural rod shape, contrasted by AgNP treated cells that displayed considerable structural damage, signifying compromised cellular integrity. Antibacterial experiments, involving MIC and MBC tests, unveiled an increased effectiveness of antibiotics when paired with AgNPs, demonstrating a remarkable synergistic relationship. Time-kill assays provided a bacterial reductions, highlighting the boosted antibacterial action resulting from the combined application of AgNPs and antibiotics. The combination of TOB with AgNPs displayed the most substantial biofilm reduction, reaching at 19.87%. Fascinatingly, the armA gene was observed in bacterial cultures exposed to a TOB (2MIC), but its non-detection in cultures treated with a mix of 2MIC TOB and AgNP stood out as particularly noteworthy. This research unveiled a crucial finding where the antibacterial effectiveness of aminoglycosides consistently improved when combined with AgNPs. The findings suggested a promising direction for further research into the synergistic effects of antibiotics and nanoparticle adjuncts. Understanding the underlying mechanisms of this interaction could provide valuable insights into combating bacterial resistance, particularly in strains that are resistant to conventional antibiotic treatments. [ABSTRACT FROM AUTHOR]

Background: The medical significance of drug resistance in Mycobacterium tuberculosis, particularly the multi-drug-resistant strains, has a significant impact on the challenge of treating the disease and controlling its prevalence. Objectives: The objective of this study was to determine the frequency of rrs and rpsL mutations in aminoglycoside-resistant Mycobacterium tuberculosis strains isolated from clinical specimens in western Iran. Methods: This descriptive cross-sectional study was conducted on positive sputum specimens obtained from 40 pulmonary disease patients referred to the Kermanshah Lung Disease Center. The sputum specimens were cultured on the Löwenstein-Jensen medium. Specimens were assessed for the presence of genes resistant and susceptible to aminoglycosides using gene expression methods. DNA extraction was performed using the G-spin kit, and the Polymerase Chain Reaction (PCR) method and hybridization technique were carried out using the AID kit. Results: Out of the 40 sputum samples, five (12.5%) were resistant to kanamycin/amikacin, and 12 (30%) showed resistance to streptomycin. Five mutation sites were identified in the codon 1400 of the rrs gene, which were associated with amikacin/kanamycin resistance. Additionally, nine other samples (22.5%) exhibited mutations in the Streptomycin-resistant rpsL A43G gene. Three samples (7.5%) showed mutations in the rrs C526T gene, conferring resistance to streptomycin. Conclusions: Our investigation revealed a significant frequency of resistance to drugs used as second-line medications. It must be noted that treating patients can be challenging when the frequency of multi-drug-resistant bacteria is high. [ABSTRACT FROM AUTHOR]

Objectives To characterize and elucidate the spread of amikacin-resistant Enterobacteriaceae isolates from environmental samples on a pig farm in the UK, following the previous identification of index Salmonella isolates harbouring the rmtB gene, a 16S rRNA methylase. Methods Environmental samples were collected during two visits to a pig farm in the UK. Isolates were recovered using selective media (amikacin 128 mg/L) followed by real-time PCR and WGS to analyse rmtB -carrying Salmonella and Escherichia coli isolates. Results Salmonella and E. coli isolates harbouring the rmtB gene were detected at both farm visits. All Salmonella isolates were found to be monophasic S. enterica serovar Typhimurium variant Copenhagen of ST34. rmtB -harbouring E. coli isolates were found to be one of three STs: ST4089, ST1684 and ST34. Long-read sequencing identified the rmtB gene to be chromosomally located in Salmonella isolates and on IncFII-type plasmids in E. coli isolates. The results showed the rmtB gene to be flanked by IS 26 elements and several resistance genes. Conclusions We report on the occurrence of rmtB -harbouring Enterobacteriaceae on a pig farm in the UK. rmtB confers resistance to multiple aminoglycosides and this work highlights the need for surveillance to assess dissemination and risk. [ABSTRACT FROM AUTHOR]

Background: Enterococcus, a low virulent yet hardy organism, is a cause of many community acquired as well as nosocomial infections. Antibiotic resistance in Enterococcus spp. is rising worldwide owing to their intrinsic resistance to multiple drugs. The combination therapy of betalactam antibiotics with aminoglycosides is the choice of treatment for this type of infection. But this is often rendered ineffective on account of high-level aminoglycoside resistance. Vancomycin resistance further complicates the scenario. Objectives: To note the predominant infections caused by Enterococcus spp. and to show their resistance pattern, with particular emphasis on vancomycin resistance. Materials and methods: This study was conducted retrospectively in our tertiary care teaching hospital in Odisha, Eastern India, where 200 consecutive, nonrepetitive Enterococcus spp obtained on culture were included. Their demographic profile was collected from the lab register, and analysis was done using MS Excel. Results: The commonest sample from which Enterococcus spp was isolated was urine (n = 82, 41%), followed by blood (n = 49, 24.5%). E. faecalis (n = 120, 60 %) followed by E. faecium (n = 55, 27.5 %) were the most common species seen. Flouroquinolones, macrolides, and tetracycline were the most resistant antibiotics for all the Enterococcus species. E. faecalis had a much higher percentage of susceptibility to penicillin and higher level gentamicin (76.5% and 55.6%, respectively) compared to E. faecium (10.7% and 13.2%, respectively). Among the total, 43 (21.5%) isolates were vancomycin resistant, and only 3 (1.5%) showed moderate susceptibility. All the isolates 200 (100%) were tigecycline susceptible. Conclusion: The present study highlights increased vancomycin resistance as noted in 21.5% Enterococcus isolates. Quinolones, macrolides, and tetracycline showed better sensitivity to vancomycin resistant Enterococcus, probably owing to lesser use in clinical scenarios. Urinary tract infection is the predominant infection caused by Enterococcus spp. Nitrofurantoin is an effective drug, particularly for E. faecalis. [ABSTRACT FROM AUTHOR]

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The Infectious Diseases Society of America (IDSA) recommends a single dose of an aminoglycoside for uncomplicated cystitis caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) and difficult-to-treat Pseudomonas aeruginosa. However, there is very little recent clinical evidence to support this recommendation. The objective of this study was to evaluate the safety and efficacy of a single-dose aminoglycoside for cystitis caused by ESBL-E or Pseudomonas aeruginosa. This was a multicenter, retrospective, cohort study. Patients who received ≥3 days of standard of care were compared to patients who received a one-time dose of an aminoglycoside with or without a short course of effective therapy before. The primary outcome was the rate of relapse defined as requiring escalation of antibiotics or starting new antibiotic therapy within 14 days after the completion of antibiotics. A total of 66 patients were included in this study, with 33 patients in each arm. There were more males and complicated cystitis patients in the standard-of-care group. There was no difference found in the rate of relapse. The length of stay was significantly shorter in the aminoglycoside group (4.5 ± 4.4 days vs. 14.1 ± 10.1 days, p < 0.0001). A one-time dose of an aminoglycoside did not increase the risk of relapse and was associated with a shorter length of stay when used to treat cystitis caused by ESBL-E or Pseudomonas aeruginosa. [ABSTRACT FROM AUTHOR]

Many studies have shown the anti-diabetic effects of medicinal plants. But their molecular mechanism has been less studied. Understanding of these mechanisms can help to better manage the treatment of diabetes by using these plants. So, this research examined the effect of Artemisia annua extract on PI3K (phosphatidylinositol 3-kinase)/AKt (serine/threonine kinase protein B) signaling pathway in liver of high-fat diet (HFD)/Streptozotocin (STZ)-induced type 2 diabetic mice. Groups of mice were control, untreated diabetic mice, diabetic mice treated with various doses (400, 200, 100 mg/kg) of methanolic and aqueous extract of A. annua and metformin for four weeks. Type 2 diabetes was produced by feeding high-fat diet following injection of low dose of STZ. After experiment duration all mice were sacrificed and blood glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), index of insulin sensitivity index (ISI) were detected and liver tissues were isolated for to detect m-RNA expression of PI3K and Akt. Extracts of aqueous and methanolic this plant markedly reduced hyperglycemia, hyperinsulinemia, HOMA-IR and elevated ISI in diabetic group in comparison with un-treated diabetic mice. In addition, they could enhance the expression of AKt and PI3K m-RNA in liver tissues in diabetic mice. Artemisia annua extract ameliorated insulin resistance and improved insulin action in liver via the high activity of PI3K/AKt signaling pathway. So, it can be a suitable alternative treatment to synthetic antidiabetic drugs to improve insulin action in condition of type 2 diabetes. [ABSTRACT FROM AUTHOR]

We determined antibiotic susceptibility and employed Oxford Nanopore whole-genome sequencing to explore strain diversity, resistance, and virulence gene carriage among methicillin-resistant Staphylococcus aureus (MRSA) strains from different infection sites and timepoints in a tertiary Kenyan hospital. Ninety-six nonduplicate clinical isolates recovered between 2010 and 2023, identified and tested for antibiotic susceptibility on the VITEK ID/AST platform, were sequenced. Molecular typing, antibiotic resistance, and virulence determinant screening were performed using the relevant bioinformatics tools. The strains, alongside those from previous studies, were stratified into two periods covering 2010–2017 and 2018–2023 and comparisons were made. Mirroring phenotypic profiles, aac(6′)-aph(2″) [aminoglycosides]; gyrA (S84L) and grlA (S80Y) [fluoroquinolones]; dfrG [anti-folates]; and tet(K) [tetracycline] resistance determinants dominated the collection. While the proportion of ST239/241-t037-SCCmec III among MRSA reduced from 37.7% to 0% over the investigated period, ST4803-t1476-SCCmec IV and ST152-t355-SCCmec IV were pre-eminent. The prevalence of Panton–Valentine leucocidin (PVL) and arginine catabolic mobile element (ACME) genes was 38% (33/87) and 6.8% (6/87), respectively. We observed the displacement of HA-MRSA ST239/241-t037-SCCmec III with the emergence of ST152-t355-SCCmec IV and a greater clonal heterogeneity. The occurrence of PVL+/ACME+ CA-MRSA in recent years warrants further investigations into their role in the CA-MRSA virulence landscape, in a setting of high PVL prevalence. [ABSTRACT FROM AUTHOR]

Simple Summary: Febrile neutropenia is associated with high mortality, and the administration of anti-pseudomonal agents is required. Traditionally, combination therapy with aminoglycosides was weakly recommended in the guidelines, but recently, with the emergence of resistant bacteria, there has been increasing hope for combination antimicrobial therapy. The purpose of this systematic review, based on RCTs published up to 2023, is to examine how much more effective combination therapy with beta-lactams and aminoglycosides is compared to monotherapy with beta-lactams. We performed a systematic review of studies that compared beta-lactams vs. beta-lactams plus aminoglycosides for the treatment of febrile neutropenia in cancer patients. Method: We searched CENTRAL, MEDLINE, and Embase for studies published up to October 2023, and randomized controlled trials (RCTs) that compared anti-Pseudomonas aeruginosa beta-lactam monotherapy with any combination of an anti-Pseudomonas aeruginosa beta-lactam and an aminoglycoside were included. Result: The all-cause mortality rate of combination therapy showed no significant differences compared with that of monotherapy (RR 0.99, 95% CI 0.84 to 1.16, high certainty of evidence). Infection-related mortality rates showed that combination therapy had a small positive impact compared with the intervention with monotherapy (RR 0.83, 95% CI 0.66 to 1.05, high certainty of evidence). Regarding treatment failure, combination therapy showed no significant differences compared with monotherapy (RR 0.99, 95% CI 0.94 to 1.03, low certainty of evidence). In the sensitivity analysis, the treatment failure data published between 2010 and 2019 showed better outcomes in the same beta-lactam group (RR 1.10 [95% CI, 1.01–1.19]). Renal failure was more frequent with combination therapy of any daily dosing regimen (RR 0.46, 95% CI 0.36 to 0.60, high certainty of evidence). Conclusion: We found combining aminoglycosides with a narrow-spectrum beta-lactam did not spare the use of broad-spectrum antibiotics. Few studies included antibiotic-resistant bacteria and a detailed investigation of aminoglycoside serum levels, and studies that combined the same beta-lactams showed only a minimal impact with the combination therapy. In the future, studies that include the profile of antibiotic-resistant bacteria and the monitoring of serum aminoglycoside levels will be required. [ABSTRACT FROM AUTHOR]

Background: Antibiotic resistance is a global public health concern that has been exacerbated by the overuse and misuse of antibiotics, leading to the emergence of resistant bacteria. The gut microbiota, often influenced by antibiotic usage, plays a crucial role in overall health. Therefore, this study aimed to investigate the prevalence of antibiotic resistant genes in the gut microbiota of Indonesian coastal and highland populations, as well as to identify vancomycin-resistant bacteria and their resistant genes. Methods: Stool samples were collected from 22 individuals residing in Pacet, Mojokerto, and Kenjeran, Surabaya Indonesia in 2022. The read count of antibiotic resistant genes was analyzed in the collected samples, and the bacterium concentration was counted by plating on the antibiotic-containing agar plate. Vancomycin-resistant strains were further isolated, and the presence of vancomycin-resistant genes was detected using a multiplex polymerase chain reaction (PCR). Results: The antibiotic resistant genes for tetracycline, aminoglycosides, macrolides, beta-lactams, and vancomycin were found in high frequency in all stool samples (100%) of the gut microbiota. Meanwhile, those meant for chloramphenicol and sulfonamides were found in 86% and 16% of the samples, respectively. Notably, vancomycin-resistant genes were found in 16 intrinsically resistant Gram-negative bacterial strains. Among the detected vancomycin-resistant genes, vanG was the most prevalent (27.3%), while vanA was the least prevalent (4.5%). Conclusion: The presence of multiple vancomycin resistance genes in intrinsically resistant Gram-negative bacterial strains demonstrated the importance of the gut microbiota as a reservoir and hub for the horizontal transfer of antibiotic resistant genes. [ABSTRACT FROM AUTHOR]

Purpose: Single doses of gentamicin have demonstrated clinical efficacy in the treatment of urogenital gonorrhea, but lower cure rates for oropharyngeal and anorectal gonorrhea. Formulations selectively enriched in specific gentamicin C congeners have been proposed as a less toxic alternative to gentamicin, potentially permitting higher dosing to result in increased plasma exposures at the extragenital sites of infection. The purpose of the present study was to compare the antibacterial activity of individual gentamicin C congeners against Neisseria gonorrhoeae to that of other aminoglycoside antibiotics. Methods: Antimicrobial susceptibility of three N. gonorrhoeae reference strains and 152 clinical isolates was assessed using standard disk diffusion, agar dilution, and epsilometer tests. Results: Gentamicin C1, C2, C1a, and C2a demonstrated similar activity against N. gonorrhoeae. Interestingly, susceptibility to the 1-N-ethylated aminoglycosides etimicin and netilmicin was significantly higher than the susceptibility to their parent compounds gentamicin C1a and sisomicin, and to any other of the 25 aminoglycosides assessed in this study. Propylamycin, a 4'-propylated paromomycin analogue, was significantly more active against N. gonorrhoeae than its parent compound, too. Conclusion: Selectively enriched gentamicin formulations hold promise for a less toxic but equally efficacious alternative to gentamicin. Our study warrants additional consideration of the clinically established netilmicin and etimicin for treatment of genital and perhaps extragenital gonorrhea. Additional studies are required to elucidate the mechanism behind the advantage of alkylated aminoglycosides. [ABSTRACT FROM AUTHOR]

Introduction: Chronic osteomyelitis in the paediatric age group is a frequent complication of improperly treated acute haematogenous osteomyelitis, leading to devastating complications such as pathological fractures and deformities in affected children. There is a growing need to comprehend the disease process and develop improved treatment strategies. Aim: To evaluate bacterial culture and antibiotic sensitivity patterns in children and adolescents with chronic haematogenous osteomyelitis in North India and to explore associations between radiological patterns and antibiotic sensitivity. Materials and Methods: The present retrospective study was conducted in the Department of Orthopaedics of tertiary care centre, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, North India, from July 2018 to June 2020. Total 100 children and young adolescents with chronic osteomyelitis who reported to OPD of hospital with pus discharge from an extremity persisting for more than six weeks, along with radiological features indicative of chronic osteomyelitis. Parameters such as site of infection, illness duration, blood parameters, bacteriological culture reports, etc., were examined. Radiological evaluation was performed using the Beit CURE (BC) classification. Data were analysed and represented in the form of frequencies and percentages. The Chi-square test was used to compare proportions, with significance set at p-value<0.05. Results: The median age of the study population was 13 years, there were 32 (32%) females and 68 (68%) males. The majority of cases (70%) belonged to the B1-B3 group. Staphylococcus aureus was responsible for 86 (86%) cases, followed by Pseudomonas aeruginosa in 7 (7%) cases. Out of the 86 Staphylococcus aureus (S. aureus) isolates, 58 (67.44%) were Methicillin-resistant Staphylococcus aureus (MRSA). Multidrug resistance was observed among gram-negative species, as well. Pseudomonas aeruginosa showed resistance to fluoroquinolones in 4 (57%) cases, aminoglycosides in 2 (28%) cases, and carbapenem in 1 (14%) case, which is considered highly effective in treating serious infections caused by multidrug resistant Gram-negative species. No significant association was found between drug sensitivity patterns and radiological features in the present study. Conclusion: Staphylococcus aureus remains the most predominant organism isolated from deep tissue cultures. Among S. aureus isolates, MRSA was the most frequently identified. Identifying the causative organism may be challenging in some cases. Among cases where the offending microbe was identified, drug resistance was widespread among both Gram-negative and Gram-positive specimens. No significant relationship was found between the radiological appearance of infected bone and the pattern of antibiotic resistance. [ABSTRACT FROM AUTHOR]

The flagellar motor proteins, MotA and MotB, form a complex that rotates the flagella by utilizing the proton motive force (PMF) at the bacterial cell membrane. Although PMF affects the susceptibility to aminoglycosides, the effect of flagellar motor proteins on the susceptibility to aminoglycosides has not been investigated. Here, we found that MotB overexpression increased susceptibility to aminoglycosides, such as kanamycin and gentamicin, in Bacillus subtilis without affecting swimming motility. MotB overexpression did not affect susceptibility to ribosome-targeting antibiotics other than aminoglycosides, cell wall-targeting antibiotics, DNA synthesis-inhibiting antibiotics, or antibiotics inhibiting RNA synthesis. Meanwhile, MotB overexpression increased the susceptibility to aminoglycosides even in the motA-deletion mutant, which lacks swimming motility. Overexpression of the MotB mutant protein carrying an amino acid substitution at the proton-binding site (D24A) resulted in the loss of the enhanced aminoglycoside-sensitive phenotype. These results suggested that MotB overexpression sensitizes B. subtilis to aminoglycosides in a motility-independent manner. Notably, the aminoglycoside-sensitive phenotype induced by MotB requires the proton-binding site but not the MotA/MotB complex formation. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of using aminoglycoside ear drops during outbreaks of superinfection in chronic otitis media. Material and Methods: An observational retrospective study was conducted, including patients with perforated eardrums who developed vestibular ototoxicity within the past 10 years following the application of topical ear aminoglycosides in a tertiary referral center. The study encompassed the assessment of the clinical presentation, treatment, quality of life, and evolution after treatment of the identified individuals. Results: During the study period, 6 patients, aged between 33 and 71 years, developed vestibular ototoxicity following the use of topical aminoglycoside drops due to infection flares in chronic otitis media. All cases involved the use of gentamicin. Two cases were unilateral, and 4 were unilateral. The onset of symptoms occurred within one to four weeks of using the drops, resulting in all patients experiencing instability without vertigo attacks. After discontinuing the drops and undergoing vestibular rehabilitation, 4 patients experienced sequelae, with 2 patients (both with bilateral vestibular hypofunction) suffering significant impairment in their quality of life. Conclusions: Vestibular ototoxicity due to the topical application of aminoglycosides during acute exacerbations of chronic otitis media is a rare occurrence. However, given its potential for severe consequences and the fact that we are still encountering patients with this condition, healthcare professionals should explore alternative antibacterial agents that offer similar efficacy. [ABSTRACT FROM AUTHOR]

Inhaled tobramycin treatment has been associated with nephrotoxicity in some case reports, but limited data are available about serum levels and its possible systemic absorption in lung transplant recipients (LTR). We conducted a single-center, observational and retrospective study of all adult (>18 years old) LTR treated with inhaled tobramycin for at least 3 days between June 2019 and February 2022. Trough serum levels were collected and >2 μg/mL was considered a high drug level. The primary outcome assessed the presence of detectable trough levels, while the secondary outcome focused on the occurrence of acute kidney injury (AKI) in individuals with detectable trough levels. Thirty-four patients, with a median age of 60 years, were enrolled. The primary indications for treatment were donor bronchial aspirate bacterial isolation (18 patients) and tracheobronchitis (15 patients). In total, 28 patients (82%) exhibited detectable serum levels, with 9 (26%) presenting high levels (>2 μg/mL). Furthermore, 9 patients (26%) developed acute kidney injury during the treatment course. Median trough tobramycin levels were significantly elevated in invasively mechanically ventilated patients compared to non-ventilated individuals (2.5 μg/mL vs. 0.48 μg/mL) (p < 0.001). Inhaled tobramycin administration in LTRs, particularly in those requiring invasive mechanical ventilation, may result in substantial systemic absorption. [ABSTRACT FROM AUTHOR]

The site‐selective modification of complex biomolecules by transition metal‐catalysis is highly warranted, but often thwarted by the presence of Lewis basic functional groups. This study demonstrates that protonation of amines and phosphates in carbohydrates circumvents catalyst inhibition in palladium‐catalyzed site‐selective oxidation. Both aminoglycosides and sugar phosphates, compound classes that up till now largely escaped direct modification, are oxidized with good efficiency. Site‐selective oxidation of kanamycin and amikacin was used to prepare a set of 3'‐modified aminoglycoside derivatives of which two showed promising activity against antibiotic‐resistant E. coli strains. [ABSTRACT FROM AUTHOR]

Purslane (P), chard (CHA), and chicory (CHI) leaf extracts are individually and traditionally used in the treatment of diabetes mellitus. Polyphenols, flavonoids, the polyphenolic profile of the extracts, and their antioxidant activity were determined. This study evaluated the antidiabetic activity of combinations of these extracts in streptozotocin-induced diabetic rats. Diabetic groups were administered orally and daily for 40 days with the investigated extracts at 250 mg/kg body weight (b.w.) or metformin (100 mg/kg b.w.) as a drug. Fasting blood glucose, oral glucose tolerance, insulin, and fructosamine were assessed. The combined extracts with high levels of P or CHI exerted potent hypoglycemic activity compared with metformin in addition to the restoration of the histopathological changes in the liver and pancreas of diabetic rats to a near-normal state. Therefore, these combined extracts could be developed as natural drugs for diabetes. [ABSTRACT FROM AUTHOR]

The relationship among gut microbiota, mitochondrial dysfunction/neuroinflammation, and diabetic neuropathic pain (DNP) has received increased attention. Ginger has antidiabetic and analgesic effects because of its anti-inflammatory property. We examined the effects of gingerols-enriched ginger (GEG) supplementation on pain-associated behaviors, gut microbiome composition, and mitochondrial function and neuroinflammation of colon and spinal cord in DNP rats. Thirty-three male rats were randomly divided into 3 groups: control group, DNP group (high-fat diet plus single dose of streptozotocin at 35 mg/kg body weight, and GEG group (DNP+GEG at 0.75% in the diet for 8 weeks). Von Frey and open field tests were used to assess pain sensitivity and anxio-depressive behaviors, respectively. Colon and spinal cord were collected for gene expression analysis. 16S rRNA gene sequencing was done from cecal samples and microbiome data analysis was performed using QIIME 2. GEG supplementation mitigated mechanical hypersensitivity and anxio-depressive behavior in DNP animals. GEG supplementation suppressed the dynamin-related protein 1 protein expression (colon) and gene expression (spinal cord), astrocytic marker GFAP gene expression (colon and spinal cord), and tumor necrosis factor-α gene expression (colon, P <.05; spinal cord, P =.0974) in DNP rats. GEG supplementation increased microglia/macrophage marker CD11b gene expression in colon and spinal cord of DNP rats. GEG treatment increased abundance of Acinetobacter, Azospirillum, Colidextribacter , and Fournierella but decreased abundance of Muribaculum intestinale in cecal feces of rats. This study demonstrates that GEG supplementation decreased pain, anxio-depression, and neuroimmune cells, and improved the composition of gut microbiomes and mitochondrial function in rats with diabetic neuropathy. GEG supplementation mitigated pain-associated behaviors, favored gut microbiome composition, and improved mitochondrial function in HFD + STZ rats. Abbreviations: GEG, gingerol-enriched ginger; HFD+STZ, high-fat diet and streptozocin. [Display omitted] [ABSTRACT FROM AUTHOR]

Aminoglycoside antibiotics were historically a cornerstone of antimicrobial therapy for many bacterial infections but as the threat of antimicrobial resistance continues to rise, the once broad-spectrum activity of these agents grows smaller. They are also plagued with the potential for severe adverse events such as nephrotoxicity and ototoxicity, and emerging evidence suggests that these risks may outweigh their benefit in many cases. With the recent introduction of newer and likely safer broad-spectrum antibiotics, do aminoglycosides still have a place in therapy in modern medicine? [ABSTRACT FROM AUTHOR]

Background and Objectives: Escherichia coli is a significant causative agent of bloodstream infections (BSIs). Aminoglycoside antibiotics play a crucial role in treating severe infections such as sepsis and pneumonia. However, resistance to these antibiotics often occurs due to the production of aminoglycoside-modifying enzymes (AMEs). This study was conducted to assess antimicrobial susceptibility patterns against various aminoglycosides and to determine the prevalence of common AME genes in E. coli strains isolated from BSIs. Materials and Methods: Sixty-five E. coli isolates were obtained from blood samples in a referral hospital in Tehran, Iran. The susceptibility patterns of aminoglycosides were determined using disk diffusion method and AMEs genes were investigated using PCR assay. Results: Resistance to aminoglycosides was observed in 64.6% (42/65) of the isolates. The most frequent resistance rate was found for kanamycin (44.6%) and gentamicin (38.5%), followed by tobramycin (29.2%) and amikacin (4.6%). The most frequent AME gene was aac(3)-IVa, which detected in 49.2% isolates, followed by aac(6)-Ib (40%), aac(3)-IIa (32.3%), and ant(2)-Ia (30.8%), respectively. Conclusion: Athough the findings of this survey are based on specimens collected from a single hospital, our study shows that the high prevalence of aminoglycoside resistance is primarily attributed to the presence of the aac(3)-Iva, aac(6)-Ib and aac(3)-IIa genes. The low rate of resistance to amikacin makes this antibiotic a good candidate for treatment of BSIs due to E. coli. [ABSTRACT FROM AUTHOR]

Purpose: Blood culture obtainment prior to antibiotic administration, in patients with suspected infection, is considered the best practice in international guidelines. However, there is little data regarding the effect of a single dose of antibiotics on blood culture sterilization. Methods: We conducted a prospective study, enrolling consecutive patients with suspected infection, hospitalized in an internal medicine ward between December 2019 and January 2023. Included patients had a positive blood culture prior to antibiotic administration and a set of blood cultures taken within 24 h after a single dose of antibiotics. The rate of patients with pathogen isolation after antibiotic administration was assessed. Logistic regression was performed to examine factors associated with blood culture positivity. Results: A total of 155 patients were recruited for the study of which 131 (50.8% female 77.5 ± 13.4 years) met the inclusion criteria. The overall rate of patients with a positive blood culture after a single dose of antibiotics was 42.0% (55/131 patients). Increasing time between antibiotic administration and post-antibiotic culture was an independent predictor for blood culture sterilization (odds ratio 0.89 [95% confidence interval, 0.83–0.97; p = 0.006] for every 60 min). Blood culture volume was an independent predictor for blood culture positivity in a sensitivity analysis which included 82 patients (OR = 1.26 [95% CI 1.03–1.57] for every 1 ml increase; p = 0.024). Conclusion: Blood culture positivity is reduced by antimicrobial therapy but remains high after a single dose of antibiotics. If cultures are not obtained prior to antibiotic administration, they should be obtained as soon as possible afterwards. [ABSTRACT FROM AUTHOR]

This document, titled "Clinical relevance of Pseudomonas aeruginosa viable but non-culturable forms in cystic fibrosis," discusses the presence and significance of viable but non-culturable (VBNC) forms of Pseudomonas aeruginosa in patients with cystic fibrosis (pwCF). VBNC cells are dormant and antibiotic-tolerant bacterial forms that are unable to grow on microbiological media but can still cause infections. The study found that VBNC P. aeruginosa cells were detected in the sputum of pwCF, particularly in those with chronic infections. Antibiotic treatments, such as aminoglycosides, were found to induce the VBNC state in some patients. The study emphasizes the need for further research to understand the role of antibiotics in VBNC cell development and to validate these preliminary findings. [Extracted from the article]

The Kir4.1 channel, an inwardly rectifying potassium ion (K+) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K+ homeostasis in supporting cells, with K+ concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient.

Antimicrobial resistance (AMR) is a significant public health issue in Bangladesh like many other developing countries where data on resistance trends are scarce. Moreover, the existence of multidrug-resistant (MDR) Escherichia coli exerts an ominous effect on the poultry sector. Therefore, the current systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was conducted to find out the AMR scenarios in E. coli isolates sourced from poultry and poultry environments in Bangladesh between 2010 and 2021. Following the PRISMA guidelines, a total of 17 published scientific articles were selected for this systematic review. This review revealed that 18 out of 64 districts in Bangladesh reported E. coli in poultry, having a higher prevalence (combined prevalence: 69.3%, 95% confidence interval, CI: 67.3-71%). Moreover, the prevalence ranged from 24.3% to 100%. This review found that E. coli isolates showed resistance to 14 antimicrobial classes and 45 different antimicrobial agents, including the last-line (reserve group) antibiotics and banned antimicrobial categories for the treatment of infections in agricultural animals. Phenotypic resistance of E. coli against penicillins and beta-lactamase inhibitors (20.2%-100%), cephalosporins (1.9%-100%), fluoroquinolones (5.98%-100%), aminoglycosides (6%-100%), tetracyclines (17.7%-100%), carbapenems (13.6%-72.7%), macrolides (11.8%-100%), polymyxins (7.9%-100%), phenicols (20%-97.2%), sulfa drugs (44.7%-100%), cephamycins (21.4%-48.8%), nitrofurans (21.4%-63.2%), monobactams (1.2%), and glycylcyclines (2.3%) was recorded in the last decades in Bangladesh. Also, 14 articles reported MDR E. coli in poultry, including a 100% MDR in nine articles and a 92.7% (95% CI: 91.2-94%) combined percentage of MDR E. coli isolates. Twenty-four different AMR genes encoding resistance to beta-lactams (bla TEM, bla CTX-M-1, bla CTX-M-2, bla CTX-M-9, bla OXA-1, bla OXA-47, bla SHV, and CITM), colistin (mcr1 and mcr3), fluoroquinolones (qnrB and qnrS), tetracyclines (tetA, tetB, and tetC), sulfonamides (sulI and sulII), trimethoprim (dfrA1), aminoglycosides (rmtB), streptomycin (aadA1), gentamicin (aac-3-IV), erythromycin (ereA), and chloramphenicol (catA1 and cmlA) were detected in E. coli isolates. The presence of MDR E. coli and their corresponding resistance genes in poultry and poultry environments is an alarming issue for all health communities in Bangladesh. We suggest a regular antimicrobial surveillance program with a strong One Health approach to lessen the hazardous effects of AMR E. coli in poultry industries in Bangladesh.

Introduction The use of gentamicin in the treatment of infectious diseases requires frequent monitoring to attain the best treatment outcomes.Objective This study aimed to evaluate the appropriateness of gentamicin therapeutic drug monitoring (TDM) at a tertiary care hospital in Qatar.Methods A one-year quantitative retrospective chart review of all gentamicin TDM records was conducted. Evidence-based criteria were applied to evaluate the appropriateness of gentamicin TDM in terms of indication, sampling times, and post-analytical actions.Results Out of 59 captured gentamicin TDM records, 58 gentamicin samples were eligible for evaluation. Overall, gentamicin TDM appropriateness was achieved in 50% (n = 29) of the evaluated records. However, 12% (n = 7) of gentamicin drug concentrations were below the assay quantification limits or were not sampled appropriately. Inappropriate post-analytical actions (22.4%, n = 13) and inappropriate sampling times (44.8%, n = 26) were recorded. Most of the gentamicin blood samples (n = 43; 74.2%) were taken appropriately at steady-state. Inappropriate sampling time relative to the last dose was captured in 31% (n = 18) of the cases. Although 27.6% (n = 16) of gentamicin concentrations were non-therapeutic, continuing gentamicin dosing without adjustment was the most frequent post-analytical action (69.8%, n = 37). Gentamicin dose regimen continuations, dose regimen decreases and dose regimen discontinuations were inappropriately applied in 27% (n = 10), 25% (n = 2) and 14% (n = 1) of the times, respectively.Conclusion Suboptimal gentamicin TDM practices exist in relation to sampling time and post-analytical actions. Studies exploring setting-specific reasons behind inappropriate TDM practices and methods of its optimisation are needed.

Background: Ferroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism. Methods: We identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real‐time PCR (qRT‐PCR) and western blot analysis. Results: The expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway. Conclusions: Collectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation of drug-drug interactions that might impact ototoxicity would facilitate design of safer multidrug regimens and mitigate unsafe polypharmacy by flagging combinations that potentially cause adverse interactions for monitoring. They may also identify protective agents that antagonize ototoxic injury. Methods: To address this need, we have developed a novel workflow that we call Parallelized Evaluation of Protection and Injury for Toxicity Assessment (PEPITA), which empowers high-throughput, semi-automated quantification of ototoxicity and otoprotection in zebrafish larvae via microscopy. We used PEPITA and confocal microscopy to characterize in vivo the consequences of drug-drug interactions on ototoxic drug uptake and cellular damage of zebrafish lateral line hair cells. Results and discussion: By applying PEPITA to measure ototoxic drug interaction outcomes, we discovered antagonistic interactions between macrolide and aminoglycoside antibiotics that confer protection against aminoglycosideinduced damage to lateral line hair cells in zebrafish larvae. Co-administration of either azithromycin or erythromycin in zebrafish protected against damage from a broad panel of aminoglycosides, at least in part via inhibiting drug uptake into hair cells via a mechanism independent from hair cell mechanotransduction. Conversely, combining macrolides with aminoglycosides in bacterial inhibition assays does not show antagonism of antimicrobial efficacy. The proof-of-concept otoprotective antagonism suggests that combinatorial interventions can potentially be developed to protect against other forms of toxicity without hindering on-target drug efficacy. [ABSTRACT FROM AUTHOR]

Purpose Our community hospital was recently charged with providing care for pediatric people with cystic fibrosis (PwCF). Pediatric PwCF generally need a higher level of care than is required by other pediatric patients cared for at our institution. This project aimed to prepare the pharmacy department to care for this specialized population safely and efficiently. Summary The implementation process was divided into 3 phases to accomplish the larger purpose. These phases were as follows: (1) creating order sets and protocols; (2) providing staff and clinical pharmacists with training and resources; and (3) creating and managing clinical decision support. The central aspect of preparing inpatient pharmacy staff to care for PwCF was the development of antibiotic dosing protocols and order sets comprised of intravenous and oral antibiotics as well as aminoglycoside and vancomycin pharmacokinetic guides. A pharmacokinetic calculator was created to assist with aminoglycoside dosing and monitoring. During phase 2, pharmacist education modules were created to provide guidance on cystic fibrosis and medications commonly used to treat it. As the newly designed protocols were enacted, education was provided on how to use them. Phase 3 occurred concurrently, as clinical decision support was vital to completing phases 1 and 2. Conclusion The phased approach was imperative to the project's success and kept individual components on track. All parts were completed in just over one year. [ABSTRACT FROM AUTHOR]

A new member of the family Flavobacteriaceae (termed Hal144T) was isolated from the marine breadcrumb sponge Halichondria panicea. Sponge material was collected in 2018 at Schilksee which is located in the Kiel Fjord (Baltic Sea, Germany). Phylogenetic analysis of the full-length Hal144T 16S rRNA gene sequence revealed similarities from 94.3 to 96.6% to the nearest type strains of the genus Maribacter. The phylogenetic tree of the 16S rRNA gene sequences depicted a cluster of strain Hal144T with its closest relatives Maribacter aestuarii GY20T (96.6%) and Maribacter thermophilus HT7-2T (96.3%). Genome phylogeny showed that Maribacter halichondriae Hal144T branched from a cluster consisting of Maribacter arenosus, Maribacter luteus, and Maribacter polysiphoniae. Genome comparisons of strain Maribacter halichondriae Hal144T with Maribacter sp. type strains exhibited average nucleotide identities in the range of 75–76% and digital DNA-DNA hybridisation values in the range of 13.1–13.4%. Compared to the next related type strains, strain Hal144T revealed unique genomic features such as phosphoenolpyruvate-dependent phosphotransferase system pathway, serine-glyoxylate cycle, lipid A 3-O-deacylase, 3-hexulose-6-phosphate synthase, enrichment of pseudogenes and of genes involved in cell wall and envelope biogenesis, indicating an adaptation to the host. Strain Hal144T was determined to be Gram-negative, mesophilic, strictly aerobic, flexirubin positive, resistant to aminoglycoside antibiotics, and able to utilize N-acetyl-β-D-glucosamine. Optimal growth occurred at 25–30 °C, within a salinity range of 2–6% sea salt, and a pH range between 5 and 8. The major fatty acids identified were C17:0 3-OH, iso-C15:0, and iso-C15:1 G. The DNA G + C content of strain Hal144T was 41.4 mol%. Based on the polyphasic approach, strain Hal144T represents a novel species of the genus Maribacter, and we propose the name Maribacter halichondriae sp. nov. The type strain is Hal144T (= DSM 114563T = LMG 32744T). [ABSTRACT FROM AUTHOR]