Potential protective effects of Acacia nilotica (L.) against gentamicin - induced nephrotoxicity by suppressing renal redox imbalance, inflammatory stress and caspase-dependent apoptosis in Wistar rats.

Gentamicin-induced nephrotoxicity limits its therapeutic use as an effective aminoglycoside. Herbal drugs have a distinct place in the world of pharmaceuticals since they are safe, effective, and cost-efficient. Acacia nilotica (L.) has long been recognized for its antihypertensive, antioxidant, anti-inflammatory, and antiplatelet aggregatory benefits in traditional medicine. Still, the protective effect of Acacia nilotica on gentamicin-induced nephrotoxicity is still unknown. Thus, the goal of this research was to examine the protection of ethanolic extract of Acacia nilotica (ANE) against nephrotoxicity triggered by Gentamicin.Thirty-six rats were randomly divided into six groups containing six rats in each group. The distilled water were given in control group. The rats in groups two and three were administered metformin and gentamicin respectively. In groups five and six, rats were administered ANE at doses of 100 and 200 mg/kg. Ten days of daily treatments were given. The urea, creatinine, uric acid, and LDH levels were analyzed on serum, whereas histological evaluation, MDA, GSH, SOD, CAT, TNF-α, IL-6, and caspase-3, were performed on kidney tissue on day 11. The gentamicin-treated group exhibited a significantly elevated MDA, and lower levels of antioxidant enzymes. Kidney function markers, inflammatory markers and caspase-3 expression were significantly elevated in the gentamicin-treated group. ANE significantly restored kidney function biomarkers, upregulated biochemical levels, inhibited TNF-α, caspase-3, cytokine expression, and reduced histological lesions.In conclusion, ANE has the ability to prevent gentamicin-induced nephrotoxicity and reduce nephrotoxic damage. As such, it may represent an effective therapy for patients receiving gentamicin treatment.

Boronic acid-functionalized magnetic covalent organic frameworks based solid-phase extraction coupled with hydrophilic interaction chromatography-tandem mass spectrometry for the determination of trace gentamicin residues in milk.

Boric acid-functionalized magnetic covalent organic frameworks (Fe3O4-TpBD-B) with large surface area and high porosity were prepared and applied for magnetic solid-phase extraction adsorbent of gentamicin from milk before UPLC-MS/MS detection. By utilizing a new HILIC chromatographic column with zwitterionic sulfoalkyl betaine stationary phase based on ethyl bridged hybrid particles (BEH), isomers of gentamicin (C1, C1a, and C2+C2a components). The developed methods demonstrated good linearity (R2 > 0.99), acceptable accuracy and good precision (<10 %), and low limit of quantitation (1.59 ng mL⁻1 for C1, 1.52 ng mL⁻1 for C1a and 2.72 ng mL⁻1 for C2+C2a). In addition, this method has been effectively applied to the analysis of real milk samples.

A smartphone-assisted portable dual-mode immunoassay of gentamicin based on curcumin nanoparticles and carbon dots.

A smartphone-assisted portable dual-mode immunoassay was constructed based on curcumin nanoparticles (CNPs) and carbon dots (CDs) for gentamicin (GEN) detection. CNPs were labeled with goat anti-mouse IgG (Ab2) to create a conjugation that coupled dual signals to concentrations of GEN antigens. CNPs were introduced to pH 7.4 water and showed insignificant color and optical responses. When exposed to the high pH environment, the structure of CNPs changed and color and optical properties were restored. Because of the inner filter effect (IFE) between CNPs and CDs, the fluorescence of CNPs at 550 nm quenched the fluorescence of CDs at 450 nm. Colorimetry and ratiometric fluorescence (F550 nm/F450 nm) dual-mode immunoassay linearly correlated with GEN ranged from 10-4 to 100 µg/mL with a detection limit (LOD) of 8.98 × 10-5 µg/mL and 4.66 × 10-5 µg/mL, respectively. This work supplied a portable, sensitive, and specific platform to detect GEN.

A novel pharmacological strategy using nanoparticles with glutathione and virgin coconut oil to treat gentamicin-induced acute renal failure in rats.

In acute renal failure (ARF), the glomerular filtration rate is reduced, and nitrogenous waste products accumulate persistently, which can last anywhere from a few hours to several days. There is hope for a reversal of the rapid loss of renal function caused by this condition. This study, with gentamicin-induced acute ARF as a prospective setting, sets out to examine the reno-protective benefits of virgin coconut oil (VCO) and GSH. Furthermore, the study evaluated the effect of medication nanoparticle compositions on several kidney function markers. The induction of ARF is achieved with the intraperitoneal injection of gentamicin. To assess renal function, rats underwent 24 h of dehydration and hunger before their deaths. The study examined various aspects, including kidney function tests, markers of oxidative stress, histology of kidney tissue, inflammatory cytokines, immunohistochemistry expression of nuclear factor-kappa B (NF-κB), and specific biomarkers for kidney tissue damage, such as kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). The results of our study indicated that the combination of VCO and GSH, using both regular and nanoparticle formulations, had a better protective impact on the kidneys compared to using either drug alone. The recovery of renal tissue and serum markers, which are symptomatic of organ damage, indicates improvement. This was also demonstrated by the reduction in tubular expression of TNF-α, IL-1ß, KIM-1, and NGAL. The immunohistochemical studies showed that the combination therapy, especially with the nanoforms, greatly improved the damaged cellular changes in the kidneys, as shown by higher levels of NF-κB. The study shows that VCO and GSH, when administered individually or combined, significantly improve ARF in a gentamicin-induced rat model, highlighting potential therapeutic implications. Notably, the combined nanoparticulate formulations exhibit substantial effectiveness.

Predictors of gentamicin therapy failure in neonates with sepsis.

Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world-wide. Gram-negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early-onset sepsis. However, therapy failure may result due to various factors. The purpose of this study was to identify predictors of gentamicin therapy failure in neonates with sepsis. This was a prospective cross-sectional study at the Neonatal Intensive Care Unit at Windhoek Central Hospital over a period of 5 months in 2019. Neonates received intravenous gentamicin 5 mg/kg/24 h in combination with either benzylpenicillin 100 000 IU/kg/12 h or ampicillin 50 mg/kg/8 h. Logistic regression modeling was performed to determine the predictors of treatment outcomes. 36% of the 50 neonates were classified as having gentamicin treatment failure. Increasing treatment duration by 1 day resulted in odds of treatment failure increasing from 1.0 to 2.41. Similarly, one unit increase in CRP increases odds of gentamicin treatment failure by 49%. The 1 kg increase in birthweight reduces the log odds of treatment failure by 6.848, resulting in 99.9% decrease in the odds of treatment failure. One unit increase in WBC reduces odds of gentamicin treatment failure by 27%. Estimates of significant predictors of treatment failure were precise, yielding odds ratios that were within 95% confidence interval. This study identified the following as predictors of gentamicin therapy failure in neonates: prolonged duration of treatment, elevated C-reactive protein, low birthweight, and low white blood cell count.

The comparison between intratympanic gentamicin prehabilitation and postoperative virtual reality exposure to standard vestibular training in patients with vestibular schwannoma.

OBJECTIVE: Resection of the vestibular schwannoma causes acute peripheral vestibular loss. The process of central compensation starts immediately afterward. The rehabilitation goal is to support this process and restore the quality of life. MATERIALS AND METHODS: In this prospective single-center study, 67 consecutive patients underwent vestibular schwannoma resection (40 females, mean age 52 ± 12 years). The patients were divided into three groups: the prehabilitation with intratympanic gentamicin group, the virtual reality group (optokinetic stimulation via virtual reality goggles in the first ten days after the surgery), and the control group. All patients were examined with objective methods and completed questionnaires before the prehabilitation, before the surgery, at the hospital discharge, and after three months. RESULTS: Intratympanic gentamicin prehabilitation leads ipsilaterally to a significant aVOR reduction in all semicircular canals (p < 0.050), the increase of the unilateral weakness in air calorics (p = 0.026), and loss of cVEMPs responses (p = 0.017). Prehabilitation and postoperative exposure to virtual reality scenes improved the patient's perception of vertigo problems according to Dizziness Handicap Inventory (p = 0.039 and p = 0.076, respectively). These findings conform with the optokinetic testing results, which showed higher slow phase velocities at higher speeds (40 deg/s) in both targeted groups compared to the control group. CONCLUSION: Preoperative intratympanic gentamicin positively affects peripheral vestibular function, influencing balance perception after VS resection. In long-term follow-up, prehabilitation and postoperative exposure to virtual reality improve patients' quality of life in the field of vertigo problems.

Characterization of the novel broad-spectrum lytic phage Phage_Pae01 and its antibiofilm efficacy against Pseudomonas aeruginosa.

Introduction: Pseudomonas aeruginosa is present throughout nature and is a common opportunistic pathogen in the human body. Carbapenem antibiotics are typically utilized as a last resort in the clinical treatment of multidrug-resistant infections caused by P. aeruginosa. The increase in carbapenem-resistant P. aeruginosa poses an immense challenge for the treatment of these infections. Bacteriophages have the potential to be used as antimicrobial agents for treating antibiotic-resistant bacteria. Methods and Results: In this study, a new virulent P. aeruginosa phage, Phage_Pae01, was isolated from hospital sewage and shown to have broad-spectrum antibacterial activity against clinical P. aeruginosa isolates (83.6%). These clinical strains included multidrug-resistant P. aeruginosa and carbapenem-resistant P. aeruginosa. Transmission electron microscopy revealed that the phage possessed an icosahedral head of approximately 80 nm and a long tail about 110 m, indicating that it belongs to the Myoviridae family of the order Caudovirales. Biological characteristic analysis revealed that Phage_Pae01 could maintain stable activity in the temperature range of 4~ 60°C and pH range of 4 ~ 10. According to the in vitro lysis kinetics of the phage, Phage_Pae01 demonstrated strong antibacterial activity. The optimal multiplicity of infection was 0.01. The genome of Phage_Pae01 has a total length of 93,182 bp and contains 176 open reading frames (ORFs). The phage genome does not contain genes related to virulence or antibiotic resistance. In addition, Phage_Pae01 effectively prevented the formation of biofilms and eliminated established biofilms. When Phage_Pae01 was combined with gentamicin, it significantly disrupted established P. aeruginosa biofilms. Conclusion: We identified a novel P. aeruginosa phage and demonstrated its effective antimicrobial properties against P. aeruginosa in both the floating and biofilm states. These findings offer a promising approach for the treatment of drug-resistant bacterial infections in clinical settings.

Two cinnamoyl hydroxamates as potential quorum sensing inhibitors against Pseudomonas aeruginosa.

Introduction: Pseudomonas aeruginosa is a ubiquitous pathogen that causes various infectious diseases through the regulation of quorum sensing (QS). The strategy of interfering with the QS systems of P. aeruginosa, coupled with a reduction in the dosage of conventional antibiotics, presents a potential solution to treating infection and mitigating antibiotic resistance. In this study, seven cinnamoyl hydroxamates were synthesized to evaluate their inhibitory effects on QS of P. aeruginosa. Among these cinnamic acid derivatives, we found cinnamoyl hydroxamic acid (CHA) and 3-methoxy-cinnamoyl hydroxamic acid (MCHA) were the two most effective candidates. Furtherly, the effect of CHA and MCHA on the production of virulence factors and biofilm of P. aeruginosa were evaluated. Ultimately, our study may offer promising potential for treating P. aeruginosa infections and reducing its virulence. Methods: The disc diffusion test were conducted to evaluate inhibitory effects on QS of seven cinnamoyl hydroxamates. The influence of CHA and MCHA on the production of virulence and flagellar motility of P. aeruginosa was furtherly explored. Scanning electron microscopy (SEM) experiment were conducted to evaluate the suppression of CHA and MCHA on the formed biofilm of P. aeruginosa. RT-qPCR was used to detect rhlI, lasA, lasB, rhlA, rhlB, and oprL genes in P. aeruginosa. In silico docking study was performed to explore the molecular mechanism of CHA and MCHA. The synergistic effects of CHA with gentamicin were detected on biofilm cell dispersal. Result: After treatment of CHA or MCHA, the production of multiple virulence factors, including pyocyanin, proteases, rhamnolipid, and siderophore, and swimming and swarming motilities in P. aeruginosa were inhibited significantly. And our results showed CHA and MCHA could eliminate the formed biofilm of P. aeruginosa. RT-qPCR revealed that CHA and MCHA inhibited the expression of QS related genes in P. aeruginosa. Molecular docking indicated that CHA and MCHA primarily inhibited the RhlI/R system in P. aeruginosa by competing with the cognate signaling molecule C4-HSL.Additionally, CHA exhibited potent synergistic effects with gentamicin on biofilm cell dispersal. Discussion: P. aeruginosa is one of the most clinically and epidemiologically important bacteria and a primary cause of catheter-related urinary tract infections and ventilator-associated pneumonia. This study aims to explore whether cinnamoyl hydroxamates have inhibitory effects on QS. And our results indicate that CHA and MCHA, as two novel QSIs, offer promising potential for treating P. aeruginosa infections and reducing its virulence.

Pharmacokinetic study of local and systemic gentamicin concentrations after subcutaneous implantation of a gentamicin-impregnated collagen sponge in dogs.

This study evaluated the pharmacokinetics of commercial gentamicin-impregnated collagen sponges (GICS) applied subcutaneously in dogs. In six healthy beagles, an 11 ×6 cm subcutaneous pocket was created, a folded 10×10 cm GICS was inserted, and saline was injected to mimic a seroma. Wound fluid samples were aspirated, and the gentamicin concentration was determined. Simultaneously, blood samples were collected to evaluate the corresponding systemic gentamicin concentration. All samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120, and 168 hours after GICS placement. The local Cmax of gentamicin was reached after 0.5 hours (range, 0.5-1.0 hours) post-implantation in 5/6 dogs at a median concentration of 2053.3 µg/mL (range, 918.0-2791.9 µg/mL). Whitin 24 hours, the local concentration dropped below the MIC for Staphylococcus sp. (4 µg/mL) in 5/6 dogs. Plasma Cmax was achieved at a median of 1.2 hours post-implantation (range, 1.0-2.0 hours) and reached a median concentration of 10.3 µg/mL (range, 8.8-18.03 µg/mL). After 6 hours, the gentamicin concentration in the plasma was below 4 µg/mL in all dogs. The GICS provided a high local concentration of gentamicin in a short time with a local Cmax:MIC ratio of 513:1, largely sufficient to eliminate susceptible bacteria, including methicillin-resistant Staphylococcus pseudintermedius (MRSP) and Pseudomonas sp., in a clinical setting. The repeated administration of saline in the present study seemed to have induced a quicker gentamicin release from the GICS than described in previous studies that typically dealt with "drier" wounds.

Evaluation of composition effects on the tissue-adhesive, mechanical and physical properties of physically crosslinked hydrogels based on chitosan and pullulan for wound healing applications.

Tissue adhesion of hydrogels plays an important role in wound healing, which can improve the efficiency of wound treatment, stop bleeding, facilitate tissue growth and wound closure. However, most non-covalent crosslinked hydrogels have weak tissue adhesion and rheological properties. Furthermore, it remains a challenge to synthesize a fully physically crosslinked hydrogel with good rheological properties without compromising its tissue adhesion strength. In this paper, a physically crosslinked hydrogel was developed from a mixture of chitosan and pullulan in different polymer volume ratios using aqueous NaOH. Fourier transform infrared spectroscopy, scanning electron microscopy, thermal analysis, rheological and lap shear tests were used to evaluate the influence of polymer volume ratios on the rheological, and tissue adhesive properties of the hydrogels. It was found that the hydrogels possessed high tissue adhesive strength ranging from 18.0 ± 0.90 to 49.0 ± 2.45 kPa and good storage moduli up to 5.157 ± 1.062 kPa. Gentamicin was incorporated into this polymer matrix and the release profile was investigated. The ratio of chitosan and pullulan to obtain hydrogels with optimum viscoelastic and tissue adhesive properties was identified to be CS/PUL 2:1. These results indicated that the synthesized hydrogels can be potential materials for biomedical applications such as medical adhesives and wound dressings.

Four three-dimensional rare earth metal - organic framework fluorescent sensor for efficient detection of gentamicin sulfate and Fe3.

Excessive use of gentamicin sulfate can cause severe nephrotoxicity and ototoxicity, abnormal levels of Fe3+ intake can also cause serious damage to body. Therefore, establishing a fast and accurate detection method for the above-mentioned substances is of great significance. However, traditional detection methods such as high-performance liquid chromatography still have certain problems such as high cost and complex operation. Fluorescent MOFs are favored by analysts due to their high specific surface area, high porosity, adjustable pore size, and good stability. In this paper, we have synthesized four rare earth MOFs based on the pyridinecarboxylic acid ligand (H2L), which are [Eu(L)1/2H2O]n, [Gd(L)1/2H2O]n, [Sm(L)1/2H2O]n, [Y(L)3/2H2O·DMF]n. The structures of four MOFs were confirmed by single crystal X-ray diffraction, which proved that MOF-1, MOF-2 and MOF-3 were isostructural, and all the four MOFs were three-dimensional structures. In the fluorescence test, gentamicin sulfate and Fe3+ can cause significant fluorescence quenching of MOF-1 and MOF-4 respectively, and show good selectivity and anti-interference performance, as well as low detection limit and wide detection range. This work may provide a possibility for the detection of gentamicin sulfate and iron ions in complex environments.

Impact of once-daily versus multiple-daily dosing of gentamicin on the incidence of acute kidney injury in patients treated with synergistic combinations of antibiotics.

BACKGROUND: Gentamicin is a commonly used antibiotic with synergistic effects that is administered once or multiple times daily. However, the influence of the daily administration frequency on renal function has not yet been identified. This study aimed to investigate the effect of the daily dosing frequency on worsening renal function in patients receiving gentamicin. METHODS: This study included 35 patients undergoing gentamicin treatment who had at least one serum trough level measured and underwent therapeutic drug monitoring (TDM). We evaluated the influence of daily dosing frequency on gentamicin trough concentration and the risk of acute kidney injury (AKI). RESULTS: Compared to patients who received gentamicin once-daily dosing (n = 22), patients who received multiple-daily dosing (n = 13) had significantly higher initial and minimum trough concentrations after TDM. The proportion of patients with trough concentrations lower than 1.0 µg/mL was significantly higher in the once-daily dosing group at the initial trough concentration, whereas there was no significant difference at the minimum trough concentration after TDM. AKI developed in nine patients; however, there was no significant difference in the incidence of AKI according to the frequency of daily gentamicin dosing. In contrast, a higher minimum trough concentration after TDM was found to be a risk factor for AKI development with an odds ratio of 9.2 (95% confidence intervals; 1.3-65.5). CONCLUSION: A higher trough concentration of gentamicin correlated with a higher incidence of AKI. The risk of developing AKI may be reduced by choosing a once-daily dosing regimen or implementing TDM.

Appropriateness of gentamicin therapeutic drug monitoring at a Middle Eastern tertiary hospital setting: a retrospective evaluation and quality audit.

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.

Binding and displacement study of gentamicin, 5-fluorouracil, oxytetracycline and rolitetracycline with (BSA: Drug2) complex using spectroscopic and calorimetric techniques: Biophysical approach.

Understanding of energetics of interactions between drug and protein is essential in pharmacokinetics and pharmacodynamics study. The binding affinity (K) helps in investigating how tightly or loosely drug is bound to protein. The binding, displacement, conformational change and stability study of drugs- gentamicin (GM), 5-fluorouracil (5FU), oxytetracycline (OTC) and rolitetracycline (RTC) with bovine serum albumin (BSA) has been carried out in presence of each other drug by fluorescence, UV-visible spectroscopy, molecular docking, circular dichroism techniques and thermal denaturation method. The site marker study and docking methods have confirmed that 5FU and GM are able to bind at site 1 and OTC and RTC at site II of BSA. The order of their binding affinities with BSA for the binary system were as GM <5FU < OTC < RTC with the order of 102 < 103 < 105 < 105-6 M-1. The displacement study has shown that higher affinity drug decreases the equilibrium constant of another drug already in bound state with BSA if both these drugs are having the same binding site. Therefore 5FU, GM (binding site 1) drugs were not able to displace OTC and RTC (binding site 2) and vice-versa as they are binding at two different sites. The binding constant values were found to be decreasing with increasing temperature for all the systems involved which suggests static or mixed type of quenching, however can only confirmed with the help of TCSPC technique. The ΔG0 (binding energy) obtained from docking method were in accordance with the ITC method. From molecular docking we have determined the amino acid residues involved in binding process for binary and ternary systems by considering first rank minimum binding energy confirmation. From CD it has been observed that RTC causes most conformational change in secondary and tertiary structure of BSA due to the presence of pyrrole ring. OTC-RTC with higher affinity showed highest melting temperature Tm values while low affinity drugs in (5FU-GM) combination showed lowest Tm value. 5FU showed large endothermic denaturation enthalpy ΔHd0 due to the presence of highly electronegative fluorine atom in the pyridine analogue.

Antibiotic-Loaded Nano-Sized Delivery Systems: An Insight into Gentamicin and Vancomycin.

The fight against infectious disease has remained an ever-evolving challenge in the landscape of healthcare. The ability of pathogens to develop resistance against conventional drug treatments has decreased the effectiveness of therapeutic interventions, and antibiotic resistance is recognized as one of the main challenges of our time. The goal of this systematic review paper is to provide insight into the research papers published on innovative nanosized drug delivery systems (DDSs) based on gentamycin and vancomycin and to discuss the opportunity of their repurposing through nano DDS formulations. These two antibiotics are selected because (i) gentamicin is the first-line drug used to treat suspected or confirmed infections caused by Gram-negative bacterial infections and (ii) vancomycin is used to treat serious Gram-positive bacterial infections. Moreover, both antibiotics have severe adverse effects, and one of the purposes of their formulation as nanosized DDSs is to overcome them. The review paper includes an introduction focusing on the challenges of infectious diseases and traditional therapeutic treatments, a brief description of the chemical and pharmacological properties of gentamicin and vancomycin, case studies from the literature on innovative nanosized DDSs as carriers of the two antibiotic drugs, and a discussion of the results found in the literature.

Revisiting the Evidence Base Informing the Use of Adjunctive Therapy for Enterococcus faecalis Endocarditis: A Systematic Review and Meta-Analysis.

BACKGROUND: Current guidelines recommend adjunctive gentamicin for the treatment of Enterococcus faecalis infective endocarditis (EFIE) despite a risk of toxicity. We sought to revisit the evidence for adjunctive therapy in EFIE and to synthesize the comparative safety and effectiveness of adjunctive use of the aminoglycosides versus ceftriaxone by systematic review and meta-analysis. METHODS: For historical context, we reviewed the seminal case series and in vitro studies informing the evolution from penicillin monotherapy to modern-day regimens for EFIE. Next, we searched MEDLINE and Embase from inception to January 16, 2024 for studies of EFIE comparing 1) adjunctive aminoglycosides versus ceftriaxone or 2) adjunctive therapy versus monotherapy. Where possible, clinical outcomes were compared between regimens by random-effects meta-analysis. Otherwise, data were narratively summarized. RESULTS: Results for the systematic review and meta-analysis were limited to 10 observational studies totaling 911 patients. All studies were at high risk of bias. Relative to adjunctive ceftriaxone, gentamicin had similar all-cause mortality (Risk Difference [RD]=-0.8%, 95% Confidence interval [95%CI]=-5.0, 3.5), relapse (RD=-0.1%, 95%CI=-2.4, 2.3), and treatment failure (RD=1.1%, 95%CI=-1.6, 3.7), but higher discontinuation due to toxicity (RD=26.3%, 95%CI=19.8, 32.7). The 3 studies comparing adjunctive therapy to monotherapy included only 30 monotherapy patients and heterogeneity precluded meta-analysis. CONCLUSION: Adjunctive therapy with ceftriaxone appeared to be equally effective and less toxic than gentamicin for the treatment of EFIE. The existing evidence does not clearly establish the superiority of either adjunctive therapy or monotherapy. Pending randomized evidence, if adjunctive therapy is to be used, ceftriaxone appears to be a reasonable option.

Fluid shear stress-induced changes in megalin trafficking enhance endocytic capacity in proximal tubule cells.

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 high-capacity, 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 FSS-cultured 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.

Optimized Electrophoretic Deposition of Chitosan/Mesoporous Glass Nanoparticles with Gentamicin on Titanium Implants: Enhancing Hemocompatibility and Antibacterial Activity.

Titanium-based implants have long been studied and used for applications in bone tissue engineering, thanks to their outstanding mechanical properties and appropriate biocompatibility. However, many implants struggle with osseointegration and attachment and can be vulnerable to the development of infections. In this work, we have developed a composite coating via electrophoretic deposition, which is both bioactive and antibacterial. Mesoporous bioactive glass particles with gentamicin were electrophoretically deposited onto a titanium substrate. In order to validate the hypothesis that the quantity of particles in the coatings is sufficiently high and uniform in each deposition process, an easy-to-use image processing algorithm was designed to minimize human dependence and ensure reproducible results. The addition of loaded mesoporous particles did not affect the good adhesion of the coating to the substrate although roughness was clearly enhanced. After 7 days of immersion, the composite coatings were almost dissolved and released, but phosphate-related compounds started to nucleate at the surface. With a simple and low-cost technique like electrophoretic deposition, and optimized stir and suspension times, we were able to synthesize a hemocompatible coating that significantly improves the antibacterial activity when compared to the bare substrate for both Gram-positive and Gram-negative bacteria.

Gentamicin combination treatment is associated with lower mortality in patients with invasive listeriosis: a retrospective analysis.

PURPOSE: Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study. METHODS: We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality. RESULTS: In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01-0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment. CONCLUSION: This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice.

Synergistic antibacterial activity of ceftazidime-avibactam in combination with colistin, gentamicin, amikacin, and fosfomycin against carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CPKP) infections seriously threaten global public health. The main objective of this study was to assess the in-vitro synergistic activity of ceftazidime-avibactam (CZA) in combination with colistin (COL), amikacin (AK), gentamicin (GEN), and fosfomycin (FOS) against CPKP isolates. The secondary goal was to determine the antibiotic susceptibility performance of BD Phoenix. OXA-48 (49.1%) was the predominant carbapenemase, followed by KPC (29.1%). We used the broth microdilution (BMD) method to determine the minimum inhibitory concentrations (MICs) of CZA, COL, AK, and GEN. Meanwhile, the MICs of FOS were determined by the agar dilution (AD) method. To examine the antibacterial activity of CZA, we conducted a checkerboard assay (CBA) with COL, AK, GEN, and FOS against CRKP isolates. We randomly selected three strains and performed synergy testing via time-kill assay (TKA). CRKP isolates were 89.1% susceptible to CZA, 16.4% to COL, 21.8% to GEN, and 29.1% to AK using BMD, 47.3% to FOS by AD. The most synergistic effects were observed in the combination of CZA-COL (78.2%) and CZA-FOS (63.6%). Given the limited therapeutic options for treating severe CRKP infections, combining CZA with COL and FOS may enhance in-vitro activity against clinical CRKP isolates.