Administration Of Gentamicin Research Articles

Effect of alpha-linolenic acid on aminoglycoside nephrotoxicity and RhoA/Rho-kinase pathway in kidney.

Aminoglycoside nephrotoxicity stands as a primary contributor to the development of acute intrinsic renal failure. Distinctive characteristic associated with this nephrotoxicity is the occurrence of tubular necrosis, which is why it is commonly referred to as acute tubular necrosis. Studies have demonstrated that inhibiting rhoA/rho-kinase pathway is beneficial for kidney damage induced by diabetes and renal ischemia. Comparable pathological conditions can be observed in aminoglycoside nephrotoxicity, like those found in diabetes and renal ischemia. Gentamicin, an aminoglycoside, is known to activate Rho/Rho-kinase pathway. The primary goal of this study is to explore influence of oxidative stress on this pathway by concurrently administering gentamicin and alpha-linolenic acid (ALA) possessing known antioxidant properties. To achieve this, gentamicin (100 mg kg-1) and ALA (70 mg kg-1) were administered to mice for a period of 9 days, and Rho/Rho-kinase pathway was examined by using ELISA. Administration of gentamicin to mice led to an elevation in RhoA and rho-kinase II levels, along with the activity of rho-kinase in kidneys. However, ALA effectively reversed this heightened response. ALA, known for its antioxidant properties, inhibited activation of Rho/Rho-kinase pathway induced by gentamicin. This finding suggests that gentamicin induces nephrotoxicity through oxidative stress.

Blood concentration monitoring and renal function changes during gentamicin administration for infective endocarditis: a retrospective observational study

BackgroundEstablished guidelines for monitoring gentamicin blood concentration are lacking; therefore, we focused on improving pharmacological interventions and ensuring their safety. We aimed to optimize gentamicin administration for infective endocarditis (IE) treatment.MethodsThe study involved adult patients diagnosed with IE and treated with gentamicin from January 2014 to December 2022. Clinical presentation and drug therapy regimen were comprehensively evaluated. We performed a retrospective chart review of the frequency of gentamicin dose adjustments and changes in renal function while on gentamicin. In addition, we attempted to extract risk factors for renal impairment using univariate analysis.ResultsOn average, a 7.1% decline [changed to − 6.7 ± 20.4 (standard deviation) mL/min/1.73 m2] in the estimated glomerular filtration rate was observed after gentamicin administration, but it was statistically insignificant. Notably, 58% of patients required dosage adjustments, with a subset requiring multiple adjustments. Among the cases in which dosage adjustments were made, 61% were within the first week of treatment. There were no patients with gentamicin levels below the target peak concentration. Furthermore, no independent risk factors were identified in patients requiring dose reduction.ConclusionsDose adjustment was necessary in many cases after treatment initiation. The time to dose adjustment varied widely. These findings highlight the importance of consistent blood concentration monitoring in patients of all demographics, at least weekly, and underscore that routine peak concentration assessments may not be essential when a 3 μg/mL target is maintained. This study provides information on monitoring gentamicin blood level, which can improve IE treatment safety.

Galangin prevents gentamicin-induced nephrotoxicity by modulating oxidative damage, inflammation and apoptosis in rats.

The well-known antibiotic gentamicin (GEN) works well against a variety of pathogenic bacteria, nevertheless its therapeutic use might be limited by the possibility of nephrotoxicity. The naturally occurring flavonoid galangin (GAL) has several interesting anti-inflammatory and antioxidant properties. The present study evaluated the nephroprotective effect of GAL on GEN-induced renal injury. Rats received GAL for 14 days and GEN from day 8 to day 14. There was a significant increase in serum urea and creatinine along with several histopathological changes in the kidney following GEN administration. GEN-treated rats also showed increased levels of kidney MDA and NO, and decreased GSH content and activities of antioxidant enzymes. Rats received GEN also demonstrated increased NF-κB p65, iNOS, TNF-α, IL-1β and IL-6 levels in the kidney. GAL remarkably prevented tissue injury, attenuated MDA and NO levels, improved antioxidants, and decreased levels of inflammatory mediators in the kidney of GEN-treated rats. Furthermore, GEN-administrated rats exhibited increased Bax and caspase-3 with concomitant decline in Bcl-2 levels in the kidney, an effect that GAL attenuated. In conclusion, GAL prevents GEN-induced nephrotoxicity by attenuating oxidative stress, inflammation, and apoptosis and augmenting antioxidant defense, suggesting its therapeutic potential against drug nephrotoxicity.

Effective biofilm eradication in MRSA isolates with aminoglycoside-modifying enzyme genes using high-concentration and prolonged gentamicin treatment.

Our analysis of 101 MRSA clinical isolates has provided valuable insights that could enhance treatment selection for biofilm infections in orthopedics. We found that high concentrations of gentamicin were effective against MRSA biofilms, and even prolonged exposure to concentrations lower than the minimum biofilm eradication concentration (MBEC) value could eliminate biofilms. The presence of the aac(6')-aph(2″) gene, an aminoglycoside resistance gene, was found to correlate with the minimum inhibitory concentration (MIC) and MBEC values of gentamicin, providing a potential predictive tool for treatment susceptibility. These results suggest that extended high concentrations of local gentamicin treatment could effectively eliminate MRSA biofilms in orthopedic infections. Furthermore, testing for gentamicin MIC or the possession of the aac(6')-aph(2″) gene could help select treatment, including topical gentamicin administration and surgical debridement.

Repetitive combined doses of bacteriophages and gentamicin protect against Staphylococcus aureus implant-related infections in Galleria mellonella.

Bacteriophages infect, replicate inside bacteria, and are released from the host through lysis. Here, we evaluate the effects of repetitive doses of the Staphylococcus aureus phage 191219 and gentamicin against haematogenous and early-stage biofilm implant-related infections in Galleria mellonella. For the haematogenous infection, G. mellonella larvae were implanted with a Kirschner wire (K-wire), infected with S. aureus, and subsequently phages and/or gentamicin were administered. For the early-stage biofilm implant infection, the K-wires were pre-incubated with S. aureus suspension before implantation. After 24 hours, the larvae received phages and/or gentamicin. In both models, the larvae also received daily doses of phages and/or gentamicin for up to five days. The effect was determined by survival analysis for five days and quantitative culture of bacteria after two days of repetitive doses. In the haematogenous infection, a single combined dose of phages and gentamicin, and repetitive injections with gentamicin or in combination with phages, resulted in significantly improved survival rates. In the early-stage biofilm infection, only repetitive combined administration of phages and gentamicin led to a significantly increased survival. Additionally, a significant reduction in number of bacteria was observed in the larvae after receiving repetitive doses of phages and/or gentamicin in both infection models. Based on our results, a single dose of the combination of phages and gentamicin is sufficient to prevent a haematogenous S. aureus implant-related infection, whereas gentamicin needs to be administered daily for the same effect. To treat early-stage S. aureus implant-related infection, repetitive doses of the combination of phages and gentamicin are required.

In Vivo Antioxidant and Nephroprotective Effects of Ethanolic Extract of Carica papaya Seeds and Its Isolated Flavonoid on Gentamicin-Induced Nephrotoxicity in Wistar Albino Rats.

Background The nephrotoxic side effects of gentamicin, a potent aminoglycoside antibiotic, significantly restrict its clinical use. Identifying compounds that can mitigate this nephrotoxicity is of paramount importance. The research examines how the ethanolic extract of Carica papaya seeds (EECPS) and isoliquiritigenin (ISL), a flavonoid separated from them, protect the kidneys and fight free radicals in gentamicin-treated Wistar albino rats. Methodology A total of 48 mature Wistar albino rats were divided into eight groups, with each group consisting of six rats. The experimental setup included a normal control group receiving oral saline as a negative control, and a standard control group administered gentamicin intraperitoneally (IP) at 100 mg/kg body weight for 13 days to induce nephrotoxicity, followed by oral silymarin at 100 mg/kg body weight as a positive control from days 14 to 21. A toxicant control group was exposed to gentamicin IP without subsequent treatment. Two test groups were given 400 mg/kg and 800 mg/kg of EECPS orally after being given gentamicin. Three other test groups were given 20 mg/kg, 40 mg/kg, and 80 mg/kg of ISL orally after being given gentamicin. Serum levels of creatinine, urea, and blood urea nitrogen (BUN) were used to test renal function. Malondialdehyde (MDA),nitric oxide (NO), and reduced glutathione (GSH), which are signs of oxidative stress, were also measured in renal tissues. Results Gentamicin administration markedly increased serum creatinine, urea, and BUN levels, confirming its nephrotoxic effect. Nephroprotection depended on the dose of EECPS and ISL used. It was found that 80 mg/kg of ISL had the most powerful effect, which was not what was thought at first. These treatments effectively reduced MDA and NO levels while enhancing GSH levels, exhibiting their strong antioxidant properties. Notably, the nephroprotective efficacy of these treatments exceeded that of silymarin, a known nephroprotective agent. Histopathological analysis confirmed reduced renal damage and enhanced tissue repair in the treated groups. Conclusions These findings demonstrate how effective EECPS and ISL are at shielding the kidneys from gentamicin-caused damage. They do this by acting as antioxidants and nephroprotectants. Their ability to protect kidney function and fight oxidative stress makes them interesting as possible treatments for gentamicin-related kidney damage. These results advocate for further investigation into the utility of these natural compounds in the management of nephrotoxicity.

Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway

ABSTRACT Objectives Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. Methods The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. Results An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. Discussion Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Protective Effect of Aspirin Against Gentamicin-Induced Hepatotoxicity in Rats Model

Gentamicin is an extensively used antibiotic with potent antimicrobial exertion, but its clinical mileage is limited by its eventuality to induce hepatotoxicity. This study aimed to probe the defensive effect of aspirin against gentamicin-convinced hepatotoxicity in a rat model. Adult manly Wistar rats were divided into four groups control, aspirin, gentamicin, and aspirin- gentamicin. The creatures were treated for 15 successive days, and colorful biochemical parameters were estimated. Pre-treatment with aspirin significantly downgraded the adverse goods of gentamicin on liver weight. It also eased the elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) situations, indicating the preservation of liver function. Aspirin treatment suppressed hepatic lipid peroxidation, as substantiated by a reduction in malondialdehyde (MDA) situations. likewise, it averted the reduction of glutathione (GSH) situations and catalase exertion convinced by gentamicin administration. These findings suggest that aspirin exerts a hepatoprotective effect by reducing oxidative stress and enhancing antioxidant defense mechanisms. The protective mechanisms of aspirin may involve its anti-inflammatory properties, as well as its antioxidant effects. Aspirin has the potential to inhibit inflammation-induced liver injury and modulate signaling pathways involved in cell survival and apoptosis. However, further investigations are needed to elucidate the precise molecular mechanisms underlying its protective effects. Overall, pre-treatment with aspirin demonstrated a protective effect against gentamicin-induced hepatotoxicity in this rat model. It mitigated liver damage, preserved liver function, and enhanced antioxidant defense mechanisms. These findings suggest that aspirin could be a potential therapeutic agent for the prevention and management of drug-induced liver injury. Further studies, including clinical trials, are necessary to determine the optimal dosage, duration, and safety profile of aspirin in humans.

Gentamicin administration leads to synaptic dysfunction in inner hair cells

Ototoxicity is a major side effect of aminoglycosides, which can cause irreversible hearing loss. Previous studies on aminoglycoside-induced ototoxicity have primarily focused on the loss of sensory hair cells. Recent investigations have revealed that aminoglycosides can also lead to the loss of ribbon synapses in inner hair cells (IHCs). However, the functional implications of ribbon synapse loss and the underlying mechanisms remain unclear. In this study, we intraperitoneally injected C57BL/6 J mice with 300 mg/kg gentamicin once daily for 3, 10, and 20 days. Then, we performed immunofluorescence staining, patch-clamp recording, proteomics analysis and western blotting to characterize the changes in ribbon synapses in IHCs and the associated mechanisms. After gentamicin treatment, the auditory brainstem response (ABR) threshold was elevated, and the ABR wave I amplitude was decreased. We also observed loss of ribbon synapses in IHCs. Interestingly, ribbon synapse loss occurred on both the modiolar and pillar sides of IHCs. Whole-cell patch-clamp recordings in IHCs revealed a reduction in the calcium current amplitude, along with a shifted half-activation voltage and altered calcium voltage dependency. Moreover, exocytosis of IHCs was reduced, consistent with the reduction in the ABR wave I amplitude. Through proteomic analysis, western blotting, and immunofluorescence staining, we found that gentamicin treatment resulted in downregulation of myosin VI, a protein crucial for synaptic vesicle recycling and replenishment in IHCs. Furthermore, we evaluated the kinetics of endocytosis and found a significant reduction in IHC exocytosis, possibly reflecting the impact of myosin VI downregulation on synaptic vesicle recycling. In summary, our findings demonstrate that gentamicin treatment leads to synaptic dysfunction in IHCs, highlighting the important role of myosin VI downregulation in gentamicin-induced synaptic damage.

Efficacy and preservation of hearing with low-dose gentamicin in unilateral meniere's disease: A clinical symptomatology-based study

PurposeMeniere's disease (MD), a disorder of the inner ear, presents numerous therapeutic challenges, and intratympanic (IT) gentamicin has been proposed for intractable cases. However, controversy regarding dosage and method persists. The purpose of this study was to assess the efficacy and safety of low-dose IT gentamicin on vertigo attacks in MD using a clinical symptomatology-based method, wherein administration was repeated only if vertigo attacks recurred, with a 2-week interval between injections. Materials and methodsThis study included 88 patients with unilateral intractable MD. All patients received one to five IT injections with 0.5 ml of 10 mg of gentamicin (80 mg/2 ml) with an interval of 2 weeks between injections. Vertigo attacks were evaluated before and after therapy and categorized into classes A–F according to the 2015 Equilibrium Committee criteria. Audiovestibular assessments, including Pure Tone Audiometry and Vestibulo-Ocular Reflex evaluations, were performed. ResultsBefore treatment, patients had an average of 4.4 vertigo attacks/month; after treatment, this average decreased to 0.52. The majority of patients (57 %) reached Class A or B vertigo control with five or fewer gentamicin injections. VOR gain was slightly affected on the healthy side and significantly reduced on the affected side. No hearing deterioration was found in any of the treated patients. ConclusionsLow-dose IT gentamicin administration based on clinical symptomatology can produce a satisfactory control of vertigo attacks after treatment. This protocol primarily affected the vestibular function, as demonstrated by the significant reduction in VOR gain on the affected side, while avoiding cochlear damage. The lack of adverse events and preservation of hearing underscore the safety and efficacy of this method. These findings have significant clinical implications, suggesting that a low-dose, clinical symptomatology-based gentamicin treatment regimen could be an effective and safe strategy for managing unilateral Meniere's disease in a larger population.

Intra-soft tissue and intramedullary antibiotic perfusion in combination with negative pressure wound therapy.

Intra-soft tissue and intramedullary antibiotic perfusion (iSAP and iMAP), which combine continuous administration of antibiotic solution to the wound and negative pressure wound therapy (NPWT), have been reported to be a useful management approach for hard-to-heal ulcers in the field of orthopaedic surgery. We report the efficacy of this treatment and discuss the key points. The recipients of this treatment had contaminated fresh severe trauma with a high risk of infection, or hard-to-heal ulcers which were expected to be difficult to manage with conventional NPWT alone. Continuous administration of 1200µg/ml of gentamicin (GM) solution to the wound was performed along with NPWT. The GM solution was administered subcutaneously using a small catheter for iSAP, while intramedullary administration used a bone marrow needle for iMAP. iSAP was employed in all 10 patients who took part, and iMAP in three of these patients. The average treatment time was 13.6 days with iSAP and 9.3 days with iMAP. The mean serum GM level during the therapy was 1.02µg/ml. Moderate GM-induced acute kidney injury was suspected in one case, but resolved spontaneously after GM administration was stopped. Favourable wound bed preparation was achieved in all cases without recurrence of infection. Combination with continuous suction by NPWT is able to keep the local concentration of antibiotic above the minimum inhibitory concentration of biofilm-coated bacteria within the wound. We have referred to this treatment as continuous local antibiotic perfusion. Further investigation of local pharmacodynamics in the wound and side-effects of this treatment are warranted.

Regional pretracheal lymphotropic antibiotic therapy for pulmonary complications of COVID-19

Purpose of the study: to study the pharmacokinetics of gentamicin in pretracheal lymphotropic antibiotic therapy and regional stimulation of interstitial lung lymphatic drainage.Material and methods. Experimental studies consisted of a single administration of gentamicin to 50 mongrel white rats, both sexes, body mass 370–400 g, at a dose of 30 mg/kg: lymphotropically pretracheal, using lidase as a lymphatic drainage stimulator, and intramuscularly, followed by thoracotomy, undertaken to remove the chest cavity organs, paratracheal lymph nodes, and femoral vein puncture, for blood sampling. A dynamic determination of the concentration of gentamicin in the blood and extracted tissues was performed. In 10 mongrel rats, both sexes, body mass 440–470 g, the rate of lymphatic drainage of the lungs was studied using the Kety radionuclide method using Albumin I-131, with pretracheal administration of a non-concentrated lidase solution.Results. Data analysis pharmacokinetics and radionuclide study of the lymph showed that the method of lymphotropic pretracheal the introduction of antibiotics and regional lymphostimulation, may have advantages over traditional methods of drug administration in the treatment of pneumonitis (interstitiopathy) at COVID-19, due to the higher and prolonged content in the tissues and the lymphatic channel of the bronchopulmonary system (p < 0,05) – the place of greatest congestion and infection, as well as lymphatic drainage of the lungs.Conclusion. The method of lymphotropic pretracheal administration of antibiotics and regional lymphostimulation may have advantages over traditional methods of drug administration in the treatment of pulmonary complications in COVID-19.

Gentamicin Administration in Dialysis Patients: Before or After Hemodialysis?

Gentamicin is used to treat severe infections and has a small therapeutic window. This study aimed to optimize the dosing strategy of gentamicin in intermittently hemodialyzed patients by simulating concentration/time profiles during pre- and post-dialysis dosing, based on a published pharmacokinetic model. Pharmacokinetic simulations were performed with virtual patients, including septic patients, who were treated with gentamicin and received weekly hemodialysis with an interval of 48h-48h-72h. The following dosing regimens were simulated: for non-septic patients, 5 mg/kg gentamicin was given 1h/2h before dialysis, or a starting dose of 2.5 mg/kg and a maintenance dose of 1.5 mg/kg immediately after dialysis; for septic patients, 6 mg/kg gentamicin was given 1h/2h before dialysis, or a starting dose of 3 mg/kg and a maintenance dose of 1.8 mg/kg immediately after dialysis. The mean Cmax, AUC24h, and target attainment (TA) of pharmacodynamic targets were calculated and compared. The following targets were adopted from literature: Cmax >8 mg/L and <20 mg/L and AUC24h >70 mg·h/L and <120 mg·h/L. In non-septic patients, postdialysis dosing resulted in a TA of 35% for Cmax >8 mg/L, 100% for <20 mg/L and AUC24h >70 mg·h/L, and 45% for <120 mg·h/L. Dosing 2h prior to dialysis resulted in a TA of 100% for Cmax> 8 mg/L, 40% for <20 mg/L, 65% for AUC24h >70 mg·h/L, and 77% for <120 mg·h/L. Simulations of septic patients resulted in comparable outcomes with higher TAs for Cmax <20 mg/L (96%), AUC24h >70 mg·h/L (90%), and <120 mg·h/L (53%) for dosing 1h prior to dialysis. Postdialysis dosing resulted in a low TA of Cmax >8 mg/L; however, predialysis dosing ensured a high TA of Cmax >8 mg/L and acceptable TA of Cmax <20 mg/L, AUC24h >70 mg·h/L, and <120 mg·h/L, which could increase the efficacy of gentamicin. Therefore, clinicians should consider predialysis dosing of gentamicin in patients undergoing intermittent hemodialysis.

Патоморфологічні зміни нирок, печінки та біохімічні показники сироватки крові червоновухих прісноводних черепах (Trachemys scripta elegans) за парентерального введення гентаміцину

Principles of reptile treatment are significantly different from the drug therapy for mammals and birds, which is primarily due to anatomical and physiological peculiarities of reptiles. Gentamicin, which has a nephrotoxic effect, is used for the treatment of reptile infectious diseases. For the purpose of studying the effects of gentamicin of reptiles a serum biochemical analysis was conducted determining aspartate aminotransferase and alanine aminotransferase activity, urea and uric acid concentration. Two research groups of red-eared sliders (Trachemys scripta elegans) were formed for the study; every 48 hours they received an injection of gentamicin in a dose 10 mg/kg into thoracic limb muscles. The animals of the first research group were withdrawn from the experiment on the 7th day, and the animals of the second group were withdrawn on the 14th day of the research. As a result of parenteral administration of gentamicin in turtles, there is an increase in the concentration of uric acid and urea, as well as the activity of aspartate aminotransferases and alanine aminotransferases in blood serum. In the kidneys, structural changes of the glomeruli were found: alternative changes in podocytes, as well as degenerative and necrotic changes in the renal tubule epithelium. Degenerative changes of nephrocytes were accompanied by the dilation of smooth endoplasmic reticulum tubules, mitochondrial crista destruction, accumulation of autophagolysosomes, cytosomes and lysosomes in the cytoplasm. Furthermore, signs of nephrocyte apoptosis with the formation of apoptotic bodies were detected. A liver examination revealed dystrophic and necrotic changes in hepatocytes, expansion and overflow of the vessels of the venous beds.

Optimizing tick artificial membrane feeding for Ixodes scapularis

Artificial membrane feeding (AMF) is a powerful and versatile technique with a wide range of applications in the study of disease vectors species. Since its first description, AMF has been under constant optimization and standardization for different tick species and life stages. In the USA, Ixodes scapularis is the main vector of tick-borne zoonoses including the pathogens causing Lyme disease in humans and animals. Seeking to improve the overall fitness of I. scapularis adult females fed artificially, here, we have optimized the AMF technique, considerably enhancing attachment rate, engorgement success, egg laying, and egg hatching compared to those described in previous studies. Parameters such as the membrane thickness and the light/dark cycle to which the ticks were exposed were refined to more closely reflect the tick’s natural behavior and life cycle. Additionally, ticks were fed on blood only, blood + ATP or blood + ATP + gentamicin. The artificial feeding of ticks on blood only was successful and generated a progeny capable of feeding naturally on a host, i.e., mice. Adding ATP as a feeding stimulant did not improve tick attachment or engorgement. Notably, the administration of gentamicin, an antibiotic commonly used in tick AMF to prevent microbial contamination, negatively impacted Rickettsia buchneri endosymbiont levels in the progeny of artificially fed ticks. In addition, gentamicin-fed ticks showed a reduction in oviposition success compared to ticks artificially fed on blood only, discouraging the use of antibiotics in AMF. Overall, our data suggest that the AMF of adult females on blood only, in association with the natural feeding of their progeny on mice, might be used as an integrated approach in tick rearing, eliminating the use of protected species under the Animal Welfare Act (AWA). Of note, although optimized for I. scapularis adult ticks, I. scapularis nymphs, other tick species, and sand flies could also be fed using the membrane described in this study, indicating that it might be a suitable alternative for the artificial feeding of a variety of hematophagous species.

Vitamin E and Silymarin Reduce Oxidative Tissue Damage during Gentamycin-Induced Nephrotoxicity.

Aminoglycoside antibiotics and gentamicin (GN), in particular, are still widely used in clinical practice. It is a well-known fact that GN causes nephrotoxicity, and redox disturbances are discussed as a factor in its side effects. Recently, a new type of cell oxidative death, named ferroptosis, was discovered; it is associated with iron accumulation in the cell, glutathione (GSH) depletion and inactivation of glutathione peroxidase-4 (GPX4), reactive oxygen species (ROS) increment with concomitant lipid peroxidation. In this regard, a possible connection between GN-induced renal damage, ferroptosis and the overall antioxidant status of the organism could be investigated. Moreover, due to its beneficial effects, GN is still one of the main choices as a therapeutic agent for several diseases, and the possible reduction of its side effects with the application of certain antioxidants will be of important clinical significance. The study was conducted with adult male white mice divided into several groups (n = 6). GN nephrotoxicity was induced by the administration of GN 100-200 mg/kg i.p. for 10 days. The control group received only saline. The other groups received either Vitamin E (400 mg/kg p.o.) or Silymarin (200 mg/kg p.o.) applied alone or together with GN for the same period. After the end of the study, the animals were sacrificed, and blood and tissue samples were taken for the assessment of biochemical parameters and antioxidant status, as well as routine and specific for GPX4 histochemistry examination. The experimental results indicate that GN-induced nephrotoxicity negatively modulates GPX4 activity and is associated with increased production of ROS and lipid peroxidation. The groups treated with antioxidants demonstrated preserved antioxidant status and better GPX4 activity. In conclusion, the inhibition of ROS production and especially the suppression of ferroptosis, could be of clinical potential and can be applied as a means of reducing the toxic effects of GN application.

Assessing the Risk of Nephrotoxicity Associated with Aminoglycosides in Brucellosis Patients: A Cross-sectional Study.

The purpose of this study was to investigate renal function in patients with brucellosis before and at the end of gentamicin therapy. To ensure the safety of therapeutic doses of gentamicin, renal functions in brucellosis patients were monitored regarding drug serum levels and check for early detection biomarkers of nephrotoxicity. In this cross-sectional study, 41 patients (25 men and 16 women, aged over 15 years) were included, with confirmed acute brucellosis that referred to Brucellosis Research Center in Hamadan, west of Iran between March 2018 to February 2019. At baseline before treatment (first step) and 7 days after gentamicin administration (second step), serum uric acid, blood urea nitrogen (BUN), serum and urine creatinine, erythrocyte sedimentation rate (ESR), quantitative C-reactive protein (CRP) and urinary β2-microglobulin (β2M) were measured. Gentamycin serum level due to the highest risk of nephrotoxicity with this drug in aminoglycoside class was also checked by HPLC method. The data were analyzed using SPSS version 22. The mean urinary β 2M level, serum and urinary creatinine, uric acid, BUN, and quantitative CRP levels in the first step and second step, there were no statistical differences between the two steps. There was a correlation between urinary creatinine and ESR. In addition, a positive correlation was found between urinary β2M and serum gentamicin level. ESR levels have been significantly reduced in the patients after the treatment compared to before it. Our findings confirm that gentamicin is safe at the dose of 5 mg/kg/day for one week intravenously in brucellosis patients.

Gentisic acid mitigates gentamicin-induced nephrotoxicity in rats

The current investigation was considered to evaluate the beneficial effects of gentisic acid (GA) on gentamicin (GEN)-induced nephrotoxicity in rat kidneys through assessment of oxidative stress, inflammatory cytokines, and histopathological changes. Rats were split into five equal groups. Rats were treated with GA (25, 50, and 100 mg/kg/day, p.o.) for 14 consecutive days and GEN (100 mg/kg, i.p.) was administrated from day 8 to day 14 of the experiment. On the 15th day, blood samples were collected to determine neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN), and creatinine (Cr) levels. Malondialdehyde (MDA), glutathione (GSH), tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), and nitric oxide (NO) levels and the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were assessed in the renal tissue. Histopathological evaluations were done to confirm the biochemical results. GEN increased the levels of NGAL, KIM-1, BUN, and Cr in serum as well as MDA, NO, GSH, TNF-α, and IL-1β in renal tissue. Moreover, GEN administration reduced the activity of CAT, SOD, and GPx in renal tissue. Nonetheless, the administration of GA before and alongside GEN mitigated these deleterious effects. In conclusion, GA has a beneficial effect on biochemical, inflammatory, and oxidative stress indices against GEN-induced nephrotoxicity.

USE OF SKULL VIBRATION-INDUCED NYSTAGMUS DURING FOLLOW-UP IN MÉNIÈRE.

Ménière's disease (MD) is an idiopathic disorder that affects patients' hearing and the inner ear balance. Intratympanic gentamicin (ITG) is also considered an effective treatment for uncontrolled MD characterized by persistent vertigo attacks despite therapy. The video head impulse test (vHIT) and the skull vibration-induced nystagmus (SVIN) are both validated test to assess the vestibular function. A progressive linear relationship has also been described between the slow-phase velocity (SPV) of SVIN with a skull vibrator at 100 Hz and the gain difference (healthy ear/affected ear) measured in vHIT. The objective of this study was to determine whether the SPV of the SVIN was correlated with the restoration of vestibular function after ITG and, consequently, whether the SVIN can predict the appearance of new vertigo attacks in patients with MD treated with ITG. A prospective longitudinal case-control study was conducted. We recorded several variables after ITG and during the follow-up and statistical analyses were performed. Two groups were compared, those who presented vertigo attacks 6 months after ITG and those who did not. Our sample included 88 patients with definite MD who were treated with ITG. Among the 18 patients who experienced vertigo attacks again, 15 showed recovery of the gain of the affected ear, while all 18 showed a reduction in the SPV of the SVIN. SPV of SVIN may have more sensitivity than vHIT for detecting recovery of vestibular function after intratympanic gentamicin (ITG) administration. To the best of our knowledge, this is the first study to describe the association between decreased SPV and the probability of vertigo attacks in patients with MD treated with ITG.

P34 Gentamicin labels: improving the timing of gentamicin levels and reducing delay in dose administrations

Abstract Background Due to its narrow therapeutic index and significant risks of ototoxicity and nephrotoxicity, gentamicin requires meticulous prescribing, administration and monitoring. Despite readily available guidelines, gentamicin use continues to be associated with errors, with recent Datix reports within NHS Lothian recording incidents such as incorrectly prescribed doses or frequencies, missed levels, and delayed or omitted doses. In response to this, an audit was undertaken to investigate errors in gentamicin use within the Acute Medical Unit (AMU) at the Royal Infirmary of Edinburgh and evaluate the barriers to adherence to guidelines to unearth possible areas for improvement. Methods The initial audit studied patients prescribed gentamicin in AMU within a 3-week period, excluding those who received prophylactic or single one-off doses of gentamicin. The following parameters were examined both on their paper and electronic prescribing charts: (i) dose, (ii) dosing interval/frequency, (iii) time of level sampling, and (iv) administration times of the first and second gentamicin doses. After identifying issues with delayed gentamicin levels and subsequent dose administration times, we introduced the use of gentamicin labels in each AMU bay, in hopes of increasing staff awareness towards patients on gentamicin, thereby promoting timely level sampling and dose administration. The aforementioned parameters were re-audited for a further 3 weeks following this intervention. Results The baseline audit highlighted that only 23/31 (74%) patients had levels taken within the recommended window, and 23/31 (74%) received their second gentamicin doses at the right time. Following the introduction of the gentamicin labels, the second audit observed a slight improvement, with 31/40 (78%) patients having their levels taken within the recommended window, and 30/40 (75%) patients receiving their subsequent doses at the right interval. Noteworthily, in both the pre- and post-intervention groups, the majority of patients who had their second doses delayed received their first doses in the emergency department (ED) prior to admission to AMU. Conclusions In addition to improving staff awareness towards patients on gentamicin, a further overarching issue needs to be addressed: the delays in gentamicin administration which more commonly occurs for patients who transition from ED into AMU. Further interventions should therefore target improving the handover of time-critical medicines between ED and AMU.