Aminoglycoside Nephrotoxicity 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.

Investigation the effects of 2-aminoethoxydiphenyl borate (2-APB) on aminoglycoside nephrotoxicity

ABSTRACT Investigation the protective effect of transient receptor potential channel modulator 2-Aminoethoxydiphenyl Borate (2-APB) on aminoglycoside nephrotoxicity caused by reactive oxygen species, calcium-induced apoptosis and inflammation was aimed. Forty Wistar rats were divided (n=8) as follows: Control group; DMSO group; 2-APB group; Gentamicin group (injected 100 mg/kg gentamicin intramuscularly for 10 days); Gentamicin+ 2-APB group (injected 2 mg/kg 2-APB intraperitoneally, then after 30 minutes 100 mg/kg gentamicin was injected intramuscularly for 10 days). Blood samples were collected for biochemical analyses, kidney tissue samples were collected for light, electron microscopic and immunohistochemical investigations. In gentamicin group glomerular degeneration, tubular dilatation, vacuolization, desquamation of tubular cells and hyaline cast formation in luminal space and leukocyte infiltration were seen. Disorganization of microvilli of tubular cells, apical cytoplasmic blebbing, lipid accumulation, myelin figure like structure formation, increased lysosomes, mitochondrial swelling and disorganization of cristae structures, apoptotic changes and widening of intercellular space were found. TNF-α, IL-6 and caspase 3 expressions were increased. BUN and creatinine concentrations were increased. Increase in MDA levels and decrease in SOD activities were determined. Even though degeneration still continues in gentamicin+2-APB treatment group, severity and the area it occupied were decreased and the glomerular and tubule structures were generally preserved. TNF-α, IL-6, caspase 3 immunoreactivities and BUN, creatinine, MDA concentrations were reduced and SOD activities were increased markedly compared to gentamicin group. In conclusion, it has been considered that 2-APB can prevent gentamicin mediated nephrotoxicity with its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

Lrpap1 (RAP) Inhibits Proximal Tubule Clathrin Mediated and Clathrin Independent Endocytosis, Ameliorating Renal Aminoglycoside Nephrotoxicity.

Proximal tubules are exposed to many exogenous and endogenous nephrotoxins that pass through the glomerular filter. This includes many small molecules such as aminoglycoside and myeloma light chains. These filtered molecules are rapidly endocytosed by the proximal tubules and lead to nephrotoxicity. To investigate whether inhibition of proximal tubule uptake of filtered toxins can reduce toxicity we evaluated the ability of Lrpap1 or RAP to prevent proximal tubule endocytosis. Munich Wistar Frömter rats were used since both glomerular filtration and proximal tubule uptake can be quantified. The injury model chosen was the well-established gentamicin induced toxicity which leads to significant reductions in GFR and serum creatinine increases. Chronic kidney disease was induced with a right uninephrectomy and left 40 minute pedicle clamp. Rats had eight weeks to recover and to stabilize GFR and proteinuria. Multiphoton microscopy was used to evaluate endocytosis in vivo and serum creatinine and 24 hour creatinine clearances were used to evaluate kidney functional changes. Studies showed preadministration of RAP significantly inhibited both albumin and dextran endocytosis in outer cortical proximal tubules. Importantly, this inhibition was found to be rapidly reversible with time. RAP was also found to be an excellent inhibitor of proximal tubule gentamicin endocytosis. Lastly, gentamicin administration for 6 days resulted in significant elevation of serum creatinine in vehicle treated rats but not those receiving daily infusion of RAP prior to gentamicin. This study provides a model for the potential use of RAP to prevent, in a reversible manner, proximal tubule endocytosis of potential nephrotoxins thus protecting the kidney from damage.

Intravesical gentamicin instillation in the prevention of recurrent urinary tract infections in children with neurogenic bladder- a single-center retrospective observational study

Recurrent urinary tract infections (UTI) in children with neurogenic bladder (NGB) put them at high risk of morbidity and mortality from urosepsis and end-stage renal disease (ESRD). Since the efficacy of low-dose prophylactic antibiotics to prevent these recurrences has been declining since the emergence of extended-spectrum beta-lactamase (ESBL) organisms, intravesical gentamicin instillation has also been used, but only scarce data in children is available in the literature. We evaluate the efficacy of intravesical gentamicin instillation to reduce UTIs in children with NGB, compare it with oral antibiotic prophylaxis and determine its effect on pathogens resistance to antibiotics. Retrospective observational study of 17 children with NGB managed in a tertiary center. Intravesical gentamicin instillation followed an initial period of oral antibiotic prophylaxis. In a conditional negative binomial regression model, a matched comparison of the rate of UTIs, the identified pathogens and their antibiotics susceptibility between the two therapies was performed for each individual child, RESULTS: When compared to antibiotic prophylaxis, intravesical gentamicin instillation showed no significant difference in the yearly rate of UTI, symptomatic UTI, or admissions for intravenous antibiotic therapy. However, it was associated with a 38% reduction in the incidence rate ratio of UTI (p=0.04) and 75% of asymptomatic UTI (p=0.006) After intravesical gentamicin instillation, five children (31%) had a gentamicin-resistant UTI, similar to before that treatment (p=0.76). Although the overall rate of UTI and of asymptomatic infections were significantly lower with intravesical gentamicin instillation than during oral antibiotic therapy, there was no significant difference in the rate of symptomatic UTIs or UTIs requiring admissions, probably because of the small sample size. In addition, neither an emergence of ESBL pathogens nor the rate of pathogens resistance to gentamicin was observed with intravesical gentamicin instillation. As to the potential nephrotoxicity of aminoglycosides, the calculated GFR for all children remained normal. Strengths of our study include the use of a matched paired comparison of each participant with him/herself with each treatment modality, thus eliminating potential confounding by some individual characteristics. In addition, and unlike previous studies, we have also used a robust multivariate statistical analysis to compare counts and rates of outcomes. Limitations include the absence of gentamicin serum levels monitoring, of hearing testing, and also the small sample size. Intravesical gentamicin instillation decreases the overall rate of UTI and asymptomatic infections in children with NGB without increasing the rate of bacterial resistance to gentamicin.

POTENTIAL RISKS IN MODERN ANTIBIOTIC THERAPY

Knowledge of the safety profile of antibacterial drugs is important for rational pharmacotherapy with antibiotics. The purpose of this information is to help the doctor, pharmacist and patient to (quickly) "navigate" in the safety of antibiotics to implement one of the basic principles of pharmacotherapy "Do no harm!". The aim of the study. Analysis of possible potential risks in modern antibiotic therapy. Materials and methods. Analysis of data from the scientific literature on the side effects of antibiotics. Results. Most antibiotics have a wide spectrum of antimicrobial action, much less of them have a narrow spectrum of activity, but all of them have side effects (SE). In particular, the neurotoxicity of penicillins and fluoroquinolones is a consequence of their antagonism with GABA. The latter mechanism is also responsible for the neurotoxicity of carbapenens, monobactams and cephalosporins. Cardiotoxicity and hematotoxicity of benzylpenicillins are the result of inhibition of tissue respiration and the process of converting fibrinogen to fibrin, which causes bleeding. The hematotoxicity of carbopenicillins, monobactams and cephalosporins is associated with the inhibition of the conversion of vicasol (vit. K) into its active form, as well as the obstruction of its synthesis due to the suppression of normal intestinal microflora (the main producer of endogenous vit. K). The nephrotoxicity of aminoglycosides and vancomycin is associated with the accumulation of these drugs in the cells of the proximal renal tubules and impaired enzyme activity (Na+-, K+-, ATP; respiratory, etc.), which leads to interstitial nephritis. Ototoxicity of antibiotics is observed when they are used over the age of 60 – a factor that predisposes to ototoxicity. Conclusions. In order to conduct effective antibiotic therapy, it is very important to take into account the side effects that are characteristic of certain groups of antibiotics and each is representatively individual.

La concentration sérique de gentamicine est-elle modifiée par une autotransfusion sanguine par cell-saver après une arthroplastie totale du genou avec de l’acide tranexamique ? Un essai contrôlé randomisé

BackgroundSelf-transfusion has been proven as an effective management of blood loss after total knee arthroplasty (TKA). Considering that the high local concentration of antibiotic from bone cement is delivered intravenously through the self-transfusion process, systematic toxicity has never been evaluated. In addition, the effectiveness of self-transfusion with the routine concomitant use of other modern blood-salvage strategies, like tranexamic acid, should also be assessed. Therefore we performed a randomized study to assess: (1) the safety of self-transfusion in TKA by comparing the gentamicin concentrations resulting from the use or not of autologous blood transfusion; (2) the efficacy of self-transfusion in TKA, with the concomitant administration of tranexamic acid. HypothesisSelf-transfusion in TKA elevates the serum gentamicin concentration and the potential risk of nephrotoxicity. MethodsThe serum concentration of aminoglycosides was measured in two groups of 20 patients each, after TKA, according to the use of self-transfusion. Hemoglobin, renal function and calculated blood loss were compared at several points in time between groups. ResultsThe only time where there was a statistically significant difference in serum gentamicin, was at 48h postoperatively between groups [0.3 ug/ml±0.21, range: 0.15 to 0.72 vs. 0.14ug/ml±0.1, range: 0 to 0.35 (p=0.02)]. There were no significant differences in total blood loss [1341ml±501, range: 830 to 2230 vs. 1263ml±459 range: 840 to 2480 (p=0.67)] and need of allogeneic blood transfusion [3 units vs. 2 units] between groups. ConclusionThe use of autologous blood transfusion was found to be safe, in terms of nephrotoxicity of aminoglycosides after TKA, but it seemed to be ineffective as a blood salvage strategy, when used concomitantly with the administration of tranexamic acid. Level of EvidenceII; low powered randomized study. ClinicalTrials.gov registration numberNCT04505748.

High-throughput identification and determination of aminoglycoside antibiotics in human plasma using UPLC-Q-ToF-MS.

Aminoglycosides are a class of broad-spectrum antibiotics with several clinical uses. Owing to the ototoxicity and nephrotoxicity of aminoglycosides, therapeutic drug monitoring is required. This study aimed to devise a high-throughput method for identification and quantitative determination of aminoglycoside antibiotics in human plasma samples using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q-ToF-MS). Plasma samples (100 µL) spiked with five aminoglycosides (streptomycin, spectinomycin, amikacin, kanamycin, and gentamycin) and an internal standard (ribostamycin) were diluted and centrifuged in aqueous formic acid and acetonitrile. The clear supernatant extract was evaporated and reconstituted in the mobile phase, of which 4 µL was subjected to UPLC-Q-ToF-MS. Prominent peaks were observed for the drugs within 3 min. The recoveries of five aminoglycosides from plasma samples were 92.6-120%. The regression equations showed excellent linearity (0.9999 ≥ r2 ≥ 0.9987) within the range of 1.0-100 µg/mL, and detection limits of 0.5-2.0 µg/mL. The coefficients of the intra- and inter-day variations for five drugs were less than 11.8%, while the accuracy of quantitation was in the range of 89-111%. In this study, a novel method was presented for identification and determination of aminoglycosides in human plasma samples using UPLC-Q-ToF-MS analysis. This method can be applied to high-throughput analysis used for clinical and environmental purposes.

Is serum gentamicin concentration modified with autologous cell-saved blood transfusion after total knee arthroplasty using tranexamic acid? A randomised control trial

BackgroundSelf-transfusion has been proven as an effective management of blood loss after total knee arthroplasty (TKA). Considering that the high local concentration of antibiotic from bone cement is delivered intravenously through the self-transfusion process, systematic toxicity has never been evaluated. In addition, the effectiveness of self-transfusion with the routine concomitant use of other modern blood-salvage strategies, like tranexamic acid, should also be assessed. Therefore, we performed a randomised study to assess: 1) the safety of self-transfusion in TKA by comparing the gentamicin concentrations resulting from the use or not of autologous blood transfusion; 2) the efficacy of self-transfusion in TKA, with the concomitant administration of tranexamic acid. HypothesisSelf-transfusion in TKA elevates the serum gentamicin concentration and the potential risk of nephrotoxicity. MethodsThe serum concentration of aminoglycosides was measured in two groups of 20 patients each, after TKA, according to the use of self-transfusion. Hemoglobin, renal function and calculated blood loss were compared at several points in time between groups. ResultsThe only time where there was a statistically significant difference in serum gentamicin, was at 48h postoperatively between groups [0.3 ug/mL±0.21, range: 0.15 to 0.72 vs. 0.14ug/mL±0.1, range: 0 to 0.35 (p=0.02)]. There were no significant differences in total blood loss [1341mL±501, range: 830 to 2230 vs. 1263mL±459 range: 840 to 2480 (p=0.67)] and need of allogeneic blood transfusion [3 units vs. 2 units] between groups. ConclusionThe use of autologous blood transfusion was found to be safe, in terms of nephrotoxicity of aminoglycosides after TKA, but it seemed to be ineffective as a blood salvage strategy, when used concomitantly with the administration of tranexamic acid. Level of evidenceII; low-powered randomised study. ClinicalTrials.gov registration numberNCT04505748.

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity

IntroductionAntimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity. MethodsWe conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin. ResultsNo randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12–0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01–0.21). ConclusionsAlthough further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.

288 Anuric AKI with Rapid Recovery Secondary to Vancomycin and Aminoglycoside Nephrotoxicity

288 Anuric AKI with Rapid Recovery Secondary to Vancomycin and Aminoglycoside Nephrotoxicity

A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis

The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87–1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.

Nephrotoxicity of Antimicrobials and Antibiotics.

Medication-induced nephrotoxicity remains one of the most common causes of acute kidney injury (AKI) among hospitalized patients. Within the extensive group of medications associated with AKI, antibiotics and other antimicrobials are well recognized triggers of structural and functional renal impairment. Clinical manifestations range from mild forms of tubular injury to significant deterioration of kidney function requiring acute renal replacement therapy. Several mechanisms are described, although the most frequent are acute interstitial nephritis, acute tubular necrosis, intratubular crystal deposition, and proximal/distal tubulopathy with electrolyte wasting abnormalities. General risk factors for antimicrobial-induced AKI include pre-existing chronic kidney disease, and concomitant use of medication with nephrotoxic potential. Prevention and early recognition of AKI represent the standard approach to mitigate AKI and avoid morbidity.

English

English

Sex differences in acute kidney injury requiring dialysis

BackgroundFemale sex has been included as a risk factor in models developed to predict the risk of acute kidney injury (AKI) associated with cardiac surgery, aminoglycoside nephrotoxicity and contrast-induced nephropathy. The commentary acompanying the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury concludes that female sex is a shared susceptibility factor for acute kidney injury based on observations that female sex is associated with the development of hospital-acquired acute kidney injury. In contrast, female sex is reno-protective in animal models. In this context, we sought to examine the role of sex in hospital-associated acute kidney injury in greater detail.MethodsWe utilized the Hospital Episode Statistics database to calculate the sex-stratified incidence of AKI requiring renal replacement therapy (AKI-D) among 194,157,726 hospital discharges reported for the years 1998–2013. In addition, we conducted a systematic review of the English literature to evaluate dialysis practices among men versus women with AKI.ResultsHospitalized men were more likely to develop AKI-D than hospitalized women (OR 2.19 (2.15, 2.22) p < 0.0001). We found no evidence in the published literature that dialysis practices differ between men and women with AKI.ConclusionsBased on a population of hospitalized patients which is more than 3 times larger than all previously published cohorts reporting sex-stratified AKI data combined, we conclude that male sex is associated with an increased incidence of hospital-associated AKI-D. Our study is among the first reports to highlight the protective role of female gender in AKI.

Key role of oxidative stress in animal models of aminoglycoside nephrotoxicity revealed by a systematic analysis of the antioxidant-to-nephroprotective correlation.

The clinical utility of aminoglycoside antibiotics is partly limited by their nephrotoxicity. Co-administration of a variety of candidate nephroprotectants has been tested at the preclinical level. According to a recent meta-analytic study, antioxidants are the only family of compounds with enough preclinical documentation to draw solid conclusions on their class nephroprotective capacity in animal models. In this study a systematic analysis of the relation between the level of antioxidation and the level of nephroprotection was performed. A regression model is presented which crosses the y-axis (i.e. the axis representing the level of nephroprotection) very nearly the zero value, meaning that maximal prevention of the oxidative stress induced by aminoglycosides results in almost maximal nephroprotection. This indicates that oxidative stress plays a central role in the hierarchy of pathophysiological mechanisms underlying aminoglycoside nephrotoxicity. In addition, this model may potentially serve: i) as a standard to evaluate the role of the antioxidant effect of candidate nephroprotectants; ii) to reveal additional, antioxidant-independent effects among those compounds providing more nephroprotection than that expected from its antioxidant activity; and thus iii) to discriminate and focus most effective nephroprotectants on clinical usage.

Population pharmacokinetic modelling, Monte Carlo simulation and semi-mechanistic pharmacodynamic modelling as tools to personalize gentamicin therapy.

Population pharmacokinetic modelling, Monte Carlo simulation and semi-mechanistic pharmacodynamic modelling are all tools that can be applied to personalize gentamicin therapy. This review summarizes and evaluates literature knowledge on the population pharmacokinetics and pharmacodynamics of gentamicin and identifies areas where further research is required to successfully individualize gentamicin therapy using modelling and simulation techniques. Thirty-five studies have developed a population pharmacokinetic model of gentamicin and 15 studies have made dosing recommendations based on Monte Carlo simulation. Variability in gentamicin clearance was most commonly related to renal function in adults and body weight and age in paediatrics. Nine studies have related aminoglycoside exposure indices to clinical outcomes. Most commonly, efficacy has been linked to a Cmax/MIC ≥7-10 and a AUC24/MIC ≥70-100. No study to date has shown a relationship between predicted achievement of exposure targets and actual clinical success. Five studies have developed a semi-mechanistic pharmacokinetic/pharmacodynamic model to predict bacteria killing and regrowth following gentamicin exposure and one study has developed a deterministic model of aminoglycoside nephrotoxicity. More complex semi-mechanistic models are required that consider the immune response, use of multiple antibiotics, the severity of illness, and both efficacy and toxicity. As our understanding grows, dosing of gentamicin based on sound pharmacokinetic/pharmacodynamic principles should be applied more commonly in clinical practice.

Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity.

Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant Staphylococcus aureus, and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney-specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin in vitro, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated via megalin in the clinical setting.

Secondary IRCT (Chronic End-Stage Renal Disease) for Aminoglycosides

The adverse renal effects of aminoglycosides are increasing, up to 20% in patients treated with this class of antibiotic, nephrotoxicity is manifested by the renal insufficiency with a variable degree, usually clinically silent but the return to the former state is not always obtained which progresses towards chronic kidney disease. After studying a declaration of an adverse case at the pharmacovigilance service of the UHE of Oran.The impact of nephrotoxicity of aminoglycosides in the aggravation of pre-existing renal insufficiency has been demonstrated according to the French and Anglo-Saxon method of accountability that is why information on pharmacological therapeutic monitoring of STP should be recommended. In conclusion, the knowledge of the factors favoring the nephrotoxicity of aminoglycosides, the respect of the dosages and the reduction of the duration of the treatment allows the practitioner to take measures in order to prevent and to reduce the frequency of the renal complications. The side effect of aminoglycoside therapy may occur in up to 20% of the exposed patients treated with this antibiotic class, this nephrotoxicity is manifested by varying degrees of renal insufficiency (IR), usually clinically silent but the return to the previous state is not always got, sometimes progress to chronic renal disease. Following the study of a case of adverse reaction reporting; has been shown by the French and Anglo-Saxon method of accountability, the impact of aminoglycosides’ nephrotoxicity in the aggravation of existing IR, why therapeutic drug monitoring TDM actualities are recommended. In conclusion, knowledge of predisposing factors nephrotoxicity of aminoglycosides, respect the doses and reducing the duration of treatment allows the practitioner to take measures in order to prevent and decrease the frequency of renal complications.

A systematic meta-analysis on the efficacy of pre-clinically tested nephroprotectants at preventing aminoglycoside nephrotoxicity.

Nephrotoxicity limits the use of aminoglycoside antibiotics. Kidney damage is produced mainly in the renal tubule due to an inflammatory and oxidative process. At preclinical level, many drugs and natural products have been tested as prospective protectors of aminoglycoside nephrotoxicity. The main objective of this work was to make a systematic literature review of preclinical studies about aminoglycoside nephrotoxicity protection and a statistical analysis based on the meta-analysis methodology. Studies published up to January 2016 were identified. After applying inclusion criteria, 54 studies were chosen. The size of the experimental groups, means and standard deviations of data on renal function (i.e. plasma creatinine and blood urea nitrogen [BUN] concentrations) were extracted and registered in a database. The studies were grouped according to the mechanism of nephroprotection and their route of administration. The Mean Difference (95% confidence interval) was calculated for each study and group. 40 of 54 products tested produced an amelioration of aminoglycoside nephrotoxicity based on creatinine results. Also a dose dependent protective effect was observed (both in creatinine and BUN). Products orally administered were more effective than via i.p. Products with attributed antioxidant activity were the most used and those which proved statistically significant nephroprotection as a class effect. Aminoglycoside tubular reuptake inhibitors, excretion inducers and calcium channel blockers also showed a promising and rather homogeneous class tendency towards nephroprotection, although more research is necessary to obtain solid and conclusive results, based on a larger number of studies.

Is gentamicin necessary in the antimicrobial treatment for group B streptococcal infections in the elderly? An in vitro study with human blood products

Background: According to expert opinions, gentamicin should be administered as an adjunct to penicillin against severe group B streptococcal (GBS) infections. Whether the adjunct is important is of particular interest for elderly patients. Not only is the risk of aminoglycoside nephrotoxicity higher in elderly persons, but their immune defence to bacterial infections may also be impaired.Method: Time-kill assays with human blood products, such as serum, neutrophilic granulocytes (opsonophagocytic assays) and whole blood from healthy, elderly volunteers were performed to evaluate the effect of gentamicin in combination with penicillin.Results: In time-kill assays with human serum and in opsonophagocytic assays, we saw a trend for faster killing with the penicillin–gentamicin combination therapy. This effect was seen 4 and 6 h after antibiotic exposure but not at time points evaluated at ≥8 h. In whole blood killing assays, no difference in killing rates was observed with adjunctive gentamicin therapy.Conclusion: The criteria for synergism were not fulfilled when the effect of penicillin–gentamicin combinations was compared with that of penicillin monotherapy. Rapid killing of GBS within the first few hours was observed in time-kill assays with human blood products. Considering that elderly people are prone to gentamicin nephrotoxicity and that in severe GBS infection a high penicillin dose is administered every 4–6 h, the prolonged use of adjunctive aminoglycosides in these infections requires caution.