RESUMEN
BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.
Asunto(s)
Lesión Renal Aguda , Febuxostat , Factor 2 Relacionado con NF-E2 , FN-kappa B , Ratas Wistar , Transducción de Señal , Vancomicina , Animales , Masculino , Ratas , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/metabolismo , Antibacterianos/farmacología , Antibacterianos/toxicidad , Ciclooxigenasa 2/metabolismo , Febuxostat/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , PPAR gamma , Transducción de Señal/efectos de los fármacos , Vancomicina/toxicidad , Vancomicina/farmacologíaRESUMEN
Vancomycin fermentation residue (VFR) is a by-product of the pharmaceutical industry with high ecotoxicity caused by the residual antibiotics, antibiotic resistance genes (ARGs), and heavy metals (HMs). In this study, the detoxification effect of hydrothermal treatment (HT) and pyrolysis for VFR was assessed using chemical analysis and toxicity tests. When VFR was subjected to HT and pyrolysis at ≥400 °C, more than 99.70 % of the residual vancomycin and all ARGs were removed. The HMs contents in VFR followed the order of manganese (676.2 mg/kg) > zinc (148.6 mg/kg) > chromium (25.40 mg/kg) > copper (17.20 mg/kg), and they were highly bioavailable and easily leached. However, HT and pyrolysis (≥400 °C) substantially reduced the bioavailable fractions and leaching properties of the HMs. After HT and pyrolysis at ≥ 400 °C, the potential ecological risk of HMs in VFR was reduced from considerable to moderate/low levels. The elutriate acute toxicity test suggested that HT and pyrolysis at ≥ 400 °C effectively reduced the toxicity of VFR to an acceptable level (p < 0.05). This study demonstrates that HT and pyrolysis (≥400 °C) are promising methods for treating VFR and detoxifying it, and the treated products are safe for further reutilization.
Asunto(s)
Fermentación , Pirólisis , Vancomicina , Vancomicina/toxicidad , Antibacterianos/toxicidad , Antibacterianos/química , Metales Pesados/toxicidad , Metales Pesados/análisis , Pruebas de Toxicidad , CalorAsunto(s)
Lesión Renal Aguda , Antibacterianos , Modelos Animales de Enfermedad , Combinación Piperacilina y Tazobactam , Vancomicina , Vancomicina/efectos adversos , Vancomicina/administración & dosificación , Vancomicina/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Combinación Piperacilina y Tazobactam/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Ratones , Sinergismo Farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Piperacilina/efectos adversos , Piperacilina/administración & dosificación , Quimioterapia CombinadaRESUMEN
The recent understanding that hydrophobic ß-lactams have greater affinity for organic anion transporter-3 (OAT-3) of the proximal renal tubule could provide valuable insights for anticipating ß-lactams that may exacerbate vancomycin-induced nephrotoxicity. Vancomycin alone provides oxidative stress on the highly metabolic proximal tubular cells. Hydrophobic ß-lactams (eg, piperacillin and anti-staphylococcal ß-lactams) could have greater OAT-3 mediated uptake into proximal tubular cells than hydrophilic ß-lactams (eg, most cephalosporins and carbapenems), thereby causing greater mitochondrial stress on these susceptible cells. It remains to be seen whether concomitant drugs that inhibit OAT-3 mediated cellular uptake of ß-lactams into proximal tubular cells or provide antioxidant effects might mitigate ß-lactam augmented vancomycin nephrotoxicity. Furthermore, the serum creatinine rise seen with vancomycin and hydrophobic ß-lactams might represent competition for creatinine-secreting transporters (of which OAT-3 is one), thus, indicating creatinine retention rather than renal injury. In the meantime, clinicians are advised to utilise less nephrotoxic combinations in both empirical and directed antibiotic selection settings until further research is conducted.
Asunto(s)
Vancomicina , beta-Lactamas , Humanos , Vancomicina/toxicidad , Túbulos Renales Proximales , Simbiosis , Creatinina , Antibacterianos/toxicidad , Antibacterianos/uso terapéuticoRESUMEN
Septic arthritis as a complication of orthopaedic joint surgery can have catastrophic outcomes for patients. To minimise infection risk associated with elective orthopaedics, topical vancomycin during surgery has become increasingly common. Evidence suggests that high concentrations of vancomycin, following direct application of the drug to the joint, are toxic towards various local cell types in the joint, including chondrocytes. However, the mechanism of this vancomycin tissue toxicity is yet to be determined. The aim of this study was to evaluate the toxicity of vancomycin on chondrocytes and the mechanisms of cell death involved. Human primary knee chondrocytes were exposed to vancomycin (1.25-10 mg/mL) for 24 h and their viability assessed using the resazurin reduction assay in vitro. Specific cell death mechanisms and their contributors, including reactive oxygen species (ROS) production and apoptosis, were measured. This study showed that high concentrations of vancomycin (5 and 10 mg/mL) were toxic towards human primary knee chondrocyte cells, while lower concentrations (1.25 and 2.5 mg/mL) were not. Cell death studies found that this occurred through an apoptotic pathway. This study provides additional support that vancomycin in high doses is toxic towards chondrocytes and preliminary evidence that this toxicity occurs via apoptotic cell death mechanisms.
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Condrocitos , Vancomicina , Humanos , Vancomicina/toxicidad , Vancomicina/metabolismo , Condrocitos/metabolismo , Apoptosis , Muerte Celular , Especies Reactivas de Oxígeno/metabolismo , Células CultivadasRESUMEN
Emerging studies support that Klotho protects against different kidney diseases. However, the role of Klotho in vancomycin induced acute kidney injury (Van-AKI) is largely unclear. Hence this study aimed to explore the regulatory mechanism of Klotho in Van-AKI. The mRNA expression of Klotho and the JAK2/STAT3/GPx3 in renal tissue were assessed by RNA sequence analysis after 600 mg/kg Van daily for seven days; Small interfering RNA and recombinant protein are applied to examine the mechanism action of Klotho in vitro and in vivo respectively. Flow cytometry and spectrophotometry detected the expression of reactive oxygen species and antioxidant enzymes. Transmission electron microscopy scanned the structural damage of mitochondria. Western blotting, qPCR, and immunofluorescence were employed to explore the JAK2/STAT3/GPx3 expression. RNA sequence analysis found that Van challenging reduced Klotho and GPx3 expression but increased JAK2/STAT3 in renal tissue. In HK-2 cells, Klotho were decreased by Van in a dose-dependent manner. Klotho siRNA enhanced the production of reactive oxygen species and the cell apoptosis ratio by regulating the JAK2/STAT3, and JAK2/STAT3 inhibitors prevented the decrease of GPx3. Meanwhile, 1 µg/ml recombinant human Klotho showed the opposite function to 120 pmol Klotho siRNA. In Van-AKI BALB/c mice, 20 µg/kg recombinant mouse Klotho once every two days improved the anti-oxidative enzyme expression, mitochondria structure, renal dysfunction, and histological damage. In conclusion, Klotho enhances antioxidant capacity through the JAK2/STAT3/GPx3 axis, which in turn improves Van-AKI.
Asunto(s)
Lesión Renal Aguda , Vancomicina , Animales , Humanos , Ratones , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Antioxidantes/farmacología , Apoptosis , Janus Quinasa 2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ARN Interferente Pequeño/genética , Factor de Transcripción STAT3/metabolismo , Vancomicina/toxicidad , Vancomicina/metabolismoRESUMEN
Perfluorooctane sulfonic acid (PFOS) is a manmade legacy compound belonging to the group of persistent per- and polyfluorinated substances (PFAS). While many adverse health effects of PFOS have been identified, knowledge about its effect on the intestinal microbiota is scarce. The microbial community inhabiting the gut of mammals plays an important role in health, for instance by affecting the uptake, excretion, and bioavailability of some xenobiotic toxicants. Here, we investigated (i) the effect of vancomycin-mediated microbiota modulation on the uptake of PFOS in adult Sprague-Dawley rats, and (ii) the effects of PFOS exposure on the rat microbiota composition. Four groups of twelve rats were exposed daily for 7 days with either 3 mg/kg PFOS plus 8 mg/kg vancomycin, only PFOS, only vancomycin, or a corn oil control. Vancomycin-induced modulation of the gut microbiota composition did not affect uptake of branched and linear PFOS over a period of 7 days, measured in serum samples. 16S rRNA amplicon sequencing of faecal and intestinal samples revealed that vancomycin treatment lowered microbial alpha-diversity, while PFOS increased the microbial diversity in vancomycin-treated as well as in non-antibiotic treated animals, possibly because an observed decrease in the Enterobacteriaceae abundance allows other microbial species to propagate. Colonic short-chain fatty acids were significantly lower in vancomycin-treated animals but remained unaffected by PFOS. Our results suggest that PFOS exposure may disturb the intestinal microbiota, but that antibiotic-induced modulation of the intestinal ecosystem does not affect systemic uptake of PFOS in rats.
Asunto(s)
Fluorocarburos , Microbioma Gastrointestinal , Microbiota , Ratas , Animales , Antibacterianos/toxicidad , Vancomicina/toxicidad , ARN Ribosómico 16S/genética , Ratas Sprague-Dawley , Fluorocarburos/toxicidad , Mamíferos/genéticaRESUMEN
Vancomycin (VCM)-induced nephrotoxicity impedes its treatment applications. Thus, it is important to clarify the relevant mechanism. This study investigated phosphoprotein changes attributable to the VCM nephrotoxicity mechanisms. Biochemical, pathological and phosphoproteomic analyses based on C57BL/6 mice were performed to explore the mechanisms.VCM-treated mice showed increased levels of blood urea nitrogen and creatinine, and signs of acute tubular necrotic lesions. Phosphoproteomic profiling identified 3025 differentially phosphorylated phosphopeptides between the model and control group. Gene Ontology enrichment analysis demonstrated that Molecular Function "oxidoreductase activity" and Cellular Component "peroxisome" were markedly enriched. KEGG pathway analysis identified an enrichment in peroxisome pathway and PPAR (peroxisome proliferator-activated receptor) signaling pathways. Parallel reaction monitoring analysis revealed a significant downregulation of CAT, SOD-1, AGPS, DHRS4, and EHHADH at phosphorylation level by VCM. Notably, the phosphorylation of ACO, AMACR, and SCPX was downregulated by VCM, which are the fatty acid ß-oxidation-related proteins involved in PPAR signaling pathways. The phosphorylated PEX5 involved in peroxisome biogenesis was upregulated by VCM. Collectively, these findings indicated that VCM-induced nephrotoxicity is closely associated with peroxisome pathway and PPAR signaling pathways. The current study provides important insight into the mechanisms of VCM nephrotoxicity and will aid in the development of preventive and therapeutic strategies against this nephropathy.
Asunto(s)
Insuficiencia Renal , Vancomicina , Ratones , Animales , Vancomicina/toxicidad , Vancomicina/metabolismo , Proteoma/metabolismo , Antibacterianos/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Ratones Endogámicos C57BL , RiñónRESUMEN
CONTEXT: Vancomycin (VCM), an important antibiotic against refractory infections, has been used to treat secondary infections in severe COVID-19 patients. Regrettably, VCM treatment has been associated with nephrotoxicity. Vitamin D3 can prevent nephrotoxicity through its antioxidant effect. OBJECTIVE: This study tests the antioxidant effect of vitamin D3 in the prevention of VCM-induced nephrotoxicity. MATERIALS AND METHODS: Wistar Albino rats (21) were randomly divided into 3 groups: (A) control; (B) VCM 300 mg/kg daily for 1 week; and (C) VCM plus vitamin D3 500 IU/kg daily for 2 weeks. All the rats were sacrificed and serum was separated to determine kidney function parameters. Their kidneys were also dissected for histological examination and for oxidative stress markers. RESULTS: Lipid peroxidation, creatinine, and urea levels decreased significantly (p < 0.0001) in the vitamin D3-treated group (14.46, 84.11, 36.17%, respectively) compared to the VCM group that was given VCM (MIC<2 µg/mL) only. A significant increase was observed in superoxide dismutase levels in the vitamin D3-treated group (p < 0.05) compared to rats without treatment. Furthermore, kidney histopathology of the rats treated with vitamin D3 showed that dilatation, vacuolization and necrosis tubules decreased significantly (p < 0.05) compared with those in the VCM group. Glomerular injury, hyaline dystrophy, and inflammation improved significantly in the vitamin D3 group (p < 0.001, p < 0.05, p < 0.05, respectively) compared with the VCM group. DISCUSSION AND CONCLUSIONS: Vitamin D3 can prevent VCM nephrotoxicity. Therefore, the appropriate dose of this vitamin must be determined, especially for those infected with COVID-19 and receiving VCM, to manage their secondary infections.
Asunto(s)
COVID-19 , Coinfección , Animales , Ratas , Vancomicina/toxicidad , Antioxidantes/farmacología , Antioxidantes/metabolismo , Colecalciferol/farmacología , Colecalciferol/metabolismo , Coinfección/metabolismo , Coinfección/patología , Ratas Wistar , COVID-19/metabolismo , Riñón , Estrés OxidativoRESUMEN
BACKGROUND: Intrawound vancomycin powder is effective in preventing surgical site infection after spine surgery. In a previous study, vancomycin-induced cytotoxicity in osteoblasts was investigated in vitro, and vitamin D3 was verified to be a candidate drug aiding recovery from vancomycin-induced cytotoxicity. The treatment practices involving osteogenesis-promoting drugs vary widely. Teriparatide, an anabolic agent, highly promotes bone formation by inducing osteoblast activation, increasing bone formation and mineral density, and preventing vertebral fractures. Hence, teriparatide may be administered in combination with vancomycin. METHODS: MC3T3-E1 cells were cultured in minimum essential medium supplemented with 10% fetal bovine serum at 37 °C in a humidified incubator containing 5% CO2. The experimental concentrations of vancomycin (2500, 5000, and 7500 µg/mL) were determined based on previous reports and our preliminary experiments. Teriparatide (100 ng/mL) was administered concomitantly to prevent cytotoxicity in osteoblasts, using pulsed vancomycin for 24 h (measured at 1, 3, and 7 days). Cell numbers and morphological changes in cells treated with vancomycin or vancomycin plus 100 ng/mL teriparatide were measured. Osteoblast differentiation was assessed using alkaline phosphatase staining, alkaline phosphatase activity, and alizarin red S staining. RESULTS: Teriparatide showed a recovery effect when vancomycin (7500 µg/mL) was administered only for 24 h. Microscopic examination revealed that teriparatide had a protective effect on osteoblasts exposed to 7500 µg/mL vancomycin. Addition of teriparatide led to the recovery of alkaline phosphatase staining and alizarin red staining. CONCLUSION: Vancomycin-induced cytotoxicity in osteoblasts could be inhibited by administering teriparatide concomitantly with vancomycin.
Asunto(s)
Teriparatido , Vancomicina , Humanos , Vancomicina/toxicidad , Teriparatido/farmacología , Teriparatido/uso terapéutico , Fosfatasa Alcalina , Diferenciación Celular , Osteogénesis , OsteoblastosRESUMEN
PURPOSE: The purpose of this study was to assess the potential of new lipoglycopeptides as novel topical therapies for improved treatment of recalcitrant ocular infections. We evaluated the in vitro antimicrobial activity of oritavancin, dalbavancin, and telavancin compared with vancomycin (VAN) against a large collection of ocular staphylococcal isolates and their cytotoxicity on human corneal epithelial cells (HCECs). METHODS: Antimicrobial susceptibility testing was performed by broth microdilution against 223 Staphylococcus spp. clinical isolates. Time-kill kinetics were determined for methicillin-resistant strains of Staphylococcus aureus (MRSA) (n = 2) and Staphylococcus epidermidis (MRSE) (n = 1). In vitro cytotoxicity assays were performed with AlamarBlue and live/dead staining on HCECs. RESULTS: All new lipoglycopeptides showed strong in vitro potency against ocular staphylococci, including multidrug-resistant MRSA strains, with dalbavancin showing a slightly higher potency overall [minimum inhibitory concentration (MIC) 90 0.06 µg/mL] compared with telavancin and oritavancin (MIC 90 0.12 µg/mL), whereas VAN had the lowest potency (MIC 90 2 µg/mL). Oritavancin exerted rapid bactericidal activity within 1 h for MRSA and 2 h for MRSE. All other drugs were bactericidal within 24 h. At a concentration commonly used for topical preparations (25 mg/mL), cytotoxicity was observed for VAN after 5 min of incubation, whereas reduction in HCEC viability was not seen for telavancin and was less affected by oritavancin and dalbavancin. Cytotoxicity at 25 mg/mL was seen for all drugs at 30 and 60 min but was significantly reduced or undetected for lower concentrations. CONCLUSIONS: Our study demonstrates that new lipoglycopeptides have substantially better in vitro antimicrobial activity against ocular staphylococcal isolates compared with VAN, with a similar or improved toxicity profile on HCECs.
Asunto(s)
Epitelio Corneal , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Vancomicina/toxicidad , Vancomicina/uso terapéutico , Lipoglucopéptidos/toxicidad , Lipoglucopéptidos/uso terapéutico , Staphylococcus , Antibacterianos/toxicidad , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
OBJECTIVE: Despite its evident renal toxicity, vancomycin is considered an effective glycopeptide antibiotic against life-threatening positive bacterial contagions. The current study aimed to investigate the potential protective effects of carvacrol as well as its underlying mechanism against vancomycin-induced nephrotoxicity. MATERIALS AND METHODS: The animals were randomly classified into four groups (8 rats per group). Group I, which served as a control group, received only vehicles. Group II received a single i.p. injection of 50 mg/kg of carvacrol for seven days. Group III received vancomycin (200 mg/kg, i.p.) as a singular daily dose for seven days. Carvacrol was administered to Group IV seven days prior to the daily vancomycin dose. RESULTS: The results revealed that carvacrol minimized vancomycin-induced renal injury as evidenced by lower serum cystatin C levels and kidney injury molecule-1 (KIM-1), in addition to a decline in renal damage caused by vancomycin as indicated in histopathological assessment. Furthermore, carvacrol significantly attenuated oxidative stress parameters and inflammatory mediators. Moreover, it downregulated Keap1, mitogen-activated protein kinase (p38MAPK), and nuclear factor kappa B (NF-κB) genes and proteins, along with controlling the NF-κB inhibitory protein (IkBα) and nuclear factor erythroid 2-related factor 2 (Nrf2) genes and proteins observed through streaming its genes. A molecular docking technique was also used to investigate the potential interactivity between carvacrol and proteins involved in regulating oxidative injury and inflammatory responses. CONCLUSIONS: The current study findings revealed that carvacrol administration before vancomycin could be a promising therapeutic approach for maceration of renal damage stimulated by vancomycin via controlling IkBα/MAPK and Keap1/Nrf2 signaling molecules.https://www.europeanreview.org/wp/wp-content/uploads/graphical-abstract-1.jpg.
Asunto(s)
Factor 2 Relacionado con NF-E2 , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ratas , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Riñón/patología , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Transducción de Señal , Vancomicina/toxicidadRESUMEN
Drug-induced nephrotoxicity is widespread and seriously affects human health. Vancomycin is a classical glycopeptide antibiotic. Vancomycin is widely used for severe infections caused by Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus but its obvious nephrotoxicity affects the safety of its clinical application. However, the etiology of vancomycin induced kidney injury is not well understood. This study aimed to explore the potential mechanism of vancomycin-induced nephrotoxicity in rats. Vancomycin (400 mgkg-1) was used to establish kidney injury models in rats. A metabonomic approach was employed using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) to delineate metabolic alterations. As a result, 15, 22, and 37 biomarkers were identified in urine samples from the treatment group compared to the control model on D2, D4, and D7, respectively. Changes in the levels of these metabolites indicated that amino acid metabolism and energy metabolism were disturbed in rats with vancomycin-associated nephrotoxicity. This study revealed the kidney effect of vancomycin, which may provide novel and promising research approaches to vancomycin-induced renal toxicity.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Vancomicina , Animales , Biomarcadores/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Humanos , Espectrometría de Masas/métodos , Metabolómica/métodos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Ratas , Vancomicina/toxicidadRESUMEN
Topical povidone-iodine, chlorhexidine, bacitracin, and vancomycin are commonly used antiseptic and antimicrobial agents to reduce risk and treat surgical site infections in numerous orthopedic procedures. Chondrocytes potentially may be exposed to these agents during operative procedures. The impact of these topical agents on chondrocyte viability is unclear. The goal of this study is to determine human chondrocyte viability ex vivo after exposure to commonly used concentrations of these topical antiseptic and antimicrobial agents. Human osteochondral plugs were harvested from the knee joint of a human decedent within 36 hours of death. Individual human osteochondral plugs were exposed to normal saline as a control; a range of concentrations of povidone-iodine (0.25%, 0.5%, and 1%), chlorhexidine (0.01% and 0.5%), and bacitracin (10,000 units/L, 50,000 units/L, and 100,000 units/L) for 1-minute lavage; or a 48-hour soak in vancomycin (0.16 mg/mL, 0.4 mg/mL, and 1.0 mg/mL) with nutrient media. Chondrocyte viability was evaluated with a live/dead viability assay at 0, 2, 4, and 6 days after exposure to bacitracin at 0, 3, and 6 days). Control subjects showed greater than 70% viability at all time points. Povidone-iodine, 0.5% chlorhexidine, and vancomycin showed significant cytotoxicity, with viability dropping to less than 40% by day 6. Chondrocytes exposed to 0.01% chlorhexidine maintained viability. Chondrocytes exposed to bacitracin showed viability until day 3, when there was a large drop in viability. Commonly used topical concentrations of povidone-iodine, vancomycin, and bacitracin are toxic to human chondrocytes ex vivo. A low concentration of chlorhexidine appears safe. Caution should be used when articular cartilage may be exposed to these agents during surgery. [Orthopedics. 2022;45(5):e263-e268.].
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Antiinfecciosos Locales , Condrocitos , Antibacterianos/uso terapéutico , Antibacterianos/toxicidad , Antiinfecciosos Locales/toxicidad , Bacitracina/toxicidad , Clorhexidina/toxicidad , Condrocitos/efectos de los fármacos , Humanos , Povidona Yodada/toxicidad , Solución Salina , Vancomicina/toxicidadRESUMEN
Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness and relatively low price. Vancomycin-associated AKI (VA-AKI) is a clinically relevant but not yet clearly understood entity in critically ill patients. The current review comprehensively summarizes the pathophysiological mechanisms of, biomarkers for, preventive strategies for, and some crucial issues with VA-AKI. The pathological manifestations of VA-AKI include acute tubular necrosis, acute tubulointerstitial nephritis (ATIN), and intratubular crystal obstruction. The proposed pathological mechanisms of VA-AKI include oxidative stress and allergic reactions induced by vancomycin and vancomycin-associated tubular casts. Concomitant administration with other nephrotoxic antibiotics, such as piperacillin-tazobactam, high vancomycin doses, and intermittent infusion strategies compared to the continuous infusion are associated with a higher risk of VA-AKI. Several biomarkers could be applied to predict and diagnose VA-AKI. To date, no promising therapy is available. Oral steroids could be considered for patients with ATIN, whereas hemodialysis might be applied to remove vancomycin from the patient. In the future, disclosing more promising biomarkers that could precisely identify populations susceptible to VA-AKI and detect VA-AKI occurrence early on, and developing pharmacological agents that could prevent or treat VA-AKI, are the keys to improve the prognoses of patients with severe infection who probably need vancomycin therapy.
Asunto(s)
Lesión Renal Aguda/diagnóstico , Antibacterianos/toxicidad , Vancomicina/toxicidad , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/terapia , Animales , Antibacterianos/farmacocinética , Biomarcadores/metabolismo , Humanos , Vancomicina/farmacocinéticaRESUMEN
AIM: Nephrotoxicity is the major limiting factor for the clinical use of vancomycin (VCM) for treatment against multi-resistant Gram-positive bacteria. The present research aimed to investigate the ability of selenium nanoparticles (SeNPs) to protect against VCM-induced nephrotoxicity in rats. MAIN METHODS: Experimental rats were divided into five groups; the first was the normal control, the second was treated with VCM (200 mg/kg twice/day, i.p.) for 7 days. The third, fourth, and fifth groups were treated orally with SeNPs (0.5, 1, and 2 mg/kg/day); respectively. SeNPs were administered for 12 days before VCM, 1 week simultaneously with VCM, and for another 1 week after its administration. KEY FINDINGS: Levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and kidney injury molecule-1 (KIM-1) were significantly increased in kidney tissue after VCM administration. Expression of adenosine 5'-monophosphate-activated protein kinase (AMPK), Bcl-2 associated X protein (Bax), caspase 3 and caspase 9 in kidney tissue was significantly increased, while the antioxidant enzymes, mitochondrial complexes, the ATP levels and B-cell lymphoma protein 2 (Bcl-2) were decreased in kidney in the VCM-treated rats compared to the normal control group. Treatment with SeNPs significantly decreased levels of MDA, iNOS, NO, TNF-α, and KIM-1 in the kidney tissue. Administration of SeNPs also downregulated the expression of the proapoptotic agents and enhanced the activities of the antioxidant enzymes and the mitochondrial enzyme complexes in the kidney. SIGNIFICANCE: SeNPs alleviated VCM-induced nephrotoxicity through their anti-oxidant, anti-inflammatory, anti-apoptotic and mitochondrial protective effects.
Asunto(s)
Antioxidantes/farmacología , Apoptosis , Enfermedades Renales/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Nanopartículas/administración & dosificación , Selenio/farmacología , Vancomicina/toxicidad , Animales , Antibacterianos/toxicidad , Antioxidantes/administración & dosificación , Regulación de la Expresión Génica , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Mitocondrias/patología , Nanopartículas/química , Ratas , Ratas Wistar , Selenio/administración & dosificaciónRESUMEN
OBJECTIVE: By creating nephrotoxicity models with cisplatin, vancomycin, and gentamicin in HK-2 (human renal proximal tubule cell) and HEK293T (human embryonic kidney epithelial cells) cell lines, we aimed to evaluate the effect of cilastatin on recovery of cell damage after toxicity had occurred. MATERIALS AND METHODS: In the first phase of the study, the doses of cisplatin, vancomycin, and gentamicin (50% inhibitive concentration; IC50) were determined. In the second phase, the effective dose of cilastatin against these drugs was determined, and IC50 doses of nephrotoxic agents were administered simultaneously. In the third phase of our study, to evaluate the possible therapeutic effect of cilastatin after toxicity had occurred, the analyses of cell viability, apoptosis, oxidative stress, expression of kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) were performed. RESULTS: In the second phase of the study, it was observed that cilastatin increased cell viability when treated simultaneously with a nephrotoxic agent. In the third phase, cilastatin provided a significant increase in cell viability. After treatment with each agent for 24 hours, we determined that adding cilastatin to the medium had an effect on the recovery of cell damage by increasing cell viability and reducing apoptosis and oxidative stress. The expression of KIM-1 and NGAL increased when nephrotoxicity occurred and decreased with the addition of cilastatin to the medium. CONCLUSIONS: The findings of the study suggest that cilastatin may have a healing effect after the development of nephrotoxicity.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Cilastatina/farmacología , Enfermedades Renales/prevención & control , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular , Cilastatina/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/toxicidad , Relación Dosis-Respuesta a Droga , Gentamicinas/administración & dosificación , Gentamicinas/toxicidad , Células HEK293 , Receptor Celular 1 del Virus de la Hepatitis A/genética , Humanos , Concentración 50 Inhibidora , Enfermedades Renales/inducido químicamente , Lipocalina 2/genética , Vancomicina/administración & dosificación , Vancomicina/toxicidadRESUMEN
Phospholipids reportedly alleviate drug-induced acute kidney injury. However, no study has compared the effect of phospholipids with different fatty acids and polar heads on drug-induced nephrotoxicity. In the present study, we aimed to compare the possible nephroprotection afforded by phosphatidylcholine and phosphatidylserine with different fatty acids in a mouse model of vancomycin-induced nephrotoxicity. Pretreatment with phospholipids rich in docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) doubled the survival time when compared with the model group. Moreover, phospholipids rich in DHA/EPA significantly reduced the serum levels of renal function biomarkers and ameliorated kidney pathologies. In terms of alleviating renal damage, no significant differences were observed between different polar heads in DHA-enriched phospholipids, while phosphatidylserine from soybean was better than phosphatidylcholine in mitigating renal injury. Furthermore, DHA/EPA-enriched phospholipids inhibited vancomycin-induced nephrotoxicity mainly by inhibiting apoptosis and oxidative stress. These results provide a scientific basis for phospholipids as potential ingredients to prevent acute kidney injury.
Asunto(s)
Antibacterianos/toxicidad , Ácidos Grasos/farmacología , Riñón/efectos de los fármacos , Fosfatidilcolinas/farmacología , Fosfatidilserinas/farmacología , Vancomicina/toxicidad , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Ácidos Grasos/metabolismo , Riñón/citología , Riñón/metabolismo , Riñón/fisiopatología , Sistema de Señalización de MAP Quinasas , Ratones , Mitocondrias/metabolismo , Análisis de SupervivenciaRESUMEN
In 2020, new vancomycin guidelines were released, recommending the transition from trough-based to AUC24 monitoring for adult and paediatric patients. Given the resources required to achieve this transition, there has been debate about the costs and benefits of AUC24-based monitoring. A recent narrative review of vancomycin therapeutic drug monitoring in paediatrics claims to have uncovered the methodological weaknesses of the data that informed the guidelines and advises against premature adoption of AUC24-guided monitoring. In this article, we present supporting arguments for AUC24-guided monitoring in children, which include that: (i) troughs alone are inadequate surrogates for AUC24; (ii) vancomycin-associated nephrotoxicity has significant consequences that warrant optimization of dosing; (iii) a substantial portion of children receiving vancomycin are at high risk for poor outcomes and deserve targeted monitoring; and (iv) limited efficacy data in support of AUC24 is not a justification to revert to a less supported monitoring approach.
Asunto(s)
Antibacterianos , Vancomicina , Antibacterianos/uso terapéutico , Área Bajo la Curva , Niño , Monitoreo de Drogas , Humanos , Pruebas de Sensibilidad Microbiana , Vancomicina/administración & dosificación , Vancomicina/toxicidadRESUMEN
BACKGROUND: Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus) are common pathogens encountered in infected cardiovascular-implantable electronic device (CIED). Continuous, in-situ targeted, ultra-high concentration antibiotic (CITA) treatment is a novel antibiotic treatment approach for localized infections. CITA provides sufficient local antibiotic concentrations to heavily infected cavities while avoiding systemic toxicity. AIM: In-vitro confirmation of the efficacy of the CITA treatment approach in simulated compartmentalized infections. MATERIALS AND METHODS: A rapid automated bacterial culture analyzing system) Uro4 HB&L™ (was applied to compare the efficacy of selected antibiotics at a standard minimal inhibitory concentration (1MIC), 4MIC, and CITA at 103MIC, for growth inhibition of high bacterial loads (106 colony-forming-units/ml) of ATCC strains of P. aeruginosa, E. coli, and S. aureus. RESULTS: The addition of gentamicin and amikacin at 1MIC concentrations only temporarily inhibited the exponential growth of E. coli and P. aeruginosa. 4MIC level extended the delay of exponential bacterial growth. Increasing concentrations of vancomycin similarly temporarily delayed S. aureus growth. All tested antibiotics at CITA of 103MIC totally inhibited the exponential growth of the tested bacteria through 72 hours of exposure. (P<0.001). CONCLUSION: In this in-vitro model, CITA at 103MIC effectively inhibited exponential bacterial growth of high loads of P. aeruginosa, E. coli, and S. aureus. This model offers preliminary laboratory support for the benefit of the in-situ antibiotic treatment, providing ultra-high concentrations directly at the compartmentalized infection site, not achievable by the conventional intravenous and oral routes.