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Serious adverse drug reactions of gentamicin (GM) significantly limit its clinical use, thus there is an urgent demand to develop reliable strategies to detect its concentration. In this study, we have developed a novel highly sensitive and portable lateral flow immunoassay (LFIA) based on CoFe PBAs/WS 2 nanozyme mediated chemiluminescence (CL) and photothermal (PT) dual-mode POCT biosensor for the detection of GM, which successfully combines sensitive laboratory analyses with portable in situ analyses in the field. In this proof-of-principle work, the dynamic detection ranges of CL-LFIA and PT-LFIA mode were 1 pg mL -1 to 100 ng mL -1 and 50 pg mL -1 to 100 ng mL -1 with the limits of detection of 0.33 and 16.67 pg mL -1 , respectively. The whole detection of CL-LFIA and PT-LFIA could be completed within 15 min and 30 min, respectively. The recoveries of GM spiked into complex matrices including milk, urine, and serum for CL-LFIA and PT-LFIA were 90.94%-109.74% and 94.49%-109.31%, respectively, indicating the reliability and applicability of the dual-mode LFIA in real samples. The dual-mode POCT biosensor could effectively overcome the false problems with improving accuracy and sensitivity, enabling user to precisely detect GM by laboratory analysis or on-site analysis depending on the source condition. Due to the complementary properties of CL-LFIA and PT-LFIA, the developed POCT biosensor can effectively ensure high-performance detection, showing the potential application of accurately detecting drug concentration in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: The optimal dosage regimen of gentamicin in horses is still under investigation. The objectives of this study were to determine gentamicin plasma concentrations in hospitalized horses treated with 10 mg/kg gentamicin (IV, q 24 h) and to determine whether a plasma concentration to minimum inhibitory concentration (MIC) ratio of 10:1 is reached for equine pathogens using this dose., Design: Prospective clinical observational study; retrospective study on MICs of 131 gram-negative bacteria isolated from horses (2012-2015)., Setting: University teaching hospital., Animals: Ninety-eight horses >6 months old, treated with gentamicin for their primary disease, consecutive samples., Measurements and Main Results: Plasma concentrations were measured 1 hour (C 1h ) and 20 hours (C 20h ) after gentamicin administration using fluorescence polarization. Presence of systemic inflammatory response syndrome (SIRS) and azotemia was recorded, as well as the reason for antimicrobial administration (primary disease) and whether administration was prophylactic or therapeutic. The target C 1h of ≥20 µg/mL gentamicin was reached in 90% of horses and was sufficient to reach a plasma concentration:MIC of 10:1 in 32 of 131 (24%) of gram-negative aerobic bacteria. A C 20h ≤ 2 µg/mL was reached in 97% horses. Therapeutic versus prophylactic administration, primary disease, azotemia, and systemic inflammatory response syndrome were not associated with a failure to reach a desired peak or trough., Conclusions: The gentamicin dose of 10 mg/kg every 24 hours should be further investigated and safety assessed because a target gentamicin plasma concentration of ≥20 µg/mL was achieved in the majority of cases. Nephrotoxic side effects were not assessed. Individual drug monitoring should be performed because clinical factors are unreliable predictors of plasma concentrations. A gentamicin target concentration of ≥40 µg/mL does not offer additional benefits compared to ≥20 µg/mL, due to the bimodal distribution of resistance in bacterial isolates., (© Veterinary Emergency and Critical Care Society 2020.)

Gentamicin sulfate (GEN), a well-known broad-spectrum antibiotic is mostly administered through intramuscular injections and entirely excreted in un-metabolized form through urination from patient's body. Quantitative detection of GEN by direct UV absorption is usually challenging due to lack of chromophores and fluorophores in structure. The current study described the hesperidin coated silver nanoparticles (HSPAgNPs) based novel colorimetric quantitative assay for GEN. HSPAgNPs, based colorimetric detection involved a transition from characteristic yellow colour to blackish brown upon addition of GEN, accompanied by a significant quenching in localized surface plasmon resonance (LSPR) band at λ max 398 nm. Moreover, the synthesized HSPAgNPs were employed to rapid and quantitative detection of GEN in concentration range of 5 to 100 μM. Limit of detection (LOD) and limit of quantification (LOQ) was calculated by standard deviation of the ordinate intercept and slope of the regression line and estimated to be 6.89 μM and 20.88 μM respectively, with a linear correlation factor R 2 equal to 0.9990 which strictly followed Beer's law. Furthermore, the utility and effectiveness of HSPAgNPs was also explored for selective recognition of GEN in tap water, serum, human blood plasma and urine.

The global burden of bacterial infection and antimicrobial resistance increases the demand to associate more than one antibiotic to fight life-threatening bacteria. Therefore, there is a great necessity to develop simple and sensitive methods for routine analysis of clinical samples. Therapeutic drug monitoring, bioequivalence, and pharmacokinetic studies are essential to ensure drug efficiency and safety. Herein, therefore, the first ecofriendly liquid chromatography -tandem mass spectrometry (LC-MS/MS) method was developed and fully validated for simultaneous determination of a commonly combined antibiotic for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin (VCM) and gentamicin (GTM), in rat plasma after parenteral administration. VCM and GTM were extracted from plasma sample using acetonitrile (ACN)/0.1% TFA-induced protein precipitation followed by the separation on an Agilent Eclipse Plus ODS (3 mm × 100 mm, 3.5 μm) column using water-enriched mobile phase consisting of water containing 0.1% THF/ACN (85:15, v/v%) at flow rates of 0.30 mL min -1 . The mass spectrometry parameters were optimized, and multiple reaction monitoring (MRM) in positive ion mode of two transitions was utilized for quantification of precursor to product ion at m / z 725.5 → 144 and 100.1 for VCM as [M + 2H] 2+ , 478.3 → 322.2 and 156.9 for GTM, and 586.3 → 162.9 and 425.3 for amikacin (AMK) internal standard, as [M + H] + . The current method has been validated as per U.S. FDA bioanalytical guidelines in terms of linearity, accuracy, precision, selectivity, recovery, matrix effects, and stability. The method was linear in the range of 1-2000 ng mL -1 and 1-1000 ng mL -1 with detection limits (S/N of 3) of 0.18 and 0.09 ng mL -1 for VCM and GTM, respectively. The selectivity and high sensitivity allow the current method to succeed in the study of pharmacokinetic parameters and drug-drug interaction between VCM and GTM after single-dose administration. VCM increased plasma clearance and elimination rate constant of GTM when coadministered and GTM also too. The change of serum chemistry analysis and significant elevation of creatinine and BUN indicate an alteration in kidney function in group III in those given the combined antibiotics. Our finding illustrated the nephrotoxicity of the two drugs when associated. The ecofriendly, simplicity, and rapidity of the current study made it a promising method for high-throughput biomonitoring in clinical samples.

Background: Aminoglycosides require highly accurate therapeutic drug monitoring owing to their narrow therapeutic windows and toxic side effects. Therapeutic drug monitoring varies in different laboratories, and this difference is mainly due to the use of different analytical techniques. This study aimed to compare the accuracy and precision of immunoassays for the measurement of gentamicin, tobramycin, and amikacin in serum., Methods: Human plasma samples were spiked with known concentrations of amikacin, gentamicin, and tobramycin and dispatched to laboratories worldwide. The percentage deviation and coefficient of variation were calculated to compare the accuracy and precision among immunoassays and among antibiotics., Results: We analyzed 273, 534, and 207 amikacin, gentamicin, and tobramycin measurement results, obtained satisfactory rates of 83.9%, 86.3%, and 93.7%, and coefficients of variation ranging from 1.1% to 15.6%, 2.9% to 25.2%, and 1.8% to 27.0%, respectively. The percentage deviation ranged from -7.5% to 6.6%, -20.8% to 18.7%, and -33.2% to 41.5% for amikacin, gentamicin, and tobramycin, respectively. Significant differences were observed in accuracy and precision among assays for all antibiotics., Conclusions: This study demonstrated high variations in results obtained from antibiotic assays conducted at different laboratories worldwide.

Purpose: The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations., Methods: In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak > 8*MIC and a trough < 1 mg/L for MIC values between 0.25 and 4 mg/L., Results: A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1 mg/L at 96 h for 92% and 34% respectively., Conclusion: The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3-8 mg/kg/day just before dialysis, taking into account the type of infection.

Introduction: Critically ill children tend to have altered gentamicin pharmacokinetics (PK); and so we carried out an audit of gentamicin use using the estimated peak concentrations (C max ), trough concentrations (C min ) and area-under-the-concentration-time curve (AUCs) by Bayesian approach., Methods: Critically ill children with at least one serum gentamicin concentrations available were recruited. We used multiple models Bayesian adaptive control to estimate C max , and AUC 0-t following each dose. Pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria was used to identify the incidence of acute kidney injury (AKI)., Results: Seventy-three children (961 doses and 143 concentrations) were analysed. AUC 0-24 was observed to be higher in earlier age groups with a steady decline in older children. Similar changes were observed in C max , C min and AUC 0-24  at steady state. Significantly higher proportions of children in the other age groups were estimated to have C max between 5 and 10 mg/L compared to neonates. Neonates had a higher risk of C max above 10 mg/L. Patients with augmented renal clearance exhibited lower AUC 0-24 and reduced proportion achieving the target AUC 0-24 levels. Nearly one-third of children were observed to meet the pRIFLE criteria for AKI., Conclusion: We observed higher initial doses and peak concentrations of gentamicin in neonates and infants compared to older age groups in critically ill children. Uniformity in the paediatric-specific standard treatment guidelines for gentamicin is the need of the hour., Competing Interests: Declaration of Competing Interest Authors do not have any conflict of interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to evaluate the analytical performance of the Alinity ® c Abbott compared to the Architect ® immunoassay system for the determination of drugs having a narrow therapeutic index., Methods: Valproic acid, amikacin, gentamicin, phenobarbital and vancomycin were analyzed using Particle-Enhanced Turbidimetric Inhibitor Immunoassay (Petinia), phenytoin and theophylline were analyzed using an immunoenzymatic method and a colorimetric method was performed to quantify lithium. The methods were validated according to the total error approach. Seven validation standards were analyzed in quintuplet during four days to establish the limits of the methods. Dilution integrity and interferences (hemolysis and high concentrations of bilirubin and lipids) were also tested. Depending on the analyte, the results obtained for twenty to forty patients on the Alinity ® were compared to those obtained on the Architect ® ., Results: The bias and the coefficients of variation for repeatability and for intermediate precision were lower than 15% for all drugs. Accuracy profiles were acceptable (acceptance limits fixed at 30%) in the validated ranges. The lower limits of quantification (LLOQ) were similar to those determined by Abbott except for gentamicin for which we determined a LLOQ at 1.22 mg/L while Abbott determined it at 0.5 mg/L. All assays diluted linear and analyte concentrations were not affected by interferences. Concentrations obtained for real samples on the Alinity ® c are comparable to those obtained on the Architect ® ci., Conclusions: The analytical validation of a method suitable for therapeutic drug monitoring of drugs on the Alinity ® c meets the requirements of European Medicines Agency.

Objective: To assess the association between gentamicin exposure in the neonatal period and hearing in school age., Methods: This study included children exposed to a high-dose (6 mg/kg) gentamicin regimen as neonates (2004-2012), invited for follow-up at school age, and a healthy age-matched control group. We assessed hearing with pure tone audiometry including the extended high-frequency (EHF) range. Outcomes were average hearing thresholds in the midfrequencies (0.5-4 kHz) and the EHFs (9-16 kHz). The measures of gentamicin exposure were cumulative dose and highest trough plasma concentration. We used linear regression models to assess the impact of gentamicin exposure, and other peri- and postnatal morbidities, on hearing thresholds., Results: A total of 219 gentamicin-exposed and 33 healthy-control children were included in the audiological analysis. In the gentamicin cohort, 39 (17%) had a birth weight <1500 g. Median cumulative doses and trough plasma concentrations were 30 (interquartile range 24-42) mg/kg and 1.0 (interquartile range 0.7-1.2) mg/L, respectively. Median hearing thresholds for the midfrequencies and the EHFs were 2.5 (0 to 6.3) dB hearing level and -1.7 (-5.0 to 5.0) dB hearing level, both of which were within the normal range. In an adjusted analysis, increasing hearing thresholds were associated with lower birth weight and postnatal middle-ear disease but not level of gentamicin exposure. After adjusting for birth weight, there was no difference in hearing threshold between the gentamicin-exposed cohort and healthy controls., Conclusions: Exposure to a high-dose gentamicin regimen in the neonatal period was not associated with an increase in hearing thresholds in schoolchildren being able to complete audiometry., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Therapeutic drug monitoring (TDM) has become standard clinical practice for gentamicin, amikacin, and vancomycin to optimize efficacy and reduce toxicity. TDM after the first dose of antibiotic was adopted in our institution. This study aims to evaluate if target therapeutic drug concentrations could be achieved more rapidly in patients with TDM performed after the first dose of gentamicin, amikacin, or vancomycin compared to TDM at steady state. A single-center retrospective cohort study was conducted at KK Women's and Children's Hospital, Singapore. Patients aged 1 month to 18 years old who received amikacin, gentamicin, or vancomycin between October 2012 to March 2016 and had at least 2 serum drug concentrations done within the same dosing interval were included. The primary objective was to compare the time taken to achieve target serum drug concentrations between first-dose and steady-state TDM. A total of 334 patients on amikacin, 211 patients on gentamicin, and 140 patients on vancomycin were included. Using Kaplan-Meier analysis, the median number of days to optimize therapy was significantly shorter after first-dose TDM was performed for amikacin (first dose, 1.51 [95% confidence interval (CI), 1.44-1.89] days vs steady state, 2.85 [95%CI, 2.50-3.25] days; P < .01] and gentamicin (first dose, 1.66 [95%CI, 1.25-2.08] days vs steady state, 3.54 [95%CI, 2.40-4.75] days; P < .01] but not vancomycin (first dose, 1.34 [95%CI, 1.06-1.52] days vs steady state, 1.42 [95%CI, 1.26-1.59] days; P = .99]. First-dose TDM for gentamicin and amikacin resulted in faster attainment of target serum concentrations but did not for vancomycin. Further validation of its impact on actual clinical outcomes may be required., (© 2019, The American College of Clinical Pharmacology.)

Gentamicin (GM) is used for neonates as the initial treatment for neonatal bacterial infection. An association between high trough GM levels and the elevation of the serum creatinine (sCr) level and hearing loss has been reported, although there have been no reports investigating the serial changes in the sCr level in preterm neonates treated with GM. The present study evaluated the serial changes in the sCr level and the incidence of hearing loss in preterm neonates treated with GM. This study included 56 neonates born at a gestational age of 32-36 weeks. Fifteen (group 1) and 20 (group 2) neonates were treated with 2.5 mg/kg of GM every 12 h and 4 mg/kg of GM every 36 h, respectively. Group 3 included 21 neonates without GM therapy. Serum GM levels, serial changes in the sCr levels, and the incidence of hearing loss were then compared among the three groups. The serum trough GM level in group 2 was significantly lower than that in group 1 (P < 0.001), whereas the serum peak GM levels in these groups were almost the same. The ratio of the sCr level at birth to that at the 5th day of life in group 1 was the lowest among the 3 groups. No neonates had hearing loss. GM therapy worsened the sCr level in late preterm neonates, especially those with multiple doses per day. The appropriate use of GM is needed in order to prevent the occurrence of nephrotoxicity.

Introduction: Optimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation., Patients and Methods: The PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry., Results: Forty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1., Conclusion: These preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets., (Copyright © 2019 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Background: Although the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG., Methods: We performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin., Results: A total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was≤41.66mL/min (OR: 11.29; 95%CI: 7.21-17.61; P<0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26-19.63; P=0.0006)., Conclusion: Our study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment., (Copyright © 2018 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Gentamicin and vancomycin meet the criteria for measuring plasma concentrations during therapy. However, compliance with the accompanying guidelines remains low. The primary objective of this study was to determine whether the implementation of a clinical decision support system, which displays an alert if a plasma concentration should be measured and a daily reviewed patient list resulted in improved compliance., Materials and Methods: This intervention study was performed at the Spaarne Gasthuis, Haarlem/Hoofddorp, the Netherlands. The authors included 261 treatments with either gentamicin or vancomycin intravenously for at least 48 h in the year before and after implementation of the clinical decision support system in May 2015. The authors analyzed whether plasma concentrations were measured sooner and more frequently after the implementation, and determined whether the time until the correct dosage, with adequate drug concentrations, was reduced after implementation., Results: Before implementation, plasma concentrations were measured within 72 h in 47% of the treatments. After implementation, this percentage increased to 80% (p < 0.01). After implementation, the time was significantly shorter until the correct dosage was given., Conclusion: The implementation of a clinical decision support system and a patient list resulted in improved compliance with the guidelines and optimized the treatment with gentamicin and vancomycin., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Intraosseous (IO) access is a recommended method when venous access cannot be rapidly established in an emergency. Experimental data suggest that major hemorrhage and catecholamine administration both reduce bone marrow blood flow. We studied the uptake of gentamicin as a tracer substance administered IO following adrenaline administration in hemorrhagic shock and in cardiac arrest., Methods: Twenty anesthetized pigs underwent hemorrhage corresponding to 50% of the blood volume. They then received injections of either; adrenaline IO (n = 5), saline IO n = 5), adrenaline IO during cardiac arrest and cardiopulmonary resuscitation (CPR, n = 5), or intravenous adrenaline. The injections were followed by an injection of gentamicin by the same route. Doses and volumes were equivalent among the groups. In all animals, mixed venous antibiotic concentrations were analyzed at 5, 15 and 30 min after administration., Results: Mean (SD) plasma gentamicin concentrations (mg x L - 1 ) at 5 min were 26.4 (2.3) in the group with previous IO adrenaline administration, 26.6 (4.5) in the IO saline group, 31. 2 (12) in the IO adrenaline + CPR group and 23 (4.5) in the IV group. Concentrations in the CPR group were significantly higher than the others., Conclusions: No impairment of drug uptake with IO administration after recent IO adrenaline exposure was demonstrable in this shock model.

Objective: Aim: To evaluate how useful it is to make measurements of gentamicin concentrations in newborns' blood in order to optimize antibiotic therapy., Patients and Methods: Material and methods: 73 newborns empirically treated with gentamicin, in doses consistent with the Neofax® guidelines. There were 152 measurements of maximum and minimum serum gentamicin concentrations. Samples were determined based on the chemiluminescence technique on the Siemens Advia Centaur analyzer. The concentrations of gentamicin that were measured were compared with various therapeutic ranges used in the literature., Results: Results: According to the standards adopted in the University Hospital in Wrocław, the maximum concentration was reached in 38.16% of all the children, while the minimum in 26.32%. In other children the concentrations were below or above the therapeutic range. According to the Neofax® guidelines, the intended maximum concentration was observed in 71.05% of the newborns, and the minimum in 32.89%. The minimum concentration of <2 mg/L was found in 93.42% of the newborns, while >2 mg/L was determined in 33.33%, despite a 48-hour dosing interval. These were premature babies (<28th week of gestational age) and 55.56% of them reached a maximum concentration of 5-12 mg/L. There was no significant correlation between maximum or minimum concentration and gestational age or body weight., Conclusion: Conclusions: 1. The dosage of gentamicin in newborns according to the Neofax® recommendations does not ensure achieving the intended serum antibiotic concentrations. 2. In order to optimize gentamicin therapy in newborns it is necessary to individualize the dose based on measurements of drug concentrations in the blood and pharmacokinetic calculations.

Background: Gentamicin pharmacokinetics may be altered in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO). Description of gentamicin pharmacokinetics and relevant variables can improve dosing., Methods: A retrospective population pharmacokinetic study was designed, and pediatric patients who received gentamicin while undergoing ECMO therapy over a period of 6 1/2 years were included. Data collection included the following: patient demographics, serum creatinine, albumin, hematocrit, gentamicin dosing and serum concentrations, urine output, and ECMO circuit parameters. Descriptive statistics were used to characterize the patient population. Population pharmacokinetic analysis was performed with NONMEM, and simulation was performed to identify empiric doses to achieve therapeutic serum concentrations., Results: A total of 37 patients met study criteria (75.7% male patients), with a median age of 0.17 [interquartile range (IQR) 0.12-0.82] years. Primary indications for ECMO included the following: congenital diaphragmatic hernia (n = 17), persistent pulmonary hypertension (n = 5), and septic shock (n = 4). Patients received a total of 117 gentamicin doses [median 1.8 (IQR 1.4-2.9) mg/kg/dose] and had 125 serum concentrations measured at a median of 22.8 (IQR 15.8-25.5) hours after a dose. Population pharmacokinetic analysis identified a 2-compartment model with additive error as the best fit. Covariates included the following: allometrically scaled fat-free mass on clearance, central and peripheral volume of distribution (VDcentral and VDperipheral), and intercompartmental clearance; serum creatinine on clearance; ultrafiltration rate on central volume of distribution. Simulation identified dosage of 4-5 mg/kg/dose every 24 hours for neonates and infants as an acceptable empiric dosing regimen. Children and adolescents had elevated trough concentrations when dosed according to traditional dosing methods., Conclusions: Fat-free mass should be used to dose gentamicin in pediatric ECMO patients. Serum creatinine is a marker of gentamicin clearance and should be used to adjust gentamicin dosing in pediatric ECMO patients.

External validation of population pharmacokinetic (PK) models is warranted before they can be clinically applied to aid in antibiotic dose selection. The primary objective of this study was to assess the predictive performance of a gentamicin population PK model in intensive care unit (ICU) patients in two independent western populations of critically ill patients., Methods: Data were collected from the ICU where the model was developed (Academic Medical Centre, Amsterdam [AMC]) and from the Centre Hospitalier Universitaire de Nîmes (CHU Nîmes). Primary endpoints were bias and accuracy. The model was regarded as valid if bias was not significantly different from 0 and accuracy was equal to or less than 2.5 mg/L. Non-linear mixed-effects modelling (NONMEM) was used for data analysis., Results: The AMC validation dataset consisted of 192 samples from 66 ICU patients and the CHU Nîmes dataset of 230 gentamicin samples from 50 ICU patients. The structural model predicted the gentamicin plasma concentrations in the AMC population with a non-significant bias (0.35, 95%CI: -0.11-0.81) and a sufficient accuracy of 2.5 mg/L (95%CI: 2.3-2.8). The gentamicin plasma concentrations were overpredicted in the CHU Nîmes population with a significant bias of 4.8 mg/L (95%CI: 4.00-5.62) and an accuracy of 5.5 mg/L (95%CI: 4.7-6.2)., Conclusion: The model is valid for use in the AMC ICU population but not in the CHU Nîmes ICU population. This illustrates that caution is needed when using a population PK model in an external population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The study objective was to evaluate the effects of age on aminoglycoside pharmacokinetics in eight young-adult (<4 years) and eight aged (≥14 years) healthy alpacas, receiving a single 6.6 mg/kg intravenous gentamicin injection. Heparinized plasma samples were obtained at designated time points following drug administration and frozen at -80°C until assayed by a validated immunoassay (QMS ® ). Compartmental and noncompartmental analyses of gentamicin plasma concentrations versus time were performed using WinNonlin (v6.4) software. Baseline physical and hematological parameters were not significantly different between young and old animals with the exception of sex. Data were best fitted to a two-compartment pharmacokinetic model. The peak drug concentration at 30 min after dosing (23.8 ± 2.1 vs. 26.1 ± 2 μg/ml, p = .043) and area under the curve (70.4 ± 10.5 vs. 90.4 ± 17.6 μg hr/ml, p = .015) were significantly lower in young-adult compared to aged alpacas. Accordingly, young alpacas had a significantly greater systemic clearance than older animals (95.5 ± 14.4 and 75.6 ± 16.1 ml hr -1 kg -1 ; p = .018), respectively). In conclusion, a single 6.6 mg/kg intravenous gentamicin injection achieves target blood concentrations of >10 times the MIC of gentamicin-susceptible pathogens with MIC levels ≤2 μg/ml, in both young-adult and geriatric alpacas. However, the observed reduction in gentamicin clearance in aged alpacas may increase their risk for gentamicin-related adverse drug reactions., (© 2018 John Wiley & Sons Ltd.)

Background Therapeutic drug monitoring is frequently used to optimize the gentamicin dose. Objective The study investigated whether a 240 mg once daily standard dose achieves the recommended target serum gentamicin concentrations. Setting The prospective, observational study took place in the 2 major public hospitals in Namibia. Method Twenty-nine female patients receiving a standard dose (240 mg gentamicin once daily) participated in the study. Two blood samples were withdrawn to estimate gentamicin pharmacokinetic parameters. Serum creatinine was used to calculate creatinine clearance with the Cockcroft-Gault formula (CL cr ), and estimate glomerular filtration rate (eGFR) by the Modified Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Main outcome measure The outcome measure was the proportion of patients receiving 240 mg gentamicin once daily having C max values above 15 mg/L. Results Total body weight (TBW) and body mass index were highly variable: 43-115 kg, and 17.3-41.3 kg/m 2 , respectively. The gentamicin dose normalized for TBW (adjusted body weight for obese patients) was relatively low, i.e. 4.2 ± 0.8 mg/kg (mean SD). Gentamicin C max was 14.4 ± 4.7 mg/L; only 9 patients (31%) had a C max > 15 g/mL. eGFR (MDRD-4) correlated well with CL cr , but eGFR (EPI-CKD) formula showed systematic deviations from CLcr. Conclusions (1) a standard 240 mg dose results in gentamicin C max values below 15 mg/L in the majority of the patients, (2) eGFR formulas to estimate kidney function will have to be evaluated for their usefulness in the Namibian patient population.

Background: Therapeutic drug monitoring and minimum inhibitory concentration (MIC) data allow more informed use of gentamicin., Hypothesis/objectives: To measure peak and trough serum gentamicin concentrations in horses after a 6.6 mg/kg dose of gentamicin given IV and the MIC of gentamicin of bacteria for which gentamicin might be selected., Methods: Retrospective analysis of hospital records. Peak and trough plasma gentamicin concentrations were measured after 6.6 mg/kg gentamicin IV in 339 hospitalized horses. The MIC of gentamicin was measured for 503 isolates from ambulatory practice and 33 from hospital practice. The distribution of gentamicin concentrations and MIC results were compared to current recommendations for MIC breakpoints., Results: The median serum gentamicin concentration at 60 minutes after administration (C 60min ) was 21.4 μg/mL with a distribution indicating that bacteria with MIC ≥2 μg/mL were unlikely to be exposed to sufficient gentamicin for effective killing. Approximately 90% of isolates from ambulatory practice and 36% of hospital isolates had MICs at or below breakpoints for susceptibility with most of the remainder unlikely to be responsive, even to higher IV doses., Conclusions and Clinical Importance: Gentamicin at a dosage of 6.6 mg/kg IV is likely to be effective against the majority of infections encountered in ambulatory practice, but less effective in an equine hospital. Because there was a dichotomy of most bacteria as being clearly susceptible or clearly resistant to gentamicin, it appears unlikely that higher doses would have been more efficacious, especially in the hospitalized population in our study., (Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Surgical site infections (SSIs) remain a morbid and costly complication in abdominal surgery. Topical antibiotic delivery via intraoperative irrigation and barrier wound protection are strategies for preventing SSI. We tested the safety and efficacy of a novel wound protector device with an integrated fluid irrigation platform in a porcine model., Methods: A simulated colorectal resection model was designed and performed on adult female pigs with a standardized concentration of 10 9 colony-forming units (CFU) of Escherichia coli administered to the wound site in 10 mL of normal saline (n = 7). The device was tested intraoperatively with and without irrigation with gentamicin-containing irrigant solution. Swab and tissue samples were obtained in addition to peripheral blood samples. Quantitative culture analysis was performed in addition to histological and immunohistochemical analysis and gentamicin concentration measurements., Results: There were no adverse events observed in the animals. Tissue protected by the device yielded exponentially lower levels of E. coli growth compared to exposed tissue, with a mean 1 × 10 2 CFU/swab. Use of the device, both with and without irrigation, was associated with an exponential reduction in quantitative bacterial load compared to the control wounds with no device, with limited growth after wound closure in the pigs receiving irrigation. Histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analysis revealed no significant damage to tissue. Serum gentamicin levels remained below the clinical threshold and decreased over time., Conclusions: This in vivo study suggests safety and efficacy of a novel device for the prevention of intraoperative wound contamination.

Background: Adequate gentamicin peak concentrations (Cmax) are important for optimal clinical efficacy. Within a critically ill patient, substantial variability in Cmax can occur over time, hampering the usefulness of therapeutic drug monitoring (TDM). The aim of this study was to evaluate the effect of gentamicin dosing based on Cmax after the first dose on gentamicin target attainment in critically ill patients., Methods: From gentamicin-treated critically ill patients, dosing information, clinical parameters, and serum concentrations were collected prospectively. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling to estimate Cmax after each dose. To evaluate the usefulness of routine TDM, percentages of Cmax within (%Cther, 15-20 mg/L), above (>20 mg/L), and below (%Csubther, <15 mg/L) the therapeutic range after the first and second doses were compared. In addition, simulations were performed to evaluate the impact of TDM., Results: Four hundred sixteen measurements from 59 patients receiving 130 gentamicin doses were included. In the 30 patients who received >1 dose, TDM increased %Cther from 40% after a first median dose of 5.0 mg/kg to 50% after the second dose, and decreased %Csubther from 47% to 30%. Simulations using a 5 mg/kg starting dose revealed %Cther after the second dose of 28.4% without and 36.8% with TDM and %Csubther of 56.9% and 29.3%, respectively. Increasing the simulated starting dose to 6 mg/kg increased %Cther after the first dose from 27.7% to 33.5% and decreased %Csubther from 58.6% to 35.6%. TDM after a first dose of 6 mg/kg had no substantial effect on %Cther or %Csubther after the second dose., Conclusions: Gentamicin dosing based on Cmax after the first dose increased %Cther and decreased %Csubther, but did not result in therapeutic Cmax in half of the patients. When simulating a higher starting dose, %Csubther after the first dose decreased, and TDM showed no additional influence. These data suggest that a starting dose of 6 mg/kg should be considered and that repeated Cmax measurements are not of added value.

Objectives: To evaluate the ability of body-weight-driven renal function assessment (RFA) formulae to predict on-target elimination rate ranges for gentamicin in patients with varying degrees of renal function., Methods: A 6 year retrospective pharmacokinetic study was conducted at a university teaching hospital., Results: A total of 85 patients met the inclusion criteria and 127 pharmacokinetic files were analysed from patients on medical-surgical wards (53%) and medical-surgical ICUs (13%) receiving intravenous gentamicin for treatment, as well as those for patients receiving it for surgical prophylaxis (34%). Each RFA formula was examined against standard dosing tables for gentamicin. A table of acceptable elimination rates was generated using a traditional peak of 8 mg/L and trough between 0.5 and 2 mg/L associated with each of the dosing interval extensions. The ability of each RFA formula to select on-target elimination rates was evaluated. The RFA formula assuming a normalized body weight of 72 kg and a modified creatinine reagent adjustment factor of 90% provided the most accurate on-target elimination rate selection. This method was superior to dosing interval selection based on the Modification in Diet Renal Disease (MDRD) formula, Sanford's guide method, as well as the Cockcroft-Gault formulae using total body weight, ideal body weight or lean body weight ( P  <   0.0001)., Conclusions: Based on the use of gentamicin as a surrogate guide for renally adjusted drugs, these results support dosing interval selection based on a normalized body weight method and a formula reagent adjustment factor of 90% within the Cockcroft-Gault formula., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Extended-interval dosing (EID) regimens of gentamicin have been validated for treating confirmed or suspected early- and late-onset sepsis in preterm infants in the first week of life. Despite the marked changes in volume of distribution and renal clearance in preterm infants after the first few days of life, few studies have validated EID regimens of gentamicin in this population. The objective of the study was to evaluate an EID regimen of gentamicin in infants born at <32 weeks' gestational age and aged >7 days., Methods: This observational study of an EID regimen was conducted in 39 infants. Dosing interval was based on the serum drug concentration at 22 hours after the administration of the first dose of 5 mg/kg. Gentamicin peak (5-12 µg/mL) and trough (<2 µg/mL) levels were compared to those in a historical control group of 39 infants who received traditional-interval dosing (TID) of 2.5 mg/kg of gentamicin with dosing intervals of 8, 12, or 24 hours., Findings: There were no differences in birthweight, gestational age at birth, postmenstrual age, weight at the start of gentamicin administration, postnatal age, small for gestational age status, antenatal corticosteroid use, or postnatal indomethacin exposure between the 2 groups. In the EID group, dosing intervals were 24 hours in 30 infants, 36 hours in 6 infants, and 48 hours in 3 infants. Compared with the TID group (n = 39), the EID group had a significantly higher peak level (median, 9.0 vs 4.7 µg/mL) and a significantly lower trough level (median, 0.7 vs 1.1 µg/mL) (both, P < 0.001). On regression analysis, the postmenstrual age was correlated significantly with trough levels in the EID group. There was no adverse effect on renal function in either group. On follow-up, 1 infant in the EID group and 2 infants in the TID group had evidence of sensorineural hearing loss., Implications: In infants born at <32 weeks' gestation and >7 days of age, an EID gentamicin regimen, with a dosing interval based on a single concentration measurement at 22 hours after the administration of the first dose, achieved therapeutic peak and trough levels and performed significantly better than did a TID regimen in reaching target peak and trough levels. Larger-scale trials are needed for assessing the clinical efficacy (treatment failure/success) of these regimens., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: Empirical gentamicin dosing based on serum creatinine (SCr) levels in premature and term neonates was evaluated., Methods: This single-center, retrospective cohort study was conducted in a standalone children's hospital with a level IIIB, 44-bed neonatal intensive care unit (NICU). Data were abstracted and collected for all neonates admitted to the NICU from March 5, 2012, through March 5, 2014. Patients were included in the study if gentamicin was administered within the first 7 days of life, a trough gentamicin level was measured, and the neonate had a baseline SCr level measured within the first 24 hours of life. A series of logistic regressions was conducted to determine if gentamicin trough levels were influenced by gestational age (≤29 weeks [group 1], 30 weeks to 34 weeks and 6 days [group 2], and ≥35 weeks [group 3]) and SCr level (0.81-0.99 mg/dL [mildly elevated] and ≥1 mg/dL [elevated])., Results: Of the 577 neonates reviewed during the study period, 507 met the inclusion criteria. Mildly elevated and elevated SCr levels were significantly associated with the presence of an elevated gentamicin trough ( p < 0.001). When the effect of gestational age was evaluated, the data suggested that SCr is a strong predictor of elevated gentamicin troughs., Conclusion: Neonates with a gestational age of ≥30 weeks who had an SCr level of ≥1 mg/dL within the first 12-24 hours of life were more likely to have an elevated gentamicin trough level than their counterparts with normal SCr levels., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Objectives: Published nomograms to monitor extended-interval dosing (EID) gentamicin therapy were based on a fixed dose of 5 or 7 mg/kg. However, the average dose used for EID gentamicin regimen in our setting was about 3 mg/kg per day. We developed a new method of monitoring based on the duration of drug-free period (DFP) in a 24-h dosing interval., Methods: Hospitalised adult patients on EID gentamicin were selected. We considered a DFP of between 2 and 8 h as appropriate. Data from two blood samples (2 and 6 h postdose) from each patient were used to estimate the duration of DFP (i.e. DFP method 1). DFP was also calculated for the same patient using an empirically estimated elimination rate constant (K e ) and the same 6 h postdose concentration value (DFP method 2). Correlation between the two methods was made. An alternative graphical method to estimate DFP was attempted., Key Findings: Correlation between K e and age was favourable (r = -0.453; P = 0.001). K e derived from this empirical relationship was used to estimate DFP method 2. DFP method 1 correlated well with DFP method 2 (r = 0.742; P < 0.001). On this basis, two curves representing minimum and maximum DFPs of 2 and 8 h, respectively, were constructed. The final coordinates, which were plotted from an empirically estimated K e and a 6 h postdose concentration, were used to determine whether the DFP was within the targeted range., Conclusions: We have proposed using DFP to monitor EID of gentamicin therapy. A graphical method offers a convenient way to estimate this parameter., (© 2017 Royal Pharmaceutical Society.)

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

Background: Accurate measurement of gentamicin concentration in serum and plasma is required for therapeutic drug monitoring to ensure appropriate treatment of patients. In this work, we present a validated LC-MS/MS-based candidate reference measurement procedure for total gentamicin quantification to be used for standardization and harmonization of routine assays applied for therapeutic drug monitoring of this compound. Total gentamicin is the sum of the concentrations of five known congeners C1, C1a, C2, C2a and C2b. To our knowledge, there is so far no LC-MS method for quantification of total gentamicin in human serum described in literature., Methods: Sample preparation was based on sample dilution with an aqueous internal standard solution followed by protein precipitation. Stable derivatives of gentamicin-glycine congeners were prepared by chemical synthesis and used as internal standards. The primary calibration material used in this assay was characterized by NMR spectroscopy and the pattern of the gentamicin congeners was determined. The total gentamicin was reported as the sum of the congeners which were quantified individually by LC-MS/MS., Results: The method allows the measurement of total gentamicin in human serum and plasma in the concentration range of 0.1 to 12.0μg/ml with an assay imprecision of ≤6% CV and an assay accuracy between 96% and 114%. LOD and LOQ for the total gentamicin were 0.04μg/ml and 0.13μg/ml, respectively. Comparative measurement of 128 native patient samples using this method implemented at two laboratory sites showed an excellent agreement., Conclusions: Validation results proved that this protocol describes a robust and reliable method which is suggested as reference measurement procedure for the standardization and harmonization of routine assays for the quantification of total gentamicin., (Copyright © 2016. Published by Elsevier B.V.)

Introduction: Pharmacokinetics of drugs can be significantly altered in burn patients. The aim of our study was to validate if the current hospital-wide standard dosage of 7mg/kg total bodyweight gentamicin is sufficient to achieve an adequate prophylactic C max (C max ≥20mg/L)., Materials and Methods: A prospective observational cohort pharmacokinetic study was conducted in burn patients undergoing surgical burn wound treatment., Results: 36/40 (90%) burn patients undergoing surgical burn wound treatment at Rotterdam Burn Centre (Maasstad Hospital), the Netherlands, achieved adequate prophylactic serum concentrations (C max ≥20mg/L) after a single prophylactic intravenous dose of 7mg/kg total bodyweight gentamicin. Total Body Surface Area (TBSA) burned and total bodyweight were statistically significantly correlated with the C max , with correlation coefficients of -0.316, 0.443 and p values of 0.047, 0.004, respectively. Other covariates (age, time after injury, serum creatinine, dose, gender, intensive care admittance) were not statistically significantly correlated. Occurrence of postoperative infection was limited (n=1), no statistically significant difference was observed between patients with a therapeutic and patients with a subtherapeutic serum concentration., Conclusion: The current hospital-wide standard dosage of 7mg/kg total bodyweight is sufficient to achieve an adequate prophylactic C max in burn patients undergoing surgical burn wound treatment., (Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.)

Objective: Gentamicin is a common antibiotic used to treat sepsis in neonates. We hypothesize that obtaining routine gentamicin trough levels may not be necessary in low-risk, term infants., Study Design: We performed a retrospective cohort study of term infants (n=346) treated with gentamicin in a single level III neonatal intensive care unit (NICU). The results of gentamicin trough levels and the correlation with risk factors and potential side effects were recorded. In addition, we conducted a survey of 75 academic NICUs across the United States regarding their gentamicin monitoring practice., Results: Routine trough levels did not predict potential gentamicin toxicity in neonates with low risk factors. Regression analysis demonstrated a positive correlation between gentamicin trough levels and serum creatinine. The survey of the NICUs in the United States demonstrated significant inconsistency in gentamicin monitoring practice., Conclusion: Obtaining gentamicin trough levels guided by risk factors is more appropriate than obtaining routine trough levels in low-risk term neonates.

Background: To develop a population pharmacokinetic model of gentamicin in children with complicated severe malnutrition and to study the influence of covariates (weight and age) on pharmacokinetic indices. In addition, we use the model to perform Monte Carlo simulations to explore the efficacy of several dosage regimens., Methods: Twenty-six children with severe complicated malnutrition were studied. Ninety-six samples of gentamicin plasma concentrations, obtained from 0.5 to 8 hours after intravenous dosing, were analyzed. Population pharmacokinetic models were built using the program Monolix 4.2 (Lixoft, Antony, France). Monte Carlo simulations were performed to evaluate optimal dosage regimens, using the final pharmacokinetic model, based on the probability of pharmacokinetic-pharmacodynamic target attainment., Results: The concentration-time data were fitted best to 1-compartment model. The estimated population clearance was 1.1 L/h, and the volume of distribution was 2.23 L, with an interindividual variability of 47.2% and 35.6%, respectively. The final models for the clearance and volume of distribution were as follows: CL (L/h) = CL = 1.15 (age/median age) and V (L) = 2.33 (weight/median weight). In Monte Carlo simulations, gentamicin given in dosages of 7.5 to 15 mg/kg optical density was effective in achieving the pharmacodynamic target Cmax:minimal inhibitory concentration >10 for minimal inhibitory concentrations ≤2.5 mg/L, with a probability lower than 1% for Cmin >1 mg/L., Conclusions: Based on the available evidence, an intravenous dose of 7.5 to 15 mg/kg once daily in children with complicated severe malnutrition and normal renal function ensures high probability of efficacy and low risk of nephrotoxicity, which gives further support to the recommendations issued by the World Health Organization treatment for this patient population.

Most studies to evaluate kidney safety biomarkers have been performed in rats. This study was conducted in Cynomolgus monkeys in order to evaluate the potential usefulness of novel biomarkers of nephrotoxicity in this species. Groups of 3 males were given daily intramuscular injections of gentamicin, a nephrotoxic agent known to produce lesions in proximal tubules, at dose-levels of 10, 25, or 50mg/kg/day for 10days. Blood and 16-h urine samples were collected on Days -7, -3, 2, 4, 7, and at the end of the dosing period. Several novel kidney safety biomarkers were evaluated, with single- and multiplex immunoassays and in immunoprecipitation-LC/MS assays, in parallel to histopathology and conventional clinical pathology parameters. Treatment with gentamicin induced a dose-dependent increase in kidney tubular cell degeneration/necrosis, ranging from minimal to mild severity at 10mg/kg/day, moderate at 25mg/kg/day, and to severe at 50mg/kg/day. The results showed that the novel urinary biomarkers, microalbumin, α1-microglobulin, clusterin, and osteopontin, together with the more traditional clinical pathology parameters, urinary total protein and N-acetyl-β-D-glucosaminidase (NAG), were more sensitive than blood urea nitrogen (BUN) and serum creatinine (sCr) to detect kidney injury in the monkeys given 10mg/kg/day gentamicin for 10days, a dose leading to an exposure which is slightly higher than the desired therapeutic exposure in clinics. Therefore, these urinary biomarkers represent non-invasive biomarkers of proximal tubule injury in Cynomolgus monkeys which may be potentially useful in humans., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Gentamicin is indicated as empiric treatment for neonatal sepsis. Plasmatic levels dosification of gentamicin is a common practice. The relationship between peak plasma concentration (Cmáx) with minimum inhibitory concentration (MIC) (Cmáx/MIC) is the parameter that best predicts treatment efficacy., Aim: To determine pharmacokinetics of gentamicin in term newborn infants., Methods: Term newborn infants receiving gentamicin, without critical illness in which plasmatic levels of gentamicin was performed were included. Elimination clearance (Cl) elimination half-life (t½) and volume of distribution (Vd) were calculated. In each case the value of Cmax/MIC parameter was calculated, considering a MIC value of 1 μg/mL for Escherichia coli., Results: Thirteen newborns were included. The mean PK values were Cl: 0.26 mL/hour, Vd: 0.54 L/kg and t½: 6.8 h. Cmax/MIC was > 8 in 6 newborns., Conclusions: Pharmacokinetic parameters of gentamicin are predictable in term newborn infants. With gentamicin doses normally used Cmax/MIC values reached 8 in 6 newborns. It is necessary to review the usefulness of plasma drug monitoring and gentamicin dosage in this group of newborns.

Objective: To investigate the absorption of gentamicin into the plasma after an intravitreal injection in dogs and to report the success rate of this procedure in lowering the intraocular pressure., Animals: Twenty-four client-owned dogs with chronic, end-stage glaucoma., Procedures: Dogs received a unilateral (22) or bilateral (2) intravitreal injection of 25-40 mg of gentamicin (mean ± SD dose 2.57 ± 1.65 mg/kg and range 0.61-7.50 mg/kg) and 1 mg of dexamethasone per eye. Blood samples were collected at various time points following the intravitreal injection. Plasma concentrations of gentamicin were determined by liquid chromatography and mass spectrometry., Results: The total plasma concentration of gentamicin ranged from 0.21 to 9.71 μg/mL (mean ± SD 2.15 ± 2.03). The mean gentamicin CMAX was 2.29 μg/mL at 2.54 h with a terminal half-life of 9.8 h. The success rate of the chemical ablation procedure was 86.4% (19/22 eyes) in dogs that had at least 1 month of follow-up., Conclusions: Intravitreal injection of gentamicin in eyes with chronic glaucoma resulted in detectable plasma levels in dogs and was successful in lowering the intraocular pressure in 86.4% of the eyes after the first procedure., (© 2015 American College of Veterinary Ophthalmologists.)

Background: Gentamicin is an aminoglycoside antimicrobial commonly used in horses at 6.6 mg/kg IV once daily. Therapeutic drug monitoring (TDM) can confirm desired peak concentration is reached for common bacterial isolates, and detect toxicosis associated with high trough values., Objectives: Determine the relationship between gentamicin dose and plasma concentration in hospitalized horses, and identify a starting dose range to achieve peaks > 32 μg/mL., Animals: Sixty-five horses (2002-2010) receiving once-daily gentamicin with TDM performed (N = 99 sets)., Methods: Retrospective study. Data from hospitalized horses including weight, dose, plasma peak, and trough gentamicin concentration, creatinine concentrations and presence of focal or systemic disease were collected from medical records. Peak concentrations measured 25-35 minutes after administration were included (N = 77). Data were divided into low (<7.7 mg/kg), medium (7.7-9.7 mg/kg) and high (>9.7 mg/kg) dose groups, and were grouped by the horse having focal or systemic disease., Results: Peak concentrations resulting from doses ≥7.7 mg/kg were 5.74 μg/mL (SE 2.1 μg/mL) greater than peaks from doses <7.7 mg/kg (P = .007). Peak concentrations was 3.6 times more likely to be >32 μg/mL if dose was ≥7.7 mg/kg (P = .04). There were no significant effects of dose on trough or creatinine concentration. At a given dose, horses with focal disease had higher peaks than those with systemic disease (P = .039)., Conclusions and Clinical Importance: These data suggest gentamicin dosage should be individually determined in horses using TDM, but support an initial once-daily dose of 7.7-9.7 mg/kg IV to achieve peaks >32 μg/mL and trough concentrations <2 μg/mL. Further studies evaluating the safety of doses >6.6 mg/kg are required., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Reasons for Performing the Study: Although gentamicin is highly active against Rhodococcus equi in vitro, its clinical efficacy has been limited presumably due to poor cellular uptake. Encapsulation of drugs in liposomes enhances their cellular uptake., Objectives: To compare the disposition of liposomal gentamicin (LG) and free gentamicin (FG) in the plasma, pulmonary epithelial lining fluid and bronchoalveolar cells of healthy foals after i.v. administration or by nebulisation, and to assess the tolerability of the drug after repeated i.v. dosing., Study Design: Experimental study., Methods: Eight healthy foals received a single i.v. or nebulised dose (6.6 mg/kg bwt) of LG or FG in a balanced Latin square design, with a 14-day washout period between treatments. Subsequently, 12 healthy foals were given either LG or FG at 6.6 mg/kg bwt i.v. q. 24 h for 7 doses and urinary protein, creatinine, γ-glutamyltransferase and electrolytes were measured on Days 0, 3 and 7 to quantify renal injury. Concentrations of gentamicin were measured using liquid chromatography-tandem mass spectrometry., Results: After i.v. administration, LG had a significantly higher mean (± s.d.) half-life (16.3 ± 3.5 vs. 6.2 ± 1.8 h) and volume of distribution (2.00 ± 1.03 vs. 0.72 ± 0.32 l/kg bwt) compared with FG. Peak gentamicin concentrations in bronchoalveolar cells were significantly higher for LG compared with FG after administration by both the i.v. (5.27 ± 2.67 vs. 2.98 ± 1.67 mg/l) and the nebulised (4.47 ± 2.66 vs. 1.49 ± 0.57 mg/l) routes. Liposomal gentamicin was well tolerated by all foals and indices of renal injury were not significantly different from those of foals administered FG., Conclusions: Administration of LG is well tolerated and results in higher intracellular drug concentrations than FG. Liposomal gentamicin warrants further investigation for the treatment of infections caused by intracellular pathogens such as Rhodococcus equi., (© 2014 EVJ Ltd.)

The aim of this study was to characterize and validate the population pharmacokinetics of gentamicin in infants and to determine the influences of clinically relevant covariates to explain the inter- and intraindividual variabilities associated with this drug. Infants receiving intravenous gentamicin and with routine therapeutic drug monitoring were consecutively enrolled in the study. Plasma concentration and time data were retrospectively collected from 208 infants (1 to 24 months old) of the Hospital Universitario Severo Ochoa (Spain), of whom 44% were males (mean age [± standard deviation], 5.8 ± 4.8 months; mean body weight, 6.4 ± 2.2 kg). Data analysis was performed with NONMEM 7.2. One- and two-compartment open models were analyzed to estimate the gentamicin population parameters and the influences of several covariates. External validation was carried out in another population of 55 infants. The behavior of gentamicin in infants exhibits two-compartment pharmacokinetics, with total body weight being the covariate that mainly influences central volume (Vc) and clearance (CL); this parameter was also related to creatinine clearance. Both parameters are age related and different from those reported for neonatal populations. On the basis of clinical presentation and diagnosis, a once-daily dosage regimen of 7 mg/kg of body weight every 24 h is proposed for intravenous gentamicin, followed by therapeutic drug monitoring in order to avoid toxicity and ensure efficacy with minimal blood sampling. Gentamicin pharmacokinetics and disposition were accurately characterized in this pediatric population (infants), with the parameters obtained being different from those reported for neonates and children. These differences should be considered in the dosing and therapeutic monitoring of this antibiotic., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or interdependent phenomena. Two groups of 9 female Sprague-Dawley rats (200-250 g), each housed separately and entrained to a 12 h light (06:00-18:00 h) - 12 h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 Hours After Lights On (HALO), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged by both body weight loss relative to the pre-treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in auditory brainstem response (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-β-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240 min post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (first two weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during the treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p < 0.05), particularly the 24 and 32 kHz ones (both p < 0.005), both at the 2 and 4 week assessments. At 32 kHz after 4 weeks of gentamicin dosing, the 2 HALO group showed an average 42 dB hearing loss, while the 14 HALO group exhibited only an average 10 dB loss. ABR response latencies were longer for the 2 than 14 HALO rats. The time course of nephrotoxicity differed from that of ototoxicity. The mean urinary NAG/CR ratio peaked after the first week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38-fold greater than baseline for the 14 HALO-treated ones. Ratio values declined thereafter; although, even after the second week of dosing, they remained greater in the 2 than 14 HALO group (averaging 8.15-fold greater and 2.23-fold greater than baseline, respectively). Pharmacokinetic analysis of the blood gentamicin values revealed slower clearance, on average by ∼25% (p < 0.001), in the rats of the 14 than 2 HALO group (x ± S.E.: 3.22 ± 0.49 and 4.53 ± 0.63 mL/min/kg, respectively). The study findings indicate robust difference of the time course in rats of both treatment groups of gentamicin-induced ototoxicity and nephrotoxicity, supporting the hypothesis these organ toxicities are independent of one another, and further suggest the observed treatment-time differences in gentamicin adverse effects may be more dependent on local cell, tissue, or organ circadian (chrono) pharmacodynamic than (chrono) pharmacokinetic mechanisms.

Aim: This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population., Methods: All gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( nonmem®)., Results: A total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h(-1) (CV 28%), central volume of distribution (Vc ) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h(-1) and peripheral volume of distribution (Vp ) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc . Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg(-1) , at extended intervals to achieve adequate concentrations., Conclusions: This observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring., (© 2014 The British Pharmacological Society.)

Background: Our institution's gentamicin dosing and therapeutic drug monitoring (TDM) practices for newborns were suspected to be very heterogeneous. Once-daily dosing (ODD) or extended-interval dosing (EID) and trough concentration measurement were recommended. Clinical decision support guidelines were developed and implemented as clinical decision support in the computerized prescriber order entry system. Impact on dosing, TDM practices, and blood sampling were evaluated., Methods: A 1-year retrospective historically controlled study before (April 2008-March 2009) and after the implementation of guidelines (January 2010-December 2010) for newborns (<30 days of life) receiving gentamicin. Blood concentrations (% of peak concentrations sampled, % of patients with zero or one concentration sampled, % of trough concentrations ≤1 mg/L) and dose regimen (ODD/EID) were compared between groups. Factors potentially associated with gentamicin concentration were analyzed (multivariate analysis)., Results: One hundred thirty-two (postguidelines) versus 102 (preguidelines) patients were included (median gestational age: 34.3 versus 35.8 weeks, P > 0.05). After implementation of the guidelines, an ODD/EID regimen was almost exclusively used (97.7% versus 61.6%, P < 0.001), the percentage of peak concentrations (0.9% versus 17.2%, P < 0.001) and the number of blood samples per patient (87.1% having 0 or 1 concentration measured versus 48.0, P < 0.001) sharply reduced. A significantly higher percentage of trough concentrations were ≤1 mg/L (68.5% versus 33.0%, P < 0.001). The probability of a trough concentration ≤1 mg/L increased with an ODD/EID regimen (odds ratio, 7.23; 95% confidence interval: 3.48-15.0, P < 0.001) and in the postguidelines group (odds ratio, 2.02; 95% confidence interval: 1.01-4.02, P = 0.045)., Conclusions: Guideline implementation generated a sharp reduction in blood sampling. Clinical benefits of better gentamicin dosing and TDM practices were evident. Cost-effectiveness and clinical benefit of reduced blood sampling should be evaluated.

Introduction: Mesh infection is a severe complication after incisional hernia repair and occurs in 1-3 % of all open mesh implantations. For this reason, topical antimicrobial agent applied directly to the mesh is often used procedure. So far, however, this procedure lacks a scientific basis., Materials and Methods: Two different meshes (Parietex™, Covidien; Ultrapro™, Ethicon Johnson & Johnson) were incubated with increasing amounts of three different Staphylococcus aureus strains (ATCC 25923; Mu50; ST239) with or without gentamicin and growth ability were determined in vitro. To further address the question of the systemic impact of topic gentamicin, serum levels were analyzed 6 and 24 h after implantation of gentamicin-impregnated multifilament meshes in 19 patients., Results: None of the gentamicin-impregnated meshes showed any bacterial growth in vitro. This effect was independent of the mesh type for all the tested S. aureus strains. In the clinical setting, serum gentamicin levels 6 h after implantation of the gentamicin-impregnated meshes were below the through-level (range 0.4-2.9 mg/l, mean 1.2 ± 0.7 mg/l). After 24 h the gentamicin serum levels in all patients had declined 90-65 % of the 6 h values., Conclusion: Local application of gentamicin to meshes can completely prevent the growth of even gentamicin-resistant S. aureus strains in vitro. The systemic relevance of gentamicin in the clinical controls showed to be very low, without reaching therapeutic concentrations.

Background: Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated., Methods: A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions., Results: Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05)., Conclusions: The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

Purpose: Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin., Methods: Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance., Results: A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty)., Conclusions: Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.

Neuroprotective controlled therapeutic hypothermia is the standard of care for newborns suffering perinatal asphyxia. Antibiotic drugs, such as amikacin, gentamicin, and vancomycin are frequently administered during controlled hypothermia, which possibly alters their pharmacokinetic (PK) and pharmacodynamic (PD) profiles. In order to examine this effect an LC-MS/MS method for the simultaneous quantification of amikacin, the major gentamicin components (gentamicin C, C1a and C2), and vancomycin in plasma was developed. In 25μL plasma proteins were precipitated with trichloroacetic acid (TCA) and detection of the components was achieved using ion-pair reversed phase chromatography coupled with electrospray ionization tandem mass spectrometry. The chromatographic runtime was 7.5min per sample. Calibration standards were prepared over a range of 0.3-50mgL(-1) for amikacin and gentamicin and 1.0-100mgL(-1) for vancomycin. At LLOQ accuracy was between 103 and 120% and imprecision was less than 19%. For concentrations above LLOQ accuracy ranged from 98% to 102% and imprecision was less than 6%. Process efficiency, ionization efficiency, and recovery were acceptable. Samples and stock solutions were stable during the time periods and at the different temperatures examined. The applicability of the method was shown by analysing plasma samples from 3 neonatal patients. The developed method allows accurate and precise simultaneous quantification of amikacin, gentamicin, and vancomycin in a small volume (25μL) of plasma., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To investigate local and systemic pharmacokinetics of gentamicin after intra-articular implantation of a gentamicin impregnated collagen sponge (GICS) in the inflamed canine joint., Study Design: Descriptive repeated measures experimental study., Animals: Dogs (n = 9)., Methods: Stifle joint inflammation was caused by urate injection. Twenty-four hours later a GICS (gentamicin dose, 6 mg/kg) was arthroscopically implanted. Synovial fluid and plasma gentamicin concentrations were measured for 14 days after implantation, and pharmacokinetic parameters modeled using statistical moment analyses., Results: Intra-articular gentamicin concentrations fell to sub-MIC for Staphylococcus sp. (4 µg/mL) by 22.4 hours (95% CI: 18.6-26.2) after sponge implantation. Cmax synovial was 2397 µg/mL (95%CI: 1161-3634 µg/mL) at 1.2 hours (95%CI: 0.5-1.8 hours). Plasma gentamicin concentrations achieved levels of Cmax plasma  = 8.0 µg/mL (95%CI: 6.1-10.0 µg/mL) at 1.5 hours (95%CI: 0.8-2.1) after GICS placement and fell below target trough of 2.0 µg/mL by 5.6 hours (95%CI: 4.7-6.5 hours) after GICS placement., Conclusions: Intra-articular gentamicin concentration after GICS placement at an IV-equivalent dose reached high levels and declined rapidly. The maximum plasma levels attained were ∼1/3 of the recommended sub-toxic target for people after parenteral gentamicin administration., (© Copyright 2014 by The American College of Veterinary Surgeons.)