Nürnberg, Univ., Diss--Erlangen, 2000. / Zsfassung in dt. und engl. Sprache.

AIMS: To assess (i) the safety of once daily dosing (ODD) of gentamicin by systematic evaluation of ototoxicity and nephrotoxicity; and (ii) the usefulness of therapeutic drug monitoring (TDM) in a paediatric cohort. METHOD: Infants and children with suspected or proven gram negative sepsis were enrolled prospectively to receive ODD gentamicin at 7 mg/kg/day. Neonates were excluded. Hearing and renal function were assessed at baseline, during and after therapy by otoacoustic emissions (OAE) and by either serum creatinine or glomerular filtration rate. Abnormal OAE were followed with audiometry. TDM was performed using an interval adjusted graphical method (Hartford nomogram) with levels taken between 6-14 hours after dose. Assessment of efficacy (clinical and microbiological) was a secondary outcome measure. RESULTS: There were 106 episodes of therapy in 79 children (median age 5.6 years; range 1 month - 16 years), 60% of which were for febrile neutropaenia. Evaluation was complete in 88% (93/106) for ototoxicity and 92% (98/106) for nephrotoxicity. Two children (1.88%, 95% CI 0.10 - 7.13) experienced permanent hearing loss. Three children did not complete full assessment after preliminary abnormalities on OAE. Incorporating these cases gives a ???worst case scenario??? incidence of 4.71% (95% CI 1.71 - 10.91) possible ototoxicity. One child (0.94%, 95% CI < 0.10 - 5.73) experienced transient nephrotoxicity. No ???toxic??? serum gentamicin levels were detected, including in those children who experienced clinical toxicity. All children with detectable toxicity were undergoing treatment for malignancies and had received nephro or ototoxic medications prior to the gentamicin course. Complete or partial efficacy was seen in 93% (non oncology) and 78% (oncology) treatment episodes, equivalent to prior literature reports. CONCLUSION: In this systematically evaluated paediatric cohort receiving ODD gentamicin, toxicity occurred infrequently and only in those with identifiable risk factors. TDM did not identify children who developed clinical toxicity. The development of toxicity appears to be associated with factors such as underlying medical condition, prior courses of gentamicin, exposure to other oto or nephrotoxic medications, all of which may be more predictive of toxicity than elevated serum gentamicin levels. TDM in healthy children on short course gentamicin appears unnecessary, but may be warranted in conjunction with renal and hearing assessments in those with risk factors.

This thesis is an investigation of a gentamicin impregnated collagen sponge (GICS) product implanted into an inflamed canine stifle joint. Project goals were to determine the duration for which drug concentrations remained above minimal inhibitory concentrations within the joint following sponge implantation; to determine whether there was systemic exposure to the drug following local implantation; to evaluate the impact of the sponge on local joint inflammation and lameness; and to evaluate whether sponge use resulted in any renal injury. The study design was a randomized controlled experimental trial (2 x n=9) performed with research hounds. GICS were arthroscopically implanted at a dose of 6mg/kg. Pharmacokinetic parameters were modeled using statistical moment analyses. Joint inflammation was measured by synovial fluid cell counts and cytokine concentrations, lameness was measured by force plate asymmetry indices, and renal function was measured by glomerular filtration rate (GFR) study using technetium 99 plasma clearance. The prevalence of lesions associated with aminoglycoside nephrotoxicity was assessed by renal biopsy and electronmicroscopy. Intra-articular gentamicin concentrations fell to sub-MIC for Staphylococcus sp. (4ug/ml) by 22.4hrs (95% CI=18.6-26.2) following sponge implantation. Cmax synovial was 2397ug/ml (95% CI=1161-3634 ug/ml) at 1.2 hrs (95% CI=0.5-1.8hrs). Plasma gentamicin concentrations achieved levels of Cmax plasma =8.0ug/ml (95% CI=6.1-10.0 ug/ml) at 1.5hrs (95% CI=0.8-2.1) following GICS placement and fell below target trough of 2.0ug/ml by 5.6hrs (95% CI=4.7-6.5hrs) following GICS placement. GICS implantation caused joint inflammation (p<0.01), lameness (p=0.04), and decreased GFR (p=0.04). No dog developed clinical renal failure. No difference was observed in the prevalence of renal lesions on biopsy between treatment and control group (p=0.49). Intra-articular gentamicin concentration following GICS placement at an IV-equivalent dose reached high levels and declined rapidly. The maximum plasma levels attained were approximately 1/3rd of the recommended sub-toxic target for human patients following parenteral gentamicin administration. GICS implantation in the inflamed joint caused additional inflammation and joint dysfunction that is likely to be of clinical relevance. GICS implantation affected renal function at the dose assessed. Renal effects may be exacerbated in septic patients, and care should be taken with GICS dosing in clinical patients. / Pet Trust

Gentamicin-induced nephrotoxicity varies temporally, with a peak being observed when this antibiotic is administered during the resting period and a trough when given during the activity period of rats. These variations are modified by fasting and by restricted feeding schedules. In this study, food and water intakes of adult female Sprague-Dawley rats were measured during pre-treatment (days 1 to 5) and during treatment (days 6 to 10) with gentamicin (80 mg/kg/day, i.p.) injected at 1300 h or 0100 h. A significantly higher level of serum creatinine was observed when gentamicin was administered at 1300 h compared to 0100 h, and a significantly lower creatinine clearance was found in rats treated with gentamicin at 1300 h compared to those treated with saline at the same time. Gentamicin treatment at 1300 h or 0100 h resulted in a decrease in the 24 h food intake. In addition, in the gentamicin-treated group at 0100 h, the maximal food intake observed at late dark during the pre-treatment period decreased during treatment, and early dark rather than late dark maximal intake occurred. Our data demonstrate that gentamicin induces a nephrotoxicity that varies temporally, and that gentamicin treatment inhibits food intake and alters its nocturnal variations.

Macronutrient composition of food was shown to have a potent impact in modulating circadian rhythms of gentamicin toxicity. In the present study, adult female Sprague-Dawley rats fully adapted to isocaloric 20 casein-containing, 20% soy-containing (both semi-purified with 10% safflower oil and 58.55% carbohydrate) or a standard chow diet (non-purified with 18.1% mixed proteins, 4.5% fat and 57.3% carbohydrate) were chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day, i.p.) or a saline solution given in the middle of their resting period or in the middle of their activity period. Body weights, 24-h, 12-h light and 12-h dark food intakes were measured before (Days 1 to 5) and during treatment (Days 6 to 15). Gentamicin nephrotoxicity indices including serum creatinine, creatinine clearance, urinary proteins, urinary enzymes activities, corticocefular regeneration and cortical accumulation of gentamicin were measured at specific time points during the experiment. (Abstract shortened by UMI.)

Septic shock due to bacterial infections is one of the main causes of death in intensive care units of the developed world. To a great extent, the efforts to improve the outcomes of life-threatening infections including septic shock have focused on the deployment of antimicrobials of ever increasing potency. However, many pathogenic bacterial strains have acquired resistance to available and even recently introduced antibiotics. Alternate pharmacokinetic strategies constitute another pathway to increased antimicrobial efficacy. In this study, we have demonstrated that a single very high dose of gentamicin can eliminate sensitive and moderately resistant bacterial strains at an accelerated rate with a lower risk of regrowth in an in vitro pharmacodynamic model compared to standard (once daily-equivalent) dosing. This approach may be clinically viable if potential toxicity concerns can be addressed.

All aminoglycosides have the potential to cause nephrotoxicity. Previous studies have shown that this toxicity was altered according to the macronutrient composition of dietary regimens offered to female rats. In a first study, adult female Sprague-Dawley rats adapted to a standard chow diet, the standard chow with 20% added casein or with 55% added casein were treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day, i.p.) or a saline solution. Food ingestion patterns and gentamicin nephrotoxicity indices were measured. In a second study, rats were fed the same diets, however, the treatment given was a sham injection. Results suggest that chronic gentamicin treatment leads to a decrease in food intake and flattening of the rhythms of food ingestion. Also, chow feeding and chow added with 20% casein were found to be more protective against gentamicin-induced nephrotoxicity than chow added with 55% casein.

AIMS: To assess (i) the safety of once daily dosing (ODD) of gentamicin by systematic evaluation of ototoxicity and nephrotoxicity; and (ii) the usefulness of therapeutic drug monitoring (TDM) in a paediatric cohort. METHOD: Infants and children with suspected or proven gram negative sepsis were enrolled prospectively to receive ODD gentamicin at 7 mg/kg/day. Neonates were excluded. Hearing and renal function were assessed at baseline, during and after therapy by otoacoustic emissions (OAE) and by either serum creatinine or glomerular filtration rate. Abnormal OAE were followed with audiometry. TDM was performed using an interval adjusted graphical method (Hartford nomogram) with levels taken between 6-14 hours after dose. Assessment of efficacy (clinical and microbiological) was a secondary outcome measure. RESULTS: There were 106 episodes of therapy in 79 children (median age 5.6 years; range 1 month - 16 years), 60% of which were for febrile neutropaenia. Evaluation was complete in 88% (93/106) for ototoxicity and 92% (98/106) for nephrotoxicity. Two children (1.88%, 95% CI 0.10 - 7.13) experienced permanent hearing loss. Three children did not complete full assessment after preliminary abnormalities on OAE. Incorporating these cases gives a ???worst case scenario??? incidence of 4.71% (95% CI 1.71 - 10.91) possible ototoxicity. One child (0.94%, 95% CI < 0.10 - 5.73) experienced transient nephrotoxicity. No ???toxic??? serum gentamicin levels were detected, including in those children who experienced clinical toxicity. All children with detectable toxicity were undergoing treatment for malignancies and had received nephro or ototoxic medications prior to the gentamicin course. Complete or partial efficacy was seen in 93% (non oncology) and 78% (oncology) treatment episodes, equivalent to prior literature reports. CONCLUSION: In this systematically evaluated paediatric cohort receiving ODD gentamicin, toxicity occurred infrequently and only in those with identifiable risk factors. TDM did not identify children who developed clinical toxicity. The development of toxicity appears to be associated with factors such as underlying medical condition, prior courses of gentamicin, exposure to other oto or nephrotoxic medications, all of which may be more predictive of toxicity than elevated serum gentamicin levels. TDM in healthy children on short course gentamicin appears unnecessary, but may be warranted in conjunction with renal and hearing assessments in those with risk factors.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 229-236).

Class of 2011 Absrtact / OBJECTIVES: The purpose of this study was to analyze various published gentamicin dosing protocols in a neonate population to determine the percentage of patients that fell within defined concentration ranges, and determine which protocol was the most efficient at being within the desired concentration ranges. METHODS: Data from three published studies were used to create a database of 331 neonates who were up to seven days old and received gentamicin. Pharmacokinetic data was obtained and applied to specific dosing protocols from six published studies. The protocols were used to simulate peak and trough concentrations for each neonate. Desired trough concentrations include < 0.5 mg/L or < 1 mg/L and peak concentrations within 7-10 mg/L. Results were analyzed for frequency of achieving pre-specified concentration ranges based on dosing protocols from the study. RESULTS: The Begg protocol was adjusted for a desired Cmax of 8.5 mg/L and an estimated volume of distribution based on weight and was found to be the most efficient at achieving the highest percentage of patients achieving peaks of 7-10 mg/L and a trough of < 1 mg/L and < 0.5 mg/L, 63.0% and 61.5%, respectively. Also, other protocols which adjusted the dose based primarily on weight or gestational age such as the Fullas, Blackmer and Darmstadt protocols frequently achieved their desired trough however the average peak varied significantly, and was higher than the pre-specified concentration range. CONCLUSION: Achieving acceptable concentration ranges was suboptimal with much variability between each protocol requiring therapeutic drug monitoring and adjusting accordingly until a more efficient protocol is developed for this patient population.