[Aerosol administration of dibekacin--the sputum concentration].
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The potential diagnostic utility of the urine gamma-glutamyl transpeptidase (GGT)-to-creatinine ratio was evaluated in an experimental canine model of aminoglycoside-induced nephrotoxicity. A therapeutic dosage of gentamicin resulted in a twofold increase in the mean urine GGT-to-creatinine ratio that was not associated with clinically significant nephrotoxicity. In dogs each given a nephrotoxic dosage of gentamicin, an increase in mean urine GGT-to-creatinine ratios approximately three times baseline values preceded clinically significant abnormalities in serum creatinine, urine specific gravity, and urine protein-to-creatinine ratio. The urine GGT-to-creatinine ratio appears superior as an early indicator of aminoglycoside-induced nephrotoxicity. Further studies in canine clinical cases are warranted.
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the influence of various concentrations of calcium on the antibacterial activity of gentamicin in urine on 10 strains of E. coli and 10 strains of P. aeruginosa was studied in vitro. It was found that calcium has a strong antagonistic effect on gentamicin activity, particularly with regard to P. aeruginosa. This effect is greatly reduced when gentamicin concentrations are increased to levels higher than those obtained in urine under conventional treatment schedules.
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Aims The excretion of phospholipids in urine may be a marker of the early renal toxicity of the aminoglycoside antibiotics. Urinary phospholipids are formed in myeloid bodies which develop in the lysosomes of proximal tubules during treatment with the aminoglycosides, and overflow into the urine. Methods Published assays were modified in order to measure the total phospholipid concentrations in human urine. Phospholipids were extracted from freeze‐dried urine samples, digested in concentrated sulphuric acid, and the inorganic phosphorus content determined by complexing with ammonium molybdate and measuring the absorbance at 820 nm. Ten septicaemic patients treated with gentamicin for 5–7 days had significantly higher urine phospholipid concentrations than 10 healthy untreated control subjects ( P <0.0001). There was a negative linear relationship between phospholipid excretion and creatinine clearance ( r 2 =0.71). Results In 34 patients with acute pyelonephritis, increased phospholipid concentrations were observed prior to treatment compared with healthy controls ( P <0.001) and did not alter during treatment with gentamicin. However, the phospholipid concentrations decreased significantly after treatment was completed ( P <0.03). Conclusions These studies suggest that urinary phospholipids may indicate early aminoglycoside toxicity but with poor specificity, as many of the infections being treated may themselves be associated with phospholipiduria.
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In cystic fibrosis (CF), the clinical effectiveness of aerosolized antibiotics is controversial. Previous investigators have not considered the type of nebulizer, droplet size, and dose to the lung in assessing the results of aerosol therapy. The present study tests the importance of these factors by standardizing an aerosol system for delivery of antibiotics and other agents to patients with CF. Particle size, distribution, and output from a commercially available nebulizer were measured. Thirteen patients with CF inhaled aerosol (MMAD = 1.1 μm) containing gentamicin (160 mg in nebulizer) and 99mTc-labeled human serum albumin. Patients' sputum and serum were analyzed for gentamicin levels by immunoenzymatic assay (Emit; Syya Corp., Palo Alto, CA). Using a gamma camera and suitable filters, central versus peripheral deposition (C/P ratio) and whole lung deposition were measured and related to sputum gentamicin levels. Gentamicin deposit averaged 12.3 mg ± 5.9 (SO) or 7.69% of the original amount placed in the nebulizer. Peak sputum levels averaged 376.6 μg/ml ± 275, whereas serum levels were undetectable in all patients. When peak sputum levels were normalized for the amount deposited, a close correlation with C/P ratio was obtained (r = 0.88, p < 0.05). Furthermore, an inverse relationship was found between the C/P ratio and the %FEV1 (r =0.76, p < 0.05). Finally, a bell-shaped relationship between deposited dose and minute ventilation was seen in the patients (r = 0.88, p < 0.05), i.e., an optimal minute ventilation was shown. These relationships may be important when designing future clinical studies.
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Using nebulization to deliver aminoglycosides may be of benefit in cystic fibrosis (CF) patients colonized by Pseudomonas aeruginosa . However, one problem with this route is the absence of clinical parameters allowing estimation of the mass of drug deposited in the lungs (MDL). The aim of this study was to assess whether aminoglycoside excretion in the urine reflects the MDL. Fourteen studies were performed in seven CF patients. Amikacin was mixed with albumin labelled with 99m Tc and nebulized with an ultrasonic nebulizer. The MDL was determined by the mass-balance technique. Urine was collected during the 24 h following inhalation and was assayed for amikacin by fluorescence polorization immunoassay (FPIA). The mean±sem MDL was 14.0±2.2% of the nebulizer charge. The mean±sem amount of amikacin excreted in the urine was 20.9±4.5 mg and correlated with the MDL (r=0.93; p=0.0001). There was, however, wide intersubject variability in both deposition and excretion in the urine. Monitoring excretion of aminoglycosides in the urine allows noninvasive estimation of the mass of drug deposited in the lung in cystic fibrosis patients, which might be useful to assess the dose-response relationship in groups of patients, but intersubject variability prevents its use for individual follow-up.
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The ototoxic antibiotic gentamicin, and the ototoxic diuretic ethacrynic acid, both produce inhibitory effects on protein synthesis in microsomes isolated from rat brain. Inhibitory effects appear to be essentially independent of each other. The inhibitory dose-response curve for gentamicin is logarithmic, while that for ethacrynic acid islinear. The dose-response curves make gentamicin the predominant inhibitor when the drugs are combined at low concentrations and ethacrynic acid the predominant inhibitor when the drugs are combined at high concentrations. Accumulation of aminoglycosidc by tissues of the inner ear may result in inhibition of protein synthesis n spite of low and transient plasma levels of the drug. Further inhibition of translation by ethacrynic acid could account, in part, for the ototoxic interaction of aminoglycosides and high ceiling diuretics.
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Aminoglycosides are a mainstay of therapy for patients with cystic fibrosis (CF) or non-CF bronchiectasis who are infected with Pseudomonas aeruginosa (Psa). Traditionally, aerosolized antibiotics are delivered by liquid nebulization. The objective of this study was to determine whether a gentamicin dry powder inhaler (DPI) is as microbiologically active and potentially safe as gentamicin inhaled via a small-volume nebulizer (SVN) or given intravenously. The study was done according to a randomized, single-dose, and triple crossover protocol. Ten patients with CF or non-CF bronchiectasis and chronically infected with Psa were recruited. Patients received a single dose of either gentamicin 160 mg via DPI or SVN, or gentamicin at 5 mg/kg by intravenous infusion. In seven of the 10 patients, the minimum inhibitory concentration (MIC) was achieved in sputum after DPI and SVN, with mean (95% confidence interval) gentamicin concentrations at 2 h after administration of 13.1 microgram/g sputum (range: 2.2 to 23.9 microgram/g) and 97.2 microgram/g sputum (range: 0.3 to 194.2 microgram/g), respectively, whereas gentamicin levels in the sputum after intravenous administration failed to reach the MIC. Gentamicin given by DPI and SVN significantly decreased the sputum Psa density (p < 0.05), by almost one order of magnitude. No significant decline in bacterial counts was observed after intravenous gentamicin. When gentamicin was inhaled, blood concentrations were minimal, and were below concentrations known to cause systemic toxicity. For treatment of Psa infections susceptible to gentamicin, gentamicin administration by DPI appeared to be as efficient as by SVN, despite the delivery of a 7-fold lower dose to the airways.
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