dibekacin and Kidney-Diseases

Sisomicin is a naturally occurring aminoglycoside antibiotic produced by Micromonospora inyoensis, while dibekacin and netilmicin are both semisynthetic aminoglycosides. Dibekacin is 3',4'-dideoxykanamycin B and netilmicin is 1-N-ethyl sisomicin. In both cases, these modifications render the agents insusceptible to some of the enzymes found in resistant strains of bacteria which inactivate the parent compounds. Antibacterial activity: All 3 drugs show bactericidal activity against a wide range of Gram-negative bacteria (including E. coli, Enterobacter, Klebsiella and Proteus spp. and Ps. aeruginosa) and also against staphylococci; however, in common with other amino-glycosides, streptococci are usually resistant (except when beta-lactam antibiotics are used in combination) and anaerobic organisms are not sensitive. Sisomicin is closely related structurally to gentamicin Cla, but in vitro studies have shown it to have superior activity to gentamicin against Ps. aeruginosa, closely paralleling the activity of tobramycin, while still possessing the high activity of gentamicin against Serratia and other Gram-negative rods. However, sisomicin is inactivated by virtually all bacterial enzymes which inactivate gentamicin and tobramycin. Nevertheless, it retains useful activity against a number of gentamicin-resistant strains of Ps. aeruginosa which are resistant by non-enzymatic (possibly permeability barrier) mechanisms; in this respect it closely resembles tobramycin. Dibekacin closely resembles tobramycin structurally and in vitro it seems to have a very similar antibacterial spectrum, including activity against some strains of Ps. aeruginosa resistant to gentamicin. Netilmicin has a generally broader antibacterial spectrum than gentamicin, tobramycin, sisomicin or debekacin and is resistant to inactivation by phosphorylating and adenylylating enzymes; however, it is inactivated by all acetylases, apart from acetylase 3-I. Its spectrum is therefore not as wide as that of amikacin against 'gentamicin-resistant' strains. Nonetheless, it is intrinsically more active than amikacin, weight-for-weight, against sensitive strains, apart possibly from Ps. aeruginosa. In fact, its activity against species of the Enterobacteriaceae and staphylococci sensitive to gentamicin is of the same order as the latter and possibly better for Klebsiella-Enterobacter species. All 3 agents show marked antibacterial synergy with a variety of beta-lactam antibiotics against a range of

Topics: Aging; Animals; Bacterial Infections; Dibekacin; Drug Interactions; Drug Resistance, Microbial; Drug Synergism; Gentamicins; Humans; Kanamycin; Kidney Diseases; Netilmicin; Sisomicin

Arbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the optimal concentration targets of arbekacin for both efficacy and safety. A pharmacokinetic-pharmacodynamic analysis was performed to relate exposure to the drug and clinical cure/improvement or nephrotoxicity. Since we have reported the population pharmacokinetic parameters for arbekacin in the preceding paper (Y. Tanigawara, R. Sato, K. Morita, M. Kaku, N. Aikawa, and K. Shimizu, Antimicrob. Agents Chemother. 50:3754-3762, 2006), individual exposure parameters, such as area under the concentration-time curve (AUC), peak concentration (C(max)), AUC/MIC, C(max)/MIC, and trough concentration (C(min)) were estimated by the Bayesian method. Logistic regression was used to describe the relationship between exposure to the drug and the probability of clinical cure/improvement or nephrotoxicity. For the clinical efficacy analysis, 174 patients confirmed to have an MRSA infection were evaluated. The C(max), C(min), and AUC of arbekacin were associated with the probability of clinical cure/improvement during monotherapy. It was shown that the probability of cure/improvement rose when the C(max) of arbekacin was increased, with an odds ratio of 6.7 for a change in C(max) from 7.9 to 12.5 microg/ml (P = 0.037). For the nephrotoxic risk analysis, 333 patients were included, regardless of whether a pathogen was identified. Logistic regression analysis revealed C(min) and AUC as risk factors of nephrotoxicity (P < 0.005). The estimated probabilities of arbekacin-induced nephrotoxicity were 2.5, 5.2, and 13.1% when the C(min) values were 1, 2, and 5 microg/ml, respectively. The present findings are useful for optimizing the individual dose of arbekacin for the treatment of MRSA-infected patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Area Under Curve; Child; Dibekacin; Drug Monitoring; Female; Humans; Kidney Diseases; Kidney Function Tests; Logistic Models; Male; Methicillin Resistance; Microbial Sensitivity Tests; Middle Aged; Risk; Staphylococcal Infections; Staphylococcus aureus

The urinary excretion of N-acetyl-beta-glucosaminidase was studied in healthy subjects during and after treatment with aminoglycosides. In terms of this parameter dibekacin appeared to be less nephrotoxic than gentamicin.

Topics: Acetylglucosaminidase; Adult; Dibekacin; Gentamicins; Hexosaminidases; Humans; Kanamycin; Kidney Diseases; Male

The protective effect of pazufloxacin (PZFX) mesilate, a parenteral quinolone antimicrobial agent, on arbekacin (ABK)-induced nephrotoxicity was evaluated with 8-week-old male Sprague-Dawley rats. Animals were injected with ABK at a dose of 32 mg/kg intramuscularly, or a combination of ABK in the same manner with PZFX mesilate at a dose of 208 mg/kg (160 mg/kg convert to PZFX, active principle of PZFX mesilate) intravenously once a day for 4 days. In consequent, ABK induced increases in protein, beta 2-microglobulin and N-acetyl-beta-(D)-glucosaminidase in urine, and histopathological phospholipidosis in kidneys. The extent of these changes was reduced when ABK was given in a combination with PZFX mesilate. Renal cortex level of ABK increased after an administration of ABK 1 hour to 4 hours; however, the increase was suppressed by coadministration of PZFX mesilate. Taken together, these results suggest that PZFX mesilate has the protective effect on ABK-induced nephrotoxicity, and that this was attributable to a suppression of uptake of ABK in cortical renal tubules.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Dibekacin; Drug Interactions; Drug Therapy, Combination; Fluoroquinolones; Kidney Cortex; Kidney Diseases; Kidney Tubules; Male; Oxazines; Rats; Rats, Sprague-Dawley

Seven N-alkylsulfonate derivatives of an aminoglycoside antibiotic, dibekacin, were prepared and their nephrotoxicity was examined. Using water-supplied and water-depleted rats and the BUN value as a nephrotoxic measure, dibekacin-di-N-methanesulfonate, pentasodium dibekacin-penta-N-methanesulfonate, -penta-N-ethanesulfonate, disodium dibekacin-di-N-methanesulfonate sesquisulfate, disodium and dipotassium dibekacin-di-N-ethanesulfonate sesquisulfates and sodium dibekacin-mono-N-ethane-sulfonate disulfate showed low nephrotoxicity as compared to that of the original dibekacin sulfate. Notably, dibekacin-di-N-methanesulfonate caused little change in the BUN value and was bioactive in vitro but not active in vivo against a Pseudomonas aeruginosa infection model in mice. Among the bioactive N-alkylsulfonates in vivo, disodium and dipotassium dibekacin-di-N-ethanesulfonate sesquisulfates showed a lower degree of elevation of BUN, urine volume and urine protein, lower mortality and better body weight gain than those of dibekacin sulfate during consecutive treatment for 12 and 28 days.

Topics: Animals; Bacteria; Blood Urea Nitrogen; Body Weight; Chemical Phenomena; Chemistry; Dibekacin; Kanamycin; Kidney Diseases; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Rats; Rats, Inbred Strains; Urodynamics

Intramuscular administration of dibekacin or gentamicin to Fischer rats at doses of 10, 20 and 40 mg/kg for 11 days gave polyuria, enzymuria and cytauria. These changes were suppressed completely or partially by the simultaneous administration of glucarolactam sodium or potassium salt. The ameliorating results were supported by serum and histopathological analyses on day 12. A rise in BUN and serum creatinine levels was partially or completely suppressed and histopathological scores were improved by co-administration of glucarolactam salts.

Topics: Animals; Body Weight; Creatinine; Dibekacin; Gentamicins; Glucaric Acid; Kanamycin; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Inbred F344; Sugar Acids; Urodynamics

Pharmacokinetics of arbekacin (HBK), a new aminoglycoside, was studied. Serum concentrations and urinary excretion were determined after single intravenous drip infusion of 100 mg HBK for 1 hour to healthy volunteers and patients with renal insufficiency of various kinds. The drug concentration was determined with bioassay, fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). Pharmacokinetic analysis was made in accordance with the two-compartment open model, and 24-hour endogenous creatinine clearance (Ccr) was used as the renal function index. In all cases peak serum levels were detected 1 hour after administration, and similar values were noted regardless of subjects' proficiencies of renal function. However, the serum clearance during beta-phase tended to be prolonged parallel with the degree of renal insufficiency. The excretion of HBK into urine was prolonged and cumulative recovery tended to be decreased in association with the decreased valued of Ccr.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Creatinine; Dibekacin; Humans; Kanamycin; Kidney Diseases; Kidney Function Tests; Reference Values

Treatment of the pregnant rat with aminoglycosides provokes nephrotoxicity in the newborn. This study compares the effects of three antibiotics belonging to this group: gentamicin (same day dose administered in one or two injections according to the groups), sisomicin and dibekacin, all administered during the last phase of gestation. Newborns were tested the day after birth, creatinine clearance was measured and then the kidneys were removed for histopathological examination. Functional variations (diuresis, creatinine clearance) and histological alterations of glomerula and tubules were observed. Slight differences suggest that, depending on the antibiotic used, intra-cellular nephrotoxic mechanisms are not completely identical. The modifications which occur after the administration of aminoglycosides, lead us to believe that further studies on the possible fetal nephrotoxic effects of drugs taken by mothers during gestation should be undertaken.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Dibekacin; Female; Gentamicins; Kidney; Kidney Diseases; Maternal-Fetal Exchange; Microscopy, Electron; Pregnancy; Rats; Rats, Inbred Strains; Sisomicin

In vitro studies of elimination of arbekacin (HBK), a new aminoglycoside antibiotic, from blood by means of hemodialysis or adsorption with charcoal, and pharmacokinetic studies in patients with renal dysfunction were examined. HBK was well eliminated by hollow fiber type artificial kidney (HFAK) with a half-life of 0.13 hr. HBK was also well eliminated by an adsorption tube containing charcoal with even shorter half-life of 0.03 hr. As to pharmacokinetics of HBK in patients with renal dysfunction, blood levels became higher with a greater reduction in 24 hr endogenous creatinine clearance (Ccr). A decreasing tendency was also seen in urinary recovery rate. These results indicated that hemodialysis and adsorption with charcoal are useful for elimination of HBK from blood. It is recommendable in patients with renal dysfunction to take some measures such as prolongation of administration interval of HBK according to the extent of decrease in Ccr.

Topics: Adsorption; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Charcoal; Dibekacin; Female; Humans; Kanamycin; Kidney Diseases; Male; Middle Aged; Renal Dialysis

Habekacin is a new aminoglycoside antibiotic. In this study we want to know the effect of increasing dose of habekacin on renal function and on renal morphology. We decide to compare the renal alterations induced by habekacin to these provoked by gentamicin, netilmicin and amikacin. Female Wistar rats received intraperitonally a single injection daily of 10, 30, 50, 150 mg/kg of habekacin for seven days. Wistar rats received also 50 mg/kg gentamicin, 50 mg/kg netilmicin and 150 mg/kg amikacin. No mortality was observed in groups treated with 10, 30, 50 mg/kg habekacin but 50 per cent of rats died with 150 mg/kg habekacin. Habekacin--30 mg/kg seven days--induced a decrease of cortical enzymatic activities, an increase of the number of lysosomes, a great accumulation of myeloid bodies, an alteration of lysosomal membranes Habekacin--50 mg/kg seven days and 150 mg/kg--induced a decrease of creatinine clearance and ultrastructural alterations of renal tubular cells. Comparative studies with other aminoglycosides showed that amikacin--150 mg/kg was the lesser nephrotoxic drug. With a same dose of 50 mg/kg, gentamicin appeared lesser nephrotoxic than habekacin and habekacin seemed to induce a same degree of renal modifications than netilmicin. With the dose of 150 mg/kg habekacin this drug was higher nephrotoxic than 50 mg/kg gentamicin. In conclusion, if it could be necessary to use habekacin and to prefer this aminoglycoside to gentamicin from an antibacterial activity point of view it is necessary to keep in mind that this drug is potentially nephrotoxic and that the dosage had to be strictly respected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Dibekacin; Female; Gentamicins; Kanamycin; Kidney Cortex; Kidney Diseases; Netilmicin; Rats; Rats, Inbred Strains

The interactions of aminoglycoside, 3',4'-dideoxykanamycin B(DKB) with ATP and its related compounds were investigated. ATP, ADP, cyclic AMP and FAD bound to the DKB-conjugated Sepharose 4B column. The binding of DKB to ATP was also confirmed by equilibrium gel filtration. In the acidic pH region, the fluorescence of nucleotides was quenched by DKB. The Stern-Volmer plots showed that the molar ratios of the complexes were 1:1. The apparent stability constant was dependent on the number of the phosphate groups of nucleotides and was in the order of ATP greater than ADP greater than AMP.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Chromatography, Affinity; Chromatography, Gel; Cyclic AMP; Dibekacin; Humans; In Vitro Techniques; Kanamycin; Kidney Diseases; Kidney Tubules, Proximal; Spectrometry, Fluorescence

To evaluate nephrotoxicity of dibekacin among elderly patients, we studied the daily urinary excretion of NAG and determined isoenzyme levels in the urine of 36 patients (mean age 80 yrs) treated with dibekacin (3 mg.kg-1.day-1). Only two patients developed transient acute renal failure during the first 10 days of treatment. Total NAG urinary activity was however important (304.5 +/- 38.6 U/mmol creat), due primarily to isoenzymes A (58.8 +/- 2.0%) and I (30.8 +/- 1.5%), while B-form excretion was moderately increased (10.3 +/- 1.0%). These results were compared with those obtained with gentamicin (28 patients, 11 transient acute renal failure). The rate of A-form was identical for both antibiotics while excretion of the B-form was significantly higher with gentamicin (p less than 0.001). These results show that nephrotoxic risk is linked to the excretion of the B-form, and allow us to oppose the notion of "functional" enzymuria (low nephrotoxic risk) linked with A- and I-forms with the notion of "lesional" enzymuria (high nephrotoxic risk) linked with the B-form.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Aged; Dibekacin; Female; Gentamicins; Hexosaminidases; Humans; Isoenzymes; Kanamycin; Kidney Diseases; Male; Middle Aged

The protective effect of fosfomycin against aminoglycoside (dibekacin)-induced ototoxicity was studied in rats. Rats were injected with 100 or 50 mg/kg of dibekacin with or without 500 mg/kg of fosfomycin for 60 or 120 consecutive days. Inner ear damage appeared to be more reduced histopathologically in animals given both dibekacin and fosfomycin than in animals given dibekacin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of dibekacin and fosfomycin. The mechanism of reduced ototoxicity may be as follows: fosfomycin inhibits the accumulation of dibekacin in the kidney, and reduces its concentration in the kidney and serum. Consequently, the amounts of dibekacin reaching the inner ear are decreased, and ototoxicity is reduced.

Topics: Acetylglucosaminidase; Aminoglycosides; Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Cochlea; Dibekacin; Fosfomycin; Hair Cells, Auditory; Kidney; Kidney Diseases; Labyrinth Diseases; Perilymph; Proteinuria; Rats

The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance, expressed as the excreted to infused aminoglycoside ratio, were concomitantly studied in male rabbits by continuous infusion of gentamicin, netilmicin, dibekacin, and amikacin. Aminoglycoside nephrotoxicity was evaluated by creatinine levels in serum and pathological renal damage after 14 days of a low- or high-dose regimen, comprising either eight, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (4 mg/kg) or amikacin (16 mg/kg); twelve, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (15 mg/kg) or amikacin (60 mg/kg); or injections of saline for the control group. Aminoglycosides exhibited three degrees of tubular reabsorption: gentamicin had the highest, netilmicin had the lowest, and dibekacin and amikacin had intermediate degrees of reabsorption. Nephrotoxicity associated with alteration in renal histology was observed with gentamicin and, to a lesser extent, with dibekacin in the high-dose regiment. No nephrotoxicity was noted with netilmicin or amikacin compared with the control group. Concentrations of the aminoglycosides in renal cortex and serum were not predictive of renal toxicity. Except for amikacin, which appeared to exhibit the lowest intrinsic renal toxicity, nephrotoxicity was correlated with the tubular reabsorption of each aminoglycoside. It was concluded that aminoglycoside renal toxicity can be determined by two major factors: importance of transport into tubular cells and intrinsic intracellular toxicity.

Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Blood Proteins; Dibekacin; Gentamicins; Kidney Diseases; Kidney Tubules; Male; Netilmicin; Protein Binding; Rabbits

Topics: Animals; Anti-Bacterial Agents; Dibekacin; Fosfomycin; Hair Cells, Auditory; Kanamycin; Kidney; Kidney Diseases; Labyrinth Diseases; Rats

Protection by fosfomycin of the nephrotoxicity of dibekacin was studied using Fischer 344 rats and urinary parameters such as volume, osmolality, protein, N-acetyl-beta-D-glucosaminidase, leucine aminopeptidase, lactate dehydrogenase and nucleated cells were determined as markers of nephrotoxicity. The duration of treatment was 11 d. Fosfomycin reduced polyuria, proteinuria, enzymuria and cyturia induced by dibekacin best by the concomitant administration, followed by pre-treatment, but not by post-treatment. Protection was effective in the dose ratio of dibekacin: fosfomycin = 1:2 - 1:32, regardless of administration routes. As judged from urinalysis, protection by fosfomycin (320 mg/kg) was almost complete for the experimental nephrotoxicity induced by 10 mg/kg of dibekacin, and still significant for that by 40 mg/kg. This was supported by the histo-pathological and ultrastructural improvement of proximal tubules and by suppressed blood urea nitrogen and creatinine values. Protective activity of fosfomycin was more potent than that of cephalothin, when compared on the weight basis.

Topics: Animals; Anti-Bacterial Agents; Cephalothin; Chemical Phenomena; Chemistry; Dibekacin; Dose-Response Relationship, Drug; Fosfomycin; Kanamycin; Kidney Diseases; Male; Rats; Rats, Inbred F344; Time Factors

Nephrotoxicity, pharmacokinetics, and therapeutic efficacy of 3',4'-dideoxykanamycin (dibekacin), a semisynthetic aminoglycoside, were evaluated in rats. As with other aminoglycosides, therapy with dibekacin led to an increased urinary cell and malic-dehydrogenase excretion. The lowest dose resulting in an increased urinary cell excretion was 2.5 mg/kg/d. Serum levels of dibekacin after i.m. injection of 5 mg/kg were similar to those of other aminoglycosides. The kidneys accumulated high amounts of dibekacin, and eliminated it with a half-life of about 7 days. After repetitive dosing a distinct tendency to accumulation (highest renal concentration: 330 microgram/g) could be detected. Experimental chemotherapy of the chronic estrogen induced pyelonephritis revealed that dibekacin and sisomicin fed to significant reductions of renal bacterial counts at a dosage of 2 x 5 mg/kg/d for 7 days. A dosage of 2 x 2.5 mg/kg/d diminished the effectiveness of dibekacin distinctly, that of sisomicin only slightly.

Topics: Animals; Dibekacin; Enzyme Activation; Female; Kanamycin; Kidney Diseases; Kinetics; Malate Dehydrogenase; Rats; Sisomicin

Topics: Animals; Anti-Bacterial Agents; Cochlea; Dibekacin; Ear; Electric Stimulation; Hair Cells, Auditory; Infusions, Parenteral; Kanamycin; Kidney Diseases; Rabbits; Tobramycin; Vestibulocochlear Nerve

Topics: Adult; Aged; Dibekacin; Dose-Response Relationship, Drug; Female; Humans; Injections, Intramuscular; Injections, Intravenous; Kanamycin; Kidney Diseases; Male; Middle Aged