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Antimicrobial Agents and Chemotherapy Feb 1984The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance,...
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
PubMed: 6712201
DOI: 10.1128/AAC.25.2.168 -
Antimicrobial Agents and Chemotherapy Dec 1980The nephrotoxicity of dibekacin was compared with those of gentamicin and amikacin in a rat model. The doses used were 3, 10, and 30 times the suggested human... (Comparative Study)
Comparative Study
The nephrotoxicity of dibekacin was compared with those of gentamicin and amikacin in a rat model. The doses used were 3, 10, and 30 times the suggested human therapeutic dose on a weight basis. Indices of glomerular and tubular function failed to clearly differentiate the drugs. Dibekacin and gentamicin produced equally severe injury to the renal tissue. Slightly less damage occurred with amikacin.
Topics: Amikacin; Animals; Dibekacin; Gentamicins; Kanamycin; Kidney; Male; Rats
PubMed: 7235685
DOI: 10.1128/AAC.18.6.983 -
Clinical Pharmacology : Advances and... 2014Arbekacin sulfate (ABK), an aminoglycoside antibiotic, was discovered in 1972 and was derived from dibekacin to stabilize many common aminoglycoside modifying enzymes.... (Review)
Review
Arbekacin sulfate (ABK), an aminoglycoside antibiotic, was discovered in 1972 and was derived from dibekacin to stabilize many common aminoglycoside modifying enzymes. ABK shows broad antimicrobial activities against not only Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) but also Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ABK has been approved as an injectable formulation in Japan since 1990, under the trade name Habekacin, for the treatment of patients with pneumonia and sepsis caused by MRSA. The drug has been used in more than 250,000 patients, and its clinical benefit and safety have been proven over two decades. ABK currently shows promise for the application for the treatment of multidrug-resistant Gram-negative bacterial infections such as multidrug-resistant strains of P. aeruginosa and Acinetobacter baumannii because of its synergistic effect in combination with beta-lactams.
PubMed: 25298740
DOI: 10.2147/CPAA.S44377 -
Antimicrobial Agents and Chemotherapy Sep 2015Corynebacterium striatum BM4687 was resistant to gentamicin and tobramycin but susceptible to kanamycin A and amikacin, a phenotype distinct among Gram-positive...
Corynebacterium striatum BM4687 was resistant to gentamicin and tobramycin but susceptible to kanamycin A and amikacin, a phenotype distinct among Gram-positive bacteria. Analysis of the entire genome of this strain did not detect any genes for known aminoglycoside resistance enzymes. Yet, annotation of the coding sequences identified 12 putative acetyltransferases or GCN5-related N-acetyltransferases. A total of 11 of these coding sequences were also present in the genomes of other Corynebacterium spp. The 12th coding sequence had 55 to 60% amino acid identity with acetyltransferases in Actinomycetales. The gene was cloned in Escherichia coli, where it conferred resistance to aminoglycosides by acetylation. The protein was purified to homogeneity, and its steady-state kinetic parameters were determined for dibekacin and kanamycin B. The product of the turnover of dibekacin was purified, and its structure was elucidated by high-field nuclear magnetic resonance (NMR), indicating transfer of the acetyl group to the amine at the C-3 position. Due to the unique profile of the reaction, it was designated aminoglycoside 3-N-acetyltransferase type XI.
Topics: Acetyltransferases; Anti-Bacterial Agents; Corynebacterium; Dibekacin; Kanamycin; Microbial Sensitivity Tests; Molecular Structure
PubMed: 26149994
DOI: 10.1128/AAC.01203-15 -
Antimicrobial Agents and Chemotherapy 2015Arbekacin is a broad-spectrum aminoglycoside licensed for systemic use in Japan and under clinical development as an inhalation solution in the United States. We...
Arbekacin is a broad-spectrum aminoglycoside licensed for systemic use in Japan and under clinical development as an inhalation solution in the United States. We evaluated the occurrence of organisms isolated from pneumonias in U.S. hospitalized patients (PHP), including ventilator-associated pneumonia (VAP), and the in vitro activity of arbekacin. Organism frequency was evaluated from a collection of 2,203 bacterial isolates (339 from VAP) consecutively collected from 25 medical centers in 2012 through the SENTRY Antimicrobial Surveillance Program. Arbekacin activity was tested against 904 isolates from PHP collected in 2012 from 62 U.S. medical centers and 303 multidrug-resistant (MDR) organisms collected worldwide in 2009 and 2010 from various infection types. Susceptibility to arbekacin and comparator agents was evaluated by the reference broth microdilution method. The four most common organisms from PHP were Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella spp., and Enterobacter spp. The highest arbekacin MIC among S. aureus isolates from PHP (43% methicillin-resistant S. aureus [MRSA]) was 4 μg/ml. Among P. aeruginosa isolates from PHP, only one had an arbekacin MIC of >16 μg/ml (MIC50 and MIC90, 1 and 4 μg/ml), and susceptibility rates for gentamicin, tobramycin, and amikacin were 88.0, 90.0, and 98.0%, respectively. Arbekacin (MIC50, 2 μg/ml) and tobramycin (MIC50, 4 μg/ml) were the most potent aminoglycosides tested against Acinetobacter baumannii. Against Enterobacteriaceae from PHP, arbekacin and gentamicin (MIC50 and MIC90, 0.25 to 1 and 1 to 8 μg/ml for both compounds) were generally more potent than tobramycin (MIC50 and MIC90, 0.25 to 2 and 1 to 32 μg/ml) and amikacin (MIC50 and MIC90, 1 to 2 and 2 to 32 μg/ml). Arbekacin also demonstrated potent in vitro activity against a worldwide collection of well-characterized MDR Gram-negative and MRSA strains.
Topics: Amikacin; Anti-Bacterial Agents; Dibekacin; Enterobacter; Humans; Klebsiella; Microbial Sensitivity Tests; Pneumonia; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Staphylococcus aureus; Tobramycin
PubMed: 25801559
DOI: 10.1128/AAC.04839-14 -
Antimicrobial Agents and Chemotherapy Mar 1978Against sulbenicillin- and gentamicin-susceptible strains of Pseudomonas aeruginosa, SCE-129 was about 10 times more active than sulbenicillin and had a similar activity... (Comparative Study)
Comparative Study
Against sulbenicillin- and gentamicin-susceptible strains of Pseudomonas aeruginosa, SCE-129 was about 10 times more active than sulbenicillin and had a similar activity to gentamicin and dibekacin. Sulbenicillin-resistant strains of P. aeruginosa were moderately resistant to SCE-129, whether these strains were gentamicin-resistant or not. Gentamicin-resistant strains of P. aeruginosa were resistant to dibekacin but not to SCE-129. Against P. maltophilia, the minimum inhibitory concentration of SCE-129 resembled those of sulbenicillin, gentamicin, and dibekacin. Most strains of P. cepacia were moderately resistant to SCE-129 and sulbenicillin and highly resistant to gentamicin and dibekacin.
Topics: Cefsulodin; Dibekacin; Gentamicins; Kanamycin; Microbial Sensitivity Tests; Penicillin G; Penicillin Resistance; Pseudomonas aeruginosa; Sulbenicillin
PubMed: 122528
DOI: 10.1128/AAC.13.3.536 -
Journal of Microbiology, Immunology,... Dec 2021Arbekacin is a broad-spectrum aminoglycoside with activity against some Gram-positive and Gram-negative bacteria.
BACKGROUND
Arbekacin is a broad-spectrum aminoglycoside with activity against some Gram-positive and Gram-negative bacteria.
METHODS
Arbekacin minimum inhibitory concentration (MIC) values were determined for 296 drug-resistant Gram-negative bacilli, and compared to previously determined plazomicin, amikacin, gentamicin, and tobramycin MIC values.
RESULTS
The MIC values required to inhibit 50% and 90% of isolates (MIC and MIC, respectively) were 16 and >128 μg/ml, respectively.
CONCLUSIONS
Arbekacin showed similar MIC values to amikacin and gentamicin, a lower MIC value than tobramycin, and a higher MIC value than plazomicin.
Topics: Anti-Bacterial Agents; Dibekacin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests
PubMed: 32962921
DOI: 10.1016/j.jmii.2020.08.018 -
Antimicrobial Agents and Chemotherapy Apr 1985The tubular disposition of five aminoglycosides was studied in humans to establish a possible relationship between tubular reabsorption and the nephrotoxicity that has... (Comparative Study)
Comparative Study
The tubular disposition of five aminoglycosides was studied in humans to establish a possible relationship between tubular reabsorption and the nephrotoxicity that has been described in the literature. Thirty-three healthy male volunteers received a continuous intravenous infusion of isotonic saline with inulin, followed 1 h later by inulin plus gentamicin, dibekacin, tobramycin, netilmicin, or amikacin (1 mg/kg per h) or amikacin (4 mg/kg per h) over a period of 2 h. Brain-stem-evoked response audiometry was performed both before and at the end of each infusion. The latency of wave V remained constant whichever antibiotic was considered. The glomerular filtration rate did not vary significantly during the infusion of each drug. The percent fractional excretion was 79 +/- 6, 81 +/- 22, 85 +/- 5, and 99 +/- 9 for gentamicin, dibekacin, tobramycin, and netilmicin, respectively, and 83 +/- 4 and 124 +/- 13 for amikacin at concentrations of 1 and 4 mg/kg per h, respectively. Net balance and renal clearance were similar for the five aminoglycosides when administered at a rate of 1 mg/kg per h. With gentamicin only, fractional excretion was correlated with the urinary flow rate. We can conclude that (i) gentamicin, generally considered the most nephrotoxic agent, had the highest degree of net reabsorption; (ii) netilmicin exhibited a net zero tubular balance; (iii) amikacin had different patterns of tubular disposition according to the dose, i.e., reabsorption at 1 mg/kg per h and secretion at 4 mg/kg per h, raising the hypothesis of a saturable process of reabsorption; and (iv) these differences in tubular reabsorption could account at least in part for the known different nephrotoxic potentials of these five aminoglycosides in humans.
Topics: Adult; Amikacin; Aminoglycosides; Anti-Bacterial Agents; Blood Proteins; Dibekacin; Electrolytes; Gentamicins; Glomerular Filtration Rate; Humans; Kidney Tubules; L-Lactate Dehydrogenase; Male; Netilmicin; Protein Binding; Tobramycin
PubMed: 4004192
DOI: 10.1128/AAC.27.4.520 -
Nucleic Acids Research Jul 2021How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action...
How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action of a clinically used, new-generation, semisynthetic aminoglycoside Arbekacin (ABK), which is designed to avoid enzyme-mediated deactivation common to other aminoglycosides. Our results portray complete picture of ABK inhibition of bacterial translation with precise quantitative characterizations. We find that ABK inhibits different steps of translation in nanomolar to micromolar concentrations by imparting pleotropic effects. ABK binding stalls elongating ribosomes to a state, which is unfavorable for EF-G binding. This prolongs individual translocation step from ∼50 ms to at least 2 s; the mean time of translocation increases inversely with EF-G concentration. ABK also inhibits translation termination by obstructing RF1/RF2 binding to the ribosome. Furthermore, ABK decreases accuracy of mRNA decoding (UUC vs. CUC) by ∼80 000 fold, causing aberrant protein production. Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors.
Topics: Anti-Bacterial Agents; Dibekacin; Kinetics; Peptide Elongation Factor G; Peptide Termination Factors; Peptides; Protein Biosynthesis; Protein Synthesis Inhibitors; RNA, Messenger; RNA, Transfer, Amino Acyl; Ribosomes
PubMed: 34125898
DOI: 10.1093/nar/gkab495 -
Antimicrobial Agents and Chemotherapy Jan 2013Aminoglycoside 2″-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci. We describe a novel...
Aminoglycoside 2″-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci. We describe a novel aminoglycoside 2″-phosphotransferase from the Gram-negative pathogen Campylobacter jejuni, which shares 78% amino acid sequence identity with the APH(2″)-Ia domain of the bifunctional aminoglycoside-modifying enzyme aminoglycoside (6') acetyltransferase-Ie/aminoglycoside 2″-phosphotransferase-Ia or AAC(6')-Ie/APH(2″)-Ia from Gram-positive cocci, which we called APH(2″)-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin, but not to any of the 4,5-disubstituted antibiotics tested. Steady-state kinetic studies demonstrated that GTP, and not ATP, is the preferred cosubstrate for APH(2″)-If. The enzyme phosphorylates the majority of 4,6-disubstituted aminoglycosides with high catalytic efficiencies (k(cat)/K(m) = 10(5) to 10(7) M(-1) s(-1)), while the catalytic efficiencies against the 4,6-disubstituted antibiotics amikacin and isepamicin are 1 to 2 orders of magnitude lower, due mainly to the low apparent affinities of these substrates for the enzyme. Both 4,5-disubstituted antibiotics and the atypical aminoglycoside neamine are not substrates of APH(2″)-If, but are inhibitors. The antibiotic susceptibility and substrate profiles of APH(2″)-If are very similar to those of the APH(2″)-Ia phosphotransferase domain of the bifunctional AAC(6')-Ie/APH(2″)-Ia enzyme.
Topics: Amino Acid Sequence; Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; Campylobacter jejuni; Cloning, Molecular; Enzyme Assays; Escherichia coli; Kinetics; Microbial Sensitivity Tests; Molecular Sequence Data; Phosphotransferases (Alcohol Group Acceptor); Recombinant Proteins; Sequence Homology, Amino Acid; Structure-Activity Relationship; Substrate Specificity
PubMed: 23129050
DOI: 10.1128/AAC.02049-12