dibekacin and isepamicin

Directed evolution by random PCR mutagenesis of the gene for the aminoglycoside 2''-IIa phosphotransferase generated R92H/D268N and N196D/D268N mutant enzymes, resulting in elevated levels of resistance to amikacin and isepamicin but not to other aminoglycoside antibiotics. Increases in the activities of the mutant phosphotransferases for isepamicin are the result of decreases in K(m) values, while improved catalytic efficiency for amikacin is the result of both a decrease in K(m) values and an increase in turnover of the antibiotic. Enzymes with R92H, D268N, and D268N single amino acid substitutions did not result in elevated MICs for aminoglycosides.

Topics: Aged; Amikacin; Amino Acid Substitution; Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; Directed Molecular Evolution; DNA Primers; DNA, Bacterial; Drug Resistance, Bacterial; Escherichia coli; Gentamicins; Humans; Kinetics; Models, Molecular; Molecular Sequence Data; Mutagenesis; Mutation; Phosphotransferases (Alcohol Group Acceptor); Protein Structure, Tertiary; Recombinant Proteins; Sequence Homology, Amino Acid

We examined antibacterial activities and PK/PD parameters of six kinds of aminoglycosides against seven bacterial species of clinical isolates in 2001. Aminoglycoseides examined were gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), netilmicin (NTL), and isepamicin (ISP), and bacterial isolates used were each 50 strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Proteus spp., Serratia marcescens and Pseudomonas aeruginosa. All aminoglycosides showed good activities with low MICs against 6 species of Enterobacteriacea except S. marcescens. Eight strains (3.2%) among them were resistant to one or more aminoglycosides. Resistance to multiple aminoglycosides were detected in 16 strains (32%) of S. marcescens, among which 13 strains were resistant to AMK but susceptible to ISP. Three (6%) strains of P. aeruginosa were resistant to multiple drugs, one of which was resistant to all six aminoglycosides, and others were moderately susceptible to AMK and ISP, and susceptible to GM, AMK and ISP. Using a ratio of peak serum concentration to MIC90 (Cmax/MIC90) or a ratio of area under the curve to MIC90 (AUC/MIC90) as a pharmacokinetic and pharmacodynamic (PK/PD) parameter, we estimated the efficacy of the drug. An excellent effect of ISP, which was injected intramuscularly or intravenously at a dose of 400 mg, was expected for strains of Enterobacteriacea except S. marcescens. The Cmax/MIC90 ratios for S. marcescens were comparably higher in GM and ISP and that for P. aeruginosa were rather high in TOB when compared to other aminoglycosides. Another PK/PD parameter, AUC/MIC90 ratio, was high enough in NTL and ISP for Enterobacteriacea, suggesting good efficacy of these drugs. The (AUC/MIC90) ratios for S. marcescens were comparably high in GM and ISP, and that for P. aeruginosa were high in TOB, DKB, and ISP.

Topics: Amikacin; Anti-Bacterial Agents; Dibekacin; Drug Resistance, Microbial; Gentamicins; Gram-Negative Bacteria; Humans; Netilmicin; Tobramycin

Aminoglycoside antibiotics are known to produce a depression of neuromuscular function which may cause prolonged paralysis of respiratory muscles. However, differences in the effects of aminoglycoside antibiotics on diaphragm and limb muscles have not been investigated. We determined the neuromuscular blocking effects of the aminoglycoside antibiotics arbekacin sulfate, astromicin sulfate, isepamicin sulfate and netilmicin sulfate on the diaphragm, tibialis anterior and soleus muscles in anesthetized rabbit nerve-muscle preparations. Neuromuscular block was assessed by mechanical response with single twitch stimulation. Cumulative drug dose-response curves were obtained for three different muscles in 24 rabbits. The mean ED(50) and ED(95) of the antibiotics in diaphragm, tibialis anterior and soleus muscles were calculated. The neuromuscular blocking effects of all the aminoglycosides on ED(50) and ED(95) values were in the order of soleus > tibialis anterior > diaphragm, and soleus > diaphragm > tibialis anterior, respectively. The ED(50) ratios for the tibialis anterior and soleus muscles were approximately 1.5 and 2.7 times greater than that for the diaphragm.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Diaphragm; Dibekacin; Dose-Response Relationship, Drug; Gentamicins; In Vitro Techniques; Male; Muscle Contraction; Muscle, Skeletal; Netilmicin; Neuromuscular Junction; Rabbits

Clinical isolates collected from clinical facilities across Japan in 1998 were tested against five aminoglycosides and three beta-lactams. The resistance of 50 strains each of methicillin sensitive Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter sp., Serratia sp., Pseudomonas aeruginosa and Proteus sp. (P. mirabilis 25 strains and P. vulgaris 25 strains) to the aminoglycosides isepamicin (ISP), amikacin (AMK), gentamicin, tobramycin and dibekacin, and to the beta-lactams imipenem, ceftazidime and piperacillin (all three known to be effective against P. aeruginosa) were investigated using a micro liquid dilution method with the following results: 1. ISP was effective against all strains except for 14% of MRSA, 2% of Proteus sp., and 4% of P. aeruginosa. 2. Six strains of MRSA were resistant to all eight drugs; however, in these cases ISP exhibited a relatively low minimum inhibitory concentration (MIC) compared to the other compounds. 3. Four strains of MRSA were resistant to all drugs except ISP. MRSA was the only isolate to demonstrate a resistance to seven or more drugs. 4. Twenty-one strains of MRSA and 1 strain of P. aeruginosa were resistant to six drugs; however, all of these were susceptible to both ISP and AMK. 5. Against all strains tested, ISP generally exhibited a lower MIC compared to AMK. These results suggest that, even ten years after its entering the market, ISP is still an aminoglycoside having a high anti-bacterial activity against a wide range of clinical isolates.

Topics: Amikacin; Anti-Bacterial Agents; Bacteria; Ceftazidime; Dibekacin; Drug Resistance, Microbial; Gentamicins; Humans; Imipenem; Piperacillin; Tobramycin

The neuromuscular blocking properties of aminoglycoside group of antibiotics arbekacin sulfate (ABK), astromicin sulfate (ASTM), isepamicin sulfate (ISP), netilmicin sulfate (NTL) and d-tubocurarine were studied in 30 rabbits anesthetized with pentobarbital. The left gastrocnemius tendon was cut and secured to a force-displacement transducer. The left tibial nerve was directly stimulated by electrodes with supramaximal square waves of 0.1 msec duration at a frequency of 0.1 Hz. The resultant force of twitch tension was recorded. The intravenous administration of ABK 60-100 mg/kg, ASTM 160-320 mg/kg, ISP 320-480 mg/kg or NTL 20-40 mg/kg resulted in dose-dependent decreases in twitch tensions. The ED50 values of 4 antibiotics were NTL = 30.2 mg/kg (4.2 x 10(-2) mmol/kg) < ABK = 78.3 mg/kg (1.4 x 10(-1) mmol/kg) < ASTM = 215.2 mg/kg (3.6 x 10(-1) mmol/kg) < ISP = 359.7 mg/kg (6.3 x 10(-1) mmol/kg), respectively. These antibiotics-induced blockades were antagonized by calcium or by neostigmine. Although the relative neuromuscular blocking potencies of 4 antibiotics equipotent to d-tubocurarine on the basis of therapeutic doses in man were below 0.6 mg, it may be concluded that the potential clinical hazard lies in the sequence of administration of the aminoglycoside group of antibiotics.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Dibekacin; Dose-Response Relationship, Drug; Gentamicins; Netilmicin; Neuromuscular Blocking Agents; Rabbits; Tubocurarine