netilmicin and isepamicin

Isepamicin is a new semisynthetic aminoglycoside derived from gentamicin B and it is effective against Gram negative bacteria. Antibiotic resistance is an emerging problem and new options need for the treatment of infections caused by Gram negative bacteria.. In this study we aimed to investigate the in vitro efficiency in carbapenem susceptible and nonsusceptible Enterobacterales and Pseudomonas aeruginosa.. A total of 214 isolates of Gram-negative bacteria (Enterobacterales n = 129 and P. aeruginosa n = 85). Identification of the bacteria was tested in Vitek MS (Biomeriux, France). Susceptibility of isepamicin, amikacin, gentamicin, tobramycin and netilmicin was determined by Kirby Bauer disc diffusion method. The breakpoints for susceptibility to isepamicin, amikacin, gentamicin, streptomycin, tobramycin and netilmicin were evaluated according to the Comité de l'Antibiogramme dela Société Française de Microbiologie (CA-SFM) and EUCAST, respectively. Aminoglycoside modifying enzyme (AME) genes were investigated by multiplex PCR method.. Isepamicin susceptibility was determined as 92.3% for Enterobacterales and 67% for P. aeruginosa and 94.4% for carbapenem resistant Enterobacterales. The most common AME gene was aac (6')-Ib in both Enterobacterales (76%) and P. aeruginosa (14.1%). Seven of the isepamicin intermediate or resistant isolates were positive aac (6')-Ib in Enterobacterales and P. aeruginosa.. In this study, isepamicin showed good efficiency against both susceptible and carbapenem nonsusceptible Enterobacterales. But amikacin was prior to isepamicin P. aeruginosa isolates. Isepamicin could be a therapeutic option for the infections caused by Enterobacterales.

Topics: Amikacin; Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Gentamicins; Gram-Negative Bacteria; Microbial Sensitivity Tests; Netilmicin; Pseudomonas aeruginosa; Tobramycin

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

Kidney cortex apoptosis was studied with female Wistar rats treated for 10 days with gentamicin and netilmicin at daily doses of 10 or 20 mg/kg of body weight and amikacin or isepamicin at daily doses of 40 mg/kg. Apoptosis was detected and quantitated using cytological (methyl green-pyronine) and immunohistochemical (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining, in parallel with a measurement of drug-induced phospholipidosis (cortical phospholipids and phospholipiduria), cortical proliferative response ((3)H incorporation in DNA and histoautoradiography after in vivo pulse-labeling with [(3)H]thymidine), and kidney dysfunction (blood urea nitrogen and creatinine). Gentamicin induced in proximal tubules a marked apoptotic reaction which (i) was detectable after 4 days of treatment but was most conspicuous after 10 days, (ii) was dose dependent, (iii) occurred in the absence of necrosis, and (iv) was nonlinearly correlated with the proliferative response (tubular and peritubular cells). Comparative studies revealed a parallelism among the extents of phospholipidosis, apoptosis, and proliferative response for three aminoglycosides (gentamicin >> amikacin congruent with isepamicin). By contrast, netilmicin induced a marked phospholipidosis but a moderate apoptosis and proliferative response. We conclude that rats treated with gentamicin develop an apoptotic process as part of the various cortical alterations induced by this antibiotic at low doses. Netilmicin, and still more amikacin and isepamicin, appears safer in this respect. Whereas a relation between aminoglycoside-induced tubular apoptosis and cortical proliferative response seems to be established, no simple correlation with phospholipidosis can be drawn.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Apoptosis; Blood Urea Nitrogen; Cell Division; Creatinine; Female; Gentamicins; In Situ Nick-End Labeling; Kidney Cortex; Kidney Tubules, Proximal; Netilmicin; Phospholipids; Rats; Rats, Wistar

The in vitro interactions of piperacillin (PIPC) and imipenem/cilastatin (IPM/CS) combined with 5 kinds of aminoglycosides (gentamicin, tobramycin, amikacin (AMK), isepamicin and netilmicin) were investigated against IPM/CS-susceptible (MIC of IPM/CS was < or = 3.13 micrograms/ml) and IPM/CS-resistant (MIC of IPM/CS was > or = 12.5 micrograms/ml) Pseudomonas aeruginosa. The following results were obtained. 1. In the checkerboard dilution studies, the combinations of PIPC with aminoglycosides showed synergistic effect for more than 50% of the each 54 strains of IPM/CS-susceptible and IPM/CS-resistant P. aeruginosa. The synergistic/additive effects of PIPC with aminoglycosides were demonstrated for all tested strains. 2. In the checkerboard dilution studies, the combinations of IPM/CS with aminoglycosides showed no antagonism against any strains. The synergistic effects of IPM/CS with aminoglycosides were demonstrated for 0 to 14.8%, and these values were smaller than the combinations of PIPC with aminoglycosides. 3. Corresponding to the results of checkerboard dilution studies, the combination of PIPC with AMK was more effective than the combination of IPM/CS with AMK on the killing curve for IPM-resistant P. aeruginosa. In conclusion, PIPC showed the synergistic effects in combinations with aminoglycosides against IPM/CS-resistant P. aeruginosa. These results suggest that the combination therapies of PIPC with aminoglycosides are useful for the clinical treatment of serious infections due to P. aeruginosa.

Topics: Amikacin; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Gentamicins; Imipenem; Netilmicin; Penicillins; Piperacillin; Pseudomonas aeruginosa; 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

This paper introduces a new method to quantify post antibiotic effect. This method was applied to the study of the effect of three aminoglycosides antibiotics on seven strains of Klebsiella pneumoniae. The antimicrobial was removed by filtration, washing with peptone broth and neutralization by heparin. Growth curves were monitored by automated measurement of optical density with Urimat-ATB (bioMérieux). The inoculum fluctuation bias was eliminated with the help of a mathematical analysis of results. Absence of carry-over was controlled for each bacteria-antibiotic combination. A significant post antibiotic effect was observed with the three antibiotics after 2 hours exposure to a concentration equivalent to 2 x MIC. There was no significant difference between the 3 aminoglycosides tested.

Topics: Amikacin; Dose-Response Relationship, Drug; Filtration; Gentamicins; In Vitro Techniques; Klebsiella pneumoniae; Netilmicin

The object of this work is to study in neutropenic mice the in vivo postantibiotic effect (PAE) of isepamicin, a new aminoglycoside, gentamicin and netilmicin on Staphylococcus aureus and Escherichia coli and in vivo killing kinetics using two different schedules (A and B) of isepamicin and gentamicin administration against S. aureus: (A) at time zero and every hour up to the 7th or 9th hour and (B) two doses only, at time zero and at the end of the PAE. The PAE of the three aminoglycosides was long (3-5 h), showing that of isepamicin to be the largest, especially on S. aureus. Both A and B treatment models show the same effectiveness for the two tested drugs. These results support the idea that the major significance of the PAE is in its application to dosing regimens.

Topics: Animals; Bacterial Infections; Disease Models, Animal; Escherichia coli; Female; Gentamicins; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Netilmicin; Neutropenia; Staphylococcus aureus; Thigh; Time Factors

The bactericidal efficacy of amikacin, isepamicin and netilmicin was studied against Pseudomonas aeruginosa and Serratia marcescens over a treatment period of 30 h using two one-compartment in-vitro models with differently designed culture compartments. High bacterial inocula were exposed to fluctuating drug concentrations, simulating human serum concentrations (t1/2 = 2 h) during clinical treatment. The same daily dose was administered as 1 h infusions given every 8 h or every 24 h, resulting in peak concentrations of 8 and 24 mg/l for netilmicin, and 24 and 72 mg/l for amikacin and isepamicin, respectively. Once-daily dosing was more bactericidal during initial treatment in the in-vitro models (P less than 0.01) and at least as effective as thrice-daily dosing in preventing bacterial regrowth, despite a prolonged period of subinhibitory drug concentration before administration of the second dose. Lower ratios of peak concentration to MIC were needed to achieve bactericidal activity (greater than 99.9% reduction of cfu) after 24 h treatment against S. marcescens compared with P. aeruginosa (P less than 0.01). All nine regimens providing peaks of at least four times the MIC were bactericidal against S. marcescens after 24 h exposure. In contrast, a bactericidal effect against P. aeruginosa occurred only during two of six experiments with peaks of four to nine times the MIC. Similar results were obtained in both in-vitro models of infection. These data suggest insufficient intrinsic activity of the aminoglycosides studied for single drug treatment of P. aeruginosa in the absence of host-defence mechanisms.

Topics: Amikacin; Anti-Bacterial Agents; Drug Administration Schedule; Fluorescence Polarization Immunoassay; Gentamicins; Netilmicin; Pseudomonas aeruginosa; Serratia marcescens

Isepamicin is a new aminoglycoside drug derived from gentamicin, which is more stable than other aminoglycosides to inactivating enzymes and experimentally is less nephrotoxic than gentamicin or amikacin. In this work a comparative study was carried out on the antibacterial activity (MIC and lethality curves) and the post-antibiotic effect (PAE) of different concentrations of isepamicin, netilmicin and gentamicin on pure cultures of S. aureus and E. coli. The MIC and curves of lethality were determined by conventional methods. The PAE was determined after exposure of the bacterial culture to the antimicrobial one for 1 h at 37 degrees C in a bath with stirring. Elimination of the drug was made by the dilution method. Isepamicin was found to have a MIC four times greater than netilmicin and gentamicin. Its activity over time was similar to that exhibited by other aminoglycosides. At concentrations higher than the MIC, a bactericidal effect was found with the three antibiotics, although isepamicin produced it at lower concentrations. The post-antibiotic effect induced by isepamicin, the same as that of netilmicin and gentamicin, was extensive and depended on the concentration and the strain used. Isepamicin shows antibiotic activity over time and a PAE similar to the other aminoglycosides tested but, unlike them, it has a faster activity, less toxicity and better resistance to inactivating enzymes. For this reason it makes a considerable contribution to antibacterial therapies in severe conditions, including immunodepressed patients who require long-term treatment.

Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Escherichia coli; Gentamicins; Microbial Sensitivity Tests; Netilmicin; Staphylococcus aureus; Time Factors

Sch 21420 is a new aminoglycoside synthesized from gentamicin B. Susceptibility tests with Sch 21420, amikacin, gentamicin, netilmicin, sisomicin, and tobramycin were performed on a variety of bacterial species including 44 with known mechanisms of resistance to aminoglycosides. Sch 21420 and amikacin had similar effects on all except Haemophilus influenzae and Neisseria species, which were more susceptible to amikacin. Except with some strains of Serratia marcescens, the drugs used were bactericidal. Sch 21420 and amikacin were more stable than the other four aminoglycosides in the presence of the inactivating enzymes produced by some strains. Strains which were very resistant to Sch 21420 and emikacin either were permeability mutants or produced AAC (6')-I inactivating enzyme. The effect of cations on the susceptibilities of these strains to Sch 21420 and amikacin was seen mostly with Pseudomonas aeruginosa and to Sch 21420 with Acinetobacter. Cations did not affect the susceptibilities of other Pseudomonas species, Enterobacteriaceae, Staphylococcus aureus, or Streptococcus faecalis to Sch 21420 or amikacin.

Topics: Amikacin; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Gentamicins; Microbial Sensitivity Tests; Netilmicin; Sisomicin; Tobramycin