In Vitro Activity of Netilmicin Compared with Gentamicin, Tobramycin, Amikacin, and Kanamycin

The in vitro activity of netilmicin was compared with that of gentamicin, tobramycin, amikacin, and kanamycin against 636 strains of bacteria recently isolated from clinical sources. Gentamicin was the most active antibiotic, but netilmicin and tobramycin closely paralleled it. Netilmicin was generally four-to eightfold less active than gentamicin against Serratia and group A streptococci, and was twofold less active against Pseudomonas aeruginosa. When effects of inoculum size and concentration of divalent cations in the media were evaluated, netilmicin was shown to be similar to gentamicin in vitro. Minimum inhibitory concentrations for P. aeruginosa were increased as much as 18-fold when the Mg²⁺ and Ca²⁺ concentrations were increased to physiological levels in Mueller-Hinton broth.     

In Vitro Activity of Netilmicin, Gentamicin, and Amikacin

The in vitro activity of netilmicin (Sch 20569), a new semisynthetic derivative of gentamicin, was compared with that of gentamicin and amikacin. One hundred and ninety-two clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus were tested using both agar and broth dilution techniques. Netilmicin was comparable to gentamicin, with the following exceptions: (i) for Serratia marcescens and P. aeruginosa, gentamicin was more active than netilmicin; (ii) all strains of Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, and Citrobacter freundii, which were resistant to gentamicin, were susceptible to netilmicin; (iii) some strains of S. marcescens, indole-positive Proteus, and Providencia, which were resistant to gentamicin, were susceptible to netilmicin. Netilmicin was more active than amikacin for all Enterobacteriaceae and S. aureus and equal to amikacin in activity against gentamicin-susceptible strains of P. aeruginosa. All strains of P. aeruginosa, resistant to gentamicin, were also resistant to netilmicin but were susceptible to amikacin. Minimal inhibitory concentrations (MICs) obtained with broth and agar showed no significant differences except for P. mirabilis, where broth MICs were twofold greater than agar MICs, and for P. aeruginosa, where agar MICs were twofold higher than broth MICs. The minimal bactericidal concentration (MBC) was either identical to or within one twofold dilution of the MIC for the strains tested. A 100-fold increase in inoculum size produced less increase in MIC and MBC with netilmicin than with gentamicin or amikacin.     

In Vitro Comparison of Gentamicin, Tobramycin, Sisomicin, and Netilmicin

The antimicrobial activity of gentamicin, tobramycin, sisomicin, and netilmicin (Sch 20569) was compared against 150 strains of organisms. Netilmicin was shown to be the least effective against Pseudomonas strains but to have slightly better activity against Staphylococcus aureus and Escherichia coli than the other agents. The effect of calcium and magnesium in enhancing the differences in activity of these aminoglycosides against Pseudomonas strains was also demonstrated.     

Antimicrobial Activity In Vitro of Netilmicin and Comparison with Sisomicin, Gentamicin, and Tobramycin

The antimicrobial activity of netilmicin, a new semisynthetic aminoglycosidic aminocyclitol, was determined against 123 recent gram-negative clinical isolates susceptible to gentamicin and 60 isolates resistant to either sisomicin, gentamicin, or tobramycin. The minimal inhibitory concentrations and minimal bactericidal concentrations of netilmicin, sisomicin, gentamicin, and tobramycin against Pseudomonas, Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, and indole-positive Proteus were, in general, quite similar. Gentamicin was the most active against Serratia. A total of 54, 67, and 88% of gentamicin-resistant Pseudomonas, Serratia, and Klebsiella, respectively, were susceptible to netilmicin. Strains of indole-positive Proteus, Acinetobacter, Providencia, and E. coli resistant to gentamicin were likely to be resistant also to netilmicin.     

Comparative In Vitro Activity of Sch 20656, Netilmicin, Gentamicin, and Tobramycin

Sch 20656 and netilmicin (Sch 20569), two new semisynthetic aminoglycosides, were as active as gentamicin and tobramycin against Enterobacteriaceae. Against Pseudomonas aeruginosa, Sch 20656 was the least active, whereas netilmicin was active against many highly gentamicin-resistant isolates.     

Comparative Activity of Netilmicin, Gentamicin, Amikacin, and Tobramycin Against Pseudomonas aeruginosa and Enterobacteriaceae

Netilmicin (Sch 20569), a semisynthetic aminoglycoside antibiotic, was compared with gentamicin, tobramycin, and amikacin against 242 clinical isolates of Pseudomonas and Enterobacteriaceae. The minimum inhibitory concentration (MIC) was determined in both solid and liquid media. Netilmicin exhibited typical aminoglycoside properties, such as little effect of inoculum size on MIC, relatively small gap between MIC and minimum bactericidal concentration, and potentiation of anti-Pseudomonas activity in the presence of carbenicillin. Netilmicin provided no advantage in antimicrobial activity over gentamicin for either Pseudomonas or Enterobacteriaceae. Nearly complete cross-resistance to netilmicin was encountered with isolates resistant to gentamicin in either solid or liquid media. Netilmicin was less active than gentamicin against isolates of Pseudomonas and Providencia. Major discrepancies between MIC values determined in agar as opposed to those determined in broth were encountered for most isolates of Pseudomonas but also, depending upon antibiotic tested, for between 15 and 40% of isolates of Enterobacteriaceae. This new aminoglycoside agent will be useful clinically only if it is shown to be significantly less toxic than presently available analogues.     

In Vitro Activity of Gentamicin, Amikacin, and Netilmicin Alone and in Combination with Carbenicillin Against Serratia marcescens

The inhibitory and bactericidal effects of gentamicin, amikacin, netilmicin (Sch 20569), and carbenicillin were tested against 55 clinical isolates of Serratia marcescens that had been subtyped into 26 strains by biotyping and serotyping. Three major patterns of resistance to gentamicin, netilmicin, and carbenicillin were recognized among these isolates. (i) Most of the 27 isolates that were susceptible to gentamicin (minimal bactericidal concentration [MBC] ≤6.25 μg/ml) were susceptible to carbenicillin (MBC ≤125 μg/ml) and resistant to netilmicin (MBC ≥12.5 μg/ml). (ii) Most of the 11 isolates with moderate resistance to gentamicin (MBC of 12.5 to 25 μg/ml) were also susceptible to carbenicillin and resistant to netilmicin. (iii) The 17 isolates with high-level resistance to gentamicin (MBC ≥ 50 μg/ml) were all highly resistant to carbenicillin (MBC ≥8,000 μg/ml) but susceptible to netilmicin (MBC ≤6.25 μg/ml). The susceptibility to amikacin was unpredictable among these groups of isolates but, overall, 80% of the isolates were killed by 25 μg of amikacin/ml, which is within the range of peak serum concentrations used therapeutically. Clinically attainable subinhibitory concentrations of carbenicillin enhanced the activity of the three aminoglycosides against all isolates with MBCs of carbenicillin ≤2,000 μg/ml. The 17 isolates with high-level resistance to carbenicillin and gentamicin, as well as the four isolates with high-level resistance to carbenicillin but not to gentamicin, were not susceptible to such enhancement of aminoglycoside activity by carbenicillin.     

In Vitro Activity of Tobramycin and Gentamicin

The in vitro antimicrobial activity of tobramycin and gentamicin was compared against 362 bacterial isolates. The minimal inhibitory concentration (MIC) of tobramycin was fourfold less than the MIC of gentamicin against most of 119 Pseudomonas organisms. Gentamicin and tobramycin had similar in vitro activity against Enterobacteriaceae and Staphylococcus aureus. Proteus rettgeri were commonly resistant to both tobramycin and gentamicin. The 10-mug tobramycin disc separated resistant (MIC >/=5 mug/ml) and susceptible (MIC <5 mug/ml) organisms in 359 of 362 tested. In disc diffusion testing, the tobramycin and gentamicin zone diameters were found to vary significantly with concentrations of magnesium ions in the media employed. The MIC of tobramycin varied with the size of the inoculum, and tobramycin was most effective at a neutral pH.     

Activity of Netilmicin Compared with Those of Gentamicin and Tobramycin Against Enterobacteria and Pseudomonas aeruginosa

The inhibitory activity of netilmicin against 500 isolates of gram-negative bacteria was compared with those of gentamicin and tobramycin. Netilmicin was considerably less active than tobramycin and slightly less inhibitory than gentamicin for Pseudomonas aeruginosa but was at least as active against Escherichia coli and Klebsiella pneumoniae as were the other two antibiotics. A few Klebsiella and Serratia isolates resistant to gentamicin and tobramycin were inhibited by netilmicin. All three antibiotics were strongly bactericidal for E. coli, K. pneumoniae and P. aeruginosa but had less lethal activity against the otherwise susceptible Serratia isolates tested. Some necessary precautions in reading minimal inhibitory concentrations on agar media are stressed, and some possible advantages of a 4-h bactericidal test, using a constant antibiotic concentration, are defined.     

Effect of Time and Concentration Upon Interaction Between Gentamicin, Tobramycin, Netilmicin, or Amikacin and Carbenicillin or Ticarcillin

An aminoglycoside antibiotic and carbenicillin or ticarcillin are widely used in the treatment of patients with gram-negative bacillus infections. This study evaluated the effect of time upon in vitro interaction between mixtures of four aminoglycosides at two concentrations with carbenicillin or ticarcillin at four concentrations. By linear regression analysis, the inactivation of each aminoglycoside was shown to be directly proportional to the concentration of carbenicillin (P < 0.001). Inactivation was significantly (P < 0.01) greater for gentamicin and tobramycin than for amikacin or netilmicin at all carbenicillin concentrations. At carbenicillin concentrations of 300 and 600 mug/ml, significantly (P < 0.005) less inactivation of amikacin occurred when compared to netilmicin. Ticarcillin produced a significant (P < 0.025) inactivation of gentamicin and tobramycin, with inactivation being directly proportional to ticarcillin concentration. No inactivation of amikacin or netilmicin activity occurred unless the ticarcillin concentration was 600 mug/ml. No significant change in aminoglycoside activity occurred when stored with ticarcillin or carbenicillin at concentrations ranging from 100 to 600 mug/ml at -70 degrees C for 56 days. When an aminoglycoside and carbenicillin or ticarcillin are indicated in patients with renal failure, this study supports the use of ticarcillin with either amikacin or netilmicin.     

In Vitro Activity of Sch 21420, Derivative of Gentamicin B, Compared to That of Amikacin

The minimal inhibitory concentration of Sch-21420 closely paralleled amikacin for 125 strains of aerobic gram-negative bacilli and Staphylococcus aureus primarily selected for testing because of resistance to other aminoglycoside antibiotics. Fifteen of 26 strains requiring 20 μg or more of amikacin per ml for inhibition were inhibited by two- to fourfold less Sch 21420. The majority of organisms resistant to both agents owed their resistance to mechanisms other than the carriage of aminoglycoside-modifying enzymes. Most strains carrying aminoglycoside 6′-acetyltransferase, capable of modifying amikacin, were susceptible to 10 μg or less of Sch 21420 per ml.     

In Vitro Study of Netilmicin Compared with Other Aminoglycosides

Netilmicin (Sch 20569) is an ethyl derivative of gentamicin C(1a) that is active against most Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus isolates. Among 342 clinical isolates tested, all staphylococci; 92% of Escherichia coli, 93% of Klebsiella pneumoniae, and 92% of Enterobacter were inhibited by 0.8 mug or less of netilmicin per ml, but only 78% of P. aeruginosa were inhibited by 3.1 mug or less per ml. Most clinical isolates of enterococci, Serratia marcescens, and Providencia were not inhibited by 3.1 mug of netilmicin per ml. Like other aminoglycosides, the netilmicin in vitro activity was markedly influenced by the growth medium used, with activity decreased by sodium, calcium, and magnesium. Netilmicin was more active at alkaline pH. Addition of magnesium to Pseudomonas or Serratia pretreated with netilmicin produced inhibition of killing. Netilmicin was more active than gentamicin, sisomicin, tobramycin, or amikacin against E. coli and K. pneumoniae. Netilmicin inhibited growth of all gentamicin-resistant isolates of Klebsiella and Citrobacter tested, but only 73% of E. coli; Pseudomonas and Providencia were resistant to netilmicin. Most Serratia (95%) and indole-positive Proteus (83%) isolates were resistant to netilmicin but were inhibited by amikacin.     

Sisomicin: Evaluation In Vitro and Comparison with Gentamicin and Tobramycin

Sisomicin is a new antibiotic produced by Micromonospora inyoensis. The in vitro activities of sisomicin, gentamicin, and tobramycin, three similar aminoglycosides, were determined against 228 clinical isolates representing 10 genera of common pathogens. No difference was noted in the activities of these antimicrobial agents when assayed by a standard broth dilution technique against Klebsiella, Enterobacter, Escherichia, Salmonella, Citrobacter, enterococci, or Staphylococcus aureus. Sisomicin was significantly more active than tobramycin against Serratia and indole-positive Proteus strains. Sisomicin was significantly more active than gentamicin against indole-negative Proteus strains and slightly more active against indole-positive Proteus strains. Tobramycin was more active than sisomicin or gentamicin against Pseudomonas and indole-negative Proteus strains. Gram-negative bacilli resistant to one of the three antimicrobial agents were not necessarily resistant to either of the other two. Activity of sisomicin was independent of the susceptibility or resistance of these isolates to nine other antimicrobial agents as assayed by the Bauer-Kirby technique. The presence of 50% human serum did not antagonize the in vitro activity of sisomicin against gram-negative isolates. Because sisomicin showed certain advantages over gentamicin or tobramycin in vitro, further investigation of this new antimicrobial agent is warranted.     

Tobramycin: In Vitro Activity and Comparison with Kanamycin and Gentamicin

The in vitro activity of the aminoglycoside antibiotic tobramycin was demonstrated by broth dilution and single-disc methods on 50 isolates each of Staphylococcus aureus, Klebsiella or Enterobacter, indole-positive and -negative Proteus, Escherichia coli, and Pseudomonas aeruginosa. All organisms were inhibited by 6.25 mug or less of the drug/ml. Pseudomonas strains resistant to kanamycin or gentamicin or both were susceptible to tobramycin. Those strains which were inhibited by 6.25 mug of tobramycin/ml by the broth dilution method had zone diameters of 16 mm or more by the single-disc method. Of 313 organisms tested by the disc method, 3 strains were found to be resistant to tobramycin, 73 were resistant to kanamycin, and 18 were resistant to gentamicin. Tobramycin was found to have satisfactory in vitro activity against many clinically important organisms, including strains resistant to gentamicin and kanamycin.     

In Vitro Studies of Tobramycin

The in vitro activity of tobramycin was studied against 457 clinical isolates of gram-negative bacilli and 151 clinical isolates of gram-positive cocci. The vast majority of the gram-negative bacilli was inhibited by tobramycin at a concentration of 1.56 μg or less per ml. Only a few isolates of Staphylococcus aureus and no isolates of Streptococcus pyogenes or Diplococcus pneumoniae were susceptible to this drug. Tobramycin was generally more active than gentamicin sulfate against gram-negative bacilli, although organisms resistant to gentamicin sulfate were also resistant to tobramycin. The major difference between the two drugs was the greater activity of tobramycin against Pseudomonas aeruginosa.     

Comparative Activity of Tobramycin, Amikacin, and Gentamicin Alone and with Carbenicillin Against Pseudomonas aeruginosa

The effect of gentamicin against 130 clinical isolates of Pseudomonas aeruginosa was compared with that of two investigational aminoglycoside antibiotics, tobramycin and amikacin. Minimal inhibitory concentration data indicated that, on a weight basis, tobramycin was two to four times as active as gentamicin against most isolates. However, 14 of 18 organisms highly resistant to gentamicin (>/=80 mug/ml) were also highly resistant to tobramycin. Amikacin was the least active aminoglycoside on a weight basis, but none of the isolates were highly resistant to this antibiotic. When therapeutically achievable concentrations were used, adding carbenicillin to gentamicin or to tobramycin enhanced inhibitory activity against those isolates susceptible (相似文献   

Frequency of Resistance to Kanamycin, Tobramycin, Netilmicin, and Amikacin in Gentamicin-Resistant Gram-Negative Bacteria

In vitro evaluation of 66 epidemiologically distinct, gentamicin-resistant, gram-negative isolates from four hospitals revealed that 92% were kanamycin resistant, 44% were netilmicin resistant, 41% were tobramycin resistant, and 6% were amikacin resistant. Combined resistance to gentamicin, tobramycin, and netilmicin occurred in 30% of the strains. Although the resistance percentage to amikacin was the lowest of the three newer agents, two strains were resistant to all of the aminoglycosides tested.     

In Vitro Studies of Tobramycin, an Aminoglycoside Antibiotic

Tobramycin is an aminoglycoside antibiotic which has excellent antibacterial activity against Pseudomonas, Staphylococcus aureus, and many members of the Enterobacteriaceae. Most strains of Serratia, Providence, Streptococcus, and Diplococcus pneumoniae were resistant to concentrations of tobramycin which could be achieved in man. Tobramycin was effective against certain Pseudomonas strains resistant to gentamicin. The growth medium used to determine the inhibitory level of tobramycin had a significant effect upon the minimal inhibitory concentration. Calcium and magnesium ions inhibited the bactericidal effect of tobramycin. Tobramycin and carbenicillin acted in a synergistic manner. Ethylenediaminetetraacetic acid did not act in a synergistic manner with tobramycin. Broth-dilution susceptibility tests and disc-diffusion tests in agar (10-μg discs) showed excellent correlation except with Proteus strains.     

In Vitro Adsorption of Gentamicin and Netilmicin by Polyacrylonitrile and Polyamide Hemofiltration Filters

Adsorption of gentamicin and netilmicin by new polyacrylonitrile and polyamide hemofiltration filters was studied over 4 h, using a single-compartment in vitro continuous venovenous hemofiltration model. After the first dose (16.6 mg of gentamicin, 19.3 mg of netilmicin), 14.9 mg of gentamicin and 19.2 mg of netilmicin were adsorbed to polyacrylonitrile filters in vitro. Adsorption by polyacrylonitrile filters was rapid and irreversible and could be increased by repeated dosing. Adsorption by polyamide filters was substantially less.Previous in vitro data have demonstrated rapid adsorption of significant amounts of amikacin to polyacrylonitrile hemofilters (5). Adsorption of tobramycin and gentamicin may also occur (1-4); however, it is unclear whether adsorption to hemofilters is a property of aminoglycosides as a class. In view of this uncertainty, we carried out an in vitro study to determine the extent and time course of adsorption of gentamicin and netilmicin to polyacrylonitrile (PAN) and polyamide hemofilters.The study used a previously described methodology involving a single-compartment in vitro model of continuous hemofiltration (5). Only changes to the methodology are given here. The blood-crystalloid mixture was made up of a unit of expired whole blood and heparinized (5,000 U heparin/liter) lactated Ringer''s solution to a total volume of exactly 1,000 ml. Of this, 500 ml was placed in a glass reservoir where it was agitated, heated, and allowed to equilibrate for at least 10 min and until the temperature reached 36°C. A nominal dose of 14 mg gentamicin or 12 mg netilmicin was then infused into the mixing chamber over 10 min to obtain a circulating concentration comparable to the in vivo peak concentration (Table ​(Table1).1). The blood-crystalloid mixture was then pumped through a continuous venous-venous hemofiltration (CVVH) circuit. Samples of the blood-crystalloid mixture were taken from the mixing chamber immediately before the start of the drug infusion (0 min) for measurement of hemoglobin and then at 10 min (immediately after drug infusion, before starting the pump), 30, 60, and 90 min for measurement of drug concentration. The actual dose administered (the amount of aminoglycoside in commercial preparations is variable) and the amount of drug circulating at any given time point were calculated from the measured concentration at that time and the circulating volume (5). Adsorption was calculated as the difference between dose and circulating amount. At 90 min, the remaining 500 ml of the blood-crystalloid mixture was added to the mixing chamber. Another sample was taken after another hour. A second dose of drug (nominal 23 mg gentamicin or 20 mg netilmicin) was then added, and blood samples were taken 30, 60, and 90 min afterwards (Table ​(Table1).1). The second dose was also calculated to produce a clinically relevant concentration based on the assumption that the majority of the previous dose was adsorbed.

TABLE 1.

Actual doses and circulating concentrations in subgroups^a

Pharmacokinetic Studies of Tobramycin and Gentamicin

Broth dilution susceptibility tests of 100 isolates of Pseudomonas aeruginosa and 101 isolates of Staphylococcus aureus against tobramycin (formerly nebramycin factor 6) and gentamicin showed that tobramycin was more effective against P. aeruginosa and less effective against S. aureus. The minimal inhibitory concentration of tobramycin against the Pseudomonas sp. isolates that required 5 mug of gentamicin per ml for inhibition ranged from 0.63 to 0.31 mug/ml. Peak concentrations in the blood of 10 healthy adults after intramuscular injection of 80 and 40 mg of tobramycin averaged 3.7 +/- 0.62 and 2.4 +/- 0.27 mug/ml, and declined to 0.56 +/- 0.05 and 0.26 +/- 0.02 mug/ml, respectively, after 6 h. The urine recovery averaged 60%. The half-life was 1.6 h. During continuous intravenous infusion of tobramycin and gentamicin (infusion rate 6.6 mg per h), blood levels at steady state were 0.94 +/- 0.10 and 1.04 +/- 0.06 mug/ml, respectively. For both antibiotics, the calculated distribution volume ranged from 15 to 17 liters. The renal clearance to tobramycin averaged 76% and that of gentamicin averaged 85% of the total clearance, indicating that the drugs are primarily eliminated by the kidneys. The present results suggest that tobramycin may be more successful in the treatment of Pseudomonas infections than gentamicin at the same dosage (80 mg intramuscularly three to four times daily).