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PubMed1980

Prospective comparative study of efficacy and toxicity of netilmicin and amikacin.

Eighty patients were treated with either amikacin or netilmicin in a prospective randomized study of serious gram-negative bacillary infections, including 11 due to gentamicin-resistant pathogens. Thirty-six treated with netilmicin and 35 treated with amikacin were evaluable for efficacy or toxicity, or both. The overall groups differed significantly only in age. There were no significant differences in efficacy of the two drugs. There were no statistically significant differences at the 95% level between the netilmicin group and the amikacin group with respect to nephrotoxic reactions (38 versus 28%, respectively) or ototoxic reactions (9 versus 25%, respectively). Further comparative trials of netilmicin and other aminoglycosides appear warranted before it is widely used.

Adult↗
PubMed1980

Pharmacokinetics and bacteriological efficacy of moxalactam (LY127935), netilmicin, and ampicillin in experimental gram-negative enteric bacillary meningitis.

Moxalactam (LY127935) is a 1-oxa-beta-lactam which was active in vitro against the majority of 128 strains of gram-negative enteric bacilli isolated from meningitis in neonates. Pharmacokinetics and bacteriological efficacy of LY127935 were studied in a lapin meningitis model. The average penetration of this investigational oxa-cephalosporin into cerebrospinal fluid of infected rabbits was 23% compared with 25% for netilmicin and 11% for ampicillin. The cerebrospinal fluid concentrations of LY127935 produced median bactericidal titers of 1:64 to 1:128 against five coliform organisms (two Escherichia coli K1 strains, Klebsiella pneumoniae, Salmonella saint-paul, and Citrobacter diversus) used in these experiments compared with median titers of 1:2 to 1:8 for netilmicin and 1:2 to 1:4 for ampicillin. LY127935 was statistically significantly more effective than netilmicin or ampicillin in reducing cerebrospinal fluid bacterial colony counts and in sterilizing cerebrospinal fluid of experimentally infected rabbits. These results suggest that LY127935 has theoretical advantages over netilmicin and ampicillin for therapy of gram-negative bacillary meningitis.

Ampicillin↗
PubMed1984

Prospective randomized double-blind comparison of nephrotoxicity and auditory toxicity of tobramycin and netilmicin.

Netilmicin or tobramycin was administered to 197 patients in a prospective randomized double-blind trial. Of these patients, 140 recipients of nine or more doses of netilmicin or tobramycin could be evaluated for nephrotoxicity. Fifty-five patients were able to cooperate in the administration of serial audiograms. Nephrotoxicity of similar severity developed in 7 of 73 (9.6%) recipients of tobramycin and in 7 of 67 (10.4%) recipients of netilmicin (P greater than 0.05). Mild or slight auditory toxicity developed in 5 of 28 (17.8%) recipients of tobramycin and in 2 of 27 (7.4%) recipients of netilmicin (P greater than 0.05).

Adult↗
PubMed1985

Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities.

Gentamicin, tobramycin, and netilmicin were given to rats in daily doses of either 5 or 20 mg/kg for 30 days to determine the renal accumulation kinetics of the compounds and to correlate steady-state renal parenchymal concentrations with nephrotoxicity. Four rats from each group were sacrificed daily and renal parenchymal tissue concentrations were determined microbiologically. Nephrotoxicity was assessed by changes in creatinine values in serum, renal creatinine clearances, and pathological scores. There was no indication of aminoglycoside-induced nephrotoxicity in any tests performed. The following steady-state levels resulted: 36, 148, and 176 micrograms/g after 5 mg/kg per day and 148, 260, and 510 micrograms/g after 20 mg/kg per day for tobramycin, gentamicin, and netilmicin, respectively. We conclude that aminoglycoside parenchymal accumulation in rats follows this order: tobramycin less than gentamicin less than netilmicin. Therefore, differences in the relative toxicities of gentamicin, tobramycin, and netilmicin do not correlate with the renal parenchymal accumulation of these agents and may be more dependent on intrinsic toxicity to the renal proximal tubule than to the concentration of the aminoglycoside in the kidney.

Animals↗
PubMed1986

Comparative uptake of gentamicin, netilmicin, and amikacin in the guinea pig cochlea and vestibule.

The kinetics of the entry of three aminoglycosides into inner-ear tissues of the guinea pig after acute and chronic administration were compared: gentamicin toxic to the cochlea and the vestibule, amikacin preferentially cochleotoxic, and netilmicin of low ototoxic liability. During constant intravenous infusion, levels of the three drugs in plasma tended to reach a plateau after 1 h, while levels in perilymph did not reach a plateau within 6 h. The drug concentrations in both vestibular and cochlear tissues quickly reached saturation. Amikacin and gentamicin concentrations were similar in vestibular and cochlear tissues, while netilmicin values were somewhat lower. After 1 week of chronic treatment (100 mg of drug per kg of body weight daily subcutaneously), levels of gentamicin and amikacin in tissue were similar to each other and were not significantly different between cochlear and vestibular tissues. Netilmicin concentrations again were somewhat lower in the tissues, but identical to those of the other drugs in the perilymph. After 3 weeks of treatment, all of the drugs were equally distributed in the inner-ear tissues. Release of the drug from the tissues after the 3-week treatment was faster for amikacin (83% decrease after 20 days) than for netilmicin and gentamicin (approximately 50% decrease). There was no correlation, under any of the experimental conditions, between the drug concentrations and their degrees of toxicity. These results demonstrate that selective aminoglycoside ototoxicity cannot be explained by a preferential uptake or accumulation of drugs in the afflicted tissues or in the perilymph.

Amikacin↗
PubMed1987

Influence of cation supplements on activity of netilmicin against Pseudomonas aeruginosa in vitro and in vivo.

In vitro studies were performed with 74 Pseudomonas aeruginosa isolates which were collected during a multicenter trial. The isolates were obtained from 70 patients who had been treated with netilmicin as the only antipseudomonal antibiotic. Clinically, 83% of the patients were cured or improved, and 64% of the Pseudomonas isolates were eliminated by chemotherapy. The 74 clinical isolates and 38 additional isolates with known mechanisms of aminoglycoside resistance were tested in three separate laboratories by disk diffusion methods and by microdilution tests with three broth media (Mueller-Hinton broth with full, half, and no cation supplements). Isolates that responded to netilmicin therapy and those that failed to respond were all susceptible by the disk test, and most were susceptible by microdilution tests with unsupplemented broth. However, over half of the clinical isolates appeared to be resistant when cations were added to the broth medium. Strains capable of producing enzymes that inactivate netilmicin were resistant by all methods tested. Broth dilution and agar dilution results were most comparable when half of the recommended cation supplements was added to Mueller-Hinton broth. Further consideration should be given to reducing the concentration of cations that are added to Mueller-Hinton broth when netilmicin susceptibility tests are being performed. However, additional studies with other aminoglycosides are needed before appropriate testing conditions can be standardized.

Adult↗
PubMed1987

Single-dose accumulation pharmacokinetics of tobramycin and netilmicin in normal volunteers.

The two-compartment tissue accumulation pharmacokinetics of tobramycin and netilmicin were compared in 11 normal volunteers by using a crossover design. After each 1.0-mg/kg (body weight) dose, serum was collected for 96 h, and complete 24-h urine collections were obtained for a total of 30 days. Two months of washout were required before crossover. Concentrations in serum and urine were measured by radioimmunoassay, and concentrations in serum and urinary excretion rates were simultaneously fitted to a two-compartment pharmacokinetic model. Netilmicin exhibited significantly lower total body clearance (48 versus 90 ml/min) and longer terminal elimination half-life (161 versus 96 h) than tobramycin. As a result of these pharmacokinetic differences, the predicted tissue accumulation of netilmicin at steady state was significantly higher than that of tobramycin (P less than 0.05). Relative rates of aminoglycoside nephrotoxicity probably depend on both the differential tissue uptake (accumulation) and the concentration of the aminoglycoside which produces intracellular toxicity. Because the steady-state tissue accumulation of netilmicin is nearly 2.5 times greater than that of tobramycin, its potency in the production of intracellular toxicity needs to be that much less for the two agents to produce the same incidence of clinical nephrotoxicity.

Adult↗
PubMed1988

Effect of cardiopulmonary bypass on vancomycin and netilmicin disposition.

The effect of cardiopulmonary bypass (CPB) on the disposition of vancomycin (15 mg/kg) and of netilmicin (3 mg/kg) was studied in 10 adults. The concentration-time profile of the drug in serum and renal clearance were characterized pre-CPB, during CPB, and post-CPB. Vancomycin and netilmicin exhibited initial decreases in mean concentrations in serum of 4.0 mg/liter (16.8%) and 2.2 mg/liter (29.1%), respectively, upon initiation of CPB. Netilmicin concentrations in serum rebounded to a mean of 0.6 mg/liter (15.4%) within 90 min on CPB and then continuously decreased. Vancomycin concentrations in serum demonstrated a rebound increase of 2.3 mg/liter (23.5%) at the end of CPB when the aorta was unclamped. Mean renal clearance throughout CPB was decreased for vancomycin (58.4 to 43.4 ml/min per m2) and netilmicin (53.4 to 31.5 ml/min per m2). The rebound in vancomycin concentration in serum strongly correlated with the length of time between unclamping the aorta and coming off CPB (r = 0.94), as well as with the increase in temperature upon rewarming (r = 0.92).

Adult↗
PubMed1980

Comparative in vitro activity of netilmicin, amikacin, tobramycin and sisomicin against gentamicin highly-resistant enterobacteriaceae.

Netilmicin was compared with sisomicin, tobramycin and amikacin against 65 recent clinical enterobacterial isolates found to be highly resistant to gentamicin (MIC larger than or equal to 80 microgram/ml). Netilmicin showed a high activity against 20 out of 65 strains tested. Most of the sensitive strains (60%) to netilmicin required a concentration of gentamicin equal or lower than 160 microgram/ml for inhibition. Amikacin proved to be extremely effective in all the organisms tested. Tobramycin was consistently less active than either netilmicin or amikacin and the same was the case with sisomicin. The MIC was determined in both solid and liquid media for 24 strains. Depending upon which aminoglycoside was used, we found that 10-30% of the enterobacteriaceae exhibited a twofold diminution of MIC when tested in broth as compared to agar, while the greater proportion of strains was characterized by a higher MIC tested in broth as compared to agar.

Amikacin↗
PubMed1984

Ceftazidime: in vitro comparison with cephalothin, cefuroxime, and netilmicin. A Norwegian study.

The in vitro activity of ceftazidime has been compared with those of cephalothin, cefuroxime, and netilmicin against a variety of gram-positive and gram-negative bacteria in order to register sensitivity patterns in the western part of Norway. An agar dilution method was used for minimal inhibitory concentration (MIC) determination. Ceftazidime was the most active agent against Enterobacteriaceae; all isolates being inhibited by 2 mg/l or less, whereas netilmicin was slightly less active, especially against Providencia. Cephalothin and cefuroxime were markedly less active than the other two agents against Enterobacteriaceae. Ceftazidime and netilmicin were active against our Pseudomonas aeruginosa isolates (MICs less than or equal to 4 and less than or equal to 8 mg/l, respectively). Only netilmicin had useful activity against Acinetobacter calcoaceticus. Ceftazidime was the least active agent against Staphylococcus aureus; nearly all the isolates had MICs of 4-8 mg/l. Cefuroxime was the most active agent against Bacteroides fragilis, whereas ceftazidime was inactive. Ceftazidime may, in the future, be a useful alternative to the aminoglycosides in the treatment of serious gram-negative infections, particularly when P. aeruginosa might be involved.

Anti-Bacterial Agents↗
PubMed1986

In vitro studies of the synergism of piperacillin and netilmicin against blood culture isolates.

The purpose of this study was to evaluate the in vitro synergism between piperacillin and netilmicin against microorganisms isolated from Danish patients with septicemia and to examine the influence of inactivation of piperacillin among these bacteria on the synergy results. A total of 132 stains was examined: Escherichia coli 20, indole-positive Proteus 17, Klebsiella pneumoniae 18, Enterobacter cloacae 20, Pseudomonas aeruginosa 20, Staphylococcus aureus 20, and coagulase-negative staphylococci 17. Synergy testing was performed by checkerboard titration in microtiter trays. The ability of the strains to inactivate piperacillin was examined by the clover-leaf test. Synergism was found for 52% of the strains and partial synergism for 32%. Antagonism was not found. Of the piperacillin-resistant strains synergism could be demonstrated in 80% compared with 33% of the piperacillin-susceptible strains (p less than 0.001). No significant correlation was seen between the results of the synergy test and the results of the susceptibility test to netilmicin. The frequency of piperacillin inactivation according to the clover-leaf test was significantly higher among the strains with synergism than among all the others (p less than 0.02). The combination of piperacillin and netilmicin gave good results concerning the in vitro synergism. This synergism was probably sometimes caused by netilmicin disturbing the bacterial production of piperacillin-inactivating proteins.

Bacteria↗
PubMed1989

Validity of N-acetyl-beta-D-glucosaminidase (NAG) determination in assessing netilmicin nephrotoxicity in preterm babies.

The supposed nephrotoxicity of netilmicin has been assessed in preterm neonates using the urinary excretion of a lysosomal enzyme as marker: N-acetyl-beta-D-glucosaminidase (NAG). 17 male preterm neonates with birth weight appropriate for gestational age were enrolled in a study where 9 received netilmicin therapy since the first day of life and 8 served as control group. We observed a significant increase in urinary NAG/creatinine ratio during the postnatal days in the netilmicin group babies followed by a regular decrease during the days after the end of therapy. If this increase in lysosomal enzymuria such as NAG could reflect netilmicin nephrotoxicity on the proximal tubular cell, many questions remain unanswered about the exact significance of this finding. In particular, its relation with tubular cell dysfunction remains to be established.

Acetylglucosaminidase↗
PubMed1978

Susceptibility of 327 clinical isolates to netilmicin.

Netilmicin, a semisynthetic derivative of sisomicin, was tested against 327 isolates of Staphylococcus aureus, Pseudomonas aeruginosa and Gram-negative enteric bacilli. Seventy-two per cent of the isolates were inhibited at a concentration of 0.5 microgram netilmicin per ml, and 93% of the isolates were susceptible to 4 microgram per ml or less. The MICs of netilmicin and gentamicin for 24 Providencia and 38 Pseudomonas isolates were compared. The activity of netilmicin closely paralleled that of gentamicin, 46% of the Providencia isolates and 32% of the Pseudomonas isolates not being inhibited by 4 microgram per ml of either drug.

Enterobacteriaceae↗
PubMed1985

A comparative study of gentamicin and netilmicin in the treatment of gram-negative infections.

Netilmicin is active in vitro against a wide variety of gram-negative bacteria, including certain gentamicin-resistant isolates, and Staphylococcus aureus. This study presents the results of a prospective, randomized, double-blinded protocol designed to determine the relative efficacy and toxicity of netilmicin and gentamicin in the therapy of gram-negative infections. The demographic make-up of both treatment groups was similar. Cure rates were 96.7 percent with netilmicin and 94.4 percent with gentamicin. Possible transient nephrotoxicity developed in nine patients receiving netilmicin and in eight patients receiving gentamicin.

Adult↗
PubMed1992

Penetration of netilmicin in the lower respiratory tract after once-daily dosing.

A major criticism of the use of aminoglycosides for the treatment of pneumonia is the poor penetration in infected airways. Once-daily dosing of aminoglycosides results in higher peak plasma concentrations without increasing toxic reactions and with optimization of pharmacodynamic properties. To predict intrapulmonary antimicrobial activity after once-daily dosing of aminoglycosides, it is necessary to determine the respective bronchial and alveolar disposition. We prospectively conducted a pharmacokinetic study of netilmicin following the first intravenous administration of a once-daily dosing schedule in 20 ventilated patients with pneumonia. A bronchoscopic sampling of bronchial secretions and a subsegmental bronchoalveolar lavage (BAL) were performed 60, 90, 120, and 180 min (five patients at each time point) on the first treatment day after intravenous administration over 30 min of 450 mg of netilmicin. The netilmicin concentrations in the alveolar lining fluid (ALF) were calculated using urea as an endogenous marker of dilution. In bronchial secretions, a peak concentration of 2.00 (SEM: 0.26) mg/L or 6 percent of the 30-min plasma concentration was reached at 120 min. In ALF, much higher levels were found. At 120 min, a peak ALF concentration of 14.7 (SEM: 2.22) mg/L or 41 percent of the 30-min plasma concentration was reached. Spearman's rank correlation testing failed to show a correlation between bronchial and ALF concentrations. Higher plasma concentrations of netilmicin after once-daily dosing give rise to ALF concentrations exceeding the minimum inhibitory concentration of susceptible respiratory pathogens involved in nosocomial pneumonia, while bronchial concentrations remain low. Aminoglycoside concentrations in bronchial secretions cannot be used to predict alveolar concentrations. Low diffusibility can no longer be considered as a disadvantage of aminoglycosides for treating pneumonias.

Adult↗
PubMedDate not supplied

Pharmacokinetics of netilmicin in renal insufficiency and haemodialysis.

The pharmacokinetics of intravenously administered netilmicin, an investigational aminoglycoside antibiotic, were studied in 38 patients with creatinine clearance ranging from 150 to Oml/min/1.73m2 in order to determine the influence of kidney function status on the disposition of the antibiotic. The serum disappearance of netilmicin followed first order kinetics and the elimination rate constant decreased proportionally with decreasing renal function. Half-lives averaged 2.2 hours in normal individuals (creatinine clearance greater than 80ml/min/1.73m2) and reached 42 +/- 10 hours (mean +/- SD) in virtually anephric patients. The elimination rate constant lowered proportionally with decreasing renal function. Several linear relationships between pharmacokinetic parameters and renal function indicators were defined. A clinically useful correlation indicates that the half-life may be approximated as 3 times the serum creatinine concentration and may be used for adjustment of dosage of netilmicin in the treatment of patients with impaired renal function. During haemodialysis, netilmicin extraction from the blood reaches 75 +/- 14% (mean +-/ 95% confidence interval) of that of creatinine and 88 +/- 19% of that of blood urea nitrogen.

Adolescent↗
PubMed1984

Sisomicin, netilmicin and dibekacin. A review of their antibacterial activity and therapeutic use.

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 bacteria. Pharmacokinetically, sisomicin, netilmicin and dibekacin all behave like gentamicin. All 3 drugs are excreted in the urine unchanged and have beta-phase elimination half-lives of around 2 to

Aging↗
PubMed1992

Comparison of ciprofloxacin with netilmicin for the treatment of acute pyelonephritis.

A prospective, randomised trial was undertaken to compare the efficacy of ciprofloxacin and netilmicin for the treatment of acute pyelonephritis. Forty-three patients were enrolled and 34 (29 women) completed the protocol. Fifteen of 17 patients treated with ciprofloxacin and 15 of 17 treated with netilmicin were cured. All patients were treated for five days. One patient relapsed after ciprofloxacin and another had a reinfection, while two relapsed after netilmicin. Five of six patients with a urinary tract abnormality were cured. Side effects were generally mild and rapidly reversible. Patients treated with ciprofloxacin spent a mean of 3.7 days in hospital compared with 5.3 days for those treated with netilmicin. The difference in duration of hospital stay was statistically significant (p less than 0.01). Both drugs proved highly effective and safe for the treatment of severe acute pyelonephritis.

Acute Disease↗