Netilmicin and Gentamicin: Comparative Pharmacology in Humans

Abstract

Thirteen male subjects received 1 mg of either gentamicin or netilmicin per kg, first intramuscularly and then intravenously. After the intramuscular dose, concentrations of gentamicin in the serum were more variable than those of netilmicin. After the intravenous dose, the distribution phase of netilmicin was twice as rapid as gentamicin. The average half-times of the elimination phase were similar, but there was marked variability among the subjects receiving gentamicin. Serum clearance of netilmicin was more rapid than that of gentamicin and could not be attributed to renal elimination. The data indicate that, after intramuscular administration, netilmicin may produce more predictable blood levels than gentamicin and suggest that the body distribution of netilmicin may differ from that of gentamicin.Netilmicin is a new semisynthetic aminoglycoside (32). Netilmicin is N-ethyl sisomicin, with the substituent attached to 2-deoxystreptamine. Another aminoglycoside in clinical use with a substitution on 2-deoxystreptamine is amikacin, a hydroxyaminobutyric acid derivative of kanamycin A. In vitro testing in our laboratory and others (8-10, 20, 23, 27, 31) indicates that the activity of netilmicin against Enterobacteriaceae, Pseudomonas, and Staphylococcus, in general, approximates that of gentamicin. Serum concentrations in animals and humans are comparable to those of gentamicin (27).Netilmicin appears to have two advantages. First, like amikacin, it is effective against some organisms resistant to gentamicin, including indole-negative proteus and strains that produce aminoglycoside-adenylating enzymes (16,23). Second, animal studies indicate that netilmicin has significantly less oto-and nephrotoxicity than does gentamicin (19, 27; R. E. Brummett and K. E. Fox, Fed. Proc. 35:621, 1976). If reduced toxicity is also found in humans, it will strongly influence the relative usefulness of this agent.Netilmicin is now in the early stages of therapeutic evaluation, and expanded information concerning its pharmacology will be of benefit to physician investigators and their patients. For this reason, we have investigated the disposition of netilmicin in humans. MATERIALS AND METHODSThirteen adult male graduate students were used in our study. The subjects underwent a complete medical history and psychological evaluation; physical examination; determination of base line blood chemistries (chloride, carbon dioxide, potassium, sodium, blood urea nitrogen and glucose, total protein, serum albumin, calcium, inorganic phosphorus, cholesterol, uric acid, creatinine, total bilirubin, alkaline phosphatase, creatine phosphokinase, lactic dehydrogenase, serum glutamic oxaloacetic transferase); complete blood count; urinalysis, including microscopic urinalysis and determination of creatinine clearance. All subjects were judged free from any recognizable illness by the above parameters. The experimental design of the project and the drugs used were explained, and informed consent was obtained from each individual. The study was appr...

Comparison of netilmicin and gentamicin pharmacokinetics in humans

“…Total body clearance calculated from our data was comparable to that reported in two studies (3,5). Although our rate was slower than that reported in three other studies (6,7,10), this is presumed to be due to the method of calculation and route of administration as noted for volume of distribution. Renal clearance in our study is somewhat lower than that previously reported (6, 10), but we observed a large intersubject variation, as did another investigator (5).…”

“…2) constant for netilnicin, calculated by a two-compartment model (5), have been reported. After intravenous administration of the drugs, the pharmacokinetics of gentamicin (1, 7) and netilmicin (3,5,7,11) have been described by a twocompartment model.…”

“…The pharmacokinetics of gentamicin in humans have been documented (1,6,7,10), and more recently those of netilmicin have been reported J3, 5,7,11). Most of these pharmacokinetic studies were based on serum concentrations obtained during the first 8 h after intravenous infusion of the drugs, using a one-or twocompartment open model.…”

Netilmicin: Clinical Efficacy, Tolerance, and Toxicity

“…Theoretical advantages of netilmicin are threefold: (i) an increased in vitro bactericidal activity over gentamicin against many strains of Enterobacteriaceae (1-3, 5, 6, 10, 11, 13, 15-17, 20, 22, 23); (ii) the inhibition of gentamicin-resistant strains when the resistance is associated with one of the gentamicininactivating acetylases (aminoglycoside acetylase-3i, -ii, or -iii) or an adenylase (aminoglycoside nucleotidylase-2"), which have been common modes of resistance among Enterobacter species, Escherichia coli, and Pseudomonas aeruginosa (4,16,18); (iii) relative freedom from ototoxicity and reduced nephrotoxicity in experimental animals (12,20). Also, there is a suggestion that the serum levels may be more predictable than those of gentamicin (19). These favorable features of netilmicin suggest the possibility of more effective therapy of serious gram-negative bacterial infections with diminished drug toxicity and formed the basis for the investigations reported here.…”

Prospective comparative study of efficacy and toxicity of netilmicin and amikacin

“…The pharmacology of netilmicin is similar to that of gentamicin (9,14,25), but the alpha phase of netilmicin is more rapid than that of gentamicin (27), and higher doses (2 mg/kg per 8 h) have been recommended to achieve equivalent serum levels (9). Initial serum levels were predictable in only a small majority of our patients, although levels were less variable than gentamicin in another study (26).…”