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Ten patients with postoperative infections were treated intramuscularly with netilmicin, a new aminoglycoside. Netilmicin was administered either with or without antibiotics. The overall cure rate was 60%. No adverse reaction was appeared in 10 patients during the course of the treatment.
This study investigated the effect of subinhibitory concentrations of netilmicin on the phenolate (enterochelin), hydroxamate (aerobactin) and total siderophores production and on the 81-kDa and 74-kDa receptors expression in Escherichia coli. Netilmicin at 1/40 MIC reduces total siderophores by 40%; the cathecols by 50% and the hydroxamate by 80%. Concomitant with siderophores reduction, the antibiotic induces the upregulation of the 81-kDa protein receptor. Both effects reduce the ability of the bacterium to survive in the host.
The antibacterial effect of tobramycin-netilmicin combination on multiresistant strains of staphylococcus was performed to determine the signification of synergy images on diffusion plates. Meticillin and gentamicin resistant strains of S. epidermidis (2 strains) and S. aureus (1 strain) were examined and showed an index of combined effect < 0.05 demonstrating synergy. These values were obtained with aminoglycoside concentrations < or = 4 mg/l, levels which can be considered as pharmacologically acceptable. This synergic action can be explained by specific inhibition of the resistance enzyme in the strains, possibly in combination with a cooperative effect on the classical targets of aminoglycosides. This type of combination using tobramycin and netilmicin could define a new use of aminoglycosides based on the conception of combining antibiotic enzyme inhibition.
Clindamycin (2.7 g/day) and netilmicin (5.6 mg/kg) were used for 6-10 days in 27 patients with laryngeal and oral cancer versus beta-lactam antibiotics and aminoglycosides received by 56 matched patients to prevent infection of the operative wound. Suppuration was observed in 11.1 and 41.4% of the patients, respectively (p < 0.05), the temperature rose over 38 degrees C in 22.2% and 42.9% of the patients, respectively (p < 0.05). The regimens showed similar toxicity. The findings proved high efficacy of clindamycin combination with netilmicin in infection prophylaxis in patients operated on for upper respiratory and digestive tract cancer.
The kinetics of netilmicin (N-ethyl-sisomicin), an investigational aminoglycoside, have been determined in man following intravenous and intramuscular administration of a dose of 2 mg/kg. After intravenous injection the serum elimination of the antibiotic obeys two-compartment open model kinetics. Distribution and elimination constants are in the range reported for other aminoglycosides, with the exception of the volume of distribution at the steady-state, which appears to be greater than that of sisomicin and of tobramycin. Urinary excretion data suggest that this antibiotic undergoes some degree of tubular reabsorption and appears to be cleared partially by extrarenal processes. After intramuscular administration, the absorption of netilmicin follows first-order kinetics and its physiologic availability is complete.
Comparative functional and histological tests were performed in eight groups of ten quinea pigs each, which were administered 50, 75, 100 and 150 mg of netilmicin respecitvely b.i.d. for 29 days, 15 and 25 mg of gentamicin and 50 and 100 mg of amikacin per kg body weight respecitvely b.i.d. and in one control group of ten animals. The tests showed a low degree of ototoxicity and nephrotoxicity of netilmicin.
A randomized trial of ticarcillin plus gentamicin (group 1), ticarcillin plus amikacin (group 2) and ticarcillin plus netilmicin (group 3) as empiric antibiotic therapy in patients with granulocytopenia and cancer was carried out at the Baltimore Cancer Research Center. The response rate for all infections was 97 per cent in group 1, 91 per cent in group 2 and 95 per cent in group 3. Patients with bacteremias showed improvement in 93 per cent (group 1), 78 per cent (group 2) and 82 per cent (group 3) of cases. All failures were among patients with gram-negative bacteremias. Both antibiotic susceptibility of the bacteremic organism and granulocyte recovery correlated with patient improvement. Nephrotoxicity and ototoxicity were rare and were not significantly different in three groups of patients. Therefore, ticarcillin plus gentamicin, ticarcillin plus amikacin and ticarcillin plus netilmicin appear to be equally efficacious and minimally toxic in this patient population. Excellent over-all results can be expected with these combinations provided the etiologic agent is susceptible.
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.
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.
We report a radioimmunoassay for the new semisynthetic aminoglycoside netilmicin with a sensitivity of 480 pg per tube and a correlation coefficient of 0.94 between this radioimmunoassay and a microbioassay for measurement of netilmicin in serum.
Netilmicin at a dose of 2 mg/kg was infused intravenously into 10 healthy volunteers. A peak serum concentration of 16.56 mug/ml was obtained at the end of the infusion. Thirty-nine percent of the infused dose was excreted in the urine during the first 8 h after infusion. The pharmacokinetic parameters of netilmicin were derived by analyzing the elimination data according to a two-compartment model.
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.
A pharmacokinetic study of netilmicin was conducted in 12 healthy subjects and 24 subjects with chronic renal failure. After intramuscular administrations of 2 and 3 mg of netilmicin per kg in normal subjects, the mean peak serum concentrations were 5.46 and 8.83 mug/ml, respectively. After intravenous infusions of identical doses, the mean maximum serum levels, occurring at the end of the infusion, were 11.79 and 15.75 mug/ml, respectively. The pharmacokinetic data were very similar via the two routes of administration and for the two doses. The elimination half-life was 2.20 h, and 80 to 90% of the injected dose was recovered in urine during the first 24 h. After intramuscular administration of 2 mg/kg in subjects with chronic renal impairment, the elimination half-life increased to 29.48 h, and urinary elimination was inversely related to the degree of impairment. A study was conducted throughout hemodialysis sessions: serum concentrations decreased by 63.3%. The linear relationships between the elimination rate constant and creatinine clearance and the elimination half-life and serum creatinine allowed us to establish dosage schedules according to the degree of renal failure.
Out of 24 patients with suspected moderate to severe infections and treated with the semisynthetic aminoglycoside netilmicin, 11 patients had decreased renal function. Non-bacterial aetiology was present in five cases. There was good netilmicin effect in 10 cases, indeterminate effect in 6 cases (due to simultaneously given other antibiotics) and failure in 3 cases. Pharmacokinetic parameters were studied. Curves are given for serum concentration patterns relative to creatinine clearance, and serum half-lives are calculated in renal dysfunction. In this series of very ill patients including impaired renal function, metilmicin proved to be an efficient antibiotic with low toxicity. Only one transient minor vestibular abnormality in an 80-year-old man with concomitant diuretic medication was registered.
The synergistic activities of netilmicin, gentamicin and amikacin combined with carbenicillin, ticarcillin, azlocillin and mezlocillin were investigated against 32 Serratia marcescens isolates. Synergy could be demonstrated by killing curve technique, isobologram plots as susceptibility data with any of the aminoglycosides and penicillins combinations. No antagonism was shown with any of the combinations. The majority of the isolates were resistant to the aminoglycosides and penicillins. Combination of either ureido-penicillin or carbenicillin with gentamicin or netilmicin did not reduce the MIC values to levels achievable in serum but did reduce the MIC levels of both agents to those achievable in urine. The combination of ureido-penicillins or carbenicillin and ticarcillin with amikacin reduced the inhibitory levels of all isolates to levels achievable in both serum and urine.
In this study, we evaluate the nephrotoxic potential of dibekacin (D) compared to gentamicin (G), tobramycin (T), amikacin (A) and netilmicin (N). The mean features of aminoglycoside nephrotoxicity are: a lysosomal membrane fragilization, a lysosomal phospholipidosis characterized by a decrease activity of sphingomyelinase, an increase lysosomal volume with both an increase of individual size and an increase number of lysosomes, a cell necrosis and renal failure. We have quantified these parameters biochemically and morphometrically. We can classify, considering doses and durations, the aminoglycosides as gentamicin greater than or equal to netilmicin greater than dibekacin = tobramycin greater than amikacin for decreasing nephrotoxic incidence.
Netilmicin sulfate, a new aminoglycoside antibiotic, was administered to ten patients with thermal burns who were suffering from septic complications, usually burn wound sepsis. There were seven survivors. Eighty-three percent of all clinical isolates recovered showed sensitivity to the drug. No renal or auditory side effects were noted in any of the patients.
Netilmicin 1.5 mg/kg body weight was administered intravenously every 8 h for 2 days to 8 patients with normal renal function. Significant elevation of mean and trough plasma concentrations was found at 05.00 h and 09.00 h. This was considered to be due to circadian variation, with possible accumulation during the night. The clinical importance of this phenomenon in relation to the development of aminoglycoside toxicity awaits further investigation.