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PubMed1985

[Comparative effects of netilmicin and 4 other aminoglycosides on 1028 bacterial strains isolated in a hospital milieu].

The activity of netilmicin and four other aminoglycosides was studied by a diffusion method against 1 028 bacterial strains isolated in hospital. Nearly all the strains of Gram-negative bacilli were susceptible to amikacin; with netilmicin, tobramycin, gentamicin and dibekacin the percentages of susceptible strains were smaller, without any statistically significant differences between them. Amikacin and netilmicin were the most effective compounds against staphylococci. Netilmicin seemed to be the most effective compound, in vitro, against streptococci. The MIC of gentamicin and netilmicin of 224 strains showed the superior activity of netilmicin against K. pneumoniae, Proteus, P. aeruginosa and S. aureus.

Aminoglycosides↗
PubMed1985

Prospective, randomized comparison of the efficacy and safety of netilmicin-clindamycin and tobramycin-clindamycin in the treatment of serious systemic infections.

Fifty-three patients with documented or suspected mixed flora infections were randomly assigned to receive either netilmicin or tobramycin in combination with clindamycin. Data from 36 patients with 43 documented infections yielding 102 clinical isolates were evaluated for efficacy. In the 18 patients receiving netilmicin-clindamycin, 90% of the infections responded favorably and 96% of the pathogens were eliminated. In the 18 patients receiving tobramycin-clindamycin, 81% of the infections resolved and 88.5% of the pathogens were eliminated. Forty-nine patients were included in the safety analysis. The incidence of nephrotoxicity was similar in both groups (netilmicin, 20%; tobramycin, 21%). Auditory toxicity occurred less frequently in the netilmicin-clindamycin group (4.5%) than in the tobramycin-clindamycin group (21.7%). These results demonstrate that both the netilmicin-clindamycin and the tobramycin-clindamycin combinations are comparable in efficacy and in potential for causing nephrotoxicity. In this study, however, netilmicin was considerably less ototoxic than tobramycin.

Adolescent↗
PubMed1984

Renal transport of netilmicin in the rat.

We examined the renal transport of [3H]netilmicin in the rat using clearance, microinjection and free flow micropuncture techniques. Netilmicin was constantly infused at rates ranging from 1.92 to 192 nmol/min and resulted in plasma concentrations of 0.4 to 40 micrograms/ml and fractional excretion rates of 94.5 +/- 3.3 to 107.9 +/- 1.7%. Although the mean fractional excretion rate of netilmicin was equal to or exceeded the filtered load, the drug continued to accumulate in renal cortex albeit in a curvilinear manner and at the highest rate of infusion attained a peak level of 447 +/- 26 nmol/g of renal cortex. The renal cortical uptake of netilmicin was inhibited in a dose-dependent fashion by the simultaneous infusion of gentamicin. In response to microinjection of [3H]netilmicin (390 +/- 56 pg) 82.0 +/- 1.8% of the dose was recovered in the urine after early proximal tubular injections, 90.5 +/- 1.1% of the dose was recovered after late proximal tubule injections and 98.5 +/- 1.3% of the dose was recovered after early distal tubule injections. In free flow micropuncture experiments the fractional delivery of netilmicin to the early proximal tubule measured 1.16 +/- 0.03, a value significantly greater than 1.0 (P less than .005). No significant change in fractional delivery was evident to the late proximal tubule (1.13 +/- 0.04), whereas it decreased to 1.02 +/- 0.04 (P less than .01) at the early distal tubule.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

In vitro comparison of netilmicin, a semisynthetic derivative of sisomicin, and four other aminoglycoside antibiotics.

One hundred isolates of Pseudomonas and Enterobacteriaceae, of which 85 were chosen because of their resistance to gentamicin or amikacin, were tested for susceptibility to netilmicin (SCH 20569), a new semisynthetic derivative of sisomicin, and to four other aminoglycosides. Tests were performed in Mueller-Hinton agar and, with 43 of these isolates, also in Mueller-Hinton broth. Most isolates of Escherichia coli, Klebsiella, Enterobacter, Citrobacter, and Serratia that were gentamicin resistant proved to be susceptible to netilmicin and amikacin. Tests of representative isolates of this group showed that they owed their resistance to the production of aminoglycoside-adenylylating enzymes. Four isolates of Serratia, detected by their resistance to amikacin, were also highly resistant to netilmicin but were susceptible to gentamicin. These isolates produced aminoglycoside-acetylating enzymes. Gentamicin-resistant Proteus and Providencia were, in general, highly resistant to netilmicin but were susceptible to amikacin. These isolates also produced aminoglycoside-acetylating enzymes. Most gentamicin-resistant strains of Pseudomonas were resistant to netilmicin, either by enzymatic aminoglycoside modification or by other undefined mechanisms. Thus, like amikacin, netilmicin extends the aminoglycoside susceptibility pattern of Enterobacteriaceae to include gentamicin-resistant isolates that produce aminoglycoside-adenylylating enzymes. It is ineffective against strains, some of them susceptible to amikacin, gentamicin, or tobramycin, that produce aminoglycoside-acetylating enzymes.

Amikacin↗
PubMed1976

Biological activity of netilmicin, a broad-spectrum semisynthetic aminoglycoside antibiotic.

Netilmicin (Sch 20569) is a new broad-spectrum semisynthetic aminoglycoside derived from sisomicin. Netilmicin was compared to gentamicin, tobramycin, and amikacin in a variety of in vitro test systems as well as in mouse protection tests. Netilmicin was found to be similar in activity to gentamicin against aminoglycoside-susceptible strains in both in vitro and in vivo tests. Netilmicin was also active against many aminoglycoside-resistant strains of gram-negative bacteria, particularly those known to possess adenylating enzymes (ANT 2') or those with a similar resistance pattern. Netilmicin was found to be markedly less toxic than gentamicin in chronic studies in cats, although gentamicin appeared less toxic in acute toxicity tests in mice. The concentrations of netilmicin and gentamicin in serum were compared in dogs after intramuscular dosing, and the pharmacokinetics including peak concentrations in serum were found to be similar.

Amikacin↗
PubMed1976

Comparative nephrotoxicities of netilmicin and gentamicin in rats.

The relative nephrotoxicities of netilmicin (Sch 20569) and gentamicin were compared in rats at doses of 30, 60, 90, and 120 mg/kg per day for 15 days. Both drugs caused proteinuria and a decrease in urine osmolality; however, netilmicin produced significantly less changes at all doses than gentamicin. Whereas gentamicin resulted in a decline in creatinine clearance at all doses, netilmicin failed to cause a decline in creatinine clearance. Renal-cortical concentrations of antibiotic at sacrifice were similar in animals receiving either drug. Light-microscopic changes were less severe with netilmicin than gentamicin. Cytosegresomes with myeloid bodies were identified electron microscopically in the kidneys of animals receiving either netilmicin or gentamicin at all doses. Electron-microscopic manifestations were similar. The data indicate that in the rat, netilmicin is distinctly less nephrotoxic than gentamicin.

Animals↗
PubMed1977

Netilmicin and gentamicin: comparative pharmacology in humans.

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.

Adult↗
PubMed1977

Netilmicin pharmacokinetics after single intravenous doses to elderly male patients.

The pharmacokinetics of the new aminoglycoside antibiotic netilmicin were examined after single intravenous injections at two different dose levels to elderly male patients. The durg obeyed two-compartment model kinetics in serum, and elimination was monoexponential from 1 to 2 h after dosing. Netilmicin levels in serum were above minimum inhibitory concentration values for most susceptible organisms for up to 8 h after dosing in normal individuals and for at least 12 h in uremic patients. Urine levels of netilmicin were uniformly above minimum inhibitory concentration values throughout 24 h after dosing. Netilmicin distribution characteristics were largely independent of both dose level and renal function. Netilmicin elimination kinetics were independent of dose level but were markedly influenced by renal function. Relationships are described between netilmicin elimination and renal function indicators, which provide a basis for dosage adjustment in individuals with renal function impairment.

Aged↗
PubMed1977

Clinical pharmacology of netilmicin.

Pharmacological studies of netilmicin were conducted in 30 cancer patients. After intravenous administration of 50 mg of netilmicin or gentamicin per m(2) over a 1-h period in 10 patients, the mean peak serum concentrations occurred at the end of the infusion and were 7.6 and 7.3 mug/ml, respectively. At 6 h, the mean serum concentrations of both drugs was 1.1 mug/ml. After intramuscular injection of 50 mg of netilmicin per m(2) to each of the same 10 patients, the mean peak serum concentration was 5.5 mug/ml and occurred at 1 h, and, at 6 h, the mean serum concentration was 1.4 mug/ml. The mean proportion of netilmicin excreted in urine during 6 h after intramuscular injection was 55%, and after intravenous injection it was 40.9%. Results were similar with gentamicin sulfate. After administering 60 mg of netilmicin per m(2) intravenously over 30 min every 6 h in 9 patients, the mean peak serum concentration (7.9 mug/ml) occurred at the end of the infusion. The concentration gradually decreased to below 2.0 mug/ml after 4 h. Continuous infusion of 60 mg of netilmicin per m(2) every 6 h after a 60-mg/m(2) loading dose in 11 patients produced levels consistently above 2.9 mug/ml, during the initial 6-h infusion, and levels above 2.0 mug/ml for at least 1 week.

Adult↗
PubMed1997

A prospective randomized trial of ceftazidime versus netilmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients.

Aminoglycosides are frequently used to treat sepsis in patients with liver disease. However, it has been suggested that cirrhotic patients are particularly sensitive to aminoglycoside-induced renal dysfunction. We investigated the efficacy and incidence of renal impairment with netilmicin plus mezlocillin compared with ceftazidime in 128 cirrhotic patients who required empirical treatment for sepsis. Renal impairment developed in 8 of 63 (13%) patients receiving netilmicin compared with 2 of 65 (3%) patients receiving ceftazidime (P < .05); it occurred despite regular monitoring of trough netilmicin levels. Renal impairment was present at the time of death in 1 of 13 (8%) patients treated with ceftazidime compared with 5 of 9 (56%) of the netilmicin patients (P < .05). Mortality rates were similar in the two groups (ceftazidime 20%, aminoglycoside 14%; P = NS). Renal dysfunction is significantly more frequent in cirrhotic patients treated with netilmicin but with careful attention to dosage and fluid management the clinical effect is likely to be relatively modest.

Adolescent↗
PubMed1990

Prospective randomized study of once-daily versus thrice-daily netilmicin regimens in patients with intraabdominal infections.

One hundred and ninety-seven patients with intraabdominal infections were enrolled in a prospective randomized multicenter study of netilmicin administered once daily (n = 98) versus thrice daily (n = 99) in combination with tinidazole administered once daily. Randomization was achieved for the infection site, clinical severity score, daily and total netilmicin dose, and duration of treatment. The mean maximum peak and trough levels of netilmicin in serum were 21.1 and 1.3 mg/l respectively for once daily treated patients, and 10.0 and 2.3 mg/l for thrice daily treated patients (p less than 0.05 for both parameters). The clinical response did not differ between patients treated once daily and those treated thrice daily. Overall rates for clinical cure, improvement and failure of therapy were 77%, 17% and 6% respectively. No significant differences were found between once daily and thrice daily regimens in the occurrence of auditory, vestibular and renal toxicity, overall rates being 5%, 1% and 10% respectively. Impairment of renal function was significantly related to higher maximum netilmicin serum trough levels during therapy, a higher clinical severity score and advanced age. It is concluded that netilmicin given once daily is as effective and safe as the multiple dose regimen. However, monitoring of aminoglycoside serum through levels is still advisable, especially in the old and severely ill patient.

Abdomen↗
PubMed1989

Once-daily versus thrice-daily administration of netilmicin in combination therapy of Pseudomonas aeruginosa infection in a man-adapted neutropenic animal model.

A granulocytopenic mouse model was used to elucidate the impact of dose spacing on the activity of netilmicin against Pseudomonas aeruginosa. A thigh infection was produced and then treated with netilmicin combined with azlocillin. Netilmicin was injected subcutaneously at decreasing doses every 20 min to result in plasma-concentration-time curves similar to those observed in patients on intravenous netilmicin treatment. A once-daily regimen was simulated and compared to a simulated conventional schedule of every 8 h. Identical total amounts of drug were used in both groups of comparatively treated mice. Therapeutic efficacy was quantitated by repeated determinations of surviving organisms in thigh homogenates. Combination therapy was significantly more effective than azlocillin treatment alone. In combination regimens the simulated once-daily netilmicin schedule killed the target organisms faster than the simulated thrice-daily regimen and was significantly more efficacious by 24 and 32 h in two out of three strains of Pseudomonas aeruginosa tested. It is concluded that the results of combination therapy of severe Pseudomonas aeruginosa infections in the immunocompromised host might be improved by choosing an aminoglycoside dosage interval of 24 h instead of the conventional 8 h.

Animals↗
PubMed2004

Shelf lives of aseptically prepared medicines--stability of netilmicin injection in polypropylene syringes.

There is no published information on the stability of netilmicin solutions in prefilled syringes. The purpose of this study was to evaluate the stability of netilmicin in polypropylene syringes and to determine the optimum validated shelf life so that they may be prepared in bulk in appropriately licensed facilities. The syringes containing netilmicin 10 or 100mg/ml were stored at 7 degrees C, room temperature in the light (RTL) and 25 degrees C/60% relative humidity for up to 300 days. Netilmicin concentration was determined by reversed phase high performance liquid chromatography (RP-HPLC) of the isoindole derivative formed with o-phthalaldehyde (OPA). The shelf lives were calculated using the maximum rate method applied to the netilmicin analytical data. At 7 degrees C 10 and 100mg/ml solutions were stable for 90 days falling to 30 days at 25 degrees C and 60% RH. At RTL the 10mg/ml solution was stable for 9 days.

Anti-Bacterial Agents↗
PubMedDate not supplied

Comparative ototoxicities of gentamicin and netilmicin in three model systems.

The ototoxic potentials of netilmicin and gentamicin were compared in three models: the standard in-vivo animal model (guinea pig), organ culture of the embryonic inner ear (mouse), and perilymphatic perfusions (guinea pig). Toxicity was assessed by light and electron microscopy of hair cells or by measurement of cochlear microphonic potentials. In vivo, netilmicin did not have any significant morphologic effect on hair cells under conditions (dose X duration) where gentamicin caused excessive hair cell loss. In organ culture, concentrations of netilmicin had to be at least tenfold higher than those of gentamicin in order to produce comparable damage. In direct applications of the drugs to the cochlea by perilymphatic perfusion, similar effects on cochlear microphonics were seen when netilmicin concentrations were more than threefold higher than those of gentamicin. It is suggested that netilmicin ototoxicity observed in vivo is low because of lesser penetration into the inner ear and lower intrinsic toxicity.

Animals↗
PubMed1989

Once-daily dosing decreases renal accumulation of gentamicin and netilmicin.

The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside-induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short-term infusion or as 24-hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short-term infusion schedule yielded cortical concentrations of 103.2 +/- 36.3 and 137.4 +/- 34.6 micrograms/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 +/- 52.9 and 178.5 +/- 21.8 micrograms/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short-term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once-daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once-a-day dosing for aminoglycosides.

Drug Administration Schedule↗
PubMed1999

Netilmicin pharmacokinetics in Hong Kong Chinese cancer patients.

OBJECTIVES: To study the pharmacokinetics of netilmicin in Chinese haematology-oncology patients and to determine the pharmacokinetic differences, if any, between this patient subpopulation of Chinese and Caucasians. METHODS: A prospective study was carried out in the adult oncology unit of a major hospital in Hong Kong. During a 6 week period in 1997, all patients commencing on netilmicin therapy were monitored; the patients' demographics, clinical status, netilmicin dose and regimen, and drug administration/blood sampling time were collected. Pharmacokinetic parameters were generated using the USC*PACK package based on specifics of the patients themselves and Caucasians matched for the same patients' parameters using the Bayesian alogrithms. RESULTS: A total of 22 patients were enrolled into the study. Twenty-nine sets of levels were drawn, but only 25 sets from 18 patients (86%) were interpretable. The predicted peak (7.47+/-1.46 microg ml-1 ) and trough levels (1.39+/-0.96 microg ml-1 ) generated by USC*PACK were found to be significantly higher than the levels observed (6.01+/-1.14 microg ml-1 and 0.93+/-0.71 microg ml-1, respectively). Netilmicin clearance, volume of distribution and rate of elimination were all significantly higher in this Chinese subpopulation than those predicted for matched Caucasians. Conclusion Alterations in the netilmicin pharmacokinetics observed in our study population might be related to the disease state and/or ethics of the study patient population. Direct application of Caucasian based population pharmacokinetic parameters to this subgroup of Chinese patients may not be appropriate and may result in underdose.

Adolescent↗
PubMed2004

Meropenem plus amikacin versus piperacillin-tazobactam plus netilmicin as empiric therapy for high-risk febrile neutropenia in children.

The aim of this study was to evaluate the efficacy and safety of meropenem plus amikacin compared with piperacillin-tazobactam plus netilmicin for initial empirical antibiotic treatment of high-risk febrile neutropenia in children with cancer. Patients with hematologic malignancy (leukemia or stage III/IV non-Hodgkin lymphoma) who presented with fever and neutropenia (ANC < 500/mm3) and patients with solid tumors who presented with fever and severe neutropenia (ANC < 100/mm3) were considered to be at high risk and eligible for this study. In this prospective study, 33 patients with 50 febrile neutropenic episodes received i.v. neropenem (20 mg/kg every 8 h) plus amikacin (15 mg/kg/d in 2 divided doses) (in 31 episodes) or piperacillin/tazobactam (100 mg/4 mg/kg every 8 h) plus netilmicin (7 mg/kg every 24 h) (in 19 episodes). Clinical response was determined at 72 h and at completion of the therapy. The groups were comparable in terms of age, sex, initial ANC, use of growth factors, and classification of the infections. An infection was documented microbiologically in 12 episodes (39%) in the meropenem plus amikacin group and in 8 episodes (42%) in the piperacillin/tazobactam plus netilmicin group. Of the 22 microbiological isolates, 37% were gram-positives, 45% were gram-negatives, and 18% were fungi. Most of the clinically documented infections were of lower respiratory tract, gastrointestinal mucosa, or urinary tract origin. The mean duration of neutropenia was 9 days in both groups. Fever persisted for 1-30 days (mean 3 vs. 5 days). The success rate with initial empiric therapy was 52% in the meropenem plus amikacin and 42% in the piperacillin/tazobactam plus netilmicin group, respectively (p = .5). Total success rate (with or without modification) was 97% vs. 90% in the episodes. Three patients died due to infection (1 vs. 2 patients). No major adverse effects were observed in each group. Empirical therapy with meropenem plus amikacin or piperacillin/tazobactam plus netilmicin for high-risk febrile neutropenia is equally effective and safe in pediatric cancer patients.

Amikacin↗
PubMed1983

Netilmicin: in-vitro activity compared with that of other aminoglycosides against Serratia marcescens.

The activity of netilmicin, a semisynthetic aminoglycoside, was compared with that of gentamicin, tobramycin, and amikacin against 100 clinical isolates of Serratia marcescens. Minimum inhibitory concentrations (MIC) were determined by an agar dilution procedure. Defining amikacin resistance as an MIC of greater than 16 mg/l, and netilmicin, gentamicin and tobramycin resistance as an MIC greater than 4 mg/l, 1% were resistant to amikacin, 3% to netilmicin, 8% to tobramycin, and 43% to gentamicin. The majority of isolates that were resistant to both gentamicin and tobramycin were sensitive to netilmicin. These results indicate that the activity of netilmicin against Ser. marcescens is closely comparable to that of amikacin.

Aminoglycosides↗