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PubMed2006

Effect of melanin on netilmicin-induced inhibition of collagen biosynthesis in human skin fibroblasts.

It is known that various drugs form complexes with melanins and that melanins are abundant constituents of the inner ear. In this study, we determined whether the aminoglycoside antibiotic, netilmicin, interacts with melanin and how this process affects collagen biosynthesis in cultured human skin fibroblasts. The obtained results indicate that netilmicin forms stable complexes with melanin characterized by the association constants K(1) approximately 10(6)M(-1) and K(2) approximately 10(3)M(-1). We have suggested that prolidase, an enzyme involved in collagen metabolism, may be one of the targets for aminoglycoside-induced inhibition of collagen biosynthesis. We found that netilmicin strongly induced inhibition of prolidase activity (IC(50)<5microM) and collagen biosynthesis (IC(50) approximately 10microM). At 10microM concentration of netilmicin, prolidase activity in human skin fibroblasts was inhibited by about 80% and DNA biosynthesis-only by about 25%. Melanin at 100microg/mL produced about 30% inhibition of collagen biosynthesis and about 30% inhibition of prolidase activity in cultured fibroblasts. However, the addition of melanin (100microg/mL) to netilmicin-treated cells (10microM) restored the prolidase activity in fibroblasts to almost 100% of control values and partially reversed the inhibitory action of the drug on collagen and DNA biosynthesis. The data suggest that the ability of netilmicin to form stable complexes with melanin may prevent its toxicity on prolidase activity and collagen biosynthesis.

Anti-Bacterial Agents↗
PubMed1983

Netilmicin and gentamicin multidose kinetics in normal subjects.

Multidose netilmicin and gentamicin kinetics were studied in 20 healthy subjects who received 1.7 mg/kg gentamicin (n = 10) or netilmicin (n = 10) as a 20-min infusion every 8 hr for 10 days (28 doses) during a randomized, double-blind comparative trial designed to study adverse effects and kinetics of netilmicin and gentamicin. Multidose kinetics were of the same order for gentamicin and netilmicin with the exception of the terminal plasma t 1/2 (94 and 156 hr) and the volume of distribution at steady state (450 and 1072 ml/kg). Mean peak plasma concentrations of netilmicin were slightly lower than gentamicin. Percentage of the dose eliminated in urine did not differ for the two aminoglycosides. Aminoglycoside was detectable in plasma and continued to be eliminated in urine for at least 6 days after the final dose. The plasma concentration-time profiles for both netilmicin and gentamicin were well fitted with the sum of three exponential terms; urinary excretion rates-time plots showed biexponential decay. None of the subjects had any auditory, vestibular, or renal toxicity. Although the data confirm a deep tissue compartment, they suggest that the kinetic processes involved may be more complex than previously supposed.

Adult↗
PubMed2003

Population pharmacokinetics of netilmicin in short-term prophylactic treatment.

AIMS: To characterize the population pharmacokinetics of netilmicin, an aminoglycoside antibiotic, in adult urology patients and to develop a covariate model for improved dose titration. METHODS: Data from 62 adult patients (55 male, seven female), undergoing urological surgery and treated with netilmicin for short-term prophylaxis, were evaluated retrospectively. The group had (median, range) ages 68, 31-92 years, weights 72, 43-106 kg and heights 167, 148-182 cm. No patient showed renal impairment before netilmicin treatment (serum creatinine </=1.9 mg dl-1). Netilmicin (100 mg) was administered as a maximum of four successive intravenous infusions of 30 min, at 8-h intervals. A total of five blood samples were collected from each patient. Prior to analysis, the dataset was divided into 'index' (n = 44) and 'validation' (n = 18) groups at random. The time courses of netilmicin concentrations from all subjects were analysed using a mixed effects, population, nonlinear modelling package (WinNonMix). For covariate model development, a stepwise procedure was used with backward elimination followed by forward inclusion based on age, sex, weight, height, creatinine clearance and type of surgery. The final covariate model parameters from the index group were used to simulate concentrations in the validation group and the bias and precision were compared with the observations. RESULTS: A bi-compartmental open model with a proportional residual error best described the data. The population parameters for central and peripheral volumes of distribution were (typical population value [interindividual CV%]) Vc = 14.5 l [56%] and Vp = 10.2 l [not estimated], and the systemic and intercompartmental clearances were CL = 3.9 l h-1[42%] and CLQ = 10.1 l h-1[not estimated], respectively. The final population covariate relationships were based on sex (SEX) and creatinine clearance (CrCL): (Vc, l) = 18.9 - 5.9 x SEX [29%] and (CL, l h-1) = 0.06 x CrCL [33%]. Compared with the observations in the validation group, this model showed a bias (95% confidence interval) of -0.028 (-0.28, 0.25) and precision of 1.22 (0.78, 1.34). CONCLUSION: Bi-compartmental pharmacokinetic parameters of netilmicin have been estimated from clinical data in urological surgery patients using a population approach. A given single dose results in large variability in plasma concentrations and thus the population covariate final model can be used for direct estimation of initial dosing in patients.

Adult↗
PubMed1988

Selection of netilmicin resistance, associated with increased 6' aminoglycoside acetyltransferase activity, in Serratia marcescens.

Eight aminoglycoside-sensitive clinical strains of Serratia marcescens were serially passaged through broth containing increasing sub-inhibitory concentrations of netilmicin. Before each subculture the aminoglycoside acetyltransferase activity of the bacteria was determined. After up to eight transfers all the strains showed an increase in resistance to netilmicin (MIC greater than 32 mg/l) and MICs for two of the strains exceeded 1000 mg/l. Six of the eight strains showed significant increases in aminoglycoside acetylating activity in accompaniment with the development of resistance. The greatest rises in enzyme activity (eight- and four-fold) were in the strains where the netilmicin MICs for the resistant derivatives exceeded 1000 mg/l. The aminoglycoside acetylating enzyme present was identified as AAC 6'-I by two methods. After five subcultures in antibiotic-free medium, the two derivatives with the highest resistance to netilmicin remained highly resistant and continued to produce AAC 6'-I copiously. These results suggest that exposure of some aminoglycoside sensitive strains of Ser. marcescens to netilmicin leads to the development of high level netilmicin resistance associated with the production of AAC 6'-I. The implication of these findings for the study of aminoglycoside resistance in Ser. marcescens are discussed.

Acetyltransferases↗
PubMed2002

Treatment of acute bacterial conjunctivitis with topical netilmicin.

PURPOSE: This study compares the clinical and microbiologic value of topical netilmicin with that of gentamicin in the treatment of acute bacterial conjunctivitis. METHODS: A double-blind, randomized, prospective, controlled study was performed in 209 patients. One to two drop(s) of either antibiotic was applied to the affected eye(s) four times a day for up to 10 days. Patients were examined at the time of diagnosis and after 3, 5, and 10 days. Clinical efficacy was measured as the cumulative sum score (CSS) of the key signs and symptoms of acute bacterial ocular infection. Sensitivity/resistance was evaluated using the disk diffusion method. RESULTS: Drug efficacy assessment was restricted only to patients with positive baseline culture results (n = 121). Of the isolated organisms, 96.9% were sensitive to netilmicin, whereas only 75.0% were sensitive to gentamicin (p = 0.00001). Netilmicin provided a broad-spectrum coverage comparable with that of ciprofloxacin, ofloxacin, and norfloxacin. Netilmicin also was more effective than gentamicin in eradicating infections (p = 0.001 at day 5 and p = 0.037 at day 10) and in ameliorating the CSS (p = 0.037 at day 3, p = 0.001 at both day 5 and day 10). Only minor adverse events occurred in patients treated with either netilmicin or gentamicin. CONCLUSIONS: This study demonstrates that netilmicin is a safe and effective antibiotic that can be used as first-line therapy for the treatment of acute bacterial conjunctivitis.

Acute Disease↗
PubMed2005

In vivo toxicity of netilmicin and ofloxacin on intact and mechanically damaged eyes of rabbit.

PURPOSE: To evaluate the in vivo toxicity of netilmicin and ofloxacin using both normal and mechanically damaged eyes of rabbit. METHODS: Male albino New Zealand rabbits were given either 0.3% netilmicin, 0.3% ofloxacin, or 0.9% sodium chloride solution by topical instillation (50 microL) into the conjunctival sac 6 times daily for 5 days. In some animals a 6-mm-diameter epithelial wound was mechanically made to the center of the cornea. Ocular toxicity on normal eyes was evaluated by impression cytology of the conjunctiva, histology of the entire globes, and scanning electron microscopy (SEM) of the cornea. Analysis of toxicity and reepithelialization on wounded corneas was evaluated by SEM with observations being made 48 and 72 hours after induction of the wound. RESULTS: Cytologic, histopathologic, and SEM analyses of normal healthy eyes following netilmicin treatment revealed no signs of toxicity, whereas those treated with ofloxacin revealed alterations in the cornea (stromal swelling) and conjunctiva (infiltration of polymorphonuclear cells) with reduced goblet cell numbers. Wounded corneas treated with netilmicin exhibited normal morphology and reepithelialization, whereas the administration of ofloxacin resulted in disordered cellular organisation and slower rates of epithelial recovery. CONCLUSIONS: Netilmicin, an antibacterial aminoglycoside, is well tolerated even in an experimental wound-healing model where the integrity of the ocular surface is compromised, whereas ofloxacin, a fluoroquinolone, appears to provoke an inflammatory response in the normal eye and a clear alteration of reepithelialization in the wounded eye. These findings suggest that netilmicin may offer a superior toxicological profile in both normal eyes and clinical situations where the integrity of the ocular epithelium is suspect.

Administration, Topical↗
PubMed2005

Cefazolin plus netilmicin versus cefazolin plus ceftazidime for treating CAPD peritonitis: effect on residual renal function.

UNLABELLED: BACKGROUND. The International Society for Peritoneal Dialysis (ISPD) treatment guidelines for continuous ambulatory peritoneal dialysis (CAPD) peritonitis 2000 recommended the use of cefazolin plus ceftazidime as the initial empirical therapy in patients with residual renal function (RRF). However, this treatment regimen has not been compared with the conventional regimen of cefazolin plus netilmicin in prospective, randomized controlled trials. METHODS: Stable CAPD patients who developed clinical evidence of peritonitis were randomized to receive intraperitoneal (i.p.) cefazolin plus netilmicin or cefazolin plus ceftazidime once daily in the long dwell for 14 days. For patients with RRF (>1 mL/minute) before entry into the study (N= 50), RRF and 24-hour urine volume were measured at days 1, 14, and 42 after commencement of i.p. antibiotic treatment. RESULTS: One hundred and two patients were recruited into the study. The primary cure rates of i.p. cefazolin plus netilmicin and cefazolin plus ceftazidime were 66.7% and 64.7%, respectively. The overall cure rate for the 2 treatment regimens was 82.3% for both. Seven patients (14%) from each treatment group required removal of the dialysis catheters due to treatment failure. Relapse of peritonitis occurred in 2 patients (4%) in both treatment groups. Thirty-six patients with RRF at baseline achieved primary cure of their peritonitis by the assigned antibiotics. In this subgroup of patients, their RRF and daily urine volume showed significant reduction at day 14 and returned to near baseline values at day 42. The degree of reduction in RRF and urine volume did not differ significantly between the patients treated with cefazolin plus netilmicin and cefazolin plus ceftazidime. CONCLUSION: Intraperitoneal cefazolin plus netilmicin and cefazolin plus ceftazidime have similar efficacy as empirical treatment for CAPD peritonitis. In CAPD patients with RRF, significant but reversible reduction in RRF and 24-hour urine volume could occur after an episode of peritonitis, despite successful treatment by i.p. antibiotics. The effect of i.p. cefazolin plus netilmicin, or i.p. cefazolin plus ceftazidime on RRF in CAPD patients with peritonitis does not appear to be different. Our findings do not support the routine use of cefazolin and ceftazidime as the empirical treatment for CAPD peritonitis.

Adult↗
PubMed1978

Nephrotoxicity of netilmicin in combination with non-aminoglycoside antibiotics.

To assess the possibility that non-aminoglycoside antibiotics may adversely affect the nephrotoxicity of the new semisynthetic aminoglycoside netilmicin, we gave ampicillin, carbenicillin, methicillin, cefamandole, and clindamycin, either singly or in combination with netilmicin, at two dose concentrations in rats. Results were compared as to the effect of netilmicin given singly and to saline-injected and noninjected controls. Antibiotic combinations resulted in no greater nephrotoxicity than did netilmicin alone. Netilmicin concentrations in renal tissue were high, and these levels were not consistently affected by the other drugs. The data suggest that in rats the nephrotoxicity of netilmicin is not affected adversely by the presence of non-aminoglycoside antibiotics.

Aminoglycosides↗
PubMed1981

Predicted tissue accumulation of netilmicin in patients.

The two-compartment pharmacokinetics of netilmicin were investigated in 11 patients with stable renal function who were being treated for gram-negative infections. The initial dosage of netilmicin ranged from 2.5 to 5.0 mg/kg per day, with subsequent changes made on the basis of serum concentrations. Venous blood samples were obtained every 2 to 4 days during therapy and daily for an average of 10 days after the final dose. Serum concentrations were measured by both microbiological assay and radioimmunoassay. Peak and trough netilmicin concentrations were significantly greater (P less than 0.01) at the end of therapy than at the first dose, even though renal function was stable throughout treatment in all patients. After the final dose, serum concentrations declined in a biphasic manner, with a first-phase half-life of 5.4 h and a terminal half-life of 198 h. The total body clearance averaged 31 ml/min. An average of 99 mg of netilmicin (approximately 5% of the total dose) was predicted to be in the tissue compartment at the end of therapy. A comparison of these pharmacokinetic parameters with those obtained in a previously reported but similar study with gentamicin showed no significant differences between the two aminoglycosides with respect to peak and trough concentrations (initially or at the end of therapy), volumes of distribution, total body clearance, or amount of drug in the tissue compartment at the end of therapy. The terminal half-life of netilmicin was significantly greater than that of gentamicin, whereas the rate constant of netilmicin for tissue influx (k12) was significantly less.

Adult↗
PubMed1992

Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children.

The efficacy and safety of netilmicin, 5 mg/kg of body weight once daily or 2 mg/kg thrice daily for 10 days, for the treatment of gram-negative pyelonephritis in children were compared in a prospective, randomized trial. Explicit criteria were used to define the site of infection, treatment outcome, and adverse effects. Netilmicin was given to 74 children once daily and to 70 children three times daily. At 1 week posttreatment, 73 (99%) of 74 children treated with netilmicin once daily and 70 (100%) of 70 children treated with netilmicin three times daily were cured. At 4 weeks posttreatment, no relapse was detected and the rate of reinfection was essentially identical in the two treatment groups. Peak serum netilmicin concentrations were higher in patients given the once-daily regimen, whereas a higher trough level was detected in patients given the three-times-daily regimen. Nephrotoxicity, which was defined as an increase in the serum creatinine level of greater than or equal to 0.3 mg/dl over the baseline, was rare (3%) and reversible and occurred regardless of the treatment regimen. Ototoxicity, which was assessed by pure-tone audiometry (250 to 8,000 Hz) and brain stem-evoked response (6,000 Hz), occurred in 2 of 32 children who were evaluated. In these two children, who were given the once-daily regimen, wave V was not evokable monolaterally below 25 and 40 dB normal hearing level, respectively. Thus, it may be possible to treat childhood pyelonephritis with netilmicin once daily. However, this new approach needs to be confirmed in other studies.

Child↗
PubMedDate not supplied

Netilmicin: in vitro activity, time-kill evaluation and postantibiotic effect on microorganisms isolated from ocular infections.

The in vitro activity of netilmicin and other antibiotics against ocular gram-positive and gram-negative microorganisms was evaluated. Netilmicin showed excellent activity against all the tested microorganisms, with more than 90% susceptibility. Many gentamicin- and tobramycin-resistant strains were still susceptible to netilmicin, although the minimum inhibitory concentration values of netilmicin were higher than those for the fully susceptible strains. In time-kill studies, netilmicin showed bactericidal activity within 1 h against Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, netilmicin showed a postantibiotic effect of 2.4 h against P. aeruginosa and 1.5 h against S. aureus. These values were longer than those showed by ofloxacin, i.e. 2.1 and 1.4 h, respectively.

Eye Infections, Bacterial↗
PubMed2004

Use of once-daily netilmicin to treat infants with suspected sepsis in a neonatal intensive care unit.

Once-daily administration of aminoglycoside antibiotics has become the most acceptable dosing schedule for the majority of patients. There are few published data on the impact of post-natal age on aminoglycoside concentrations in preterm infants receiving once-daily dosage regimens. Netilmicin was administered as a once-daily dose of 4 mg/kg. In 141 episodes of suspected sepsis in 123 babies, trough netilmicin concentrations ranged from undetectable to 4.0 mg/l. Netilmicin concentrations were above a level of 2 mg/l in 10.6% of episodes. Netilmicin concentrations decreased with increasing post-natal age and weight. Levels were higher in males compared to females. Increased creatinine concentrations were associated with higher netilmicin concentrations. This study emphasises the importance of post-natal age as a determinant of aminoglycoside concentrations with a once-daily dosing regimen in a neonatal intensive care population. Trough levels should be carefully monitored and consideration given to extending dosage intervals particularly when netilmicin is administered once daily to preterm infants in the first week of life.

Aging↗
PubMed1980

Netilmicin: its in vitro activity and synergism with penicillin compounds.

The in vitro efficacy of netilmicin and its synergism with penicillins were examined. Netilmicin was effective against E. coli, indole-negative and -positive Proteus, Klebsiella, Enterobacter, Salmonella, Shigella and Serratia. Netilmicin was less effective than other aminoglycosides against Citrobacter and Pseudomonas. A combination of netilmicin and piperacillin synergistically inhibited Enterococci. Netilmicin was not synergistic with either penicillin or carbenicillin against Enterococci. Netilmicin with either carbenicillin, ticarcillin or piperacillin synergistically inhibited Pseudomonas aeruginosa, but no such synergism was noted against highly resistant strains of Pseudomonas.

Amikacin↗
PubMed1992

A comparison of netilmicin and tobramycin therapy in patients with renal impairment.

We evaluated the toxicity and efficacy of netilmicin and tobramycin in 89 older adults with serious bacterial infections and pre-existing renal impairment in a prospective, blinded, randomized trial. Complete resolution or improvement of infection occurred at 34/36 (94%) evaluable sites in netilmicin-treated patients and at 26/31 (84%) evaluable sites in tobramycin-treated patients. 10/44 (23%) netilmicin- and 7/45 (16%) tobramycin-treated patients experienced nephrotoxicity during treatment. The mean serum creatinine level improved significantly at the end of therapy compared to pre-treatment in those patients who did not experience nephrotoxicity in both treatment groups. 5/19 (26%) netilmicin-treated patients and 2/18 (11%) tobramycin-treated patients assessable for ototoxicity experienced decrements in auditory thresholds. Ototoxic netilmicin-treated patients had higher serum netilmicin levels than did non-ototoxic patients. Patients who experienced ototoxicity were not more likely to have experienced nephrotoxicity. The rates of toxicity were not statistically different and were similar to those seen in studies of patients with normal pre-treatment renal function.

Aged↗
PubMed1999

Topical netilmicin compared with tobramycin in the treatment of external ocular infection.

In a pilot double-blind, randomized, prospective controlled study the effectiveness and safety of 0.3% netilmicin ophthalmic solution were compared with those of 0.3% tobramycin in treating external bacterial ocular infections in 45 eligible patients. The treatment with both study medications resulted in a significant (p < 0.001, Wilcoxon test) reduction in the mean cumulative score of the signs and symptoms. However, no statistically significant differences were observed between the two groups. The clinical improvement rate was almost complete with either antibiotics. There was a statistically positive trend in the netilmicin group with regard to the microbiological improvement that was achieved in (87% of the netilmicin patients) compared with 77% of the tobramycin patients (77%). Antibiotic sensitivity revealed that 84% of the organisms isolated were sensitive to netilmicin whereas only 64% of them were sensitive to tobramycin. Only minor adverse events occurred in patients treated with either netilmicin or tobramycin. In conclusion, this study demonstrates that netilmicin is a promising new antibiotic for treating external ocular infections.

Administration, Topical↗
PubMed2000

A randomized controlled clinical trial on etimicin, a new aminoglycoside antibiotic, versus netilmicin in the treatment of bacterial infections.

OBJECTIVE: To compare the efficacy and safety of two aminoglycoside antibiotics, etimicin and netilmicin, in the treatment of bacterial infections. METHODS: A randomized, open label, controlled clinical trial was conducted for the treatment of 65 patients hospitalized with respiratory tract infections, urinary tract infections, and skin and tissue infections. Thirty-four patients received etimicin and thirty-one patients received netilmicin at a dose of 100 mg every 12 hours by intravenous infusion. The duration of treatment was 7-10 days in both groups. RESULTS: 47 patients were enrolled in the etimicin group; 35 patients were assessable for safety and 34 patients were assessable for efficacy, 46 patients were enrolled in the netilmicin group; 32 patients were assessable for safety and 31 patients were assessable for efficacy. The results show that overall efficacy was 85.3% for the etimicin group and 83.9% for the netilmicin group, whereas bacterial clearance rates were 87.5% for the etimicin group and 89.7% for the netilmicin group. The incidence of adverse reactions was 8.6% (3/35) and 9.4% (3/32), respectively. CONCLUSION: Etimicin and netilmicin were effective and safe for the treatment of respiratory tract infection, urinary tract infection, and skin and tissue infections. The results show there was no statistically significant difference between the two groups (P > 0.05).

Adolescent↗
PubMed1987

Netilmicin in the treatment of clinical peritonitis in chronic renal failure patients managed by continuous ambulatory peritoneal dialysis.

The efficacy and systemic absorption of netilmicin following intraperitoneal instillation were studied during ten episodes of clinical peritonitis in chronic renal failure patients managed by CAPD. Episodes were unselected for sensitivity of microorganism in vitro to netilmicin. Five subjects studied as inpatients had sequential dialysate and frequent plasma samples assayed for netilimicin up to 110 hours of therapy. Five patients who managed their peritonitis at home had dialysate and plasma netilmicin levels estimated at two and six days. In a dose of 10 mg/l, netilmicin was curative in the majority of patients (70%). Toxic blood levels were not found. Experience with netilmicin compared favourably with that observed in eight consecutive episodes of outpatient peritonitis managed with intraperitoneal cefamandole, the first line treatment for CAPD peritonitis in our unit (75% cure). No side effects were recorded with either agent. We conclude that netilmicin can be used effectively in the majority of microbiologically undifferentiated episodes of CAPD peritonitis, including in the home setting.

Absorption↗
PubMed1986

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Adult↗