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PubMed1978

Netilmicin synergy with carbenicillin or cefamandole against Serratia.

Twenty clinical isolates of Serratia sp. were tested against netilmicin, gentamicin, carbenicillin and cefamandole alone (broth and agar dilution) and in combination (agar dilution). Broth and agar dilution minimal inhibitory concentrations agreed to within a two-fold dilution in 96% of the tests. Overall, 95% of the isolates were susceptible to netilmicin regardless of susceptibility to gentamicin or carbenicillin. Netilmicin-carbenicillin synergy was seen in 55% of the strains and netilmicin-cefamandole in 70%. These results indicate that combinations of netilmicin with carbenicillin or cefamandole may be clinically useful.

Carbenicillin↗

PubMed1978

Comparative ototoxic liability of netilmicin and gentamicin.

Netilmicin sulfate is a new aminoglycoside antibiotic currently undergoing clinical investigation. All of the aminoglycoside antibiotics now in clinical use are ototoxic. This study was done to determine the ototoxic liability of netilmicin when it is compared directly with gentamicin sulfate. Groups of ten guinea pigs each were given doses of 0, 50, 100, or 150 mg/kg of either gentamicin or netilmicin daily for four weeks. After a two-week stabilization period, the Preyer pinna reflex, the cochlea's ability to generate the ac cochlear potential, and the missing hair cells from the cochleas were determined. Additionally, the pharmacokinetics of both drugs in the plasma and perilymph were determined. Little or no cochlear damage was detected with netilmicin, even at the highest dose, while even the smallest dose of gentamicin produced measurable changes in cochlear function.

Acoustic Stimulation↗

PubMed1986

Pharmacokinetics of netilmicin in premature infants.

The pharmacokinetics of netilmicin were studied in 12 premature infants with proven or presumed sepsis during the first month of life. Eleven of 12 patients received netilmicin 2.5 mg/kg intravenously every 12 h while one 770-gram birth weight infant received 2.5 mg/kg every 18 h. Mean steady-state peak and trough concentrations were 8.9 micrograms/ml and 2.8 micrograms/ml, respectively. Of twelve patients, 11 had trough serum concentration above 2 micrograms/ml and four had trough serum concentrations above 3 micrograms/ml. Mean total body clearance of netilmicin was 0.84 ml/min/kg. The mean clearance of 0.72 ml/min/kg was substantially lower in patients with a mean postnatal age of 2.7 days than the clearance of 1.10 ml/min/kg in patients with a mean postnatal age of 23 days. The mean apparent volume of distribution was 0.63 l/kg; and the mean elimination halflife was 8.6 h. A three-fold interpatient variation in pharmacokinetic parameters was seen. These data suggest the need for careful monitoring of netilmicin serum concentration in premature infants.

Female↗

PubMed1982

Comparative synergistic activity of netilmicin-piperacillin versus gentamicin-piperacillin.

The synergistic action of the combination netilmicin-piperacillin in comparison to gentamicin-piperacillin was studied in 206 clinical isolates of staphylococci, enterococci, Enterobacteriaceae and Pseudomonas aeruginosa by means of the checkerboard technique. Overall, netilmicin-piperacillin acted synergistically against 31% and gentamicin-piperacillin against 14% of the 206 strains. In particular, synergism was more frequently observed with netilmicin-piperacillin against Escherichia coli, Citrobacter spp., indole-positive Proteus spp. and Pseudomonas aeruginosa. Synergy was uncommon with either combination against enterococci, Staphylococcus epidermidis and Serratia spp. Only partial synergy or indifference was seen with both combinations against Klebsiella spp. The interaction of netilmicin would appear to be superior to that of gentamicin in combination with piperacillin.

Bacteria↗

PubMed2000

Postantibiotic effects of gentamicin and netilmicin on Serratia marcescens: effects on hydrophobicity and motility.

The impact of postantibiotic effect (PAE) of aminoglycosides (gentamicin, netilmicin) on cell-surface hydrophobicity and motility of a clinical isolate Serratia marcescens was evaluated. For the induction of PAE 2x and 4xMIC concentrations of both antibiotics were used. Gentamicin and netilmicin induced a PAE of similar duration after 2xMIC concentration (2.7 and 2.8 h, respectively). Both aminoglycosides demonstrated concentration-dependent PAE. At a concentration of 4xMIC they produced PAEs of 5.9 and 8.2 h, respectively. The evaluation of hydrophobic properties of S. marcescens after affecting PAE showed that both aminoglycosides inhibited adherence to xylene. This inhibition was also concentration-dependent. More expressive was netilmicin which inhibited the adhesion by 70.5% at 2xMIC and by 85.2% at 4xMIC. Netilmicin inhibited also the adhesion to nitrocellulose filter by 34.7% at 4xMIC. Exposure of the bacterial cells to suprainhibitory concentrations of both aminoglycosides resulted only in moderate inhibition of motility of strain tested compared to the unexposed cells.

Anti-Bacterial Agents↗

PubMed1993

Synthesis of 5-deoxy-5-fluoro- and 5-deoxy-5,5-difluoro-netilmicin.

5-Deoxy-5-fluoro- (9) and 5-deoxy-5,5-difluoro-netilmicin (27) have been prepared from the corresponding 5-epi and 5-oxo derivatives of netilmicin by treatment with DAST. Structures of the fluorinated by-products (10, 11, and 12) obtained in one of the synthesis of 9 were determined. 5-Epi-netilmicin (13) and 5-epi-6'-N-methyl-netilmicin (21) have also been prepared.

Animals↗

PubMedDate not supplied

Aminoglycoside ototoxicity in the chick (Gallus domesticus) inner ear: I. The effects of kanamycin and netilmicin on the basilar papilla.

A single dose (100 mg/kg of egg weight) of kanamycin or netilmicin was injected into the yolk sacs of 7-day-old chick (Gallus domesticus) embryos. Embryos were collected every 24 hours and processed for light and transmission electron microscopy. Morphologic study of the medial basilar papilla disclosed that both kanamycin and netilmicin are toxic to the hair cells in this region. Intoxication was manifested by an increased number of dense osmiophilic bodies, swollen mitochondria, agglomerated chromatin, and occasional disorganization of the kinocilium basal bodies. The cytologic changes observed in the hair cells of embryos injected with netilmicin and kanamycin were similar. However, mitochondrial damage was more severe in the chicks after kanamycin than after netilmicin injection. Some of the cytologic alterations described here are comparable to those already reported for aminoglycoside-intoxicated hair cells in several mammalian species. This study and previous work indicate that the chick embryo provides a satisfactory developmental model for testing ototoxicity of drugs in vivo.

Animals↗

PubMed1989

Determination of the aminoglycoside antibiotics sisomicin and netilmicin in dried blood spots on filter discs, by high-performance liquid chromatography with pre-column derivatization and fluorimetric detection.

A simple method for the determination of the aminoglycoside antibiotic sisomicin or its 1-N-ethyl derivative, netilmicin in whole blood, using dried blood spots (DBSs) on filter-paper punched discs has been developed. Sisomicin or netilmicin in the DBSs were recovered most effectively in 0.5 M Na2HPO4 using ultrasonication. The eluates from the DBSs were treated by ultrafiltration for deproteinization and subjected to pre-column fluorescent derivatization using o-phthalaldehyde and beta-mercaptopropionic acid in 0.05 M KH2PO4-borate buffer (pH 9.0), followed by determination by reversed-phase high-performance liquid chromatography. The detection limits of sisomicin and netilmicin in the DBSs on punched discs (10.1 microliters of whole blood) were 0.053 and 0.50 micrograms per ml of whole blood, respectively (signal-to-noise ratio greater than or equal to 2). The method permits a simple collection of blood at the microlitre level and should prove particularly useful for monitoring sisomicin and netilmicin in blood at therapeutic levels in geriatric and paediatric patients.

Chemical Phenomena↗

PubMed1995

Synthesis and antimicrobial and toxicological studies of amino acid and peptide derivatives of kanamycin A and netilmicin.

Amino acid and peptide derivatives of aminoglycosides have been obtained by substitution of the 1-N or 6'-N amino functions of kanamycin A and netilmicin via the temporary complexation of vicinal and nonvicinal amino and hydroxy functions by copper ion [1-N kanamycin A derivatives: L-Ala (6a), D-Ala (6b), Gly (6c), L-Asp (6d), L-Ala-L-Ala (6e). 6'-N kanamycin A derivatives: L-Ala (3a), D-Ala (3b), Gly (3c), L-Ala-L-Ala (3e), L-Leu (3f). 6'-N netilmicin derivatives: L-Ala (9a), D-Ala (9b), Gly (9c), L-Asp (9d), L-Ala-L-Ala (9e)]. Characterization was made by FAB-MS, IR, 1H-NMR, and 13C-NMR. All derivatives were essentially inactive. The nephrotoxic potential of the derivatives obtained in sufficient quantities (3b,e and 9a-e) was assessed by measuring their inhibitory potential toward the activity of lysosomal phospholipase A1 acting on phosphatidylcholine embedded in negatively-charged membranes. One compound, 6'-N-L-Ala-netilmicin (9a), showed a 2-fold decrease of inhibitory potency compared to its parent drug. A conformational analysis revealed that it adopts two equally probable conformations and orientations when interacting with phosphatidylinositol. The first in which the drug lies parallel to the hydrophobic-hydrophilic interface, is similar to that of netilmicin. The second, in which the drug inserts itself in the bilayer across the hydrophilic/hydrophobic interface, is similar to that described for streptomycin, an almost non-nephrotoxic aminoglycoside.

Amino Acids↗

PubMed2000

Population pharmacokinetic analysis of netilmicin in neonates and infants with use of a nonparametric method.

BACKGROUND: Although the therapeutic and toxic effects of netilmicin are related to its plasma concentration, its pharmacokinetics in neonates and infants and the influence of clinical and biological variables have been only partially assessed. METHODS: Therapeutic drug monitoring data collected from 186 neonates and 95 infants receiving netilmicin were analyzed with a nonparametric population approach. The influence of gestational and postnatal age, weight, Apgar score, and creatinine and urea plasma concentrations on the pharmacokinetic parameters was assessed. The neonate and infant groups were each randomly divided into a learning sample and a validation sample. The population analysis was performed on each learning subgroup with the nonparametric maximum likelihood (NPML) method. In the validation group, the data were used to assess the concentration predictability. Because there is no specific netilmicin formulation for neonates and infants, an error model was proposed to account for errors attributable to dilution processes when preparing the infusion. RESULTS: In neonates, the covariates that reduced expected variance of plasma clearance by more than 10% were postnatal age, body weight, and plasma creatinine, as well as plasma urea and creatinine in infants. Body weight and sex played a significant role in explaining the variability of the volume of distribution. The accuracy of the concentration predictability assessed in the validation samples was satisfactory, and no significant bias was found. CONCLUSION: These findings help explain the large interindividual variability of the pharmacokinetics of netilmicin and the influence of the clinical and laboratory covariates in neonates and infants.

Age Factors↗

PubMed2004

Validation of a simplified netilmicin dosage regimen in infants.

The aim of this study was to validate a simplified high-dosage, extended-interval netilmicin dosage regimen for infants. A total of 129 infants receiving 163 treatment courses of netilmicin (6 mg kg every 24 or 36 h depending on gestational age (GA), postnatal age and postmenstrual age) was analysed. Serum netilmicin concentrations were monitored before (Cmin), 30 min (C0.5h) after and 7.5 h (C7.5h) after the third dose. In 110 patients during first week of life mean C0.5h was 10.5 mg/l. Mean C0.5h was significantly lower (9.0 mg/l) in 38 infants older than 1 week of age. 14 of 15 patients with Cmin levels > or = 2 mg/l receiving netilmicin every 36 h were < 28 weeks of gestation. In the first week of life significant correlations between GA and elimination half-life (p < 0.001) and between plasma creatinine and elevated Cmin (p < 0.002) were found, but no correlation between C0.5h and GA. In this high-dosage regimen a dosing interval of 48 h for GA < 29 weeks, 36 h for GA 29-36 weeks and 24 h for full term babies seems appropriate, during first week of life, to avoid the majority of elevated trough levels and still obtain maximal therapeutic efficacy.

Ampicillin↗

PubMed1990

Prophylactic mezlocillin-netilmicin combination in permanent transvenous cardiac pacemaker implantation: a single-center, prospective, randomized study.

A prospective, randomized study was carried out in order to assess the efficacy and safety of the mezlocillin-netilmicin combination in the prophylaxis of first permanent transvenous cardiac pacemaker implantation. Five hundred and fifty-two consecutive patients were randomly administered either 2 g mezlocillin and 200 mg netilmicin both as an i.v. bolus before implantation or 2g mezlocillin before and then 6 and 12 hours after surgery and 200 mg netilmicin before and then 12 hours after implantation. No adverse events were seen. Neither pocket nor electrode infections were observed in the 457 subjects still alive (mean follow-up: 29.2 months) or in patients who died after 1 year of follow-up (mean follow-up: 20.1 months) or before this time (mean follow-up: 4.7 months). The serum and pocket concentrations of mezlocillin and netilmicin at the end of surgery were found to be adequate to cover microorganisms that most often cause infections, including methicillin-resistant staphylococci.

Bacterial Infections↗

PubMed1990

A comparative study of intravenous ciprofloxacin and benzylpenicillin versus netilmicin and piperacillin for the empirical treatment of fever in neutropenic patients.

We examined the efficacy of ciprofloxacin as an empirical treatment for fever in 97 neutropenic patients in a randomized study of ciprofloxacin and benzylpenicillin versus netilmicin and piperacillin. Benzylpenicillin was included because of evidence of in-vitro resistance to ciprofloxacin in some streptococci. Clinical response rate was similar in the two groups (46% resolution for ciprofloxacin/benzylpenicillin and 52% for netilmicin/piperacillin). Microbiological assessment revealed more pathogens eradicated by ciprofloxacin and benzylpenicillin (66%) and fewer persisting (3%) than in patients receiving netilmicin and piperacillin (52% and 13% respectively). Staphylococcus epidermidis was the commonest pathogen, accounting for 38% of all isolates and 30% of all treatment failures. There were no treatment failures or superinfections due to streptococci. More therapy-related adverse reactions were seen in patients on netilmicin and piperacillin (28%) compared with those on ciprofloxacin and benzylpenicillin (10%). The combination of ciprofloxacin and benzylpenicillin is as effective as a standard regimen of netilmicin and piperacillin, with fewer adverse effects, and is highly attractive as empirical therapy for the febrile, neutropenic host. The inclusion of benzylpenicillin prevents streptococcal-associated treatment failure.

Adult↗

PubMed2003

In vitro toxicity of netilmicin and ofloxacin on corneal epithelial cells.

PURPOSE: To evaluate the in vitro cytotoxic effect of the aminoglycoside antibiotic netilmicin on rabbit corneal epithelial cells (SIRC) compared with ofloxacin, a commonly used fluoroquinolone ocular antibiotic. METHODS: SIRC cell cultures were incubated for 8 to 72 h in the presence and absence of netilmicin (1.5, 3, and 6 mg/mL) and equal concentrations of ofloxacin. Cell viability in treated and untreated SIRC cells was measured by both neutral red and MTT colorimetric assays at 8, 24, and 72 h, whereas changes in cell morphology were examined at 8, 24, 48, and 72 hours by the use of phase-contrast microscopy. RESULTS: Netilmicin, at all tested concentrations, failed to alter SIRC cell viability or morphology. In contrast, all concentrations of ofloxacin caused statistically significant dose- and time-dependent reductions in cell viability even after 8 h. After 72 h there was complete loss of cell viability. Morphologic examination of SIRC cells after 8 h of incubation with ofloxacin revealed that the fluoroquinolone antibiotic, at all concentrations, produced large numbers of dead cells, compromised intercellular contacts, and altered general morphology. After 48 h the cell monolayer was observed to be completely destroyed. CONCLUSION: Netilmicin, at the concentrations used, is an antibiotic devoid of obvious cellular toxicity and may also be considered as a suitable first-choice drug in the treatment of those pathologies that compromise the integrity of the ocular surface.

Animals↗

PubMed1989

Netilmicin sulfate as single-agent therapy for Pseudomonas infections.

In a prospective multicenter clinical trial, 69 patients with Pseudomonas infections were treated with netilmicin sulfate as the only antipseudomonal antibiotic. Clinical resolution or improvement was observed for 81% of the infections, whereas 19% were considered treatment failures. The bacteriologic response, based on follow-up culture results, showed elimination of Pseudomonas from 62% of the infection sites, with persistence in 30%. All isolates were susceptible by disk susceptibility testing (zone greater than or equal to 15 mm), and by microdilution testing in unsupplemented broth. The majority of isolates, however, were resistant in cation supplemented media. The clinical failures could be accounted for by factors other than netilmicin failure. In conclusion, netilmicin appeared effective as treatment for netilmicin-susceptible Pseudomonas infections in nonneutropenic adults. A low incidence of nephrotoxicity (12%) occurred despite careful monitoring of serum levels.

Adult↗

PubMed1983

Clinical use of a one-compartment model for determining netilmicin pharmacokinetic parameters and dosage recommendations.

To determine netilmicin pharmacokinetic parameters and to evaluate the use of a one-compartment pharmacokinetic model, 32 patients receiving netilmicin for suspected gram-negative sepsis were enrolled in our study protocol. Dose and dosage interval for each patient were determined by one-compartment pharmacokinetic analysis of six postinfusion netilmicin serum samples (0.16, 0.33, 0.5, 1, 2, and 3 h) measured by radioimmunoassay. In patients with a normal serum creatinine, mean (+/- SD) half-life and distribution volume were 1.9 +/- 1.1 h and 0.2 +/- 0.8 L/kg, respectively. The average daily dose and mean days of therapy were 5.1 +/- 1.9 mg/kg/day for 7.3 +/- 2.8 days. Serum creatinine changes of greater than 0.5 mg% occurred in 2 of 28 (7%) patients. Substantial variability in half-life and distribution volume occurred in patients. Initial dosages of 5-7 mg/kg/day in divided dosages seem appropriate for adult patients with normal renal function. Monitoring of serum levels and adjustment of dose and dosage interval are necessary to maintain therapeutic antibiotic concentrations. As with other aminoglycosides, the one-compartment pharmacokinetic model proved to be an acceptable method for measuring netilmicin pharmacokinetic parameters and individualizing therapy.

Adolescent↗

PubMed1979

Netilmicin in gram-negative bacterial infections.

Netilmicin, a new semisynthetic aminoglycoside, was used in the treatment of 42 patients with serious gram-negative bacterial infections. Of the 40 evaluable patients, 24 (60%) were cured, and 8 (20%) had a favorable clinical response, for a total clinical response rate of 80%. Eight patients failed to respond; of these, three had undrained abscesses and two had severe granulocytopenia. Three of the patients who failed had organisms in which resistance to netilmicin developed during therapy, and in two of these three netilmicin was the only aminoglycoside to which resistance developed. Of the 37 patients evaluable for toxicity, 8 (22%) developed renal insufficiency. Two patients had mild but persistant elevation in serum creatinine. Three patients had nephrotoxicity while on gentamicin in the past. Pre- and posttherapy audiograms were done on 26 patients; none had hearing loss. Four patients had mild, transient asymptomatic elevations in alkaline phosphatase. The pretreatment clinical isolates were tested for in vitro susceptibility. The median minimal inhibitory concentration of netilmicin, gentamicin, and tobramycin ranged between 0.5 and 2 mug/ml. The median minimal inhibitory concentration of amikacin was approximately twofold higher. No clear in vitro superiority of one aminoglycoside over another was observed.

Bacterial Infections↗

PubMed1979

Effect of time and concentration upon interaction between gentamicin, tobramycin, Netilmicin, or amikacin and carbenicillin or ticarcillin.

An aminoglycoside antibiotic and carbenicillin or ticarcillin are widely used in the treatment of patients with gram-negative bacillus infections. This study evaluated the effect of time upon in vitro interaction between mixtures of four aminoglycosides at two concentrations with carbenicillin or ticarcillin at four concentrations. By linear regression analysis, the inactivation of each aminoglycoside was shown to be directly proportional to the concentration of carbenicillin (P < 0.001). Inactivation was significantly (P < 0.01) greater for gentamicin and tobramycin than for amikacin or netilmicin at all carbenicillin concentrations. At carbenicillin concentrations of 300 and 600 mug/ml, significantly (P < 0.005) less inactivation of amikacin occurred when compared to netilmicin. Ticarcillin produced a significant (P < 0.025) inactivation of gentamicin and tobramycin, with inactivation being directly proportional to ticarcillin concentration. No inactivation of amikacin or netilmicin activity occurred unless the ticarcillin concentration was 600 mug/ml. No significant change in aminoglycoside activity occurred when stored with ticarcillin or carbenicillin at concentrations ranging from 100 to 600 mug/ml at -70 degrees C for 56 days. When an aminoglycoside and carbenicillin or ticarcillin are indicated in patients with renal failure, this study supports the use of ticarcillin with either amikacin or netilmicin.

Amikacin↗