The primary molecular target of Netilmicin Sulfate is the bacterial ribosome, specifically the 30S ribosomal subunit. As an aminoglycoside antibiotic, Netilmicin binds to the A site of the 16S rRNA in the 30S ribosomal subunit, causing misreading of the genetic code and inhibition of protein synthesis. The binding of Netilmicin to the ribosome leads to the incorporation of incorrect amino acids into growing polypeptide chains, resulting in the production of non-functional or toxic proteins. This ultimately leads to bacterial cell death. The compound's 1-N-ethyl modification provides resistance to several aminoglycoside-modifying enzymes, including acetyltransferases, phosphotransferases, and adenyltransferases, which are responsible for resistance to other aminoglycosides such as gentamicin and tobramycin. Netilmicin's spectrum of activity includes Gram-negative bacteria (E. coli, Klebsiella, Pseudomonas, Enterobacter, Proteus) and some Gram-positive bacteria (Staphylococcus).

Netilmicin Sulfate is a semisynthetic derivative of sisomicin. It shows activity against aminoglycoside-resistant bacteria and much decreased chronic toxicity in animals relative to sisomicin, gentamicin and tobramycin. Netilmicin Sulfate shows high activity against E. coli, Klebsiella, Enterobacter, Citrobacter, Proteus spp and Staph. Aureus. In addition, 87% of indole-positive Proteus strains, 90.7% of Serratia and 83.5% of Ps. Aeruginosa strains are sensitive to Netilmicin Sulfate.

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Netilmicin showed high in vitro activity against clinical isolates: E. coli (99% susceptible), Klebsiella and Enterobacter (98%), Citrobacter (98%), indole-negative Proteus (93%), Staph. aureus (98%), indole-positive Proteus (87%), Serratia (90.7%), Ps. aeruginosa (83.5%) from over 8000 isolates (Schering Corporation, 1980). [1]
In a Swiss study of over 12,000 strains, similar susceptibility rates were found (Kayser, 1981). [1]
Netilmicin activity against Ps. aeruginosa is reduced by high concentrations of magnesium or calcium ions, but not affected by up to 10% serum; more active at pH 8.2 than pH 6.6. Inoculum size (up to 10^7 CFU/mL) does not significantly affect activity except for some Serratia, Providencia, and Proteus. [1]
Netilmicin is resistant to adenylylating enzymes (2' and 4' hydroxyl groups) and phosphorylating enzymes (3' and 2' hydroxyl groups), but is inactivated by acetylating enzymes (2', 6', and 3' positions) except AAC 3-I (produced mainly by Ps. aeruginosa and some Klebsiella). In a US study of 1300 aminoglycoside-resistant strains, 46.9% had adenylylation (netilmicin active), 9.6% phosphorylation (active), 37.9% acetylation (mostly inactive except 7% AAC 3-I), and 5.2% permeability resistance (active). Thus netilmicin is active against over 60% of gentamicin-resistant strains in the US, but less active in regions where acetylation predominates (e.g., Chile, Japan). [1]
Netilmicin shows synergy with beta-lactams (carbenicillin, mezlocillin, azlocillin, cephaloxin, cefamandole) against Gram-negative rods, Staph. aureus, and enterococci, comparable to other aminoglycosides. It showed synergy with penicillin G against enterococci, even those highly resistant to streptomycin and kanamycin. [1]
In vitro antibacterial activity of Netilmicin Sulfate is characterized by its potency against a broad range of bacterial pathogens. Against aminoglycoside-susceptible Gram-negative strains, MIC₉₀ values typically range from 0.25 to 4 μg/mL. Against E. coli, MIC₉₀ values are typically 0.5-2 μg/mL. Against Pseudomonas aeruginosa, MIC₉₀ values are typically 2-8 μg/mL. Against Klebsiella pneumoniae, MIC₉₀ values are typically 0.5-4 μg/mL. Netilmicin is active against some aminoglycoside-resistant strains that are resistant to gentamicin. The compound's activity is concentration-dependent, with higher concentrations achieving more rapid bacterial killing. Netilmicin shows synergistic activity with β-lactam antibiotics (e.g., penicillins, cephalosporins) against certain organisms. In time-kill assays, Netilmicin exhibits rapid bactericidal activity, with a >3 log10 reduction in CFU/mL within 4-8 hours at concentrations ≥ MIC. The compound's activity is reduced in the presence of divalent cations (Mg²⁺, Ca²⁺), acidic pH, and anaerobic conditions.

In mouse protection tests, netilmicin demonstrated efficacy comparable to or better than gentamicin against various pathogens (data not detailed). [1]
In an experimental E. coli meningitis rabbit model, netilmicin produced good bactericidal effect (though not directly compared in detail). [1]
Clinical studies: In open studies, netilmicin (mean dose 4.4 mg/kg/day) cured 84% of 25 patients with severe Gram-negative rod sepsis, including 6 of 9 with gentamicin-resistant pathogens. [1]
Haverkorn (1983): 33/34 patients with systemic infections (peritonitis, septicaemia) responded successfully with median peak serum concentrations of 8 mg/L. [1]
Buckwold et al. (1979): clinical improvement in 36/37 (97%) Gram-negative infections (pyelonephritis, osteomyelitis, etc.). [1]
Nordstrom et al. (1979): 44/52 patients improved (21 by netilmicin alone, 23 by combination). [1]
Geisler et al. (1980): 72% clinical improvement in 36 febrile leukaemia/lymphoma patients with proven infection, using netilmicin 2.5-3 mg/kg q8h initially then 1.5-2.5 mg/kg q8h, combined with ampicillin and methicillin. [1]
Aroney et al. (1981): 13/17 (76.5%) cancer patients with serious infections responded to netilmicin 2 mg/kg q8h. [1]
Jahre et al. (1979): 28/33 (85%) complete clinical and bacteriological cure, including all 18 with bacteraemia. [1]
Mummery (1982): 96% clinical response, 73% bacteriological response in 25 patients with severe infections (netilmicin 150 mg q12h). [1]
Cox (1979): 86% success in 22 hospitalised patients with urinary tract infection and bacteraemia (netilmicin 2 mg/kg q8h). [1]
Peddie et al. (1980): 14/15 (93%) cured with netilmicin 2 mg/kg q12h for complicated urinary tract infections. [1]
Hellum et al. (1980): 94% success (33/35) using higher dose (200 mg q8h, mean peak 12.6 mg/L), including 12/14 septicaemias. [1]
Perera et al. (1982): 27/31 (87%) with life-threatening sepsis responded to netilmicin 200 mg twice daily (6.0-7.2 mg/kg/day); 13/14 bacteraemias, 9/12 pneumonias improved. [1]
Hann et al. (1983): netilmicin (2 mg/kg q8h) combined with beta-lactams in neutropenic patients with suspected septicaemia gave 74% success in microbiologically documented Gram-negative and staphylococcal infections. [1]
Comparative studies: Frazier et al. (1980): netilmicin vs gentamicin (both 8 mg/kg/day in children with malignancies) – all 15 patients with documented sepsis responded to each. [1]
Varghese et al. (1983): netilmicin (2.5 mg/kg q8h) vs gentamicin – all patients responded. [1]
Schnider et al. (1979): netilmicin (2 mg/kg/day) vs gentamicin (3 mg/kg/day) for pelvic inflammatory disease – 85.7% vs 75.8% response (not significant). [1]
Weissenbacher (1981): netilmicin vs gentamicin (100 mg q8h) – cure rates 87% vs 95% (NS). [1]
Love et al. (1979): netilmicin (280 mg/m2/day) vs gentamicin (200 mg/m2/day) vs amikacin (600 mg/m2/day), each with ticarcillin, in febrile neutropenic patients – overall 72% of bacteraemias improved, no significant difference. [1]
Herting et al. (1981) multicentre: netilmicin (4-6.5 mg/kg/day) vs gentamicin (3-5 mg/kg/day) in 755 patients; favourable clinical response 94.2% vs 89.6% (p=0.05 for bacteriological response, 95.7% vs 91%). Netilmicin better for K. pneumoniae (97.7% vs 86.0%), Enterobacter (96% vs 84%), P. mirabilis (96.3% vs 84.4%), Ps. aeruginosa (88.4% vs 80.0%). [1]
Barza et al. (1980): netilmicin (2.5 mg/kg q8h) vs amikacin (5 mg/kg q8h) – all 18 evaluable patients responded. [1]
Hewitt et al. (1979): netilmicin vs amikacin with carbenicillin or cefazolin in neutropenics – efficacy 83.3% vs 80.1% (NS). [1]
Lerner et al. (1983) multicentre: netilmicin (4 mg/kg/day) vs tobramycin (3 mg/kg/day) each with ticarcillin – clinical recovery 91% vs 93%, bacteriologic response 89% vs 87% (NS). Netilmicin had significantly lower ototoxicity (3% vs 12%, p=0.037). [1]
In vivo activity of Netilmicin Sulfate has been demonstrated in animal models of infection and in clinical use. In murine models of sepsis and pneumonia caused by Gram-negative bacteria, Netilmicin administered intravenously or intramuscularly at doses of 2.5-10 mg/kg reduces bacterial loads and improves survival. In clinical studies, Netilmicin is used for the treatment of serious infections including sepsis, pneumonia, urinary tract infections, intra-abdominal infections, and skin and soft tissue infections, particularly those caused by gentamicin-resistant organisms. The compound is administered intravenously or intramuscularly, typically at doses of 4-7.5 mg/kg/day in divided doses. Netilmicin's efficacy is comparable to that of gentamicin and tobramycin, but with potentially reduced nephrotoxicity in some studies. The compound's clinical efficacy depends on achieving adequate peak serum concentrations (Cmax/MIC ratio ≥ 8-10) and appropriate dosing based on renal function.

For in vitro antibacterial susceptibility testing with Netilmicin Sulfate, the following protocol is used following CLSI guidelines: Bacterial isolates are cultured on appropriate agar media. A bacterial suspension is prepared in sterile saline to a turbidity equivalent to a 0.5 McFarland standard (approximately 1-2 × 10⁸ CFU/mL). The suspension is diluted 1:100 in cation-adjusted Mueller-Hinton broth (CAMHB) to achieve a final inoculum of approximately 5 × 10⁵ CFU/mL. Netilmicin is serially diluted two-fold in 96-well microtiter plates in CAMHB to achieve final concentrations ranging from 0.06 to 64 μg/mL. The bacterial suspension is added to each well, and the plates are incubated at 35-37°C for 16-20 hours. The MIC is determined as the lowest concentration of the compound that completely inhibits visible bacterial growth. Quality control strains (e.g., E. coli ATCC 25922, P. aeruginosa ATCC 27853, S. aureus ATCC 29213) are included in each run. For time-kill assays, bacteria are treated with Netilmicin at concentrations of 1-4 × MIC, and aliquots are plated at various time points for CFU enumeration.

In vitro activity determined by twofold dilution tests on Mueller-Hinton agar at pH 7.2-7.4 with inoculum of 10^3-10^4 organisms, incubated 24-48 hours (Miller et al., 1976). [1]
Synergy studies: checkerboard or time-kill methods with various beta-lactams. [1]
For in vitro cell-based assays with Netilmicin Sulfate, the following typical protocol is used: For cytotoxicity assessment, mammalian cells (e.g., HEK293 kidney cells, HepG2 liver cells, or renal proximal tubule epithelial cells) are cultured in appropriate media at 37°C in 5% CO₂. Cells are seeded in 96-well plates at 5,000-10,000 cells per well and allowed to adhere overnight. Netilmicin is dissolved in water or culture medium to final concentrations ranging from 0.1 to 1000 μg/mL. Cells are treated for 24-72 hours. Cell viability is assessed using the MTT or CellTiter-Glo assay to determine the CC50. For assessment of nephrotoxicity, renal proximal tubule epithelial cells are treated with Netilmicin, and markers of kidney injury (KIM-1, NGAL) are measured by ELISA. Apoptosis is assessed by Annexin V-FITC/PI staining and flow cytometry. Oxidative stress is assessed using DCFH-DA staining. For assessment of antibacterial mechanism, bacterial cells are treated with Netilmicin and protein synthesis is measured by [³H]-leucine incorporation. Ribosomal binding is assessed using ribosome isolation and fluorescence labeling.

For in vivo animal studies with Netilmicin Sulfate, the following general protocol is used: For efficacy studies, female BALB/c mice (6-8 weeks old, 18-22 g) are infected intraperitoneally with a lethal dose of a bacterial pathogen (e.g., E. coli or P. aeruginosa, 10⁶-10⁷ CFU). Netilmicin is administered subcutaneously or intravenously at doses of 1, 3, 10, and 30 mg/kg, typically 1 and 4 hours post-infection, or twice daily for 3 days. Survival is monitored for 7-14 days. For thigh infection models, mice are rendered neutropenic by cyclophosphamide treatment, infected intramuscularly in the thigh, and treated with Netilmicin. Thighs are harvested for bacterial CFU enumeration. For pharmacokinetic studies, blood and tissue samples (kidney, liver, lung) are collected at various time points after dosing, and Netilmicin concentrations are analyzed by immunoassay or LC-MS/MS. For toxicology studies, animals are treated with Netilmicin at various doses for up to 28 days, and renal function (BUN, creatinine), auditory function (auditory brainstem response), and histopathology (kidney, inner ear) are assessed.

Absorption, Distribution and Excretion
After intramuscular injection, it is rapidly and completely absorbed, reaching peak serum concentrations within 30-60 minutes. Aminoglycosides are poorly absorbed orally. Local absorption is also poor unless severe skin damage is present. Netilmicin is poorly absorbed in the intact gastrointestinal tract after oral administration. After intramuscular injection, the drug is rapidly and completely absorbed. Following absorption, netilmicin is rapidly distributed to tissues, sputum, and pericardial, synovial, and peritoneal fluids…primarily in extracellular fluid…volume of distribution…approximately 20% of body weight. Protein binding has been reported to be 0-30%. Netilmicin crosses the placenta and is detectable in umbilical cord blood. A small amount of the drug is distributed into breast milk. …It is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. In adults with normal renal function, 74% of a 2 mg/kg dose of netilmicin is excreted unchanged within 24 hours; in adults with creatinine clearance of 30-80 or 10-30 mL/min, or in adults without renal function, 55%, 25%, and 15% of the dose are excreted in the urine within 24 hours, respectively. Netilmicin can be removed by hemodialysis. It can also be removed by peritoneal dialysis, but less effectively than hemodialysis. Metabolites/Metabolites: There is no evidence of metabolic conversion; typically 80% is recovered in the urine within 24 hours. Biological Half-Life: 2.5 hours. In adults with normal renal function, the plasma elimination half-life after a single intravenous or intramuscular injection of netilmicin is approximately 2-2.5 hours. The serum half-life has been reported to be 18 hours in adults with creatinine clearance of 10-30 mL/min, while in adults without renal function, the serum half-life exceeds 30 hours. The elimination half-life of netilmicin in neonatal plasma is negatively correlated with birth weight, gestational age, and postnatal age. It has been reported that the elimination half-life of plasma in newborns less than 7 days old weighing 1.5-2 kg is approximately 8 hours, and in newborns weighing 3-4 kg it is approximately 4.5 hours. The elimination half-life of plasma in children 6 weeks of age and older is 1.5-2 hours.

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Animal: Guinea-pig pharmacokinetics after single IV injection of 40 mg/kg; netilmicin entered perilymph more rapidly and cleared more rapidly than gentamicin or tobramycin (Chung et al., 1982). [1]
Human: In normal volunteers, netilmicin has elimination half-life of about 2.5 hours, volume of distribution ~23% of body weight, renal clearance ~70% of creatinine clearance. Over 70% of dose recovered in urine in 24 hours. Urine concentrations ~150 mg/L after 2 mg/kg dose. Peak serum concentrations ~3.5 times the IM dose in mg/kg, achieved within 30-60 min. Detectable serum concentrations persist 8-12 hours. Penetrates sputum, pericardial, pleural, peritoneal, synovial fluids; low bile concentrations; poor blood-brain barrier penetration even with inflammation. No evidence of metabolism. Long terminal half-life ~33 hours in healthy adults (Kahlmeter, 1980). [1]
In patients with renal impairment: clearance reduced; half-life increases sharply when creatinine clearance ≤40 mL/min but cannot be accurately predicted (Kahlmeter, 1980). [1]
In neonates (preterm <34 weeks): half-life ~5 hours (Kahlmeter, 1980). Chindasilpa et al. (1980): 2 mg/kg dose gave mean peak 4.4 mg/L; half-life 3.8 hours in infants <1 week, 3 hours in >1 week. Recommended larger dose (3 mg/kg) and loading dose. Peitersen et al. (1980): 6-7 mg/kg/day in neonates gave mean peak 7.7 mg/L, trough 2.1 mg/L. [1]
Varghese et al. (1983): in children (2 months-13 years), netilmicin 2.5 mg/kg IM gave mean 1-hour concentration 6.0 mg/L (significantly higher than gentamicin 4.3 mg/L), half-life 194 min (similar to gentamicin), volume of distribution 0.326 L/kg (significantly less than gentamicin 0.425). [1]
The pharmacokinetic properties of Netilmicin Sulfate are well-characterized. After intravenous or intramuscular administration, Netilmicin is rapidly distributed into the extracellular fluid, with a volume of distribution of approximately 0.2-0.3 L/kg. The compound does not bind significantly to plasma proteins (<10%). Netilmicin is primarily excreted unchanged in the urine by glomerular filtration, with an elimination half-life of approximately 2-3 hours in patients with normal renal function. The half-life is prolonged in patients with renal impairment, requiring dose adjustment. Netilmicin penetrates poorly into the cerebrospinal fluid, but achieves therapeutic concentrations in most tissues, including the lungs, kidneys, and soft tissues. The compound is not significantly metabolized. The pharmacokinetics of Netilmicin are linear over the therapeutic dose range. Monitoring of peak and trough serum concentrations is recommended to optimize dosing and minimize toxicity. Peak concentrations of 6-10 μg/mL and trough concentrations of <2 μg/mL are typically targeted.

Protein Binding
Protein binding rates are low and depend on test conditions (primarily the concentration of cations in the test medium). Interactions The simultaneous or sequential use of two or more aminoglycoside antibiotics should be avoided, regardless of the route of administration. Concurrent use of capreomycin and aminoglycoside antibiotics should also be avoided, as this may increase the risk of ototoxicity, nephrotoxicity, and neuromuscular blockade; hearing loss may occur, and may progress to deafness even after discontinuation of the drug; hearing loss may be reversible but is usually permanent; neuromuscular blockade may lead to skeletal muscle weakness and respiratory depression or paralysis (apnea). Furthermore, the simultaneous use of two or more aminoglycoside antibiotics may reduce bacterial uptake of each drug because these drugs compete for the same uptake mechanisms. /Aminoglycosides/
When used concurrently with drugs that have neuromuscular blocking effects, including halogenated hydrocarbon inhaled anesthetics, opioid analgesics, and large citrate anticoagulant infusions, close monitoring is necessary because the neuromuscular blocking effect may be enhanced, leading to skeletal muscle weakness and respiratory depression or paralysis (apnea). Caution is advised when using these drugs and aminoglycosides concurrently during or after surgery, especially in cases where incomplete reversal of neuromuscular blockade may occur postoperatively. Treatment with anticholinesterase drugs or calcium salts may help reverse the blockade. /Aminoglycosides/
Vancomycin and aminoglycosides are often used concurrently for the prevention of bacterial endocarditis, treatment of endocarditis caused by streptococci and corynebacteria, treatment of drug-resistant staphylococcal infections, or in patients with penicillin allergy. Appropriate monitoring helps reduce the risk of nephrotoxicity or ototoxicity; renal function tests, serum aminoglycoside and vancomycin concentration monitoring, dose reduction and/or dosing interval adjustments, or the use of other antibacterial drugs may be required. /Aminoglycosides/
Concurrent or sequential use of these drugs (nephrotoxic or ototoxic drugs) with aminoglycosides may increase the risk of ototoxicity or nephrotoxicity; hearing loss may occur, which may progress to deafness even after discontinuation of the drug, and may be reversible but is usually permanent; a series of hearing function tests may be required when using other ototoxic antibacterial drugs concurrently or sequentially; renal function tests may be required. /Aminoglycosides/
For more complete interaction data on netilmicin (9 drugs in total), please visit the HSDB record page.

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Nephrotoxicity: In open studies, incidence varied: Edelstein & Meyer (1978) 26% (rise in serum creatinine ≥50%); Buckwold et al. (1979) 14%; Panwalker et al. (1978) 8% probable; Nordstrom et al. (1979) 10% (≥30% rise); Geisler et al. (1980) 14%; Aroney et al. (1981) 17%; Jahre et al. (1979) 3%; Cox (1979) 18% possible; Peddie et al. (1980) 27% (in patients with underlying renal disease); Hellum et al. (1980) 6% (rise >30 μmol/L); Perera et al. (1982) 10% (≥50% rise); Hann et al. (1983) 7% overall, 2.4% without concomitant amphotericin B. [1]
Comparative studies: Frazier et al. (1980) – no nephrotoxicity in 30 children. Varghese et al. (1983) – transient creatinine rise >50% in 1/13 (8%) netilmicin vs 4/11 (36%) gentamicin. Schnider et al. (1979) – 0/42 netilmicin vs 1/33 gentamicin. Weissenbacher (1981) – 1/40 each. Barza et al. (1980) – 3/37 (8%) netilmicin vs 4/32 (13%) amikacin. Hewitt et al. (1979) – 3% netilmicin vs 2% amikacin. Love et al. (1979) – 2/50 (4%) netilmicin vs 5/58 (9%) gentamicin vs 4/52 (8%) amikacin. Herting et al. (1981) – probable nephrotoxicity 2.2% netilmicin (8/362) vs 3.9% gentamicin (14/362) (NS). Lerner et al. (1983) – 1/116 (1%) netilmicin vs 5/114 (4%) tobramycin (p=0.12). Kahlmeter and Dahlager (1983) review of 139 trials: average nephrotoxicity – netilmicin 8.7% (2360 patients), gentamicin 14.0% (4023), tobramycin 12.9% (2130), amikacin 9.4% (1144). [1]
Ototoxicity: In open studies with audiograms, very low incidence: Edelstein & Meyer (1978) 0/16; Buckwold (1979) 0/34; Panwalker (1978) 1/21; Jahre (1979) 0/5; Peddie (1980) 0/15; Hellum (1980) 0/31; Perera (1982) 0/22; Nordstrom (1979) 0/47; Geisler (1980) 0/55; Hann (1983) 3/70 (2 had prior aminoglycosides). Overall ~1% cochleotoxicity. Vestibular toxicity 0/172 tested. Tjernstrom (1980) and Vesterhaug (1980) prospectively studied 106 patients with ENG and audiograms – only 1 possible subclinical reversible vestibular dysfunction. [1]
Comparative studies: Varghese (1983) 0/8 netilmicin vs 0/3 gentamicin; Weissenbacher (1981) 0/15 netilmicin vs 1/21 gentamicin; Barza (1980) 3/34 (9%) netilmicin vs 7/30 (23%) amikacin; Hewitt (1979) 5/76 (6.6%) netilmicin vs 13/80 (16.3%) amikacin; Love (1979) 1/29 (3%) netilmicin vs 2/32 (6%) gentamicin; Herting (1981) 1/168 (<1%) netilmicin vs 1/29 (3%) amikacin; Lerner (1983) 2/73 (3%) netilmicin vs 10/84 (12%) tobramycin (p=0.037). Kahlmeter and Dahlager (1983) review: cochlear toxicity – netilmicin 2.4% (1338 patients), gentamicin 8.3% (1895), tobramycin 6.1% (572), amikacin 13.9% (713); vestibular toxicity – netilmicin 1.4% (1990 patients), gentamicin 3.2% (535), tobramycin 3.5% (289), amikacin 3.7% (162). [1]
Neuromuscular blockade: not a problem in clinical trials but potential risk. Other rare adverse effects: headache, malaise, visual disturbances, disorientation, tachycardia, paraesthesia, rash, chills, fever, fluid retention, vomiting, diarrhoea; lab abnormalities: increased blood sugar, alkaline phosphatase, AST, ALT, decreased Hb, WBC, platelets, eosinophilia, increased prothrombin time. [1]
The toxicity profile of Netilmicin Sulfate is characterized by its nephrotoxicity and ototoxicity, which are common to aminoglycoside antibiotics. Nephrotoxicity is caused by the accumulation of Netilmicin in renal proximal tubule cells, leading to cellular damage and decreased renal function. The risk of nephrotoxicity is dose-dependent and is increased in patients with pre-existing renal impairment, advanced age, and concomitant use of other nephrotoxic drugs. Ototoxicity, which can affect both hearing (cochlear toxicity) and balance (vestibular toxicity), is caused by the accumulation of Netilmicin in the inner ear. Netilmicin may have a lower risk of nephrotoxicity compared to gentamicin and tobramycin in some studies. Other adverse effects include neuromuscular blockade, allergic reactions, and gastrointestinal disturbances. Netilmicin is contraindicated in patients with known hypersensitivity to aminoglycosides. Monitoring of renal function and auditory function is recommended during therapy. The compound should be used with caution in patients with renal impairment, neuromuscular disorders, and during pregnancy.

Drugs.1984 Jun;27(6):548-78.

According to state or federal labeling requirements, netilmicin sulfate may cause developmental toxicity. Netilmicin is a semi-synthetic 1-N-ethyl derivative of sisomicin, an aminoglycoside antibiotic with similar effects to gentamicin but less toxic to the ears and kidneys. Netilmicin inhibits protein synthesis in susceptible organisms by binding to the bacterial 30S ribosomal subunit, interfering with mRNA binding and receptor tRNA sites. The bactericidal mechanism of action of netilmicin is not fully elucidated. Netilmicin is an aminoglycoside antibacterial drug. Netilmicin is a semi-synthetic, water-soluble aminoglycoside antibiotic derived from sisomicin, a naturally occurring antibiotic produced by the fermentation of Micromonospora inyoensis. Netilmicin binds irreversibly to the 16S rRNA and S12 protein of the bacterial 30S ribosomal subunit. Therefore, this drug interferes with the assembly of the initiation complex between mRNA and bacterial ribosomes, thereby inhibiting the initiation of protein synthesis. Furthermore, netilmicin induces mRNA template misreading and causes frameshift translation, leading to premature translation termination. This ultimately results in bacterial cell death. Netilmicin sulfate is the sulfate form of netilmicin, a semi-synthetic, water-soluble aminoglycoside antibiotic. Netilmicin is derived from sisomicin, a naturally occurring aminoglycoside antibiotic produced by the fermentation of Micromonospora inyoensis. Netilmicin binds irreversibly to the 16S rRNA and S12 protein of the bacterial 30S ribosomal subunit. Therefore, this drug interferes with the assembly of the initiation complex between mRNA and bacterial ribosomes, thereby inhibiting the initiation of protein synthesis. Furthermore, netilmicin can induce mRNA template misreading, leading to frameshift translation, resulting in premature translation termination. This ultimately results in bacterial cell death. Netilmicin is a semi-synthetic 1-N-ethylsimethicone derivative. Simethicone is an aminoglycoside antibiotic with similar activity to gentamicin but less toxic to the ears and kidneys. Indications: Used to treat bacteremia, sepsis, respiratory infections, skin and soft tissue infections, burns, wounds, and perioperative infections caused by susceptible strains of bacteria. Mechanism of Action: Aminoglycoside antibiotics like netilmicin bind irreversibly to specific 30S subunit proteins and 16S rRNA. Specifically, netilmicin binds to four nucleotides of 16S rRNA and one amino acid of the S12 protein. This interferes with the decoding site near nucleotide 1400 in the 30S subunit 16S rRNA. This region interacts with the wobble base in the tRNA anticodon. This leads to interference with the initiation complex, misreading of mRNA, resulting in the insertion of incorrect amino acids into the polypeptide chain, producing nonfunctional or toxic peptides, and causing polyribosomes to dissociate into nonfunctional monomeric ribosomes, preventing bacteria from synthesizing proteins essential for their growth. Aminoglycosides are generally effective against bacteria. Although their exact mechanism of action is not fully elucidated, these drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to the 30S ribosomal subunit. /Aminoglycosides/
/Aminoglycosides/ Inhibit protein biosynthesis and reduce the fidelity of genetic code translation. /Aminoglycosides/

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Therapeutic Use
Gentamicins
Netilmicin is indicated for the treatment of biliary tract infections caused by susceptible bacteria. /Included in US Product Label/
Netilmicin is indicated for the treatment of bone and joint infections caused by susceptible bacteria. /Included in US Product Label/
Netilmicin is indicated for the treatment of central nervous system infections caused by susceptible bacteria. /Included in the US product label/
For more complete therapeutic use data for netilmicin (13 in total), please visit the HSDB record page.

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Drug Warnings
It has been reported that central nervous system depression, manifested as coma, hypotonia, drowsiness, or deep respiratory depression, may occur in infants and young children receiving streptomycin if the dose exceeds the maximum recommended dose. However, all aminoglycosides carry the potential risk of causing neuromuscular blockade. /Aminoglycosides/
Caution should be exercised in premature infants and newborns, including with aminoglycosides, as their renal function is not yet fully developed, which may lead to prolonged elimination half-life and toxicity associated with aminoglycosides. Dosage adjustments may be necessary for pediatric patients.
Caution should be exercised in elderly patients due to the toxicity of aminoglycosides, and they should only be used after considering alternatives with less toxicity and/or finding them ineffective. Elderly patients are more prone to age-related renal decline. The recommended dose should not be exceeded, and patients' renal function should be closely monitored during treatment. Elderly patients may need to reduce their daily dose of aminoglycosides based on their age, declining renal function, and weight loss. Furthermore, hearing loss may occur even in patients with normal renal function. /Aminoglycosides/
Neuromuscular blockade, respiratory paralysis, ototoxicity, and nephrotoxicity may occur after topical application of aminoglycosides during local irrigation and surgery. /Aminoglycosides/
For more complete data on drug warnings for netilmicin (17 in total), please visit the HSDB record page.

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Pharmacodynamics
Netilmicin is a semi-synthetic, water-soluble aminoglycoside antibiotic produced by fermentation of Micromonas ineos, a species of actinomycete. Aminoglycosides are primarily used to treat infections caused by aerobic Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. Low concentrations of netilmicin are active against a variety of pathogens, including Escherichia coli, Klebsiella pneumoniae-Enterobacter-Serratia marcescens, Citrobacter spp., and Proteus spp. (indole-positive and indole-negative), including Proteus mirabilis, Pseudomonas Morganella, Pseudomonas repens, Proteus vulgaris, Pseudomonas aeruginosa, and Neisseria gonorrhoeae. Netilmicin is also active in vitro against isolates of Haemophilus influenzae, Salmonella spp., and Shigella spp. It is effective against both penicillinase-producing and non-penicillinase-producing staphylococci (including methicillin-resistant strains). Some Providencia spp., Acinetobacter spp., and Aeromonas spp. strains are also sensitive to netilmicin. Many of these strains are resistant to other aminoglycoside antibiotics (such as kanamycin, gentamicin, tobramycin, and sisomicin) but sensitive to netilmicin in vitro. Occasionally, strains resistant to amikacin but sensitive to netilmicin are also found. Netilmicin, when used in combination with penicillin G, exhibits synergistic bactericidal activity against most Enterococcus faecalis strains. Netilmicin, when used in combination with carbenicillin or ticarcillin, shows synergistic effects against many Pseudomonas aeruginosa strains. Furthermore, netilmicin, when used in combination with carbenicillin, azlocillin, mezlocillin, cefamandole, cefotaxime, or cefadroxil, can inhibit many multi-antibiotic-resistant Serratia isolates. Aminoglycoside antibiotics are mostly ineffective against anaerobic bacteria, fungi, and viruses.

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Netilmicin is a semisynthetic derivative of sisomicin with an ethyl group at the 1-N position of the deoxystreptamine ring. It was selected for its activity against aminoglycoside-resistant bacteria and reduced chronic toxicity in animals. It is resistant to inactivation by adenylylating and phosphorylating enzymes but susceptible to most acetylating enzymes except AAC 3-I. Netilmicin is indicated for serious Gram-negative infections, especially in immunocompromised hosts, and is recommended where ototoxicity is a particular risk (e.g., dialysis patients, blind, elderly, neonates, patients needing prolonged or repeated aminoglycoside therapy). Dosage: adults with normal renal function – 4.0-7.0 mg/kg/day in 3 divided doses (or 2 divided doses) for urinary or systemic infections; up to 7.5 mg/kg/day for life-threatening infections. Children ≤12 years – 6-7.5 mg/kg/day (2-2.5 mg/kg q8h). Neonates >1 week – 7.5-9 mg/kg/day (2.5-3 mg/kg q8h); neonates ≤1 week – 6 mg/kg/day (3 mg/kg q12h). In renal impairment, increase dosing interval (e.g., multiply serum creatinine in mg/100mL by 8 to get interval in hours) or reduce maintenance dose. Haemodialysis removes ~50% over 8 hours. Intrathecal dose: 10 mg daily (pure sterile compound, not the IV formulation containing preservatives). [1]
Netilmicin Sulfate (SCH-20569) (CAS# 56391-57-2) is a semisynthetic aminoglycoside antibiotic for serious infections, particularly gentamicin-resistant strains. It has a molecular formula of C21H41N5O7·2.5H2SO4 and a molecular weight of approximately 720.8 g/mol. Future research could focus on developing new aminoglycosides with reduced nephrotoxicity and ototoxicity, investigating novel dosing regimens to optimize efficacy and safety, and exploring combination therapies to overcome resistance.

C21H41N5O7.2.5H2O4S

1441.55

475.3

C, 43.97; H, 7.56; N, 12.21; O, 30.68; S, 5.59

56391-57-2

441306

Solid powder

1.32 g/cm3

684.3ºC at 760 mmHg

>194ºC (dec.)

367.7ºC

1.504

8

12

8

33

673

11

O([C@]1([H])[C@@]([H])([C@]([H])([C@](C([H])([H])[H])(C([H])([H])O1)O[H])N([H])C([H])([H])[H])O[H])[C@]1([H])[C@]([H])([C@@]([H])([C@]([H])(C([H])([H])[C@@]1([H])N([H])C([H])([H])C([H])([H])[H])N([H])[H])O[C@]1([H])[C@@]([H])(C([H])([H])C([H])=C(C([H])([H])N([H])[H])O1)N([H])[H])O[H]

PQHZSWZPVGHDEZ-UIQTUGNFSA-N

InChI=1S/C21H41N5O7.H2O4S/c1-4-26-13-7-12(24)16(32-19-11(23)6-5-10(8-22)31-19)14(27)17(13)33-20-15(28)18(25-3)21(2,29)9-30-20;1-5(2,3)4/h5,11-20,25-29H,4,6-9,22-24H2,1-3H3;(H2,1,2,3,4)/t11-,12+,13-,14+,15-,16-,17+,18-,19-,20-,21+;/m1./s1

(2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4-Amino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol sulfate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 1 mg/mL (1.39 mM)
H2O : 100~288 mg/mL (138.74 mM)

Solubility in Formulation 1: 50 mg/mL (69.37 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)