Netilmicin Sulfate, a semisynthetic and water soluble analog of sisomicin, is a member of the aminoglycoside family of antibiotics. It is active against most Gram-negative and some Gram-positive bacteria, including certain strains resistant to gentamicin. 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.

Physicochemical Properties

Molecular Formula	C21H41N5O7.2.5H2O4S
Molecular Weight	1441.55
Exact Mass	475.3
Elemental Analysis	C, 43.97; H, 7.56; N, 12.21; O, 30.68; S, 5.59
CAS #	56391-57-2
Related CAS #	56391-57-2
PubChem CID	441306
Appearance	Solid powder
Density	1.32 g/cm3
Boiling Point	684.3ºC at 760 mmHg
Melting Point	>194ºC (dec.)
Flash Point	367.7ºC
LogP	1.504
Hydrogen Bond Donor Count	8
Hydrogen Bond Acceptor Count	12
Rotatable Bond Count	8
Heavy Atom Count	33
Complexity	673
Defined Atom Stereocenter Count	11
SMILES	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]
InChi Key	PQHZSWZPVGHDEZ-UIQTUGNFSA-N
InChi Code	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
Chemical Name	(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
Synonyms	Sch-20569; Sch 20569; Sch 20569
HS Tariff Code	2934.99.9001
Storage	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.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In vitro activity: 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.
ln Vivo
Animal Protocol
ADME/Pharmacokinetics	Absorption, Distribution and Excretion Rapidly and completely absorbed after IM administration, peak serum levels were achieved within 30-60 minutes. Aminoglycosides are poorly absorbed orally. Topical absorption is also poor unless severe skin damage is present. Netilmicin is poorly absorbed from the intact GI tract following oral administration. The drug is rapidly and completely absorbed following IM administration. Following absorption, netilmicin rapidly distributes into tissues, sputum, and pericardial, synovial, and peritoneal fluids. ...distributed principally in the extracellular fluid volume... The volume of distribution ...is approximately 20% of body weight. The drug is reportedly 0-30% protein bound. Netilmicin crosses the placenta and has been detected in cord blood. Small amounts of the drug are distributed into milk. ...is not metabolized and is excreted unchanged in urine mainly by glomerular filtration. In adults with normal renal function, 74% of a 2 mg/kg dose of netilmicin is excreted unchanged within 24 horus: in adults with creatinine clearances of 30-80 or 10-30 mL/min or in anephric adults, 55, 25, or 15% of the dose is excreted in urine within 24 hours, respectively. Netilmicin is removed by hemodialysis. The drug is also removed by peritoneal dialysis but less readily than by hemodialysis. Metabolism / Metabolites No evidence of metabolic transformation, typically 80% is recoverable in the urine within 24 hours Biological Half-Life 2.5 hours The plasma elimination half-life on netilmicin is about 2-2.5 hr following IV or IM administration of a single dose in adults with normal renal function. The serum half-life is reported to be 18 hr in adults with creatinine clearances of 10-30 mL/min and more than 30 hr in anephric adults. The plasma elimination half-life of netilmicin in neonates is inversely related to birthweight and gestational and postnatal age and has been reported to be about 8 or 4.5 hr in neonates less than 7 days of age weighing 1.5-2 or 3-4 kg, respectively. The plasma elimination half-life for children 6 weeks of age and older is 1.5-2 hr.
Toxicity/Toxicokinetics	Protein Binding Protein-binding of is low and depends on the test conditions (mainly the concentration of cations in the test medium). Interactions Concurrent and/or sequential use of 2 or more aminoglycosides by any route or concurrent use of capreomycin with aminoglycosides should be avoided since the potential for ototoxicity, nephrotoxicity, and neuromuscular blockade may be increased; hearing loss may occur and may progress to deafness even after discontinuation of the drug; loss of hearing may be reversible, but usually is permanent; neuromuscular blockade may result in skeletal muscle weakness and respiratory depression or paralysis (apnea). Also, concurrent use of 2 or more aminoglycosides may result in reduced bacterial uptake of each one since the medications compete for the same uptake mechanism. /Aminoglycosides/ Concurrent use of medications with neuromuscular blocking activity, including halogenated hydrocarbon inhalation anesthetics, opioid analgesics, and massive transfusions with citrate anticoagulated blood, with aminoglycosides should be carefully monitored since neuromuscular blockade may be enhanced, resulting in skeletal muscle weakness and respiratory depression or paralysis (apnea); caution is recommended when these medications and aminoglycosides are used concurrently during surgery or in the postoperative period, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively; treatment with anticholinesterase agents or calcium salts may help reverse the blockade. /Aminoglycosides/ Vancomycin and aminoglycosides must often be administered concurrently in the prophylaxis of bacterial endocarditis, in the treatment of endocarditis caused by streptococci and Corynebacteria species, in the treatment of resistant staphylococcal infections, or in penicillin-allergic patients; appropriate monitoring will help to reduce the risk of nephrotoxicity or ototoxicity; renal function determinations, serum aminoglycoside and vancomycin concentrations, dosage reductions, and/or dosage interval adjustments, or alternate antibacterials, may be required. /Aminoglycosides/ Concurrent or sequential use of these medications /nephrotoxic or ototoxic medications/ with aminoglycosides may increase the potential for ototoxicity or nephrotoxicity; hearing loss may occur and may progress to deafness even after discontinuation of the drug and may be reversible, but usually is permanent; serial audiometric function determinations may be required with concurrent or sequential use of other ototoxic antibacterials; renal function determinations may be required. /Aminoglycosides/ For more Interactions (Complete) data for NETILMICIN (9 total), please visit the HSDB record page.
References	Drugs.1984 Jun;27(6):548-78.
Additional Infomation	Netilmicin Sulfate can cause developmental toxicity according to state or federal government labeling requirements. Netilmicin is a semisynthetic 1-N-ethyl derivative of sisomycin, an aminoglycoside antibiotic with action similar to gentamicin, but less ear and kidney toxicity. Netilmicin inhibits protein synthesis in susceptible organisms by binding to the bacterial 30S ribosomal subunit and interfering with mRNA binding and the acceptor tRNA site. The bactericidal effect of netilmiicin is not fully understood. Netilmicin is an Aminoglycoside Antibacterial. Netilmicin is a semisynthetic, water soluble aminoglycoside derived from sisomicin, a naturally occurring antibiotic produced by the fermentation of Micromonospora inyoensis. Netilmicin irreversibly binds to the 16S rRNA and S12 protein of the bacterial 30S ribosomal subunit. As a result, this agent interferes with the assembly of initiation complex between mRNA and the bacterial ribosome, thereby inhibiting the initiation of protein synthesis. In addition, netilmicin induces misreading of the mRNA template and causes translational frameshift, thereby results in premature termination. This eventually leads to bacterial cell death. Netilmicin Sulfate is the sulfate salt form of netilimicin, a semisynthetic, water soluble aminoglycoside antibiotic. Netilmicin is derived from sisomicin, a naturally occurring aminoglycoside antibiotic produced by the fermentation of Micromonospora inyoensis. Netilmicin irreversibly binds to the 16S rRNA and S12 protein of the bacterial 30S ribosomal subunit. As a result, this agent interferes with the assembly of initiation complex between mRNA and the bacterial ribosome, thereby inhibiting the initiation of protein synthesis. In addition, netilmicin induces misreading of the mRNA template and causes translational frameshift, thereby results in premature termination. This eventually leads to bacterial cell death. Semisynthetic 1-N-ethyl derivative of SISOMYCIN, an aminoglycoside antibiotic with action similar to gentamicin, but less ear and kidney toxicity. Drug Indication For the treatment of bacteremia, septicaemia, respiratory tract infections, skin and soft-tissue infection, burns, wounds, and peri-operative infections caused by susceptible strains. Mechanism of Action Aminoglycosides like netilmicin "irreversibly" bind to specific 30S-subunit proteins and 16S rRNA. Specifically netilmicin binds to four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes, leaving the bacterium unable to synthesize proteins vital to its growth. Aminoglycosides are usually bacterial in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/ /AMINOGLYCOSIDES/ INHIBIT PROTEIN BIOSYNTHESIS & DECR FIDELITY OF TRANSLATION OF GENETIC CODE. /AMINOGLYCOSIDES/ Therapeutic Uses Gentamycins Netilmicin is indicated in the treatment of biliary tract infections caused by susceptible organisms. /Included in US product labeling/ Netilmicin is indicated in the treatment of bone and joint infections caused by susceptible organisms. /Included in US product labeling/ Netilmicin is indicated in the treatment of central nervous system infections caused by susceptible organisms. /Included in US product labeling/ For more Therapeutic Uses (Complete) data for NETILMICIN (13 total), please visit the HSDB record page. Drug Warnings CNS depression, characterized by stupor, flaccidity, coma, or deep respiratory depression, has been reported in very young infants receiving streptomycin at doses that exceeded the maximum recommended amount. However, all aminoglycosides have this potential to cause neuromuscular blockade. /Aminoglycosides/ These aminoglycosides /including netilmicin/ should be used with caution in premature infants and neonates because of these patients' immature renal capability, which may result in prolonged elimination half-life and aminoglycoside-induced toxicity. Dosage adjustments may be required in pediatric patients. Because of their toxicity, aminoglycosides should be used with caution in elderly patients, only after less toxic alternatives have been considered and/or found ineffective. Elderly patients are more likely to have an age-related decrease in renal function. Recommended doses should not be exceeded, and the patient's renal function should be carefully monitored during therapy. Geriatric patients may require smaller daily doses of aminoglycosides in accordance with their increased age, decreased renal function, and, possibly, decreased weight. In addition, loss of hearing may result even in patients with normal renal function. /Aminoglycosides/ Neuromuscular blockade, respiratory paralysis, ototoxicity, and nephrotoxicity may occur following local irrigation and following topical application of aminoglycosides during surgery. /Aminoglycosides/ For more Drug Warnings (Complete) data for NETILMICIN (17 total), please visit the HSDB record page. Pharmacodynamics Netilmicin is a semisynthetic, water soluble antibiotic of the aminoglycoside group, produced by the fermentation of Micromonospora inyoensis, a species of actinomycete. Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. It is active at low concentrations against a wide variety of pathogenic bacteria including Escherichia coli, bacteria of the Klebsiella-Enterobacter-Serratia group, Citrobacter sp., Proteus sp. (indole-positive and indole-negative), including Proteus mirabilis, P. morganii, P. rettgrei, P. vulgaris, Pseudomonas aeruginosa and Neisseria gonorrhoea. Netilmicin is also active in vitro against isolates of Hemophilus influenzae, Salmonella sp., Shigella sp. and against penicillinase and non-penicillinase-producing Staphylococcus including methicillin-resistant strains. Some strains of Providencia sp., Acinetobacter sp. and Aeromonas sp. are also sensitive to netilmicin. Many strains of the above organisms which are found to be resistant to other aminoglycosides, such as kanamycin, gentamicin, tobramycin and sisomicin, are susceptible to netilmicin in vitro. Occasionally, strains have been identified which are resistant to amikacin but susceptible to netilmicin. The combination of netilmicin and penicillin G has a synergistic bactericidal effect against most strains of Streptococcus faecalis (enterococcus). The combined effect of netilmicin and carbenicillin or ticarcillin is synergistic for many strains of Pseudomonas aeruginosa. In addition, many isolates of Serratia, which are resistant to multiple antibiotics, are inhibited by synergistic combinations of netilmicin with carbenicillin, azlocillin, mezlocillin, cefamandole, cefotaxime or moxalactam. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.

Solubility Data

Solubility (In Vitro)	DMSO : 1 mg/mL (1.39 mM) H2O : 100~288 mg/mL (138.74 mM)
Solubility (In Vivo)	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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	0.6937 mL	3.4685 mL	6.9370 mL
	5 mM	0.1387 mL	0.6937 mL	1.3874 mL
	10 mM	0.0694 mL	0.3468 mL	0.6937 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.