NETILMICIN

Description

This is a semisynthetic derivative of sisomicin, which was developed by ethylation of the 1-N position of the deoxystreptamine ring of sisomicin . Clinically, netilmicin is used as a sulfate. Netilmicin has a similar in vitro antibacterial spectrum to that of gentamicin but, unlike sisomicin, it is active against a proportion of gentamicin-resistant Gram-negative bacilli. However, netilmicin is not active against as wide a range of gentamicin-resistant Gram-negative bacilli as amikacin. Nevertheless, it may be occasionally indicated as an alternative to amikacin for the treatment of infections caused by gentamicin-resistant but netilmicin-susceptible Gram-negative organisms. The following details apply only to netilmicin

Originator

Netromycine,Schering,Switz.,1980

Manufacturing Process

To a solution of 5 g of sisomicin in 250 ml of water add 1 N sulfuric acid until the pH of the solution is adjusted to about 5. To the solution of sisomicin sulfuric acid addition salt thereby formed, add 2 ml of acetaldehyde, stir for 10 minutes, then add 0.85 g of sodium cyanoborohydride. Continue stirring at room temperature for 15 minutes, then concentrate solution in vacuo to a volume of about 100 ml, treat the solution with a basic ion exchange resin [e.g., Amberlite IRA 401S (OH-)], then lyophilize to a residue comprising 1-Nethylsisomicin.
Purify by chromatographing on 200 g of silica gel, eluting with lower phase of a chloroformmethanol-7% aqueous ammonium hydroxide (2:1:1) system. Combine the eluates as determined by thin layer chromatography and concentrate the combined eluates of the major component in vacuo to a residue comprising 1-N-ethylsisomicin (yield 1.25 g). Further purify by again chromatographing on 100 g of silica gel eluting with a chloroform-methanol- 3.5% ammonium hydroxide (1:2:1) system. Pass the combined, like eluates (as determined by thin layer chromatography) through a column of basic ion exchange resin and lyophilize the eluate to obtain 1-N-ethylsisomicin (yield 0.54 g).
There is also a fermentation route to netilmicin as noted by Kleeman & Engel.

Therapeutic Function

Antibiotic

Antimicrobial activity

It is active against a wide range of enterobacteria as well as many Acinetobacter, Pseudomonas, Citrobacter, Proteus and Serratia spp. Staphylococci, including methicillin-resistant and coagulase-negative strains, are usually susceptible. Nocardiae are inhibited by 0.04–1 mg/L. Providencia spp. and anaerobic bacteria are generally resistant.
It is active against some gentamicin-resistant strains, particularly those that synthesize ANT(2″) or AAC(3)-I. It exhibits typical aminoglycoside properties: bactericidal activity at or close to the MIC; greater activity at alkaline pH; depression of activity against Pseudomonas by divalent cations; and synergy with β-lactam antibiotics. Bactericidal synergy can be demonstrated regularly with benzylpenicillin against viridans streptococci and E. faecalis, but seldom against E. faecium, which characteristically synthesizes AAC(6′), to which netilmicin is susceptible.

Acquired resistance

It is resistant to ANT(2), AAC(3)-I and AAC(3)-III, but sensitive to AAC(6). AAC(3)-II confers resistance, but generally to a lesser degree than to gentamicin.
Resistance rates are generally about the same as, or a little lower than, those for gentamicin.

Pharmacology

Netilmicin is also highly effective with respect to Gram-negative microorganisms (blue-pus and colon bacilli, rabbit fever, serratia, providencia, enterobacteria, proteus, salmonella, shigella), as well as a few Gram-positive microorganisms (staphylococci and a few strains of streptococci).
It is used for severe bacterial infections that are caused by microorganisms sensitive to the drug. Synonyms of this drug are netillin, zetamycin, and others.

Pharmacokinetics

C_max 1 mg/kg intramuscular： 4–6 mg/L after 0.5–1 h
2 mg/kg intravenous 30-min infusion： c. 12 mg/L end infusion
5 mg/kg： >10 mg/L after 1 h
Plasma half-life： 2–2.5 h
Volume of distribution： 0.25 L/kg
Plasma protein binding： <10%
The pharmacokinetics are similar to those of gentamicin. In patients receiving 200 mg (2.2–3.6 mg/kg) intramuscularly every 8 h for 10 days, a mean peak plasma concentration of around 14 mg/L was found. Peak concentrations of about 10 mg/L were found in children with pyelonephritis treated with 5 mg/kg per day, compared with peaks of about 5 mg/L in children given 2 mg/kg every 8 h. The serum half-life is linearly inversely related to creatinine clearance in patients with renal impairment. Plasma concentrations decreased by 63% during hemodialysis. In older patients with a mean creatinine clearance of 63 mL/min, the half-life was 6.2 h after a dose of 2 mg/kg.
In the newborn, intramuscular injection of 2.5 mg/kg produced peak plasma concentrations of 1–5 mg/L 1 h after the dose, with a plasma half-life of 4 h. In newborns given 6 mg/kg per day, plasma concentrations were 7.4–13.2 mg/L after 2 h. Half-lives were greater (mean 6.7 h) than in those of >36 weeks postmenstrual age (mean 4.6 h), and pre-dose concentrations were 2.1 and 1.6 mg/L, respectively, suggesting that a lower daily dose (4.5 mg/kg) may be appropriate. Children with cystic fibrosis had a higher total body clearance.
Distribution
Netilmicin is distributed in the extracellular water and in patients with cystic fibrosis the apparent volume of distribution seems not to be increased.
Very little reaches the CSF even in the presence of inflammation. Concentrations of 0.13–0.45 mg/L were found in patients without meningeal inflammation following an intravenous dose of 400 mg. In patients with meningitis, the drug was undetectable, although concentrations of 0.2–5 mg/L could be found later in the course of treatment in some cases.
Excretion
It is excreted unchanged in the urine in the glomerular filtrate, with some tubular reabsorption. Over the first 6 h, about 50% and by 24 h about 80% of the dose appears. No metabolites are known and it is likely that this represents binding to tissues.Clearance on hemodialysis is similar to that reported for gentamicin.

Clinical Use

Severe infections (including septicemia, lower respiratory tract infections, urinary tract infections, peritonitis, endometritis) caused by susceptible strains of Gram-negative bacilli and staphylococci

Side effects

It is considered to be less nephrotoxic than gentamicin, a difference not easily explained since the renal clearance and renal and medullary concentrations of the drugs appear to be similar. Both vestibular and cochlear toxicity appear to be low and vestibular toxicity without audiometric abnormality is rare. In some patients, plasma concentrations up to 30 mg/L over periods exceeding 1 week have not resulted in ototoxicity. Evidence of some renal toxicity in the excretion of granular casts has occurred fairly frequently in patients receiving 7.5 mg/kg per day, and is more likely to occur in the elderly and in those receiving higher doses or longer courses. In patients treated for an average of 35 days with 2.4–6.9 mg/kg per day, there was no effect on initially normal renal function, even in the elderly. Long-term treatment led to an increase in elimination half-life from 1.5 to 1.9 h. Nephrotoxicity has been observed in some diabetic patients. Overall estimates of the frequency of nephrotoxicity have ranged from 1% to 18%. Increases in serum transaminase and alkaline phosphatase concentrations have been seen in some patients without other evidence of hepatic impairment.
Once-daily dosing is thought to be safer than twice or three times daily dosing.

Synthesis

Netilmicin, O-3-deoxy-4-C-methyl-3-(methylamino)-β-L-arabinopyranosyl (1→4)-O-[2,6-diamino-2,3,4,6-tetradeoxy-α-D-glycero-hex-4-enopyranosyl]-(1→6)- 2-deoxy-N3 -ethyl-L-streptamine (3.4.10), is also a semisynthetic antibiotic that is synthesized in two stages from another known antibiotic, sisomicin (3.4.11), which is produced by a culture of M. inyoensis. In the first stage of synthesis, reacting sisomicin with acetaldehyde in a specific acidic medium of pH 5 is successful in selectively giving an imine at the 3-amino group of the 2-deoxystreptamine region of the molecule. The resulting imine is then hydrogenated by sodium cyanoborohydride to an ethylamino derivative —netilmicin (32.4.12).

Drug interactions

Netilmicin is inactivated less than gentamicin and tobramycin by high concentrations of various penicillins . At the highest penicillin concentration studied (500 mg/ml), inactivation of netilmicin was a little higher than amikacin. The in vivo inactivation of netilmicin was compared with gentamicin in patients with end-stage renal disease. The terminal elimination half-life for gentamicin decreased from 60 to 25 hours, whereas the values for netilmicin remained essentially the same at 42 to 40 hours. Such patients receiving combinations of netilmicin and various penicillins will not require further dose adjustment. Netilmicin differed from other aminoglycosides by reducing T3 or triiodothyroxime levels in serum.