Netilmicin

Netilmicin is a semi-synthetic aminoglycoside derived from sisomicin (4,5-dehydrogentamicin-C1a), a naturally occurring antibiotic produced by fermentation of Micromonospora inyoensis. Its pharmaceutical use is netilmicin sulphate, a white to yellowish white hygroscopic powder which is easily soluble in water but insoluble in acetone and 96 % ethanol. Netilmicin has very low oral bioavailability. Therefore the active ingredient is only suitable for intravenous or topical application. The average half-life is about 2.5h.

Netilmicin irreversibly binds to the 16S rRNA and the S12 protein of the bacterial 30S ribosomal subunit. Consequently, this agent interferes with the formation of the initiation complex between mRNA and the bacterial ribosome, thereby inhibiting the initiation of protein synthesis. In addition, netilmicin induces reading errors at the mRNA template and thus causes a shift of the translation frames, which leads to a premature termination of protein synthesis. As with other amoinoglycoside antibiotics, this ultimately leads to bacterial cell death.

Like other aminoglycosides, the spectrum of activity also includes numerous Gram-negative bacteria. Aminoglycosides are mainly useful for infections with aerobic, Gram-negative bacteria such as Pseudomonas, Acinetobacter and Enterobacter. It is effective in low concentrations against a wide range 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 gonorrhea.

Netilmicin is also effective 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 resistant to other aminoglycosides such as kanamycin, gentamicin, tobramycin and sisomicin are sensitive to netilmicin in vitro. The combination of netilmicin and penicillin G has a synergistic bactericidal effect against most strains of Streptococcus faecalis (Enterococcus). The combined action of netilmicin and carbenicillin or ticarcillin is synergistic for many strains of Pseudomonas aeruginosa. In addition, many isolates of Serratia that are resistant to several antibiotics are inhibited by synergistic combinations of netilmicin with carbenicillin, azlocillin, mezlocillin, cefamandol, cefotaxime or moxalactam. Aminoglycosides are usually ineffective against anaerobic bacteria, fungi and viruses. Netilmicin is less effective against Pseudomonas aeruginosa than other aminoglycosides.

Netilmicin has a nephrotoxic and ototoxic potential. Nephrotoxicity occurs via drug accumulation in renal proximal tubular cells, leading to cell damage. Tubular cells can regenerate despite continued exposure and nephrotoxicity is usually mild and reversible. Netilmicin is less nephrotoxic than neomycin, gentamicin, tobramycin and amikacin.

Otoxicity occurs as a result of irreversible damage to the hair cells of the cochlea and/or the peak of the ampoule crystals in the vestibular complex, causing drug accumulation in the endolymph and perilymph of the inner ear. Otoxicity appears to correlate with total exposure and may be cumulative with further doses of aminoglycosides or other ototoxic drugs (e.g. cisplatin, furosemide). A high-frequency hearing loss is followed by a low-frequency hearing loss, which may be followed by retrograde degeneration of the auditory nerve. Vestibular toxicity can cause dizziness, nausea and vomiting, vertigo and balance problems.

According to some studies, toxicity (inner ear, kidney) is somewhat less pronounced than with tobramycin or gentamicin.

1. Hemsworth S et al (2005) Once-daily netilmicin for neutropenic pyrexia in paediatric oncology. Acta Paediatr 94:268-274
2. Klingenberg C et al (2004) Validation of a simplified netilmicin dosage regimen in infants. Scand J Infect Dis 36:474-479.
3. Brooks JR et al (2004) Use of once-daily netilmicin to treat infants with suspected sepsis in a neonatal intensive care unit. Biol Neonate 86:170-175.