Gentamicin - BioPharma Notes

Gentamicin is aminoglycoside antibiotics used to treat infections caused by aerobic gram-negative bacteria. It is produced by Micromonospora purpura.
Gentamicin is aminoglycoside of first choice because of its reliability, availability and low cost. It is available as sulphate salt. It was discovered in 1963 and was introduced for parenteral use in 1971.

Indications of gentamicin

To treat UTI (Urinary Tract Infection).
Used topically to treat various skin infections, nasal infections, bed sores, eye infection like keratitis and conjunctivitis.
Used in combination with penicillin G and ampicillin to treat bacterial endocarditis caused by Streptococcus viridans and Streptococcus fecalis respectively.
It is used to treat serious gram- negative Bacillary infection like meningitis, osteomyelitis, pneumoniae, otitis and speticemia.

It exerts bacteriostatic effect in low concentration and bactericidal effect in high concentration. Its bactericidal action is concentration dependent; there is progressive increase in bactericidal action along with concentration.
It is mainly effective against gram- negative bacteria. The species sensitive to gentamicin include members of Enterobacteriaceae family (E. Coli, Enterobacter spp., Klebsiella pneumoniae etc), P. aeruginosa, group A beta hemolytic streptococci. It is also effective against Staphylococci including those which are resistant to penicillin.
Its activity against P. aeruginosa is 5-10 times more compared to kanamycin. It is also more effective than streptomycin against P. aeruginosa. It is also effective against M. tuberculosis and Mycoplasma pneumoniae.

Resistance against gentamicin may develop slowly. Mechanisms involved are
decreased cell permeability to antibiotic which prevent drug from reaching the ribosomes.
Single step mutation which affect ribosomal proteins. This is uncommon and is specific for streptomycin.
R factor mediated resistance which means drug inactivation by modifying enzymes acquired by conjugative transfer of R plasmids.

Figure- Mechanism of action of gentamicin (aminoglycoside antibiotics) (Source- Lippincott’s Illustrated Reviews)

Like other aminoglycosides, it also acts by inhibiting protein synthesis. It diffuses through porin channels of gram-negative bacteria and enter periplasmic space. Once inside the cell, it binds to side of 16S rRNA of 30S ribosomal subunit and interfere with protein synthesis initiation, block translation of m-RNA and prematurely terminate the synthesis.
They cause misreading of genetic code by 30S ribosomal subunit leading to production of abnormal proteins. These proteins when inserted into the cell membrane results in alteration of permeability, disruption of cell membrane and further stimulate transport of gentamicin.
Its passage through gram- negative membrane via oxygen- dependent active transport. Hence, it is not effective against anaerobic bacteria.

It is administered through various routes including parenteral (IV and IM), topical and ophthalmic route. Ophthalmic preparation available are ointment and solution and both have concentration of 0.3%. Oral route is not preferred due to por GIT absorption. When administered through IM route, peak plasma level reaches within 30- 60 minutes and its effect lasts for 6-8 hours.
Around 25-30 % of drugs bind to plasma proteins. It is excreted unchanged in urine via glomerular filtration. The concentration in urine is around 100-fold higher than in serum.

It has less adverse effects compared to streptomycin and kanamycin.
When used through topical route, it can cause allergic reactions and photosensitivity reactions. Parenteral dose may cause vestibular damage and ototoxicity. The first manifestation of ototoxicity is tinnitus. The symptoms of vestibular damage are nausea, vomiting, vertigo and balance disorder within first two weeks. This risk is more in renal patients.
Nephrotoxicity is another common adverse effect which occurs due to its accumulation and retention in proximal tubular cells. It can cause mild albuminuria or acute tubular necrosis. Chances of azotemia is rare.
Acute neuromuscular blockade may occur due to rapid increase in concentration or concurrent administration with neuromuscular blockers. Patients with myasthenia gravis are more susceptible. It may be reversed with calcium gluconate infusion or by neostigmine.

When used in combination with beta-lactam antibiotics and metronidazole, it produces synergistic effect.
Its effect is decreased when used in combination with tetracyclines and chloramphenicol.

Contraindicated in patients with history of hypersensitivity to gentamicin or other aminoglycoside antibiotics.
Its dose should be adjusted in patients with renal impairment.
Systemic gentamicin falls in pregnancy category D drugs. It is used if its benefits outweigh its risk in pregnant women.

https://www.ncbi.nlm.nih.gov/books/NBK557550/
https://go.drugbank.com/drugs/DB00798
Pharmacology and Pharmacotherapeutics. 24^th edition.
Lippincott Illustrated Reviews Pharmacology, 6^th edition.
A Textbook of Clinical Pharmacology and Therapeutics.
Goodman and Gillman’s Manual of Pharmacology.
Rachel S et al. SYSTEMATIC REVIEW AND META‐ANALYSIS Adverse effects of a single dose of gentamicin in adults: a systematic review. Br J Clin Pharmacol. 2018: 84; 223–238.
Journal of the Formosan Medical Association. 2014; 113(2): 72-82.