• Aminoglycoside are important group of antibiotics which act against gram-negative bacteria. The name ‘aminoglycoside’ is given as the structure consist of 2 amino sugars joined by glyosidic linkage to central hexose nucleus. They are either derived from Streptomyces (ends in -mycin) or Micromonospora (ends in micin).
• Streptomycin is the first aminoglycoside antibiotic isolated in 1943. It is derived from Streptomyces griseus. Some other examples of aminoglycoside include:
– Kanamycin
– Tobramycin
– Neomycin
– Amikacin
– Gentamicin
– Sisomicin
Mechanism of action of aminoglycosides
Figure 1- Mechanism of action of aminoglycoside
• Aminoglycosides possess bactericidal activity. Aminoglycosides diffuse through porin channels of gram-negative bacteria and enter periplasmic space. Once inside the cell, they bind to 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 aminoglycoside transport.
• The bactericidal effect is concentration dependent. They possess post-antibiotic effect which means bactericidal activity persists even after serum drug concentration fall below minimum inhibitory concentration (MIC).
Antibacterial spectrum of aminoglycosides
• Aminoglycosides are effective against aerobic gram-negative bacilli including those that may be multi-drug resistant like Pseudomonas aeruginosa, Klebsiella pneumoniae and Enterobacter sp. Aerobic gram-negative bacilli vary in their susceptibility towards aminoglycoside.
• They are little effective against anaerobic microorganisms or facultative bacteria under anaerobic conditions.
• They are used in combination with beta-lactam antibiotics to produce synergistic effect against Enterococcus faecalis, Enterococcus faecium, streptococci and staphylococci.
Aminoglycoside resistance
• Microorganisms may develop resistance to aminoglycosides. 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.
• Amikacin is less vulnerable to these modified enzymes due to R factor. Hence, microorganisms resistant to other aminoglycosides may be susceptible to amikacin.
• Some important examples which show resistance include S. pneumoniae, M. tuberculosis, E. coli, H. influenzae, Brucella, Staph. Aureus, Enterococcus faecalis, E. faecium and Strep. faecalis.
Pharmacokinetics of aminoglycosides
Figure 2- Administration and fate of aminoglycosides (Source- Lippincott’s Illustrated Reviews, 6th edition)
Absorption
• Due to their highly polar, polycationic structure, they are poorly absorbed from GI tract and hence oral route is not preferred. All aminoglycosides must be given parenterally to achieve adequate serum level. They are absorbed rapidly after intramuscular injection.
• Neomycin is exception. It is not administered parenterally due to severe nephrotoxicity. It is administered topically for skin infection or orally for bowel preparation before colorectal surgery.
Distribution
• Most of the aminoglycosides don’t bind with plasma proteins except streptomycin.
• Due to their hydrophilicity, their concentration in tissue and secretions are low. High concentration are found in renal cortex and inner ear responsible for nephrotoxicity and ototoxicity.
• Concentration in CSF (Cerebrospinal fluid) after parenteral administration is inadequate (˂ 10% of those in plasma, around 25% with meningitis). So, intrathecal route is preferred for CNS infection.
• All aminoglycosides cross placental barrier and may accumulate in amniotic fluid and fetal plasma.
Elimination
• Around 90 % of all parenteral aminoglycosides are excreted unchanged in urine. However, in patients with renal dysfunction, accumulation may occur and hence, dose adjustment is required. The plasma half-life may vary from 2 hours in a person with normal renal function to 30-60 hours in a person who are functionally anephric.
• The half-life of aminoglycosides in renal cortex is approximately 100 hours so repetitive administration may cause nephrotoxicity.
Therapeutic Uses
• Used in serious, life-threatening gram-negative infections.
• Used in complicated skin, bone or soft tissue infection or complicated urinary tract infection. E.g. gentamicin is used in skin infection in case of burns infected with pseudomonas, bed sores.
• In septicemia.
• In severe pelvic inflammatory disease, peritonitis and other severe intra-abdominal infections.
• To treat neonatal sepsis.
• Topically used in ocular infection and otitis externa.
• Used with penicillin in serious infection with susceptible enterococci.
Adverse Effects
• Aminoglycosides have narrow therapeutic index so, therapeutic drug monitoring is required to ensure adequacy of dosing and minimize dose related toxicities.
• Ototoxicity (vestibular and auditory) is directly related to high peak plasma level and duration of treatment. Deafness may be irreversible and may also affect developing fetus. Patients with pre-existing auditory impairment are more likely to develop hearing loss.
• Nephrotoxicity is another common adverse effect which occurs due to accumulation and retention of aminoglycosides in proximal tubular cells. Neomycin, gentamicin and tobramycin are most nephrotoxic aminoglycosides. The kidney damage may be mild, reversible renal impairment or severe, irreversible, acute tubular necrosis.
• 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.
• Other adverse effects include allergic reaction like contact dermatitis with topical application (vey unusual), dysfunction of optic nerve, peripheral neuritis (rare).
Note- FDA has issued black box warning for aminoglycosides taken orally or intravenously.
Drug Interaction
• Concomitant administration with drugs like loop diuretics and cisplatin having ototoxic properties increases chance of ototoxicity. So, they should be avoided if possible.
• When administered together with neuromuscular blocker, increases chance of neuromuscular paralysis.
Contraindication
• They should be avoided in patients with myasthenia gravis.
• They should be avoided if patients is allergic to aminoglycosides or any inactive ingredients present.
• Should be used with caution in elderly patients (65 years old ore more), in newborn or very young baby.
• Should be used with caution in patients with kidney problem or hearing problem.
References
- errolozdalga.com/medicine/pages/OtherPages/AntibioticReview.ChanuRhee.html
- https://www.everydayhealth.com/aminoglycosides/guide/
- Guo L, Wan Y, wang X, Wang PG, Zhao W. Development of Aminoglycoside Antibiotics by Carbohydrate Chemistry. Mini-Reviews in Medicinal Chemistry. 2012; 12(14): 1533 – 1541.
- Aminoglycosides: Mechanisms of Action and Resistance from book Antimicrobial Drug Resistance: Mechanisms of Drug Resistance. 2009; pp.171-181.
- Germovsek E, Barker CI, Sharland M. What Do I Need to Know About Aminoglycoside Antibiotics? Arch Dis Child Educ Pract Ed. 2017; 102(2): 89-93.
- Jiang M, Karasawa T, Steyger PS. Front. Aminoglycoside-Induced Cochleotoxicity: A ReviewCell. Frontier Cell Neurosci. 2017; 11(308): 1-14.
- Gonzalez US, Spencer JP. Aminoglycosides: A Practical Review. Am Fam Physician. 1998; 58(8): 1811-1820.
- Pharmacology and Pharmacotherapeutics. 24th
- Lippincott Illustrated Reviews Pharmacology, 6th
- A Textbook of Clinical Pharmacology and Therapeutics.
- Goodman and Gillman’s Manual of Pharmacology.