Aminoglycosides

·        Chemistry.

·        Mechanisms of action.

·        Pharmacokinetics.

·        Adverse reactions.

·        Therapeutic indications.

Chemistry

1.       Aminoglycosides are a group of antibiotics produced by fungi of the order actinomycetes and genus streptomyces and genus micromonospora.

2.       Those derived from the genus:

a.       Streptomyces are named “mycins”.

b.       Micromonospora are named “micins”.

3.       Classification:

a.       Natural: streptomycin, gentamicin, tobramycine, kanamycin, neomycin.

b.       Semi-synthetic: amikacin, netilmicin.

4.       Chemical properties:

a.       Contain sugars in glycosidic linkages to a hexose nucleus.

b.       Basic drugs, water soluble and stable.

c.    More active in alkaline medium.

d.    May form complexes with beta lactam antibiotics in vitr and lose some activity.

5.       Mechanism of action:

a.       Rapidly bactericidal.

b.       Inhibit protein synthesis by binding to receptors on the 30S subunit of bacterial ribosomes.

c.       Cause incorrect amino acid sequences to be entered into peptide chains.

6.       Bacterial resistance:

a.       Failure of permeation of antibiotic.

b.    Low affinity of the drug for bacterial ribosome.

c.       Inactivation of drug by microbial enzymes – acetylase, adenylylase, phosphorylase.

Pharmacokinetics

1.       Absorption:

a.    Poor oral bioavailability.

b.       Given i.v. or i.m or systemic use.

2.       Distribution:

a.    Half-life: 2 – 5h.

b.       Negligible binding to plasma proteins.

c.       Volume of distribution equals to the volume of extracellular fluids.

d.       Widely distributed into body fluids including ascitic, pericardial, peritoneal, pleural, synovial and abscess fluids.

e.    Poor penetration into the CSF and the eye even in the presence of inflammation.

f.       Cross the placenta readily.

3.       Excretion:

a.       Excreted unchanged by the kidneys mainly by glomerular filtration.

b.       Accumulate in renal impairment.

c.    Due to individual variation in their handling, monitoring of serum concentration is essential.

Adverse effects

1.       Aminoglycosides have a very narrow therapeutic / toxic ratio.

2.       Aminoglycoside toxicity is a risk when:

a.    dose administered is high.

b.       duration of therapy is long.

c.    renal clearance is inefficient.

d.       patient is dehydrated.

3.       Ototoxicity:

a.    Both vestibular and auditory damage may occur, causing hearing loss, vertigo and tinnitus which may be permanent.

b.       Preferential toxicity: streptomycin and kanamycin produce auditory toxicity; tobramycin affects both.

c.       Tinnitus may give warning of auditory nerve damage.

d.    Early signs of vestibular toxicity: motion-related headaches, dizziness or nausea.

e.       Serious ototoxicity can occur with topical applications, including ear drops.

4.       Nephrotoxicity:

a.       Aminoglycosides are concentrated in the renal cortex and urine.

b.       Incidence and severity of nephrotoxicity is related to the dose and duration of therapy.

c.    Risk factors: low blood pressure, loop diuretics and advanced age.

5.       Neuromuscular blockade:

a.    May impair neuromuscular transmission.

b.       Aggravate myasthenia gravis, or cause a transient myasthenic syndrome in normal patients.

c.       Large doses can cause respiratory paralysis.

6.       Hypersensitivity:

a.       Rash.

b.       Blood dyscrasias: marrow depression, haemolytic anaemia.

7.    Drug interactions:

a.       Cephalosporins and furosemide: increased nephrotoxicity.

b.       Ethacrynic acid: increased ototoxicity.

c.       Curariform drugs: increased neuromuscular blockade.

Spectrum of antimicrobial activity

1.       Sensitive bacteria:

2.       Aminoglycosides are in general active against staphylococci and aerobic Gram-negative organisms including almost all the Enterobacteriaeae.

3.       Bacteria variably resistant:

a.       Pseudomonas aeruginosa.

b.       Providencia.

c.       Serratia.

4.       Bacteria resistant:

a.       Streptococcus pneumoniae.

b.       Streptococcus pyogenes.

c.       Anaerobic bacteria.

Therapeutic indications

1.       Gram-negative bacillary infection:

a.       Septicaemia.

b.       Pelvic and abdominal sepsis.

c.       Gentamicin remains the drug of choice but tobramycin should be used for infections caused by Pseudomonas aeruginosa.

d.       Amikacin has the widest antibacterial spectrum of aminoglycosides but is best reserved for gentamicin-resistant organisms.

e.    An aminoglycoside may be included in the initial best-guess regimen for treatment of serious septicaemia before the causative organism is identified.

2.       Bacterial endocarditis:

a.    An aminoglycoside, usually gentamicin is used in combination with benzylpenicillin or vancomycin.

b.       Effective against enterococcal, streptococcal or staphylococcal infection of the heart valves.

3.       Other infections:

a.       Tuberculosis.

b.       Tularaemia.

c.       Plague.

d.       Brucellosis.

4.       Topical uses:

a.       Neomycin and framycetin: topical treatment of infections of the conjunctiva or external ear.

b.    They are used in antimicrobial combinations to sterilize the bowel of patients who are to receive intense immunosuppressive therapy.

c.    They are too toxic for systemic use.

Individual aminoglycosides

1.       Gentamicin:

a.       Active against Gram-negative bacilli including Escherichia coli, Enterobacter, Klebsiella pneumoniae, Proteus and Pseudomonas aeruginosa.

b.    Drug of choice for serious Gram-negative septicaemia, abdominal and pelvic sepsis in combination with metronidazole against Bacteroides fragilis.

c.    In the best-guess treatment of septicaemia, gentamicin should be combined with a beta-lactam antibiotic or an anti-anaerobic agent, e.g. metronidazole, or with both.

d.       Streptococcal and enterococcal endocarditis: gentamicin + benzylpenicillin.

e.       Staphylococcal endocarditis: gentamicin + cloxacillin.

f.       Enterococcal endocarditis: gentamicin + ampicillin.

2.       Streptomycin:

a.    Drug of choice in treatment of tularemia and plague.

b.    Use concurrently with other drugs in the treatment of tuberculosis.

c.    Used with penicillin G or ampicillin for the treatment of endocarditis caused by Streptococcus faecalis.

3.       Tobramycin:

a.       Similar to gentamicin in spectrum of antibacterial activity.

b.    More active against most strains of Pseudomonas aeruginosa.

c.    Less nephrotoxic.

4.       Amikacin:

a.       Broad spectrum of activity against Gram-negative bacilli including Pseudomonas aeruginosa.

b.       Reserved for treatment of gentamicin-resistant organisms.

5.       Neomycin:

a.       Ophthalmic solution and ointment: principally used topically for skin, eye and ear infections.

b.    Gut sterilization (oral): to reduce bacterial load in the colon in preparation for bowel surgery, or in hepatic failure.

c.       Bladder washout.

6.       Spectinomycin:

a.       Clinical use is confined to gonorrhoea in patients allergic to penicillin.

b.       Resistance is reported.