Aminoglycosides

Important group discovered after penicillin. 1^st member discovered was Streptomycin, which was discovered from mold, streptomycis. A large number of compounds were discovered afterwards.

Classification According to Source

1.	Streptomyces	griseus	Streptomycin
2.	Streptomyces	fradiae	Neomycin-B
3.	Streptomyces	kanamyceticus	Kanamycin
4.	Actinomycetes	micromonospora	Gentamicin Netilmicin
5.	Streptomyces	tenebrarius	Tobramycin
6.	Semi Synthetic:	Amikacin Derivative of Kanamycin
		Netilmicin Derivative of Sisomicin

Drugs obtained from Streptomyces end in “mycin”.

Drugs obtained from micromonosporas end in “micin”.

Chemistry

• Two or more aminosugars
• In glycosidic linkages
• Bind to hexose (aminocyclitol) nucleus

Mechanism of Action

These drugs act by inhibiting the synthesis of proteins in bacteria. Action is bactericidal.

1. Enter bacterial cells by passive diffusion through aqueous channels in outer membrane

2. Active transport through inner cytoplasmic membrane (oxygen dependent process)

There are certain conditions where decreased entry occurs:

• Calcium and magnesium ions
• Hyperosmolarity
• Decrease in pH
• Anaerobic conditions

3. Binding to 30S ribosomal subunit after reaching ribosomes
4. Misreading of the genetic code of mRNA templat
5. Incorrect amino acid sequences
6. Abnormal polypeptide chains
7. Bactericidal action

When given in combination with penicillins, increased entry into cells occurs (synergism) due to damaged cell wall.

Mechanism of resistance

1. Failure of permeation:
   a. Cations (Ca & Mg),
   b. Hyperosmolarity
   c. Reduction in pH
   d. Anaerobic condition

2. Inactivation by acetyltransferase, nucleotidyl transferase and phospho transferase (enzymes produced by bacteria)
3. Alteration in the ribosomes
4. Low affinity for bacterial ribosomes

Antibacterial Spectrum

Mainly effective due to damaged cell wall. Effect gram negative organisms, no effect on gram positive organisms. Narrow spectrum:

1. Aerobic gram negative bacilli
2. E-coli
3. Haemophilus
4. Pseudomonas aeruginosa
5. Gram negative enteric organisms e.g. proteus, enterobacter,  klebsiella, Enterococcus, Listeria
6. Mycobacterium tuberculosis

Pharmacokinetics

Highly polar compounds present in ionized form.

Administration and absorption –cannot be given orally (not absorbed). If given orally, 97-99% of drug is excreted as such in feces. Given by parenteral route. I/M and I/V but can be given intrathecally. Also applied topically.

Absorption is increased from damaged skin and wound ulcers

It is also increased when given into serosal cavitiesk peritoneum and pericardium.

Mostly given I/M.

Plasma protein binding –after I/M administration, PPC occurs after 30-90 minutes and is less than 30%.
Distribution –as are highly polar, penetration of body cavity is less. They cannot penetrate CNS, pericardium, peritoneum until inflamed.

Attain high concentration in perilymph and endolymph of inner ear and renal cortex. They can also penetrate placenta if given in pregnancy, attaining high concentration in fetal plasma and amniotic fluid.
Half life – between 2-5 hours. Some of these drugs are present in urine even after 10-20 days because of high concentration in renal cortex where they accumulate.

Elimination –mostly excreted unchanged in in urine within 12-24 hours.

Toxicity or Adverse Drug Reactions

1. Ototoxicity

Occurs in both ccochlea and vestibular division of nerve affected due to increased concentration in perilymph and endolymph of inner ear. Ototoxicity is proportional to plasma concentration of these drugs. It is mainly due to damage to sensory cells present in these areas. Elderly are more prone. Dose is decreased in them. Various symptoms are:

• May cause tinnitus
• Vertigo
• Headache
• Nausea
• Vomiting
• Change in behavior of patient
• May lead to ataxia in severe cases

Effects are reversible if drug is withdrawn earlier, but irreversible if continued.

2. Nephrotoxicity

Due to accumulation in renal cortex, always reversible when drug is withdrawn. Various symptoms are:

• Decrease in GFR
• Proteinurea
• Increase in plasma urea and creatinine levels
• One very important effect due to decreased GFR is increased plasma urea and decreased excretion of drug, leading to increased chances of ototoxicity.

3. Neuromuscular blockade

Due to decrease in release of acetylcholine from nerve endings. Main symptoms are muscular weakness, leading to apnea and paralysis, especially in higher doses and by intraperitoneal or I/V route.

All above mentioned effects can be reversed by administration of calcium, because calcium decreases the penetration of these drugs in cells.

NM blockage is also reversed by administration of neostigmine.

4. CNS

Main effects are on PNS. May cause:

1. Peripheral neuritis
2. Parasthesias
3. Skin rash
4. Articaria
5. Anaphylaxis; although less common than penicillin, but may occur

5. Allergic reactions

Contraindications

1. Renal disease
2. Pre-existing auditory/vestibular dysfunction
3. Myasthenia gravis
4. Pregnancy

Drug Interactions

1. Ototoxicity is increased by loop diuretics (Furesemide)
2. Nephrotoxicity is increased by:

1. Cisplatin
2. Amphotericin-B
3. Cephalosporins 

Streptomycin

Uses

1. Tuberculosis treatment in combination with other anti tuberculosis drugs.
2. Bacterial endocarditis in combination with penicillins
3. Tularemia (like plague, spread by rabbits, symptoms are like plague, pneumonia and death due to pneumonia)
4. Plague –spread by rodents
5. Brucellosis in combination with doxychycline

Streptomycin is toxic so only given for 7-10 days but in case of tuberculosis, it is given for two  months in combination with other anti tuberculosis drugs.

In bacterial endocarditis it is combined with penicillin for 4-6 weeks, while for other diseases it is 7-10 days.

Dose: 0.75g to 1g or 30mg/kg

Gentamicin

Gentamicin is more commonly used than streptomycin. In fact it is the most commonly used aminoglycoside.

Uses

1. UTI –esp. caused by proteus and pseudomonal infections as is cost effective.
2. Pneumonia caused by gram negative organisms
3. Meningitis caused by gram negative organisms
4. Peritonitis esp. after peritoneal dialysis
5. Infected burns
6. Gram negative sepsis (neutropenic patients)
7. Bacterial endocarditis, with penicillins
8. Topical uses –very important, in form of ointments, creams, eye drops

Dose: 80mg TDS I/V or I/M

Amikacin

• Differs from gentamicin as has broadest spectrum in aminoglycosides
• Least affected by aminoglycosides modifying enzymes so resistance is less
• Uses same as that of gentamicin, but reserved for resistant infections

Dose: 15mg/kg/d in 2 or 3 divided doses

Kanamycin

Limited spectrum

Uses:

1. Resistant cases of tuberculosis (not responding to streptomycin or others)
2. As an adjunct in hepatic coma/encephalopathy (orally) because it is not absorbed orally, having local effect. It kills ammonia producing organisms causing hepatic encephalopathy

Dose: 15mg/kg in 2 or 3 divided doses

Oral dose: 8 to 12g/d in divided doses

Neomycin & Framycetin

• Too toxic to be used parenterally
• Even topically not used for more than 3 weeks especially in children because some drug may be absorbed causing toxicity.

Uses:
Topically for burns, wounds, ulcers and skin infections
orally for hepatic surgery and hepatic coma

Paromomycin:

Used for intestinal amoebiasis having local effect in intestine. It is given orally.