Tetracyclines:

• These are group of broad-spectrum antibiotics having a nucleus of four cyclic rings
• They are either obtained naturally from soil actinomycetes or prepared semi-synthetically.
• These antibiotics were produced by systemic screening of soil microorganism. Chlortetracycline was first member of this group derived from Streptomyces aureofaciens introduced in 1948. It is then followed by oxytetracycline in 1952.

Classification:

They are generally classified according to their duration of action:

Mechanism of action:

• Inhibit protein synthesis and are primarily bacteriostatic
• Action of tetracyclines are also divided into two process:

1. Passage of tetracyclines into bacterial cell
2. Interaction of tetracycline with bacterial ribosome

Tetracyclines enters the gram -ve bacteria by two transport mechanism: active and passive process. Passive diffusion is through porin channels to outermembrane of bacteria.

Then they enter into bacterial cytoplasm by active process

After reaching cytoplasm, they bind with 30 S ribosomal subunit

Prevention of binding of aminoacyl t-RNA to acceptor site (A) on mRNA-ribosome complex.

Prevention of addition of amino acids to growing peptide chain

Inhibition of protein synthesis.

• They are highly effective against multiplying microorganisms and are more active at pH 6-6.5.

Antimicrobial spectrum:

• They are broad-spectrum antibiotics.
• They are active against a wide range of aerobic and anaerobic gram +ve and gram -ve bacteria.
• They are also active against Mycoplasma, Rickettsia, Chlamydia & some protozoa like Anaplasma, Haemobartonella and Amoebae.
• Pseudomonas aeruginosa, Proteus, Serratia, Klebsiella, Salmonella, Staphylococcus & Corneybacterium species are resistant.
• They are ineffective against fungi & viruses.

Bacterial resistance:

• Resistance develops slowly in a graded manner.
• Resistance is acquired by three mechanism:

1. Decreased penetration of drug into previously sensitive microorganism
2. Enzymatic inactivation

• Ribosomal protection
• Decreased penetration of drug may be either due to decreased antibiotic influx into bacterial cell or due to energy dependent efflux of antibiotic from bacterial cell by a modified protein carrier.
• Resistance may be plasmid mediated and transmitted through transduction or conjugation.

Pharmacokinetics:

• Oral absorption is variable with older drugs being less bioavailable and newer lipid soluble tetracyclines being 100% bioavailable.
• Absorption of tetracyclines from G.I tract is decreased in presence of polyvalent cations which are present in food, milk & milk products.
• They bind to plasma proteins in varying degree & are widely distributed in most tissues including liver, kidneys, lungs, bile & bones.
• These are stored in reticuloendothelial cells of liver, spleen and bone marrow.
• Except lipid soluble tetracyclines, tetracyclines antibiotics are not metabolized in body.
• Most tetracyclines are excreted in urine (~60%) by glomerular filtration and in faeces (~40%) by biliary excretion.

Side effects/Adverse effects:

• All tetracyclines produce G.I irritation after oral administration. Anorexia, abdominal pain, diarrhoea, nausea and vomiting in small animals may occur.
• Oral administration in horses may lead to fatal diarrhoea and indigestion in ruminants.
• They may deposit in growing teeth and bones. They form tetracycline-calcium orthophosphate complex, which inhibits calcification and results in permanent discolouration of teeth.
• Delay fracture healing due to interference with calcium deposition in bones.
• In high dose, they may produce fatty infiltration of liver.
• Hepatotoxicity with jaundice has been reported in pregnant women and some animals.
• Potentially nephrotoxic in renal insufficiency patient.
• Rapid IV administration may produce hypotension, collapse and sudden death in animals.
• Swelling, necrosis and yellow discoloration may occur at injection site.

Contraindications:

• In hepatic insufficiency, renal disease and hypersensitive to drug
• In pregnant animals
• It should not be used beyond expiry date because they cause damage to proximal renal tubule.
• It should not be administered with food, milk and milk products.
• It should not be given intrathecally.

Indications:

• In treatment of bacterial infection, Mycoplasma, Chlamydia, Rickettsia, Anaplasma, Haemobartonella, Ehrlichia and Borrelia.
• For treatment of psittacosis in birds.
• In urinary tract infections, metritis, mastitis, prostatis, cholangitis and pyodermatitis.

# Short acting tetracyclines:

Oxytetracycline:

• It is one of the most commonly used tetracyclines.
• It is obtained from actinomycetes Streptomyces rimosus.
• It is broad-spectrum antibiotic active against bacteria, mycoplasma, spirochetes, chlamydia & rickettsia.
• Readily absorbed after oral administration with bioavailability of 60-80%
• After IM administration, its peak plasma levels may be achieved in 0.8-2 hrs.
• They are widely distributed in body tissues & fluids, except in CSF & brain
• Excreted mainly unchanged in urine and bile and also in milk.
• Elimination half-lives varies with species; dogs & cats= 4-6 hrs, cattle= 4-10 hrs, horses=8-10 hrs, swine= 6-7 hrs & sheep= 3.5 hrs.
• Mainly used in treatment of respiratory and urinary tract infection, skin, ear & eye.
• Also used in treatment of spirochetal infection, clostridial wound infection and anthrax
• Contraindicated in hepatic insufficiency, renal insufficiency, pregnant animals
• Adverse effects are similar to other tetracyclines.

Dose:

Dogs & cats: 5-10 mg/kg, SC or IM, 1-2 times daily

Cattle, sheep, goats & pigs: 5-10mg/kg, IM or slow IV, once daily

Calves, foals, lambs & piglets: 10-20 mg/kg, IM or IV, once daily

Poultry: 10-25 g/100 litre drinking water

# Intermediate acting tetracyclines:

Demeclocycline:

• It is intermediate acting tetracycline derived from strain of Streptomyces aureofaciens
• It is rapidly absorbed after oral administration.
• It is widely distributed in body.
• Plasma half-life varies from 10-18 hours
• It is used for treatment of animal disease caused by susceptible bacteria
• It is occasionally used in the treatment of hyponatremia.

# Long acting tetracyclines:

Doxycycline:

• It is semi-synthetic tetracycline derived from oxytetracycline or metacycline
• It is more lipophilic than older drugs and has longer duration of action.

Antimicrobial spectra:

• It is broad-spectrum antibiotics.
• It is usually more effective against staphylococci than older tetracyclines.

Pharmacokinetics:

• It is rapidly and nearly completely absorbed from G.I tract after oral administration.
• Absorption is less affected by food, milk and calcium salts.
• It has greater plasma protein binding~90%.
• It is significantly metabolized in body and excreted as inactive metabolites in faeces.
• Elimination half-lives varies from 10-20 hours.

Side effects/Adverse effects:

• It has lesser side effects than other tetracyclines.
• In horse, collapse and death may occur after IV administration.
• Nausea, vomiting in dogs & cats.
• Photosensitivity, hepatotoxicity, nephrotoxicity.

Indications:

• In treatment of ehrlichiosis in dogs
• Psittacosis in poultry
• Anaplasmosis in calves
• Anthrax

Dose:

Dogs & cats: 5-10 mg/kg, PO or IV, once daily

Horses and swine: 10mg/kg, PO, 2 times daily

Birds: 15-25 mg/kg, PO, 2 times daily

            130 mg/litre drinking water