Macrolides:

• These are group of bacteriostatic antibiotics which consist of large lactone ring attached to one or more deoxy sugars.
• They exert their antibacterial effect by inhibiting protein synthesis in bacteria by binding irreversibly to 50S subunit of bacterial ribosomes.
• These include erythromycin, oleandomycin, troleandomycin, spiramycin, josamycin, tilmicosin and tylosin.
• It consist of one large lactone ring usually 14-16 atoms attached to one or more deoxy sugars; cladinosine and desosamine by glycosidic linkage.
• It is mostly obtained from various species of soil-borne bacteria

Classification:

• These are broader group of antibiotics and consist of new subgroups due to structural resemblance.

Mechanism of action:

Macrolide penetrate bacterial cell wall by active transport system

Macrolides bind to 50S ribosomal subunit

Blocks the translocation of peptidyl t-RNA from acceptor site to peptidyl site

Failure of translocation stops protein synthesis

Antimicrobial spectrum:

• They are effective against most aerobic and anaerobic gram +ve bacteria.
• β-hemolytic streptococci, staphylococci, pneumonia & enterococci are usually susceptible to macrolides.
• They are not active against gram -ve bacteria except some strains of Pasteurella, Haemophilus and Neisseria.
• They are active against Mycobacterium, Mycoplasma, Chlamydia and Rickettsia.
• They are ineffective against protozoa, viruses and fungi.

Bacterial resistance:

• Resistance acquired through changes in ribosomal structure and loss of macrolide affinity.
• Decreased permeability of drug, efflux of drug by active pump mechanism and increased production of inactivating enzymes are also responsible
• Bacterial resistance is mostly plasmid mediated. Cross-resistance may occur to other macrolides, lincosamides & chloramphenicol due to similar binding sites of ribosome.

Pharmacokinetics:

• They are rapidly absorbed from G.I tract if not inactivated by gastric acid. Absorption is rapid after IM or SC injection.
• Peak plasma concentration occur within 1-2 hours after oral dosing.
• They are widely distributed in tissues and tend to accumulate in some cells including macrophages & leukocytes due to ion trapping.
• They cross placenta but not blood-CSF and blood brain barrier.
• Drugs bind to plasma proteins to about 70-80% mainly α₁-acid glycoproteins.
• They undergo extensive biotransformation (~80%) in liver through microsomal enzyme system.
• They are excreted mainly in bile in both active and inactive forms
• Plasma half-lives ranges 1-3 hours.

Side effects/Adverse effects:

• Most macrolide donot produce serious side effects in domestic animal. But some of effects include:
• GI disturbances like vomiting, diarrhoea, regurgitation & epigastric pain may be observed.
• Hepatotoxicity and cholestasis in higher doses
• Hypersensitivity occasionally
• Pain and swelling at injection site
• Some macrolide may produce cardiovascular toxicity.

Contraindications and precautions:

• In patients those are hypersensitive to drug
• They should be used cautiously in patients with hepatic dysfunction.
• They should not be used in non-ruminant herbivores as they may cause fatal G.I disturbances.
• Their use in lactating animals should be avoided
• They should be used cautiously in pregnant animals.

Drug interactions:

• They should not be used with chloramphenicol or lincosamides because they compete for same binding sites on ribosome

Indications:

• In treatment of both systemic and local infections
• Upper respiratory tract infection
• Bronchopneumonia
• Enteritis
• Metritis
• Urinary tract infections
• Mastitis
• Arthritis

Macrolide antibiotics:

Erythromycin:

• It is mostly and widely used and prototype drug of this class
• It was isolated from a strain of Stretomyces erythreus in 1952
• It consist of 14 atom macrolide ring attached to sugar desosamine and cladinose
• Antibacterial activity is more pronounced in alkaline medium.

Antimicrobial spectrum:

• It is narrow spectrum antibiotic active against most gram +ve and few gram -ve organism
• It is effective against gram +ve cocci like Streptococci & Staphylococci and bacilli like Corneybacterium. Other susceptible organism include Campylobacter, Chlamydia, Mycoplasma, Haemophilus, Pasteurella, Brucella, Listeria, Clostridium & Erysipelothrix.
• Most strains of Enterobacteriaceae are resistant.

Pharmacokinetics:

• They are inactivated by gastric acid and absorption is delayed by food.
• Oral administration is thus given in enteric-coated form
• Absorption is slow after IM administration
• Bioavailability after IM or SC administration is only about 40-60%.
• It is well distributed throughout the body fluids, tissues & phagocytes.
• It is 70-80% plasma protein bound.
• Partly metabolized in liver and primarily excreted in bile in active form.
• Half-lives varies with species; cattle=3 hrs, horse= 1 hrs, dogs & cats=1-1.5 hrs.

Side effects/Adverse effects:

• It can cause GI disturbances like anorexia, vomiting & diarrhoea
• Diarrhoea may be fatal in adult horse, rodents & rabbits.
• Rectal edema and partial anal prolapse in swine
• Cholestasis hepatitis
• Hyperthermia
• Respiratory distress in foals

Contraindications:

• In adult horses, rabbit and rodents

Indications:

• Respiratory infection
• Soft-tissue infection
• Skin infection
• Staphylococcal and streptococcal infection

Dose:

Dogs & cats: 2-10mg/kg, PO, 3 times daily

Cattle: 8-15 mg/kg, IM, 1-2 times daily

Foals: 25 mg/kg, PO or IM, 3 times daily

Sheep & swine: 2-6 mg/kg, IM, once daily

Poultry: 25g/100 litres drinking water

Azalide antibiotics:

• Sub-class of macrolide antibiotics which contain a nitrogen in macrolide ring
• Azithromycin is most widely used in veterinary medicine

Azithromycin:

• It is recently introduced azalide-macrolide antibiotics
• It differs from erythromycin in chemical structure that a methyl-substituted nitrogen atom is incorporated into lactone ring, making lactone ring 15-membered.

Mechanism of action:

Binds to 50S ribosomal subunit

Prevents growth of bacteria by interfering with protein synthesis similar to other macrolide.

Antimicrobial spectrum:

• Comparatively less active against gram +ve cocci than erythromycin
• More effective against gram -ve bacteria, particularly Haemophilus influenzae.
• It also shows good activity against Chlamydia and Toxoplasma
• It is also active against Mycobacteria and Mycoplasma.

Pharmacokinetics:

• They are readily absorbed after oral administration, but absorption is greater in empty stomach.
• Accumulation in some tissues like respiratory tract, leukocytes, macrophages and fibroblast 100-200 times than in plasma.
• Intracellular stores of azithromycin in leucocytes & macrophages facilitate drug delivery to infected tissues.
• Plasma half-lives; 18 hrs in horses, 30 hrs in dogs and 35 hrs in cats.
• Eliminated mostly in bile in unchanged form

Side effects/Adverse effects:

• It has lesser side effects
• Nausea, vomiting
• Abdominal pain
• Diarrhoea

Indications:

• In respiratory tract infection
• Genital tract infection
• Skin infection
• Soft tissue infection

Dose:

Dogs & cats: 5-10 (up to 40) mg/kg, PO, once daily

Cats: 5 mg/kg, PO, once daily

Foals: 10 mg/kg, PO, once daily followed every alternate day

Calves: 30 mg/kg, PO, once daily for 7 days

Ketolide antibiotics:

• It is new sub-group of antibiotics belonging to macrolide group
• It is derived from erythromycin by substituting cladinose sugar with ketogroup and attaching a cyclic carbamate group in lactone ring.
• Only one drug is used clinically.

Telithromycin:

• It is derived from erythromycin by substituting cladinose sugar with ketogroup and attaching a cyclic carbamate group in lactone ring.
• Inhibits protein synthesis by binding to 50S of bacterial ribosome
• Fairly rapidly absorbed after oral administration.
• Diffuses into most tissues and phagocytes
• Largely metabolized in liver and excreted mainly in bile.
• Primarily used in human medicine for treatment of mild to moderate infections of upper and lower respiratory tracts
• It is useful in the treatment of acute sinusitis, tonsillitis, bronchitis, bronchiolitis and lobar pneumoniae.
• Most common side effects of telithromycin are gastrointestinal disturbances including diarrhoea, nausea, abdominal pain and vomiting. Blurred vision, palpitations, rashes and damage to liver may also occur rarely.