Macrolides

                                                            Macrolides

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These constitute a group of bacteriostatic antibiotics that possess a complex chemical structure consisting of a large lactone ring (usually having 14-16 atoms) to which deoxy sugars are attached by means of glycosidic bonds. Macrolides are mostly obtained from Streptomyces bacteria but some of them are semi-synthetically prepared. Erythromycin (isolated from Streptomyces erythreus in 1952), Tylosin (obtained from Streptomyces fradiae), Tilmicosin, Clarithromycin (semi-synthetic derivative of Erythromycin), Azithromycin and Oleandomycin are important drugs included in this family.

 

Mechanism of action: Macrolides are transported into the cytoplasm of susceptible micro-organisms by an active transport system. Gram positive bacteria accumulate about 100 times more antibiotics than do the gram negative bacteria. Inside the cytoplasm of bacterial cell, Macrolides bind to 50S-ribosomal subunit and block the translocation step of bacterial protein synthesis (in which a newly synthesized peptidyl tRNA moves from the acceptor (A) site on ribosomal-mRNA complex to the peptidyl (P) site. Thus failure of translocation stops the protein synthesis as the A-site is not available for the next coming amino-acyl tRNA and ribosomal complex cannot move to the next codon. The binding site of Macrolides on the ribosomes is adjacent but not identical to that of Amphenicols. Macrolides generally do not bind to mammalian ribosomes.

 

Bacterial resistance: Acquired bacterial resistance to Macrolides results mainly from mutation in ribosomal structure, efflux of drugs by an active pump mechanism and production of drug-inactivating enzymes.

 

Pharmacokinetics: Macrolides are lipid soluble drugs that are rapidly absorbed from GIT, if not inactivated by the gastric acid. Oral preparations are often enteric-coated to prevent the inactivation of Macrolides by the gastric acid. In ruminants the absorption of Macrolides from rumen and reticulum is usually delayed and unreliable. Due to their alkaline nature, they are concentrated in acidic fluids like milk and prostatic fluid and some body cells (like macrophages) through the mechanism of “ion trapping”. Their concentration in milk is usually several times greater than in plasma. They undergo ionization in acidic environment and remain in un-ionized state at alkaline P_H (therefore they are more effective at alkaline P_H). They can cross the placenta but not the blood brain barrier. Macrolides undergo extensive biotransformation in the liver through microsomal enzymes. Renal excretion of Macrolides is minor but it may become significant after parentral administration.

 

Antimicrobial spectrum: Macrolides are effective against most aerobic and anerobic gram positive bacteria but not gram negative bacteria (except Pasteurella and Haemophilus). Most members of enterobacteriaceae are resistant to Macrolides. They can be successfully used to treat infections caused by Mycoplasma, Mycobacterium, Chlamydia and Rickettsiae but protozoa, fungi and viruses are not susceptible to them. The antimicrobial spectrum of Macrolides resembles that of Penicillins and hence they are often used as Penicillin substitutes. 

 

Clinical uses: Erythromycin is the most widely used Macrolide antibiotic and it is having a narrow antimicrobial spectrum (including mainly gram positive and a few gram negative bacteria). Its antibacterial spectrum is similar to that of Penicillin G. It is considered as the drug of choice for Compylobacteriosis and Rhodococcus equi infection in foals. It can be used as an alternative to Penicillins for the treatment of Staphylococcal and Streptococcal infections. It is commonly used to treat bacterial infection of throat in human patients. The potential of Erythromycin to stimulate motilin receptors of intestine enables it to be used as a prokinetic (prokinetics are drugs that can restore the motility of individual intestinal segment). Tylosin is mostly used to treat respiratory tract infections (such as pleuropnemonia, hemorrhagic septicemia and avian mycoplasmosis/CRD) in animals. Tilmicosin can be used to treat Pasteurellosis and Mycoplasmosis but it is not commonly used due to high risk of cardiovascular side effects. Oleandomycin is used as feed additive for growth promotion in food producing animals.  In combination with H₂-receptor blockers (such as Cimitidine and Ranitidine) and Bismith subsalicylate (antidiarrheal agent), Clarithromycin is used to treat Helicobacter pylori-induced gastric ulcer in humans.

 

Adverse effects: Most Macrolides do not cause serious side effects in domestic animals. However the following adverse effects may possibly occur in exposed animals.

Ø  Gastro-intestinal disturbances: With oral administration of Macrolides, diarrhea, regurgitation and epigastric pain may be observed. These GI upsets are less commonly seen in animals than in humans. However horses are more susceptible to Macrolide-induced gastro-intestinal disturbances that can be serious and fatal.

Ø  Hypersensitivity reactions: The hypersensitivity reactions to Macrolides occasionally occur and these are manifested in terms of rashes, fever and skin eruptions. 

Contraindications: The administration of Macrolides should be contraindicated in horses due to high risk of fatal GI upsets. As they concentrate in milk, their use in lactating animals must be avoided or alternatively an optimal withdrawal period should be followed.

 

Drug interactions: Macrolides should not be used along with Amphenicols or Lincosamides because they compete for the binding/target site on 50S-ribosomal subunit. Erythromycin inhibits microsomal enzymes and thus it can depress the biotransformation of some drugs like Warfarin (anticoagulant drug) and Carbamazepine (anticonvulsant drug).