Dr Dibyajyoti KalitaHead-Technical & Regulatory, Zenex Animal Health
Macrolide class of antimicrobial drugs have been used widely for treatment of various infectious diseases in humans and animals. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone. The macrolide class is large and structurally diverse; classified according to macrocyclic lactone ring containing 14, 15, or 16 atoms. Due to their wide range of activity, macrolides are used to treat both systemic and local infections. General indications of macrolides include upper respiratory tract infections, bronchopneumonia, bacterial enteritis, metritis, pyodermatitis, urinary tract infections, arthritis, and others. Examples of macrolides include erythromycin, gamithromycin, spiramycin, tylosin, tylvalosin, azithromycin, tildipirosin, tilmicosin and tulathromycin. The first veterinary macrolide was spiramycin (1960s) and for human use was erythromycin (1952).
Macrolide antimicrobials are active against many Gram-positive bacterial genera such as Streptococcus, Staphylococcus, Enterococcus and Trueperella (Arcanobacterium), as well as against Gram negative organisms like Actinobacillus, Haemophillus, Histophillus, Mannheimia, Pasteurella, Moraxella, Bordetella, Campylobacter and Lawsonia. Anaerobes including Fusobacterium, Clostridium and Bacteroides spp. are usually susceptible. In addition, the spectrum covers spirochaetes (Leptospira, Brachyspira), and Mycoplasma. However, substantial differences exist between macrolides in their activity & potency against different organisms.
Macrolides differ from one another with respect to the chemical substitutions on the various carbon atoms in the structure and the type of saccharides attached to the lactone ring. The antimicrobial mechanism seems to be the same for all of the macrolides. They interfere with protein synthesis by reversibly binding to the 50S subunit of the ribosome. Their effect is basically confined to rapidly dividing bacteria and mycoplasmas. Macrolides are considered as bacteriostatic but exhibit bactericidal activity at high concentrations; more active at higher pH ranges (7.8–8), and decreased activity in acidic environments such as abscesses. Macrolides achieve wider tissue distribution and high intracellular concentrations that contribute to their efficacy.
Apart from these direct antimicrobial effects, macrolides are known for their modulating effect on many components of the immune system. By influencing the production of cytokines, they exert inhibitory effect on the pro-inflammatory responses.
Macrolides in Veterinary Practice
The macrolides are used to treat both systemic and local infections. Macrolides are considered important antimicrobials for the treatment of various infections in cattle, sheep, pig and poultry because of their advantageous pharmacokinetic characteristics such as good penetration into tissues and high intracellular concentrations; makes them an attractive choice for several indications.
Macrolides are widely used for treatment of diseases that are common in food producing animals. This class has been categorised as critically important for veterinary medicine (VCIA) in the OIElist of antimicrobials of veterinary importance, updated in June 2021 (OIE, 2021). Macrolides are among few alternative antibiotics for treatment of Bovine respiratory disease in cattle, haemorrhagic digestive tract disease in pigs (Lawsonia intracellularis), foot-rot in sheep and for various infections in dogs and cats (dermatological, urogenital, respiratory tract and otitis media). They are very important for the treatment of mycoplasma infections in cattle, pigs and poultry. Newer macrolides are among few alternatives for treatment of respiratory tract infections caused by bacteria that are resistant to other class of antibiotics. Macrolides in food animals (cattle, swine) are used to treat infections but also for medication of large groups of animals as mass medication or metaphylaxis. Macrolides could be regarded as an alternative for treatment of mastitis caused by beta-lactam resistant Staph. Aureus.
The most prominent member of the macrolide is tylosin, an important veterinary antibiotic, used extensively. Tilmicosin, tildipirosin,gamithromycin, and tulathromycin are newer generation macrolide which are exclusively for veterinary use. These agents are primarily intended for use in treatment of respiratory diseases associated with M haemolytica, P multocida, and Histophilus somni.
Tylosin is indicated for oral administration in chickens& swine, and IM in cattle. Erythromycin is labelled for administration IM in dogs and cats and intra-mammary use in cattle; Tiamulin is for oral administration in swine; Tulathromycin as SC in cattle or IM in swine and tildipirosin is for SC use in cattle. Tilmicosin is labelled for SC administration in cattle and sheep and PO in swine.
Tilmicosin- An exclusive Antibiotic for Veterinary Use:
Tilmicosin is a 16-membered semi-synthetic broad-spectrum macrolide antibiotic and was developed exclusively for veterinary use. The first injectable, long-acting macrolide with a one-dose only regimen for food animal use was tilmicosin. Other macrolides authorised with this regimen are tulathromycin, gamithromycin and tildipirosin.
Tilmicosin is a mainly bactericidal semi-synthetic antibiotic of the macrolide group. It acts by affecting protein synthesis. Tilmicosin has an antibacterial spectrum that is predominantly effective against Mycoplasma, Gram-negative bacteria like Pasteurella, and Haemophilus spp. and various Gram-positive organisms such as Staphylococcus spp.
The pharmacokinetic profile of Tilmicosin is characterized by low plasma concentrations and high tissue concentrations. Being a weak base (phosphate), it concentrates in tissues with low pH (generally, tissues have a lower pH than plasma). Pathologically affected tissues (e.g., lung, mammary glands, foot rot) tend to lower their pH further, which creates an ideal environment for a higher concentration of Tilmicosin in those affected tissues.
Tilmicosin is preferably administered by subcutaneous (SC) route. Following subcutaneous injection, tilmicosin is distributed throughout the body, but especially high levels are found in the lung & mammary tissues. The concentrations found in lung and mammary gland are significantly higher than the serum concentrations. The high concentrations of the antibiotics in the milk& pulmonary tissues following subcutaneous administration could be explained by non-ionic passive diffusion.
Absorption of the injectable formulation is good in cattle and sheep, with maximum concentrations in blood observed in 6-12 hours after subcutaneous administration at the recommended dose of 10 mg/kg BW. The serum elimination half-life of Tilmicosin in cattle, sheep & chicken is 29h, 33h, 30.18–45.0 h, respectively. Residues are distributed primarily in the liver and kidneys, with much lower residues found in normal muscle tissue and fat. Significant residues may remain at injection sites for some time following treatment. As per EMEA, the MRL established for tilmicosin in cow’s milk is 50𝜇g/kg.
Scientific evidence suggests that tilmicosin act synergistically with the host immune system. Tilmicosin appears to enhance phagocyte killing of bacteria. Tilmicosin has a strong penetration in macrophages and thus it affects the microorganisms that are phagocytosed.
Tilmicosin is mainly used for treating respiratory tract infection, mixed infection of Mycoplasma and Escherichia coli, other various pneumonia and pulmonary infectious diseases of livestock and poultry caused by Pasteurella, the Mycoplasma, and the like. It is also used for the treatment of mastitis associated with Staphylococcus aureus and Mycoplasma species. Additionally, it is recommended to use in the treatment of interdigital necrobacillosis in cattle (bovine pododermatitis) and ovine foot rot.
Tilmicosin is one of the ideal choice for the control of respiratory disease in cattle because of its single dose administration and longer duration of activity. Tilmicosin concentrations in lung tissue found to be many times higher than in serum at least for 96 hours after a single subcutaneous administration.The preferential activity of macrolide against extracellular pathogens in the lung has been demonstrated conclusively in vitro in a lung infection model.
There is increasing evidence that Tilmicosin modify the host inflammatory cell function and thereby limit tissue damage associated with lung infection. Tilmicosin treatment demonstrated a marked reduction of cytokines & other inflammatory cell infiltrations in peri-bronchial and perivascular areas. Other beneficial effects of Tilmicosin includes reduction in mucus secretion, epithelial cell disruption and reduced airway resistance. It is postulated that efficacy of Tilmicosin and other macrolides may be related to anti-inflammatory and immunomodulatory properties in addition to anti-bacterial activity.
Moreover, the greater susceptibility of staphylococci to Tilmicosin, suggests it as an excellent choice for the treatment of intra-mammary infection. After subcutaneous administration, Tilmicosin rapidly and extensively penetrates from the blood stream into mammary gland, but eliminated slowly. However, administration of Tilmicosin to lactating cows requires a long withdrawal period for milk, hence use of the antibiotic in dairy cattle should be carefully planned in view of the risk of residues associated with its therapeutic administration.
Tilmicosin is not recommended in equine, goat, pig and lambs weighing below 15 kg. It is recommended to use in cattle and sheep at the dose rate of 10 mg/kg bw through subcutaneous route only as a single dose treatment.
Like other macrolides, Tilmicosin when given as injection causes severe tissue irritation that leads toa soft diffuse swelling at the injection site but this disappears within three to seven days. Injection of Tilmicosin in humans can be fatal, therefore extreme caution need to be taken to avoid accidental self-injection. Due to longer elimination period of the drug for milk & meat, benefit-risk assessment need to be made before its use in lactating animals and in animals intended for meat purpose; need to be adhered to the stated withdrawal periods.
Macrolide antibiotics are categorised as critically important for veterinary medicine (VCIA) in the OIElist of antimicrobials of veterinary importance. Tilmicosin is the first injectable, long-acting macrolide with a single dose regimen for use in cattle & sheep. Tilmicosin has an excellent distribution in the body tissues; concentrations of the drug found in lung and mammary gland are significantly higher than the serum concentrations. Because of the pharmacokinetic profile and its efficacy against mycoplasma, G+ve organisms and certain G –ve organisms, Tilmicosin is considered as ideal therapy for multifactorial disease complex like respiratory disease. However, due to its persistent residual effect, compliance to established MRLs need to followed religiously. Apart from antimicrobial properties, macrolides are known to possess anti-inflammatory & immunomodulatory effect that helps in limiting tissue damage associated with infections and results in faster recovery.