Preface
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 Fusob
acterium, 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 OIE list 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.
Pharmacology:
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 29 h, 33 h, 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.
Therapeutic Uses:
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.
Precautions:
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
to a 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.
Conclusion:
Macrolide antibiotics are categorised as critically important for veterinary medicine (VCIA) in
the OIE list 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.
