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Macrolide Use in Animals


Melissa A. Mercer

, DVM, MS, DACVIM-LA, Virginia Maryland College of Veterinary Medicine

Last full review/revision Sep 2022 | Content last modified Sep 2022
Topic Resources

The macrolide antimicrobials typically have a large lactone ring in their structure and are much more effective against gram-positive than gram-negative bacteria. They are also active against mycoplasmas and some rickettsiae. ( See also Polyene Macrolide Antimicrobials for Use In Animals Polyene Macrolide Antimicrobials for Use In Animals Polyene antifungals are the oldest class of systemic antifungal agents. These antifungals are large molecules, consisting of a long polyene, a lipid-soluble component and a markedly hydrophilic... read more .)


Macrolides fall into multiple classes, depending on the size of the macrocyclic lactone ring. None of the 12-membered ring group is used clinically. Erythromycin and the closely related oleandomycin and troleandomycin belong to the 14-membered ring group. Azithromycin (synthesized from erythromycin) and gamithromycin are 15-ring members, a subclass referred to as azalides. Of the 16-membered ring group, spiramycin, josamycin, tylosin, and tilmicosin and tildipirosin (both synthesized from tylosin) are used clinically. Tulathromycin contains three amine rings and is classified as a triamilide. Ketolides, which include tylosin and spiramycin, are closely related macrolides.

General Properties

A macrolide is actually a complex mixture of closely related antimicrobials that differ from one another with respect to the chemical substitutions on the various carbon atoms in the structure and in the amino sugars and neutral sugars. For example, erythromycin is mostly erythromycin A, but B, C, D, and E forms may also be included in the preparation.

The macrolide antimicrobials are colorless, crystalline substances. They contain a dimethylamino group, which makes them basic. Although they are poorly water soluble, they do dissolve in more polar organic solvents. Macrolides are often inactivated in basic (pH > 10) as well as acidic environments (pH < 4 for erythromycin). The multiple functional groups make it possible for them to undergo a large number of chemical reactions. More stable ester forms (eg, acetylates, estolates, lactobionate, succinates, propionates, and stearates) are commonly used in pharmaceutical preparations.

Antimicrobial Activity

Mode of Action of Macrolides in Animals

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, similar to the phenicols ( see Phenicols Use in Animals Phenicols Use in Animals Chloramphenicol is a highly effective and well-tolerated broad-spectrum antimicrobial. However, because it causes blood dyscrasias, it is prohibited for use in food-producing animals in several... read more ). They appear to bind at the donor site, thus preventing the translocation necessary to keep the peptide chain growing. The effect is essentially confined to rapidly dividing bacteria and mycoplasmas. Macrolides are regarded as being bacteriostatic but demonstrate bactericidal activity at high concentrations. Macrolides are considerably more active at higher pH ranges (7.8–8), and therefore have decreased activity in acidic environments such as abscesses. Macrolides are considered to be time dependent in terms of antimicrobial efficacy.

The macrolides appear to have immunomodulatory effects useful to treat respiratory infections, in particular, those associated with Pseudomonas aeruginosa, based on efficacy at doses (concentrations) considered ineffective against susceptible bacteria.

Bacterial Resistance to Macrolides in Animals

Lack of cell wall permeability renders most gram-negative organisms inherently resistant to macrolides. There are a few exceptions, and gram-negative forms without cell walls are usually susceptible. Resistance to macrolides in gram-positive organisms results from alterations in ribosomal structure (target site methylation or mutation) and loss of macrolide affinity. Posttranslational methylation results in cross-resistance to lincosamides and streptogramins (macrolide-lincosamide-streptogramin B, or MLSB, resistance).

MLSB resistance has been recently reported in some isolates of Rhodococcus equi. Macrolide resistance may be intrinsic or plasmid-mediated (via production of esterases) and constitutive or inducible. Resistance may develop rapidly (erythromycin) or slowly (tylosin) and generally results in cross-resistance between macrolides. Efflux from cells is a second important mechanism of resistance for some members of this class, as is, less frequently, drug inactivation.

Antimicrobial Spectra of Macrolides in Animals

Macrolides are active against most aerobic and anaerobic gram-positive bacteria, although there is considerable variation as to potency and activity. In general, macrolides are not active against gram-negative bacteria; however, some strains of Pasteurella, Haemophilus, and Neisseria spp may be susceptible. Exceptions include tilmicosin, gamithromycin, and tulathromycin, for which the spectra are characterized as broader and include Mannheimia haemolytica and Pasteurella multocida, as well as some gram-negative bacteria (ie, some strains of Pasteurella, Haemophilus, and Neisseria spp). Helicobacter also is generally included in the spectrum. Azithromycin, derived from erythromycin, includes Bordetella in its spectrum.

Bacteroides fragilis strains are moderately susceptible to macrolides. Macrolides are active against atypical mycobacteria, Mycobacterium, Mycoplasma, Chlamydia, and Rickettsia spp but not against protozoa or fungi. In vitro synergism occurs with cefamandole (against B fragilis), ampicillin (against Nocardia asteroides), and rifampin (against R equi).

Pharmacokinetic Features

Absorption of Macrolides in Animals

Macrolides are readily absorbed from the GI tract if not inactivated via gastric acid. Oral preparations are often enteric coated, or stable salts or esters (eg, stearate, lactobionate, glucoheptate, propionate, and ethylsuccinate) are used. If the enteric-coated tablets are crushed or divided, the macrolides are degraded in the stomach via gastric acid, and therefore enteric-coated forms must be administered whole. Esterified formulations must be hydrolyzed into their active form.

Plasma concentrations peak within 1–2 hours in most cases, although absorption patterns may be erratic because of the presence of food and may depend on the salt or ester used. Absorption from the ruminoreticulum is usually delayed and is unreliable. Macrolides tend to be characterized by high oral bioavailability, but this is variable among species, drugs, and salts. For example, oral bioavailability for tylosin is 35% for the tartrate salt versus 14% for the phosphate. For azithromycin, oral bioavailability is 39%–56% in foals 6–10 weeks old, 59% in cats, and 97% in dogs. Clarithromycin and azithromycin have similar bioavailability in foals—56% and 57%, respectively.

Erythromycin is labeled for administration IM in dogs and cats, PO in chickens and turkeys, and intramammary use in cattle. Tylosin is labeled for administration PO in cattle, swine, honeybees, chickens, and turkeys, and IM in cattle and swine. Tulathromycin may be administered SC in cattle or IM in swine. Gamithromycin is labeled for SC administration in beef and nonlactating dairy cattle. Tilmicosin is labeled for SC administration in cattle and sheep and PO in swine and cattle. Tiamulin is labeled for administration PO in swine, and tildipirosin is labeled for SC use in cattle.

Clarithromycin and azithromycin are not labeled for veterinary use in the US, but are frequently prescribed for extralabel oral use. Tilmicosin, gamithromycin, and tulathromycin are administered SC, except in swine, for which an oral tilmicosin preparation is available. Absorption after injection is rapid, but pain and swelling can develop at the injection sites.

Distribution of Macrolides in Animals

Macrolides become widely distributed in tissues, and concentrations are about the same as in plasma or even higher in some instances. They actually accumulate within many cells, including macrophages, in which they may be ≥20 times the plasma concentration; WBCs will then facilitate distribution to the site of inflammation. This accumulation accounts in part for the long dosing interval that characterizes some macrolides (eg, tilmicosin). With spiramycin, the tissue concentrations remain especially high, even though plasma concentrations are rather low.

Macrolides tend to concentrate in the spleen, liver, kidneys, and particularly the lungs. They enter pleural and ascitic fluids and concentrate in the eye but do not distribute to the eye or the CSF (only 2%–13% of plasma concentration unless the meninges are inflamed). Concentrations of azithromycin and clarithromycin in the pulmonary epithelial lining fluid greatly exceed serum concentrations after treatment. Tulathromycin also concentrates in bronchoalveolar cells, with concentrations still detectable for at least 8 days after single-dose administration. Due to their nature as a weak base, macrolides concentrate in the bile, CSF, and milk due to ion trapping. Up to 75% of the dose is bound to plasma proteins, and they bind to alpha1-acid glycoproteins rather than to albumin.

Biotransformation of Macrolides in Animals

Metabolic inactivation of the macrolides is usually extensive; however, the relative proportion depends on the route of administration and the particular antimicrobial. After administration PO, 80% of an erythromycin dose undergoes metabolic inactivation, whereas tylosin appears to be eliminated in an active form. Erythromycin and its degradation products interfere with cytochrome P450-mediated metabolism of a number of other drugs via cytochrome P450 inhibition. Azithromycin is not highly metabolized, whereas clarithromycin is extensively metabolized and produces an active metabolite, 14-hydroxy-clarithromycin.

Excretion of Macrolides in Animals

Macrolide antimicrobials and their metabolites are excreted mainly in bile (> 60%) and often undergo enterohepatic cycling. Urinary clearance may be slow and variable (often < 10%) but may represent a more consequential route of elimination after parenteral administration. For example, in people, 14% of azithromycin and 20%–40% of clarithromycin is excreted unchanged in urine. The concentration of macrolides in milk often is several times as great as in plasma, especially in mastitis.

Pharmacokinetic Values of Macrolides in Animals


The accumulation of macrolides among different tissues contributes to the large volume of distribution (for azithromycin, 12 L/kg in dogs, 23 L/kg in cats, and 22 L/kg in foals 6–10 weeks old 1 References The macrolide antimicrobials typically have a large lactone ring in their structure and are much more effective against gram-positive than gram-negative bacteria. They are also active against... read more ) and long elimination half-life ( see Elimination and Distribution of Macrolides Elimination and Distribution of Macrolides Elimination and Distribution of Macrolides ). For tulathromycin, the elimination half-life is 65 hours in calves and 69 hours in pigs 2–3 months old. Because of these long half-lives, time to steady state may be prolonged, and a loading dose may be indicated for multiple dosing. Tylosin, however, is an exception, with a volume of distribution approximating 1.4 L/kg and a half-life of 1–5 hours in most species.


  • Jacks S, Giguère S, Gronwall RR, et al. Pharmacokinetics of azithromycin and concentration in body fluids and bronchoalveolar cells in foals. Am J Vet Res 2001;62:1870–1875.

Therapeutic Indications and Dose Rates

The macrolides are used to treat both systemic and local infections. They are often regarded as alternatives to penicillins for treatment of streptococcal and staphylococcal infections. General indications include upper respiratory tract infections, bronchopneumonia, bacterial enteritis, metritis, pyodermatitis, urinary tract infections, arthritis, and others. Macrolides such as erythromycin, azithromycin and clarithromycin are indicated for treatment of Rhodococcus respiratory tract infections in foals.


Formulations to treat mastitis are also available and often have the advantage of a short withholding time for milk. Tilmicosin, gamithromycin, tildipirosin, and tulathromycin are approved for use in treatment of bovine respiratory diseases associated with M haemolytica, P multocida, and Histophilus somni. In swine, tilmicosin phosphate is added to feed or water for control of swine respiratory disease.

A selection of general dosages for some macrolides is listed in Dosages of Macrolides Dosages of Macrolides Dosages of Macrolides . The dose rate and frequency should be adjusted as needed for the individual animal.

Special Clinical Concerns

Adverse Effects and Toxicity

The incidence of adverse effects from macrolides and azalides is dependent on animal species; in general, they are well tolerated in dogs and cats. Adverse effects after administration IM have been noted in a variety of species, due to the irritating nature of macrolides. Therefore, injection site reactions and thrombophlebitis are not uncommon after administration. Hypersensitivity reactions occasionally occur. Erythromycin estolate may be hepatotoxic and cause cholestasis. Additionally, erythromycin is a motilin receptor agonist that operates via both cholinergic and noncholinergic pathways and therefore may also induce vomiting and diarrhea, particularly when high doses are administered.

Adult horses are sensitive to macrolide-induced GI disturbances that can be serious and even fatal, such as antimicrobial-induced colitis. Care should be taken when treating foals so that the mare is not exposed to macrolides. Rabbits have been reported to develop potentially fatal typhlocolitis after macrolide treatment. Oral administration of erythromycin has also been associated with severe diarrhea in calves.

Erythromycin has been associated with acute respiratory distress syndrome, hepatotoxicity, and gastroenteritis in foals. In foals treated with macrolides, drug-induced anhidrosis may develop, leading to severe hyperthermia. Erythromycin is most frequently associated with drug-induced anhidrosis, followed by azithromycin and clarithromycin. Drug-induced anhidrosis is reversible and may take up to 10 days after cessation of treatment to resolve. The IM formulation of erythromycin can be fatal if injected IV in horses.

In pigs, tylosin may cause edema of the rectal mucosa, mild anal protrusion with diarrhea, and anal erythema and pruritus. Tylosin has been reported to cause fatal antimicrobial-induced colitis in horses and is therefore not indicated in this species. In cattle, IV administration of tylosin can cause shock, depression, and dyspnea. At doses of 5 mg/kg/day, dogs had a greater tendency to develop ventricular tachycardia and fibrillation during acute myocardial ischemia. Tilmicosin is characterized by cardiac toxicity (tachycardia and decreased contractility). Parenteral (but not oral) administration should be avoided in swine, and extralabel use should be avoided. Cattle have died after IV injection of tilmicosin, horses have a low tolerance for tilmicosin via any route, and human injury is possible after accidental exposure.

Interactions With Macrolides and Azalides in Animals

Macrolide antimicrobials probably should not be used with chloramphenicol or the lincosamides because they may compete for the same 50S ribosomal subunit binding site, although the in vivo relevance of this potential interaction is unclear. Activity of macrolides is depressed in acidic environments. Macrolide preparations for parenteral administration are incompatible with many other pharmaceutical preparations. Erythromycin and troleandomycin and other macrolides are microsomal enzyme inhibitors that depress CYP3A4 (in people) and thus the metabolism of many drugs, including theophylline, midazolam, carbamazepine, omeprazole, and ranitidine. Macrolides also are substrates for and potentially potent inhibitors of P-glycoprotein efflux pumps.

Macrolides combined with rifampicin remain a mainstay of treatment for R equi pneumonia in foals; however, drug-drug interactions may decrease overall treatment efficacy. Rifampicin induces intestinal p-glycoprotein efflux pumps that affect the oral absorption and distribution of macrolides, such as clarithromycin, to the lungs. Coadministration of rifampicin and clarithromycin decreases clarithromycin's bioavailability by up to 90%. Coadministration of tulathromycin and rifampicin in foals has also led to greatly decreased concentrations of tulathromycin in the lungs. Coadministration of gamithromycin and rifampicin in foals leads to considerably increased plasma exposure to gamithromycin due to rifampicin's inhibition of hepatic elimination mechanisms.

Effects of Macrolides and Azalides on Laboratory Tests in Animals

Macrolides and azalides may increase bilirubin concentration, bromsulphthalein concentration, total WBC count, eosinophil count, alkaline phosphatase activity, AST activity, and ALT activity. Cholesterol concentrations may decrease.

Drug Withdrawal and Milk Discard Times of Macrolides and Azalides in Animals

In general, macrolides are very lipophilic and tend to stay in the milk for a long time at low concentrations. Therefore, with extralabel use in lactating animals, prolonged milk discard times should be anticipated. Withdrawal times can vary between products, even for the same drug. Therefore, when using products according to label recommendations, it is imperative to follow the label meat and milk withdrawal times for the particular product used.

For instances of extralabel drug use (ELDU), it is recommended to contact a country-specific advisory program to obtain evidence-based withdrawal recommendations extrapolated from known species pharmacokinetics. In the US, veterinarians may contact the Food Animal Residue Avoidance Databank (FARAD, for withdrawal recommendations. Regulatory requirements for withdrawal times and milk discard times vary among countries. These should be followed carefully to prevent food residues and consequent public health implications.

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