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Importance of Macrolides in Veterinary Medicine Mike Apley, DVM, PhD Diplomate, American College of Veterinary Clinical Pharmacology Veterinary Diagnostic and Production Animal Medicine Iowa State University

Macrolides in Veterinary Medicine 14 member ring erythromycin 16 member ring tylosin, tilmicosin

Macrolide Susceptibility Testing The macrolide breakpoints reported here are adapted from the NCCLS M31-A2 document. The extended range information reflects extended dilutions used by some diagnostic laboratories utilizing microwell dilution systems. Of the macrolides, only tilmicosin has NCCLS validated breakpoints for veterinary applications.

NCCLS macrolide breakpoints Drug Susceptible ( g/ml) Intermediate (g/ml) Resistant (≥g/ml) Extended Range Erythromycin (Adapted from human) 0.25 - 4 Organisms other than streptococci 0.5 1 - 4 8 Streptococci 0.25 1 Tilmicosin (Veterinary derived) 4 – 32 Cattle (BRD) P. hemolytica 16 32 Swine respiratory disease Actinobacillus pleuropneumoniae, Pasteurella multocida

Label Applications Label applications in this presentation are adapted from labels as presented in the Compendium of Veterinary Products (North American Compendiums). The listing of a label application does not indicate the frequency or extent of use in animals.

Label Applications in Food Animals Tylosin Label Indications

Tylosin Injectable solution In beef cattle and nonlactating dairy cattle: indicated for use in the treatment of bovine respiratory complex (shipping fever, pneumonia) usually associated with Pasteurella multocida and Actinomyces pyogenes; foot rot (necrotic pododermatitis) and diphtheria caused by Fusobacterium necrophorum, and metritis caused by Actinomyces pyogenes.

Tylosin Injectable solution In swine: indicated for use in the treatment of swine arthritis caused by Mycoplasma hyosynoviae, swine pneumonia caused by Pasteurella spp., swine erysipelas caused by Erysipelothrix rhusiopathiae, acute swine dysentery associated with Brachyspira (formerly Serpulina or Treponema) hyodysenteriae when followed by appropriate medication in the drinking water and/or feed.

Tylosin Phosphate Feed Additive Beef Cattle: For reduction of incidence of liver abscesses caused by Fusobacterium necrophorum and Actinomyces pyogenes.

Tylosin Phosphate Feed Additive Swine: For increased rate of weight gain and improved feed efficiency, For prevention and/or control of porcine proliferative enteropathies (ileitis) associated with Lawsonia intracellularis, For prevention of swine dysentery (bloody scours) caused by Serpulina hyodysenteriae,

Tylosin Phosphate Feed Additive Swine (cont.): For maintaining weight gains and feed efficiency in the presence of atrophic rhinitis, For treatment and control of swine dysentery (bloody scours) caused by Serpulina hyodysenteriae following initial medication with tylosin soluble in drinking water.

Tylosin Phosphate Feed Additive Chickens: For increased rate of weight gain and improved feed efficiency. Laying Chickens: For improving feed efficiency. Broiler and Replacement Chickens: To aid in the control of chronic respiratory disease caused by Mycoplasma gallisepticum.

Tylosin Tartrate Water Medication Swine: For the treatment and control of swine dysentery caused by Serpulina hyodysenteriae or other pathogens sensitive to tylosin

Tylosin Tartrate Water Medication Chickens: As an aid in the treatment of chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum sensitive to tylosin in broiler and replacement chickens. For the control of chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum sensitive to tylosin at time of vaccination or other stress in chickens. For the control of chronic respiratory disease (CRD) caused by Mycoplasma synoviae sensitive to tylosin in broiler chickens.

Tylosin Tartrate Water Medication Turkeys: For maintaining weight gains and feed efficiency in the presence of infectious sinusitis caused by Mycoplasma gallisepticum sensitive to tylosin.

Tylosin Tartrate as part of cattle ear implants One product line of cattle growth promoting ear implants is available containing a pellet of tylosin tartrate (29 mg) in addition to the hormone-containing pellets.

Label Applications in Food Animals Tilmicosin Label Indications

Tilmicosin Injectable Solution Cattle and Sheep… indicated for the treatment of bovine respiratory disease (BRD) and ovine respiratory disease (ORD) associated with Mannheimia (Pasteurella) haemolytica. Cattle … indicated for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia (Pasteurella) haemolytica.

Tilmicosin Feed Additive Swine: … for the control of swine respiratory disease associated with Actinobacillus pleuropneumoniae and Pasteurella multocida. Animal feed bearing or containing this veterinary feed directive drug shall be fed to animals only by or upon a lawful veterinary feed directive issued by a licensed veterinarian in the course of the veterinarian's practice.

Label Applications in Food Animals Erythromycin Label Indications

Erythromycin Injectable Solution Beef Cattle: Shipping fever, pneumonia (or pneumonia-enteritis complex), foot rot, stress (handling, transporting to feedlot, vaccination, dehorning, etc.), metritis.

Erythromycin Injectable Solution Dairy Cattle: Pneumonia, foot rot, metritis, shipping fever, stress (handling, transporting to and from pasture, etc.).

Erythromycin Injectable Solution Swine (Hogs): pneumonia, rhinitis, bronchitis. Sows: metritis, leptospirosis (at farrowing time). Baby Pigs (one week of age or older): “scours".

Erythromycin Injectable Solution Sheep: Prevention of "dysentery"** in newborn lambs, upper respiratory infections. ** Where organisms susceptible to erythromycin may be the infective agent.

Erythromycin Mastitis Syringe A mastitis syringe for lactating cows that is effective against the leading mastitis-causing organisms: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis… A mastitis syringe for nonlactating cows that is effective against the following major mastitis-causing organisms: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus nonagalactiae

Erythromycin Thiocyanate Feed Additive Chickens and Turkeys: As an aid in the prevention and reduction of lesions and in lowering severity of chronic respiratory disease. Chickens: As an aid in the prevention of infectious coryza. As an aid in the prevention of chronic respiratory disease during periods of stress.

Erythromycin Phosphate Water Medication Solution In Broilers and Replacement Chickens: As an aid in the control of Chronic Respiratory Disease due to Mycoplasma gallisepticum susceptible to erythromycin. In Replacement Chickens and Chicken Breeders: As an aid in the control of Infectious Coryza due to Haemophilus gallinarum susceptible to erythromycin.

Erythromycin Phosphate Water Medication Solution In Growing Turkeys: As an aid in the control of Bluecomb (Non-specific Infectious Enteritis) caused by organisms susceptible to erythromycin.

Data Related to Use National Animal Health Monitoring Service http://www.aphis.usda.gov/vs/ceah/ncahs/nahms/index.htm Beef – Feedlot, 1999 Swine, 2000

NAHMS Beef Feedlot Data Survey conducted in 12 states Approximately 84% of U.S. feedlot inventory The survey estimated that 14.4% of all cattle placed in feedlots developed “respiratory disease such as shipping fever” after arrival.

NAHMS Beef Feedlot Data “Approximately 2/3 of the metaphylactically treated cattle in both large and small feedlots were administered tilmicosin. These cattle represent 6.7% of cattle placed on feed.”

NAHMS Beef Feedlot Data “Tilmicosin, florfenicol, and tetracyclines were the primary antimicrobial drugs for the initial treatment of bovine respiratory disease (BRD).” Tilmicosin 31.3% Florfenicol 21.9% Tetracyclines 21.6%

NAHMS Beef Feedlot Data “Percent of feedlots that used the following antimicrobials in feed or water as a health or production management tool by antimicrobial used and by feedlot capacity.” Tylosin, 1000 – 7999 capacity, 12.1% Tylosin, 8000 or more capacity, 41.5%

NAHMS Beef Feedlot Data “For all cattle placed in the specified feedlot size groups, percent of cattle that received each of the following antimicrobials in the feed or water as a health or production tool by feedlot capacity.” Tylosin, 1000 – 7999 capacity, 16.1% Tylosin, 8000 or more capacity, 47.2% Tylosin, all feedlots, 42.3%

NAHMS Beef Feedlot Data For feedlots that used the specified antimicrobials in the feed or water as a health or production management tool, average number of days … by arrival weight. Tylosin, less than 700 lbs, 145 days Tylosin, 700 lbs or greater, 138 days

NAHMS Swine Data A 2000 – 2001 survey conducted in 17 states representing 94% of the U.S. pig inventory.

NAHMS Swine Data For sites that had any grower/finisher pigs, percent of sites that gave the following antimicrobials in water to grower/finisher pigs in the previous 6 months by the primary reason for giving them. Tylosin, respiratory disease treatment, 1.2% Tylosin, enteric disease treatment, 2.7% Tylosin, any reason (includes above), 4.1% Duration in water (all reasons) averaged 4.9 days

NAHMS Swine Data For sites that had any grower/finisher pigs, percent of sites that gave the following antimicrobials by injection to grower/finisher pigs in the previous 6 months by the primary reason for giving them. Tylosin, disease prevention, 3.5% Tylosin, respiratory disease treatment, 13.8% Tylosin, enteric disease treatment, 11.1% Tylosin, any reason (includes above), 30.7%

NAHMS Swine Data For sites that had any grower/finisher pigs, percent of sites that gave the following antimicrobials in feed to grower/finisher pigs in the previous 6 months by the primary reason for giving them. Tylosin, growth promotion, 31.3% Tylosin, disease prevention, 13.2%% Tylosin, respiratory disease treatment, 1.4% Tylosin, enteric disease treatment, 10.3% Tylosin, any reason (includes above), 56.3% Average number of days in feed (all reasons), 62.3

NAHMS Swine Data For sites with nursery-age pigs, percent of sites that used the following antimicrobials or feed additives in the feed of nursery age pigs…. Tilmicosin, 3.6%, average days of 28.5 Tylosin, 23.2%, average days of 26.7 Tylosin/sulfamethazine, 6.6%, average days of 23.7

Extralabel Uses of Macrolides Erythromycin oral use in dogs and cats Very limited use Significant gastrointestinal upset is possible Use of veterinary macrolides is not advisable in non-ruminant herbivores (horses, rabbits) Adverse effects related to enteric flora imbalance

Macrolide Use in Foals Oral use in foals for Rhodococcus equi respiratory infection. Resistance to erythromycin/rifampin combination is being encountered Erythromycin-related hyperthermia has been reported in foals. Recent work has characterized a combination of clarithromycin/rifampin as superior to azithromycin/rifampin and erythromycin/ rifampin for this application1 1Gigure, et al. Retrospective comparison of azithromycin, clarithromycin, and erythromycin for the treatment of foals with Rhodococcus equi pneumonia. J Vet Intern Med 18(4): 568-73, 2004