9 – Macrolides Flashcards
Think of macrolides in groups:
- Tylosin
- “respiratory disease
- Azithromycin (human formulation): small animals
Tylosin
- Used in large animal production and a bit in small animal
- Feed premix, medicated water or infectable
- Variety of label claims
- *compounded forms used for small animal GI conditions
What are some label claims of Tylosin?
- Swine dysentery and porcine liver enteropathy
- Reduction in liver abscesses in feedlot cattle
- Aid in treatment of respiratory disease and necrotic enteritis in broiler chickens
What are some respiratory disease macrolides for vet use?
- Tilmicosin
- Tulathromycin
Tilmicosin (Micotil)
- For SC use ONLY in cattle and sheep
- -oral premix and liquid for swine, feedlot cattle and rabbits
Tulathromycin (Draxxin)
- SC in cattle
- IM in swine
Azithromycin (Zithromax)
- Human formulation widely used in vet med small animal practice
- Variety of oral tablet and suspension formulation
- Commonly used EXTRA-LABEL in small animal practice
Lincosamides
- Different structure, but similar to macrolides
What is an important lincosamide in vet med?
- Clindamycin
- (Lincomycin: widespread resistance, not used as much anymore)
Clindamycin (Antirobe/Clinacin oral capsules or solution)
- Increased antimicrobial activity compared to Lincomycin
- Commonly used for skin, dental, bone or anaerobic infections
o Used for protozoal diseases - Resistance emerges rapidly
Pleuromutilins: Tiamulin
- Denagard liquid solution or feed premix
- Brachyspira hydodysenteriae to prevent and treat swine dysentery
Streptogramins: Virginiamycin
- Stafac, V-max feed premix
- Feedlot cattle
- Swine
- *poultry: prevent necrotic enteritis caused by C. perfringens
Macrolides and lincosamides mechanism of action
- Binds to bacterial ribosomal 50S sub-unit
o Not same spot as phenicols, but same effect
o Causes incorrect tRNA translation
o Disrupts bacterial protein synthesis - *activity may be pH-dependent
ML and lincosamides may be pH-dependent
- Basic amine groups are ionized in acidic pH, with DECREASED entry into bacterial cell
- *still clinically effective though due to high DRUG CONCENTRAION
ML and lincosamides: usually time-dependent
- But azithromycin shows some CONCENTRATION-dependent effects too
- *can administer relatively infrequently
ML and lincosamides: spectrum of activity, generally effective
- Most gram +
- Some gram –
- Some anaerobes
- Helicobacter
- Some mycoplasma (in vitro, but not really in the real world)
- Intracellular pathogens (Lawsonia and Rhodococcus)
- Others: Spirochetes, Chlamydia, Toxoplasma/Neospora)
ML and lincosamides: spectrum of activity, NOT/LESS effective
- Most gram negative enterics
- Pseudomonas
- Enterococcus
- *resistance emerges rapidly in many bacterial species: cross-resistance is common
What are some mechanisms of resistance?
- Inability to bind to bacterial ribosome
o rRNA methylation (erm gene)
o mutations to ribosomal binding sites (uncommon) - efflux pumps/decreased entry
- enzymatic inactivation of drugs
- plasmid mediated resistance genes: cross resistance
Plasmid mediated resistance genes
- resistance develops and transfers quickly
- *cross resistance to multiple ML/lincosamides is common
- But differences between 14, 15, 16 member ring cross-resistance
Feedlots and antimicrobial use
- Probably now more macrolides than tetracyclines used now
o Especially tulathromycin
Absorption of macrolides and lincosamides
- Lots of variation in oral F between them
o Azithromycin and clindamycin=well absorbed
o Some need special coating (ex. erythromycin) - *food may alter absorption (read the label)
Distribution of macrolides and lincosamides
- Generally highly lipophilic
o Low plasma concentrations
o **Very high Vd - Very high ‘lung’ concentrations
- CSF: lincomycin and clindamycin have increased distribution
- Accumulates in leukocytes
Macrolides and lincosamides: accumulates in leukocytes
- Effective against (some) intracellular pathogens
- Delivered to site of infection
Elimination of macrolides and lincosamides
- Varies depending on drug
- Typically hepatic metabolism
- Excretion via bile or urine
Some macrolides have very long half-lifes: examples and info
- Tilmicosin, tulathromycin, gamithromycin, tildopirosin
- Once distributed into tissue, it is SLOWLY elimininated from the body
o Re-distribution back to plasma before elimination
o ‘different’ plasma and tissue half-lives - *long withdrawal periods, but not prohibitive
o Concentrations not that high in edible tissues
Draxxin administration via pneumatic dart gun
- Big difference in drug exposure compared to if you administered it normally
- Not all the animals that ‘got darted’ had successful injections
- More damage when darted
**What is the adverse event of Tilmicosin?
- Cardiovascular toxicity
o Not an issue if used according to label SC ose in cattle and sheep
o Fatal when injected IV - Might be fatal if administered parenterally in humans, goats, dogs
o *Calcium channel blockage/depletion
o Tachycardia, but negative inotrope (poor contractility)
o IV Ca 2+ may be protective
What are some other adverse events of macrolides and lincosamides?
- GI toxicity after oral administration
o Vomit/diarrhea=common
o GI flora changes (clostridial overgrowth) - Injection site reactions
- Hyperthermia
- Generally minimal drug interactions
AE: vomit/diarrhea
- Especially oral erythromycin
- Maybe some GI irritation or altered motility?
AE: GI flora changes (clostridial overgrowth)
- Fatal colitis reported in horses after erythromycin use
- *caution when using lincosamides (clindamycin)in rodents/lagomorphs (hindgut)
o But macrolides are OK (ex. oral tilmicosin approved for meat rabbits)
AE: injection site reaction
- Most have some degree
- Very irritating
o Tilmicosin (must go SC)
o Erythromycin IM injections
AE: hyperthermia
- Reported after erythromycin injections in foals
Drug interactions
- Some are CYP inhibitors
o Ex. erythromycin - Antagonism when used with phenicols
o BOTH bind to parts of ribosomal 50S submit
o Macrolides do NOT cause bone marrow toxicity
What are some non-antimicrobial properties of macrolides?
- Erythromycin: GI prokinetic (motilin receptor receptor)
- Anti-inflammatory and immunomodulation
o Inhibit production of many pro-inflammatory cytokines
o Decrease neutrophil migration
o Ex. Tylosin commonly used as GI anti-inflammatory
