Macrolides Flashcards
Macrolides vs. Lincosamides
-different structures, but similar
Tylosin
-feed premix, medicated water, injectables
-often in production animals
Tylosin uses
-Swine: swine dysentery, porcine proliferative enteropathy
-Cattle: reduction in liver abscesses in feedlots
-Chickens: respiratory disease and necrotic enteritis in broilers
-rarely used in small animals… compounded forms for GI conditions
Respiratory disease macrolides
-Tilmicosin (Micotil)
-Tulathromycin (Draxxin)
-Tildipirosin
-Gamithromycin
Tilmicosin
-SQ use in cattle and sheep ONLY
-oral pulmotil premix and liquid for swine, feedlot cattle and rabbits
Tulathromycin
*Draxxin
-Used SQ in cattle and IM in swine
Azithromycin
-human macrolide used extra-label in small animal practice because many pediatric medicine
-oral tablets and suspension formulations
Erythromycin
-feed premix licensed for poultry
-used as a pro-kinetic drug sometimes post surgery,
and in aquaculture
Lincosamide options
-lincomycin
-clindamycin
Clindamycin (Antirobe/Clinacin oral capsules)
-increased antimicrobial activity compared to lincomycin
*resistance emerges rapidly
-commonly used for skin, dental, bone or anaerobic infections and protozoal diseases (neospora, toxoplasmosis)
Tiamulin
-type of Pleuromutilins
-Denagard solution or feed premix
-Treatment and prevention of swine dysentery caused by spirochete Brachyspira hyodysenteriae
Virginiamycin
-type of Streptogramins
Uses:
-liver abscesses of feedlot cattle
-Swine dysentery
-necrotic enteritis from Clostridium perfingens in broilers
Macrolides and Lincosamides mechanism of action
-binds to bacterial ribosomal 50S subunit, causing incorrect tRNA translation and disrupts bacterial protein synthesis
*not same spot as phenicols but same effect
-considered time dependent!
What effects macrolides and licosamides mechanism of action?
-activity may be pH dependent
-basic amine groups on some macrolides are ionized in acidic pH with a decreased entry into bacterial cell but still effective because high drug concentrations
Are macrolides and lincosamides bacteriostatic?
Typically
but depends which macrolide/pathogen combo
Spectrum of activity of macrolides and lincosamides
-most gram +
-some Gram - bacteria (usually BRD and SRD pathogens)
-some anaerobes (esp. clindamycin)
-Helicobacter (esp. azithromycin)
-some mycoplasma (in vitro)
-intracellular pathogens like Lawsonia and Rhodococcus
-other spirochetes (brachyspira), Chlamydia, Toxoplasma/Neospora (clindamycin)
Typical gram negatives that macrolides work well against?
-histophilus somni
-Mannheimia haemolytica
-pasteurella multocida
When not to use macrolides and lincosamides?
-most gram - enterics
-pseudomonas
-enterococcus
**resistance emerges rapidly in many bacterial species
-cross resistance is common
Mechanisms of resistance
- inability to bind to bacterial ribosome
-rRNA methylation (erm gene)
-mutations to ribosomal binding sites - efflux pumps/ decrease entry
- Enzymatic inactivation of drugs
- Plasmid-mediated resistance genes
Importance of plasmid-mediated resistance
-likely cross resistance to multiple macrolides/lincosamides
*but there are differences between 14,15,16 member ring cross-resistance
Macrolides and lincosamines absorption
Lots of variation between macrolides
-Azithromycin and clindamycin well absorbed
-sometimes need special coating (eg. erythromycin)
-food may alter absorption
Macrolides and lincosamides distribution
-usually highly lipophilic (so low plasma concentrations but very high Vd)
Which tissues are the macrolides and lincosamides mostly distributing to?
-Very high lung concentrations
-CSF (lincomycin and clindamycin)
Macrolides and lincosamindes within leukocytes?
Macrolides and lincosamides accumulate in the leukocytes
-effective against some intracellular pathogens
-delivered to site of infection
**but does not mean they will go to all sites of infection
Macrolides and lincosamides elimination
-Some hepatic metabolism
-excretion in bile or urine
*neither effects drug dosing etc.
-Very long half lives
Why do macrolides and lincosamides have such long half lives?
Because they have high Vd
-distributed to tissues (eg. lungs!) and then drug is slowly re distributed back to plasma and then eliminated from body
Which macrolides have long half lives?
Tilmicosin
Tulathromycin
Gamithromycin
Tildopirosin
Withdrawal periods of macrolides and lincosamides
Long but not prohibitive (28-49 d)
*concentrations are not that high in edible tissues
Use of draxxin through darts
- much lower in darts than normal injection
-more damage was seen with darts= Creatine kinase and AST= tissue damage
**darting for immobilization can see results immediately… cannot do this with antimicrobials because cannot see result immediately so cannot confirm anything
Tilmicosin adverse events
Cardiovascular toxicity
-not an issue if used SC for cattle and sheep
-fatal when injected IV (humans, goats, dogs, etc.)
How does tilmicosin cause cardiovascular toxicity?
-Ca channel blockage/Ca depletion
-Tachycardia but neg ionotropy
**Need to administer Ca IV to be protective
Macrolides and lincosamides adverse events
- GI toxicity
- injection site reactions
- hyperthermia
- drug interactions
GI toxicity adverse events
- vomiting and diarrhea (especially oral erythromycin)
-GI irritation or altered motility - GI flora changes (clostridial overgrowth)
-fatal colitis in horses after erythromycin
-clyndamycin in rodents /lagomorphs BUT other macrolides are ok and oral tilmicosin approved for meta rabbits
Injection site reactions
-most injectable macrolides/lincosamides cause some degree of injection site irritation
*very irritating- Tilmicosin (must go SC), and erythromysin IM
Hyperthermia
-repoorted after erythromycin injections in foals
Drug interactions
- generally low but some macrolides are CYP inhibitors
- Antagonism when used with phenicols because both bind to similar parts of the ribosomal 50S subunit BUT macrolides don’t cause bone marrow toxicity
Non antimicrobial use of Erythromycin
GI prokinetic
-motilin receptor agonist
-may stimulate cholinergic neurons
anti-inflammatory and immunomodulation of macrolides
- Macrolides inhibit the production of many pro-inflammatory cytokines
-decrease neutrophil migration
-possible reason for clinical improvement when treating resp disease - Tylosin- used for GI anti-inflammatory
