pharm 8 part 2 (50S protein synthesis inhibitors)

50S drugs (phenicols, macrolides, lincosamides)

Antibacterial classes acting at the 50S ribosomal subunit; Exam 2 covers phenicols and macrolides (about 1 question)

50S drug shared properties

Inhibit protein synthesis, bacteriostatic, moderate post-antibiotic effect, moderate oral absorption in most non-ruminants, extensively metabolized and eliminated by the liver

50S drug distribution

Widely distributed, lipophilic, moderate protein binding (30-50%), concentrate intracellularly and reach high concentrations in abscesses

50S drug PK/PD

Parameters are not well defined, and plasma concentrations are not always predictive of treatment success

50S drug interactions

Phenicols, macrolides, and lincosamides should not be co-administered because they compete at the same binding site and may decrease each other’s effectiveness

Phenicols

Chloramphenicol and its derivatives; 50S protein synthesis inhibitors

Phenicol drugs and species

Chloramphenicol (oral) in dogs, cats, and horses; florfenicol in food animals (injectable in cattle, feed in swine, water in fish)

Phenicol spectrum

Broad: gram-positive and gram-negative, aerobes and anaerobes, Rickettsia, Chlamydia, Mycoplasma; unpredictable against gram-negative enterics, poor against Pseudomonas

Florfenicol clinical use

Treats BRDC in cattle

Chloramphenicol oral absorption

Formulation matters (e.g., chloramphenicol palmitate has poor absorption in cats)

Chloramphenicol distribution

Distributes well to protected sites

Chloramphenicol metabolism

Metabolized by conjugation, which is deficient in cats and very young animals of any species, so half-life is prolonged and toxicity risk is increased

Chloramphenicol hematologic toxicity

Dose-dependent inhibition of mitochondrial protein synthesis in bone marrow; cats are most susceptible; rare neutropenia and aplastic anemia reported in dogs

Chloramphenicol aplastic anemia in people

Idiosyncratic and irreversible (1 in 10,000 to 30,000); can occur with small exposures such as ophthalmic ointment or residues, and the drug is easily absorbed across the skin

Chloramphenicol in food animals

Prohibited from use in food animals

Chloramphenicol client education

Wear gloves, dissolve don’t crush tablets, and use proper restraint

Chloramphenicol other adverse effects

Anorexia, diarrhea, vomiting, and depression (overdose); unpleasant taste

Chloramphenicol drug interactions

Inhibits hepatic CYP450 enzymes, which may decrease metabolism and clearance of phenobarbital, phenytoin, and propofol (not the safest with euthanasia drugs)

Florfenicol adverse effects

Lacks the para-nitro group responsible for bone marrow toxicity, so use and extralabel use in food animals is permissible; dose-dependent reversible toxicity still seen; injection site reactions and diarrhea in horses; fewer drug interactions

Phenicol resistance

Acetylation and inactivation by bacterial enzymes; cross-resistance does not always occur and florfenicol is more resistant to bacterial enzymes

Macrolides

Drugs ending in -thromycin and -osin; 50S protein synthesis inhibitors

Macrolide drugs in dogs, cats, and foals

Erythromycin, clarithromycin, azithromycin

Macrolide drugs in food animals

Erythromycin (poultry; the only one approved for laying hens), tulathromycin (Draxxin), tilmicosin (Micotil), gamithromycin (Zactran), tildipirosin (Zuprevo), and tylosin

Macrolide spectrum

Relatively broad but drug-dependent: gram-positive aerobes (R. equi, streptococci, staphylococci), some anaerobes (azithromycin most active), L. intracellularis, Mycoplasma, gram-negative BRD pathogens, sometimes Salmonella

Macrolide pharmacokinetics

Oral bioavailability about 30-40%; Vd 12-13 L/kg (wide distribution to milk, cells, and lungs); metabolized by the liver with few active metabolites (clarithromycin)

Macrolide half-life and dosing intervals

Half-life ranges from 1-2 hours (erythromycin) to 1-2 days; dosed q6-8h (erythromycin), q48h (azithromycin), and once (tulathromycin); no need to memorize

Macrolide intracellular concentrations

Cmax in cells is about 200x higher than in plasma and stays detectable about 4 days longer

Macrolide gastrointestinal adverse effects

Vomiting and diarrhea in dogs and cats; severe, potentially fatal colitis in horses and rabbits; erythromycin is most common because it activates motilin receptors, increasing motility and causing diarrhea

Macrolide hyperthermia

Seen in foals (anhidrosis)

Macrolide injection site reactions

Common adverse effect

Tilmicosin cardiotoxicity

Fatal IV in any species; do not use in cats, dogs, or horses; injection in humans has been associated with fatalities

Macrolide drug interactions

Erythromycin inhibits CYP450 enzymes and may increase plasma concentrations and toxicity of other drugs; rifampin lowers macrolide bioavailability through P-glycoprotein induction, but the two are still used together for synergism

Macrolide key concepts

Bacteriostatic, 50S protein synthesis inhibitor, love the lungs, lipophilic and accumulate intracellularly and in abscesses, gram-positives, gram-negative BRD pathogens and mycoplasma, diarrhea in adult horses, hyperthermia in foals, tilmicosin cardiotoxicity

Phenicol key concepts

Bacteriostatic, 50S protein synthesis inhibitor, lipophilic, accumulates intracellularly and in abscesses, broad spectrum, bone marrow toxicity (florfenicol vs chloramphenicol), chloramphenicol prohibited in food animals