Lecture 4: Ribosomal Inhibiting Antibacterial Agents

What are the five main tetracyclines used in veterinary medicine?

Oxytetracycline, chlortetracycline, tetracycline, doxycycline, minocycline

What is the newer tetracycline derivative?

Tigecycline

What is the mechanism of action of tetracyclines?

Reversible inhibition of the 30S ribosomal subunit → blocks tRNA binding → inhibits protein synthesis → bacteriostatic

What is the spectrum of tetracyclines?

Doxycycline is effective against Gm(±) aerobes and anaerobes, L-form bacteria, Brucella, Rickettsia, Chlamydia, spirochetes, and some Mycoplasma

What is the main resistance mechanism for tetracyclines?

Efflux pumps; doxycycline and tigecycline are least affected

Why are tetracyclines effective against L-form bacteria?

L-forms lack peptidoglycan and efflux pumps, making them susceptible to tetracyclines

What are two non-antimicrobial effects of tetracyclines?

Neuroprotective (inhibits neuronal apoptosis); inhibits collagen contraction (used for contracted tendons in foals)

How do divalent cations affect tetracyclines?

Ca²⁺ and Mg²⁺ chelate tetracyclines → reduce absorption and cause deposition in teeth and bones

What are side effects of tetracyclines?

Nephrotoxicity (except doxycycline), esophageal strictures in cats, injection site irritation, photosensitivity, yellow teeth, dysbiosis in horses

Why is doxycycline a poor choice for UTIs?

It is reabsorbed from renal tubules and does not concentrate in urine

What are clinical uses of doxycycline?

L-form abscesses, Chlamydia, rickettsiae, spirochetes, Lyme disease, BRD (limited)

Which tetracycline is FDA-approved for BRD but clinically ineffective?

Oxytetracycline

Which tetracycline is used to treat contracted tendons in foals?

Tetracyclines (especially oxytetracycline)

What is the VFD status of tetracyclines?

Oxytetracycline banned for BRD metaphylaxis; chlortetracycline allowed for liver abscess prevention (Rx only)

What is the mechanism of action of aminoglycosides?

Irreversible binding to the 30S ribosomal subunit → inhibits protein synthesis → bactericidal

What is the mechanism of action of aminocyclitols?

Reversible binding to the 30S ribosomal subunit → bacteriostatic

What is the spectrum of aminoglycosides?

Gm(-) aerobes and some Gm(+) cocci; ineffective against anaerobes

Why are aminoglycosides ineffective against anaerobes?

Uptake is oxygen-dependent

What is the main resistance mechanism for aminoglycosides?

Bacterial enzymes that modify and inactivate the drug (e.g., acetylation)

What are major toxicities of aminoglycosides?

Nephrotoxicity, ototoxicity, neuromuscular blockade, drug incompatibility

Which aminoglycoside is most nephrotoxic?

Neomycin

Which aminoglycosides are least nephrotoxic?

Streptomycin and tobramycin

Which aminoglycosides cause cochlear toxicity in dogs?

Kanamycin, amikacin, neomycin

Which aminoglycosides cause vestibular toxicity in cats?

Streptomycin, gentamicin, tobramycin

What is the issue with aminoglycosides and ruptured tympanic membranes?

Can cause ototoxicity if the drug enters the middle/inner ear

Why are aminoglycosides poor for long-term at-home therapy?

No oral formulations; require injections

Why are aminoglycosides effective for cystitis but not nephritis?

Excreted unchanged into urine → active in bladder but poor renal tissue penetration

What is the post-antibiotic effect of aminoglycosides?

Even brief exposure can suppress bacterial growth long after drug levels fall

What is the VFD status of aminoglycosides?

Neomycin is feed-grade but requires a prescription

What are clinical uses of gentamicin?

Topical (skin, ear, eye), injectable (equine, swine), intrauterine (equine)

What are clinical uses of amikacin?

Injectable for resistant Gm(-) infections; used in joints and limbs

What is plazomicin?

A newer aminoglycoside with reduced nephrotoxicity and potential use for chronic infections

Name three human macrolides used in veterinary medicine.

Erythromycin, clarithromycin, azithromycin

Name five veterinary-specific macrolides.

Tulathromycin, tilmicosin, tylosin, gamithromycin, tildipirosin

What is the mechanism of action of macrolides?

Reversible inhibition of the 50S ribosomal subunit → bacteriostatic

What is the spectrum of macrolides?

Gm(+) aerobes, anaerobes, Mycoplasma; azithromycin covers some Gm(-) (not Pseudomonas)

What is the main resistance mechanism for macrolides?

Ribosomal methylation → cross-resistance with other 50S inhibitors (MOPLS)

What are four side effects of erythromycin?

Drug interactions, sterile abscesses, GI hypermotility, rectal edema/prolapse

What are side effect issues with tilmicosin?

Fatal IV dose in cattle; cardiotoxic in humans; safe orally; precautions required during injection

What are favorable PK properties of tulathromycin and related drugs?

Concentrate in lungs and macrophages; long-acting single-dose formulations

What are clinical uses of tulathromycin?

BRD metaphylaxis, pinkeye, swine respiratory disease

What are clinical uses of tylosin?

IBD in dogs, tear staining prevention, liver abscess prevention in cattle, Mycoplasma in swine/poultry

What are clinical uses of clarithromycin?

Equine Rhodococcus (with rifampin)

What are clinical uses of azithromycin?

Feline respiratory disease

What is the VFD status of tylosin and tilmicosin?

Tylosin allowed for liver abscess prevention (Rx); tilmicosin allowed under strict feedlot conditions

Why is florfenicol superior to chloramphenicol?

Bactericidal, less resistance (one acetylation site), no risk of aplastic anemia

What is the relationship between phenicols and neurologic disease?

Florfenicol penetrates CSF (~60%); good for meningitis; pairs well with neuroprotective β-lactams

Why is chloramphenicol banned in food animals?

Causes fatal aplastic anemia in humans due to mitochondrial ribosome inhibition

What are Herxheimer's reactions?

Iatrogenic endotoxicosis from rapid bacterial death and endotoxin release

What are two major clinical indications for florfenicol?

Bovine respiratory disease (long-acting), swine respiratory disease (injectable or water)

What type of Gm(+) bacteria does clindamycin target?

Anaerobes and Toxoplasma

What is the major side effect of clindamycin and how is it treated?

Pseudomembranous colitis due to C. difficile overgrowth; treated with metronidazole

Why is pirlimycin used only in uncomplicated mastitis?

Only effective against Gm(+) bacteria; not suitable for coliform mastitis

What are clinical indications for clindamycin?

Dental infections, osteomyelitis, anal sacculitis; penetrates bone well

Why are most 50S inhibitors bacteriostatic despite targeting essential protein synthesis?

They bind reversibly, allowing bacterial dormancy; bactericidal 50S inhibitors include florfenicol and some streptogramins

What is a common resistance theme among 50S inhibitors?

Ribosomal methylation → cross-resistance across macrolides, oxazolidinones, pleuromutilins, lincosamides, streptogramins (MOPLS)

Why is virginiamycin banned in Europe?

Used as a growth promoter; concern over resistance transfer to human pathogens

What PK properties of streptogramins affect food safety and pathogen clearance?

Long tissue persistence (food safety hazard); macrophage penetration helps eliminate intracellular pathogens

Tiamulin is primarily used in which species?

Swine and poultry