8c – Tetracyclines

Question 1

What are the NEED to know vet med tetracyclines?

Answer 1

• Tetracycline (TC)
• Oxytetracycline (OTC)
• Chlortetracycline
• *Doxycycline: ‘different one’

Question 2

Tetracycline (TC): formulations

Answer 2

• Licensed in food animals and horses
• Water-soluble (oral) powders
• Oral/intrauterine boluses
• Some human oral capsules used extra label in dogs/cats

Question 3

Oxytetracycline (OTC): formulations

Answer 3

• Licensed in food animals ONLY
• Oral: feed premix or water soluble powder
• Intrauterine suspension
• Injectable products: 2 differnet ones
• Some human oral capsules used extra label in dogs/cats

Question 4

*What are the 2 injectable products of oxytetracycline?

Answer 4

• Short-acting: 100mg/mL “LP” formulations, for IM or IV use
• Long-acting: 200-300mg/ml “LA” formulations, for IM or SC use
  o ‘nasty’ ingredients/carriers=for consistent pH, stability, sterility (can be irritating though!)

Question 5

Onycin: tetracycline HCl powder

Answer 5

• Yellow power
• Wrap on wounds

Question 6

Chloretetracycline: formulation

Answer 6

• Oral premixes
• Boluses for food animals

Question 7

Doxycycline: formulations

Answer 7

• Primarily in small animals (and horses)
• Oral formulations: human tables or capsules used (100mg)
• Vet formulations were available, but NOT anymore (dental gel)

Question 8

Oral formulations of doxycycline: ‘smaller doses’ (from human med)

Answer 8

• Smaller ‘modified release’ capsules may NOT be appropriate
  o Intended for non-antimicrobial purposes
  o Wont be released until it is too late
• May need compounded forms to get appropriate size for small patients

Question 9

What are the tetracyclines mechanism of action?

Answer 9

• Binds to bacterial ribosomal 30S sub-unit
  o Cause incorrect tRNA translation
  o Disrupts bacterial protein synthesis
• *requires energy-dependent transport into bacterial cell to reach binding sites (by the bacteria)
  o Animals lack tetracycline transporters=safe in mammalian species (no protein inhibition)

Question 10

TCs have multiple charges on functional groups: what are they at physiological pH?

Answer 10

• Mostly zwitterion form
  o Both + and – but overall=NEUTRLAL

Question 11

TC are TIME-dependent antimicrobials

Answer 11

• *Try for prolonged exposure, not high peak concentration
• *only ones that are concentration dependent=aminoglycosides so far)

Question 12

Antimicrobial activity and potency of tetracyclines

Answer 12

• All basically the same
• *differences in clinical efficacy due to PK (likely NOT big)
  o Maybe something with absorption
  o Doxycycline may have increased permeability and activity

Question 13

What are tetracyclines potentially effective for?

Answer 13

• Some gram + and –
  o Respiratory disease in food animals
• Many anaerobes
• Some Mycoplasma: DON”T believe it is suceptible
• ***FANTASTIC:
  o Tick-borne bacteria, Chlamydia (phenicols first), protozoa, spirochetes
  o Ex. Potomac horse fever (Neoricketssia), Rocky Mountain spotted fever (Rickettsia)

Question 14

What are tetracyclines potentially NOT/LESS effective?

Answer 14

• Lots of resistance
• Staphylococci often resistant
• Gram – enterics
• Pseudomonas
• Enterococcus
• *resistance emerges rapidly in many bacterial species

Question 15

Susceptibility testing

Answer 15

• Good idea
• Could work, but likely to be resistant!

Question 16

What are some mechanisms of resistance to tetracyclines?

Answer 16

• Plasmid-mediated tet resistance genes=widespread and FAST!
  o Significant to impact clinical usefulness
• Decreased tetracycline in bacterial cell
  o Failure of active transport into bacterial cell
  o Increased efflux from the cell
• Enzymatic inactivation of tetracycline
• Production of proteins that protect bacterial ribosome

Question 17

Tetracycline absorption PK

Answer 17

• CTC/OTC: poor oral bioavailability
• Doxycycline: much higher oral bioavailability
  o Varies with feed status and formulation
• INJECTABLE: high bioavailability
  o LA formulation=flip-flop kinetics (SLOW absorption, drives rate of elimination)

Question 18

Tetracycline oral bioavailability in pigs example

Answer 18

• *Tetra and CTC=higher oral bioavailability in fasted state
• variance becomes important when LOW bioavailability (ex. if 80+% bioavailability variance is NOT a big deal)

Question 19

What is the impact of variance in for low bioavailability drugs? (ex. bioavailability %=3 +/- 3)

Answer 19

• Spread from 0-6=big difference!
• *variance is magnified
  o 6% already is not good, but better than 1%

Question 20

Tetracycline distribution PK

Answer 20

• Good distribution to most tissues and fluids (better than beta-lactams, aminoglycosides and sulfas)
  o Vd=1L/kg in most species
  o EXCEPTION: doesn’t penetrate CSF well
• Low/moderate protein binding
  o EXCEPTION: DXC (~90%)
• **bind to Ca/Mg (divalent cations)

Question 21

If TCs binds to Ca/Mg, which tissues might be affected?

Answer 21

• BONE (+ teeth in kids)
• NOT a food safety risk as not really consuming bones
  o Doesn’t look great when things glow under black light

Question 22

Tetracycline elimination PK

Answer 22

• Metabolism: very LITTLE
• Small amounts excreted via
  o Feces: biliary+P-gp (some enterohepatic circulation can occur)
  o **more important for doxycycline
• Uncharged TC mainly excreted by kidneys=high concentrations in urine (useful for UTI)
  o Longer T half life with renal failure (but dose modification NOT necessary)
  o May still be useful even if susceptibility report says R
  o Exception: doxycycline=more in feces

Question 23

Tetracyclines half life elimination

Answer 23

• 6-8hrs
  o Don’t need to dose a bunch of times a day (even though time-dependent)
• Except long acting: 24hrs

Question 24

Tetracycline AE

Answer 24

• Generally safe
• Nephrotoxicity=unlikely (higher dose and dehydration=risk factor)
• CV collapse with rapid IV injection (ex. short acting): dilute and inject slowly
  o Long acting=NOT given IV (only IM/SC)
• Chelation by calcium and heavy metals
• Gi: vomit/diarrhea
• Injection site reaction: depends on drug carrier

Question 25

Chelation by calcium and heavy metals: tetracycline AE

Answer 25

• Recommended to NOT administer oral tetracyclines with dairy products=decrease ORAL bioavailability
• Administration in young animals=teeth staining (but not a big deal)

Question 26

What is a non-antimicrobial use of tetracyclines?

Answer 26

• Can RELAX flexor tendons
  o High dose IV given to neonatal foals with angular limb deformity
  o Mechanism: maybe inhibits matric metalloproteinase enzymes
• Mild anti-inflammatory effects