What are the two families of tetracyclines and what are their members?
- Tetra-, oxytetra-, and chlortetracycline (older water soluble drugs)
- Doxycycline and minocycline (newer drugs; commonly used in small animal medicine)
Are tetracyclines time dependent or concentration dependent? How does that affect the way the drugs are dosed?
-Time dependent; they need to be dosed more frequently
Are tetracyclines considered broad spectrum or narrow spectrum?
-Broad spectrum
Are tetracyclines bactericidal or bacteriostatic?
Bacteriostatic (are -cidal when higher doses are used)
Which tetracycline member is preferred to be used in large animal because of cost and availability of FDA approved products?
Oyxtetracycline is preferred over tetracycline for use in food animal medicine.
Which tetracycline member is preferred for use in small animal medicine?
-Doxycycline has largely replaced tetracycline and oxyetetracycline in small animal medicine due to its broader spectrum and greater ability to penetrate barriers
What is the primary target for the action of tetracycline family of drugs?
What does it do there?
Primary Target: Bacterial ribosomes (30s unit)
•MOA:
- disrupts the binding of tRNA to the mRNA copy –> Bacterial protein synthesis is disrupted (bacteriostatic action).
- Some protein production still occurs.
- It does not disrupt it so extensively that the bacterial cell dies.–> reduced ability
Secondary Targets: Bacterial ribosomes (50s unit)
•MOA:
- drug disrupts the bacterial cell membrane integrity allowing more drug in and electrolytes out.
** At high enough concentrations, the drug can disrupt mammalian cell protein synthesis!
What is the mechanism by which bacteria have resistance to most tetracyclines?
How does it involve the bacterial genome?
-Tetracyclines enter bacteria→combine with Mg++ ion→tetracycline-Mg complex removes inhibition on gene that codes for proteins that forms an efflux pump→tetracycline is actively pumped from the bacteria (unable to significantly disrupt protein synthesis
What is the preferred route of administration for the older tetracyclines: tetracycline, oxytetracycline, and chlortetracycline?
What is the problem with giving these drugs PO?
Preferred route: IV or IM
– Can be given PO and absorbed on an empty stomach! However, don’t give PO with food.
• food –> reduce bioavailability by 50%
- the drugs chelate with polyvalent cations (Ca++, M++, Fe++, Al+++)→chelated tetracycline precipitates out of solution and is NOT absorbed!
•Ex: Dairy products (Ca++) given PO (e.g. nursing calves) will precipitate out tetracycline
Besides dairy products, what other drugs, compounds or products should tetracyclines (especially the older ones) NOT being given PO with?
How do they need to be given if tetracycline and any of these drugs must be used PO?
Don’t give the following with tetracyclines PO: • Oral iron supplements (Fe++) • Sucralfate • Kaopectate • Pepto Bismol • Antacids (Ca++, Al+++, Mg++)
Alternative: if must be given together PO, give the tetracycline 1st, wait 2 hours, and then give the chelating agent
Why are tetracyclines used for growth promotion not simultaneously good for controlling bacterial infections?
- Low dose tetracyclines are used for growth promotion in livestock and poultry.
- Growth promotion effect is thought to be the result of local effect within the lumen of the GI tract. Lack of absorption is likely due to more ionized state of drug while IN the GI tract.
- amount absorbed systemically is well below MIC for anything but the most susceptible bacteria found in infections.
How do the different families of the tetracycline class differ in their ability to be absorbed from the GI tract with or without food?
What is the mechanism by which food can decrease the bioavailability of PO administered tetracycline and oxytetracycline?
- Doxycycline and Minocycline do NOT have the same degree of chelation as the older family of drugs.
- Absorption PO of doxy- and minocycline is much better even in the presence of food or Ca++, Mg++, etc. because the drugs are not as ionized in the GI tract like tetracycline and oxytet.
- Bioavailablity is 90-100% in humans and monogastric veterinary patients (90-100% makes it to systemic circulation)
- Less well absorbed in diets with high fiber because fiber diets chelate more (equine)
List the three groups of intracellular pathogens against which tetracyclines are most commonly used.
In addition to the intracellular pathogens, what other group of bacteria (such as those found in leptospirosis) are tetracyclines used?
Effective against intracellular pathogens
• Mycoplasma
• Rickettsia
• Chylamydia
- Also effective against spirochetes (leptospirosis)
Are tetracyclines as a group effective against Pseudomonas? Are they effective against anaerobes?
o Not effective against most anaerobes
o Does NOT get Pseudomonas
What is the agent of Lyme disease?
What kind of an organism is it?
Which tetracycline family member is one of the key drugs indicated for treatment of Lyme disease?
Why would it be better than oxytetracycline?
o Agent = Borrelia burgdorferi, a spirochete.
o CNS signs of Lyme disease are treated with doxycycline.
o Doxy penetrates CNS better than oxytetracycline because it is more lipophilic and can better penetrate tissue barriers.
Why can tetracyclines kill mycoplasma organisms when beta lactams cannot?
- Mycoplasma doesn’t have a cell wall (nothing for beta lactam to disrupt!)
- Tetracyclines are very lipophilic so readily passes into organism and accumulates
What is the organism that causes Rocky Mt. Spotted Fever?
What kind of organism is it?
Why are tetracyclines effective in killing this organism?
- Rickettsia = intracellular organisms
- Tetracyclines penetrate cells to reach pathogen and disrupt Rickettsia life cycle.
What organism causes chlamydia in birds? What is the treatment of choice?
- Chylamydophila psittaci = intracellular organism
- Doxycycline treats Chlamydia in birds.
What advantage do tetracyclines have in treating respiratory infections that beta lactams and aminoglycosides do not?
- Tetracyclines accumulate in secretions
- It is delivered directly to the bacteria, while most drugs do not reach the surface of the airway.
Why have tetracyclines been used in the past to try to treat epiphora (red stain in white dogs)?
- Tetracyclines have been used to chelate iron in tears to reduce epiphora stain. The oxidized iron in the tears stains the hair
Why is oxytetracycline used to treat BRD?
-Oxytet- accumulates at high concentrations in respiratory secretions and penetrates the lung parenchyma.
LA, Liquamycin, 200 formulation oxytet- provides 24 hours of drug concentrations above the MIC (may get 3-5 days for some pathogens).
What is the basis for saying that tetracyclines can reduce some inflammation?
- Tetracyclines concentrate in neutrophils.
- It reduces neutrophil chemotaxis and movement of neutrophils into area of infection or inflammation.
- Less cellular destruction occurs, therefore, less inflammation occurs.
Why is doxycycline advocated by some as an adjunct treatment for heartworm disease in dogs?
- Doxy is advocated to kill Wolbachia
- an organism that lives within adult canine heartworms (Dirofilaria immitis) & needed for D. immitis to survive. - Wolbachia surface proteins (WSP)
- liberated at time of adult heartworm death –> dangerous inflammatory response in the lungs.
Why isn’t doxycycline universally accepted as a treatment adjunct for heartworm disease?
- Additional 4 week doxy therapy = heartworm pathology progresses (even without the WSP) versus elimination of WSP and less inflammation at time of adulticide treatment.
