TETRACYCLINE ANTIBIOTICS
Outline

Overview

• Broad spectrum including some protozoans
• Relatively safe
• Major differences are pharmacokinetic
• Cross resistance frequent

Members

• Group 1
  • Tetracycline
  • Oxytetracycline
• Group 2
  • Demeclocycline
  • Methacycline
• Group 3
  • Doxycycline
  • Minocycline

Structure and chemical characteristics

• [pic] Four fused 6-membered rings
• Source: Streptomyces spp
• Amphoteric, but usually formulated as chlorides
• Groups time of introduction & pharmacokinetics
  • Group 1
    • Older
    • Dose intervals shorter
    • More use in veterinary medicine
  • Group 2
    • Intermediate intervals
  • Group 3
    • Newer derivatives
    • Dose intervals longer
    • Some uses in veterinary medicine

Mechanism of action

• Inhibit protein synthesis
  • bind reversibly to 30S ribosomal subunit
  • decrease aa-tRNA to "acceptor" site
• Static
• Higher concentrations affect mammalian ribosomes

Resistance

• Significant resistance, but still useful
• Cross-resistance significant
• Plasmid-borne transporter pumps drug out

Pharmacokinetics

Absorption/administration

• IM -- only oxytetracycline and tetracycline
  • Others -- sterile abscesses!
• IV -- SLOW to avoid cardiovascular collapse
  • oxytetracycline
  • tetracycline
  • doxycycline
• Primarily PO
  • F varies widely with drug & effect of food
  • F = 90 to 100%
    • doxycycline
    • minocycline
  • F=58 to 77%
    • Others
    • Food decreases
    • Insoluble chelates -- Ca⁺⁺, Al⁺⁺⁺, Mg⁺⁺
    • MILK?, Antacids?
    • Some laxatives have Mg⁺⁺

Distribution

• Doxycycline
  • Rx in eye
  • Rx in genitourinary tract
• All
  • most body fluids
  • CNS rel. poor, not ideal (10-25% of plasma)
  • Intracelluar
  • Rate: Ziv and Sulman (1974) with Cattle
    • Time to reach given ratio milk:serum
      

      Time to reach stated ratio

      Drug	Time	Ratio reached
      Doxycycline & Minocycline	20 min	>1.5
      Tetracycline	60 min	1.25
      Oxytetracycline	60 min	0.5

  
  
• Volumes of distribution --
  • Bind to intracellular nucleic acids
  • Bind to Ca⁺⁺ bones & teeth
• Volumes of distribution -- comparative
  

  Species Differences in Vd

  Drug	Species	Vd (L/Kg)
  Doxycycline	Humans	0.7
  Minocycline	Dogs	1.9
  	Humans	0.4
  Oxytetracycline	Horses	1.4
  	Cattle	0.8
  	Dogs	2.1
  	Cats	2.1
  	Humans	1.9

Elimination

• Both renal & biliary
• Significant enterohepatic circulation
• Doxycycline & minocycline -- primarily bile
• Others -- primarily urine
  Most active form
• Elimination half-lives
  • 6-11 hr -- tetracycline & oxytetracycline Anuria -- incr. to 57 to 108 hr
  • 11-23 hr -- doxycycline & minocycline
    anuria little change
  • Horses & cattle -- similar to humans
    BUT: horses & donkeys may be longer -- see significant toxicity in these species [Bowersock 1995]
  • Dogs / humans -- comparison
    • 6 / 9.5 hr -- oxytetracycline
    • 6 / 10.6 hr -- tetracycline
    • 6 / 17.5 hr -- minocycline
• Drug interaction
  • Doxycycline half-life may be decreased >50% by
    phenytoin and barbiturates induce hepatic enz

Adverse effects

• Considered relatively non-toxic

Allergies

• Not major problem

Biological adverse effects

• Important!
  • Access!
  • Spectrum!
• Superinfection
  • Especially if poor F adm PO
  • Nearly always alter the intestinal flora
  • Effect w/in 24-48 h
  • Yeasts / other pathogens
  • Horses!
• Signs of altered flora
  • Diarrhea
  • Indigestion
    • ruminants
    • horses
    • rabbits, etc.
  • Yeast overgrowth -- Sore mouth and perineal itching

Direct toxicity

Irritation

• Gastric mucosa -- cramps / burning
• Nausea / vomiting
• Can add food if minocycline & doxycycline
• IM/SC injections
  • Usually prohibited
  • Pain on injection
  • Sterile abscesses

Deposition in calcified tissues

• Borwn discoloration of teeth
• Teeth fluoresce under UV
• Deformatin of bone

Dizziness/light headedness

• Minocycline -- caused CDC to recommend avoiding if non-essential
• Due to vestibular or CNS toxicity

Antianabolic effect

• Decreased protein synthesis
• If decreased renal funcitn, increased Serum Urea Nitrogen (SUN)

Photosensitivity

• All
• Especialy demeclocycline
• Avoid sunlight

Clinical application

• Long list -- Consult current therapy
• Wide range of organisms including bacterial & protozoans
• Gram-negative and Gram-positive bacteria
  • Examples include Brucella, Francisella, Pseudomonas pseudomallei, Neisseria gonorrhoea, and Treponema pallidum.
  • Many Pasteurellae and Borrelia hurgdorferi (Lyme disease)
  • Common in Vet Med
    • combination with sulfas (e.g., sulfadimethoxine [Albon] with which they are synergistic. Used to treat most Strept, Staph, Pasteurella infections in cattle
      [Bowersock 1995].
• Rickettsial infections
  • eg., Q fever and Rocky Mountain Spotted Fever,
• Mycoplasmas and Chlamydia
  • Often pneumonia and genitourinary tract infections
  • Psittacosis --Chlamydia psittaci
• Malaria and ameobiasis in combo with other drugs
• Demeclocycline --
  • SIADH -- syndrome of inappropriate (excess) antidiuretic hormone
  • Non-infectious
  • Inhibits ADH-induced water reabsorption

References

1. Ziv & Sulman, Am. J. Vet. Res. 35:1197, 1974.
2. USPDI, 11th edition, 1991
3. USPDI, 15th edition, 1995
4. BM6th88, Huber, W.G., Tetracyclines, in Veterinary Pharmacology and Therapeutics, 6th edition, eds. Booth, N.H. and McDonald, L.E., Iowa State University Press, 1988.
5. Rang, H.P. and M.M. Dale. Pharmacology, Churchill Livingstone, New York 1987, Chapter 30.
6. Bowersock, T., 1995. Personal communication.

Study Questions

1. What is the major basis for selecting one drug from among the tetracycline group? Assuming you answered pharmacokinetic properties, how could this be reconciled with the fact that specific tetracyclines are often recommended for specific infectious processes?
2. Minocycline used to be the recommended treatment for meningococcal carriers, but CDC in Atlanta no longer recommends this? What specific toxicity is associated with minocycline? What does the change in this recommendation imply about cost-benefit ratios for some uses of drugs?
3. In what way are the tetracyclines (and sulfonamides to be studied later) different from other antibacterials in their action on protozoans? Be able to name two protozoan diseases for which the tetracyclines are reasonable parts of the therapy.
4. Why do you suppose a group of drugs is generally regarded as non-toxic when they produce so many adverse effects?
5. You should be able to recognize and discuss the basis of each of the tetracycline adverse effects, e.g., superinfections, diarrhea, and increased SUN. You should be able to list and discuss at least two representative effects from each of the two important (for the tetracyclines) categories of adverse effects.
6. How does the cross resistance of bacteria to tetracyclines compare to that of the beta-lactams and aminoglycosides?
7. What special precautions must be taken with the tetracyclines when used P.O.? Which two are apparently not affected by this problem?
8. Why are many of the tetracyclines never used IM or SC?
9. Why is intravenous administration of tetracyclines dangerous, despite the fact that it is one of the important means of use? Note that some persons believe calcium chelation is the cause of this hypotension, but that is not necessarily true. Addition of calcium salts to infusions is not considered good practice. Slow administration is!
10. Explain how the apparent Vd of some tetracyclines can be greater than the total body water?
11. What is the effect of poor renal or hepatic function on the elimination rate of the tetracyclines. Name one that is primarily eliminated via the kidney and one that is primarily eliminated via the bile.
12. How could the concomitant administration of phenytoin or phenobarbital result in drug failure with doxycycline?

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Gordon L. Coppoc, DVM, PhD
Professor of Veterinary Pharmacology
Head, Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907-1246
Tel: 317-494-8633Fax: 317-494-0781
Email: coppoc@vet.purdue.edu

Last modified
1:10 PM on 4/17/96
GLC