Chapter 3 - THE TETRACYCLINES

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I. History:

A. These antibiotics were developed as a result of systematic screening of soil samples collected from many parts of the world for antibiotic- producing microorganisms.

B. Chlortetracycline was introduced in 1948. It is elaborated by Streptomyces aureofaciens.

C. In 1950 oxytetracycline became available and is elaborated by Streptomyces rimosus.

D. Tetracyline is produced semi-synthetically from chlortetracycline.

E. Other semisynthetic derivatives are:

Demeclocycline

Doxycycline

Methacycline

Minocycline

A. Chemical structure of tetracycline and derivatives(Fig 5)

Congener Substituent(s) Position(s)

Chlortetracycline -Cl (7)

Oxytetracycline -OH, -H (5)

Demeclocycline -OH, -H, -Cl (6; 7)

Methacycline -OH, -H; = CH2 (5; 6)

Doxycycline -OH, -H; -CH2, -H (5; 6)

Minocycline - H, -H; -N (CH3)2 (6; 7)

B. Chemical Reactions and preparations:

1. Forms soluble salts with hydrochloric acid.

2. Is stable in the dihyform and unstable in aqueous solutions as the hydrochloride

3. Soluble injectable preparations of oxytetracycline.

a. LiquamycinR

i) Buffered, dissolved in propylene glycol, pH 7.5

ii) Stable in solution up to 45oC for a year.

iii) Stability decreases as pH increases (above 7.5)

b. Polyotic soluble powder of 1 part tetracycline and 19 parts dextrose or sucrose plus dye.

i) Is intended for oral use.
ii) Sugar will give a diuretic effect.

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III. Mechanism of Action

 

A. Bacteriostatic: Inhibit protein synthesis.

1. Bind to the bacterial 30 S ribosomal units

2. Prevent access of amino-acyl-RNA

3. May involve chelation of Fe & Mg

B. Penetrate but non-toxic to mammalian cells

A. Broad spectrum, including rickettsia.

1.Gram positve bacteria are susceptible. Generally inferior to penicillins.

2. Gram negative bacteria susceptible: E. coli, Shigella, Salmonella, Proteus Pseudemonas. Some are strains highly resistant.

3. E. histolytica - partly effective - Not important here.

B. General range of sensitivity - 0.02 to 5 mcg/ml.

C. Importance of host defenses

A. Common problem, among both gram positive and gram negative organisms.

B. Cross-resistance with other tetracyclines

C. Cross-resistance with chloramphenicol may occur with some gram negative organisms

D. Resistance may involve decreased bacterial permeability.

E. Infectious drug resistance - Transfer of OTC-resistance capability from one resistant bacterium to an originaly sensitive one.

 

A. Oral

1. well absorbed.
2.Inhibited by milk, Al(OH)3 + Al2 (PO4)3 gels, Fe, Calcium, and Mg salts.
3. Inadequate for full therapeutic effects in ruminants .

 

B. Intravenous

1. Immediate high levels, maintained for 24 hours
2.Caution, Anaphylactic shock.
3.Give with saline or give slowly.

 

C. Intramuscular

1. OTC in propylene glycol solution.
2. Levels above 0.5 to 1 mcg/ml for 24 hrs in ruminants.
3.Occasionally, anaphylactic shock.

D. Intraperitoneal

1. Irritating not used.

VII.Distribution:

A. Tetracyclines bind reversibly to protein

B. Large volume of distribution i.e. greater than total body water. This means that the drugs are sequestered in body tissues, i.e.bone, teeth, etc.

1. Milk concentrations of tetracycline are 1.4 to 4 times the concurrent unbound plasma level.

Note: Mastitis cannot be treated effectively via I.V. or I.M. route.

2. Ocular, capsular, and cerebrospinal fluid concentrations are 0.25 times plasma concentrations.

3. Gut and pleural fluid concentrations are 0.5 - 1 times plasma concentrations.

4. Respiratory tract, placental and ascitic fluid concentrations are 0.5 times plasma concentrations.

5. Tetracyclines undergo enterohepatic circulation.

D. Excretion

1. Renal- Glomerular filtration. This route is of importance in cases of urinary tract infections.

2. Biliary- Enterohepatic circulation.

A. Acute collapse: "Anaphylactoid" reactions with parenteral use (cattle).

B. Pain, irritation, abscessation and discoloration at site of I.M. infection.

C. In beef cattle injection site should be trimmed at slaughter.

C. Oral administration

1. Nausea and vomiting will occur due to local irritation of the G.I. tract.

2. Alteration of gut flora.

i. Anorexia, diarrhea, or constipation is observed(weaned dairy calves and swine).

ii. Growth of fungi, staphlococci, enterococci, etc.

This conditdion may be controlled by administering nystatin concurrently with tetracycline therapy.

iii. Discoloration of teeth and bone. Seen in young animals prior to first or second dentition.
iv. Inhibition of human fetal growth.
v. Inhibit bone healing due to sequestration of drug in the callus.
vi. Photosensitization.
vii. Inhibition of hepatic microsomal induction. This is not surprising because of its mechanism of action.

IX. Clinical Uses in Veterinary Medicine

A. Small Animals

1. Wide range of gram positive and gram negative infection, i.e. Enteric diseases, urinary tract infection,pneumonia, secondary invaders, leptospirosis, pneumonitis, panleucopenia, etc.

2. Dose: IV, IM: 6-8 mg/kg, BID. Halved in large dogs. May be doubled in small dogs. Oral: 10-15 mg/lb, TID

B. Large Animals

1. Cattle, horses, sheep, goats, - primarily parenteral.

i. Wide variety of infections: Leptospirosis, metritis, pneumonia-shipping fever, mastitis, listeriosis, anaplasmosis, actinomycosis and actino- bacillosis, enteric infections. Anthrax (penicillin considered better).

ii. Doses:- 5mg/lb IM or IV once a day, or divided into 2 equal doses. (2.5 mg/lb, BID) 5 days. Intrauterine- Boluses or solution. Can be absobed from uterus. Intramammary- 400mg ointment form.

2. Swine- Enteritis, pneumonia, etc.

3. Poultry- CRD, sinusitis, PPLO, erysipelothrix

4. Low-level Feeding of Tetracycline

Poultry: 10 to 500 gms/ton Feed. Combination with amprolium, arsenicals, hygromycin, buquinolate, zoalene, aklomide etc. Used mainly for coccidiosis.

Swine: 10 to 400 gms/ton Feed. Combination with arsenicals, hygromycin.

Cattle: Use to control liver abscesses, shipping fever, enteritis and anaplasmoisis. Combination with sulfamethazine and neomycin are used.

The student should have a full understand of the following aspects of tetracycline pharmacology:

1. Be able to identify sources of the tetracycline antibiotics.

2. Have an understanding of the general chemical characteristics of the tetracyclines.

3. Know the mechanism of action of the tetracyclines and be able to compare this mechanism of action with other antibiotics covered.

4. Be able to discuss the development of resistance of organisms to tetracycline antibiotics.

5. Become familiar with the various compounds, or substances which might inhibit tetracycline efficacy.

6. Be able to compare tetracycline distribution with other antibiotics discussed.

7. Discuss enterohepatic circulation. How would this process contribute to tetracyclines efficacy? Toxicity?

8. Why would you not administer tetracyclines orally in lactating dairy cows?