Tetracycline antibiotics have a broad spectrum of activity, are relatively safe, can be used by many routes of administration, and are widely used. They even have antiprotozoal activity. The major difference among the tetracyclines is in their pharmacokinetic properties. Cross resistance among members of the group is frequent. On the other end of the spectrum, antibiotics are a poor choice for one who has been affected by fungal exposure; especially systemically.  These should be avoided at all costs.  There are substitutes on the market, both holistically and scientifically.

Structure and chemical characteristics

Four fused 6-membered rings, as shown in the accompanying figure, form the basic structure from which the various tetracyclines are made. The various derivatives are different at one or more of four sites on the rigid, planar ring structure. The classical tetracyclines were derived from Streptomyces spp., but the newer derivatives are semisynthetic as is generally true for newer members of other drug groups. Stability of tetracyclines in solution varies with pH and derivative. The drugs are amphoteric, meaning they will form salts with both strong acids and bases. Thus, they may exist as salts of sodium or chloride.

There are no rigid subgroupings of the tetracyclines, but as you study this material, you might note how frequently their characteristics place them in one of the 3 classes below. These are based on dosage and frequency of oral administration. Group 1 includes such older derivatives as chlortetracycline (now little used), oxytetracycline, and tetracycline. Group 2 includes demeclocycline and methacycline. Group 3 includes newer drugs such as doxycycline and minocycline.

Mechanism of action

Tetracyclines bind reversibly to the small subunits of bacterial (and eukaryotic) ribosomes where they interfere with binding of charged-tRNA to the "Acceptor" site. They are "bacteriostatic" rather than cidal. Tetracyclines can also inhibit protein synthesis in the host, but are less likely to reach the concentration required because eukaryotic cells do not have a tetracycline uptake mechanism.


Tetracyclines are increasingly met by resistant organisms when used in clinical practice, but are still considered to be useful. Sensitive organisms accumulate tetracyclines intracellularly because of active transport systems. There are no known enzymes that inactivate the tetracyclines. Resistance to one tetracycline usually implies resistance to the others, although some research studies have observed differences in MICs for various tetracycline derivative - isolate pairs. These differences are not large and are not uniform throughout the country.

Resistance is transferred in plasmids that code for proteins that "pump" the drugs out of the cells. The intracellular concentration represents the balance between the input and output mechanisms. There is conceptual similarity in this resistance mechanism and that of cancer cells that develop resistance to different anticancer drugs in one step.


Note the similarity between doxycycline and minocycline pharmacokinetics in the discussion that follows. They are relatively new tetracyclines that have been developed to overcome deficiencies in the older derivatives.


Tetracyclines are primarily used by oral administration, but topical, IM, and IV forms exist. Only oxytetracycline and tetracycline have IM dose forms; the others cause sterile abscesses. IV injections are given by infusion to avoid cardiovascular collapse. IV dose forms exist for minocycline, doxycycline, and the two that also have IM dose forms, oxytetracycline and tetracycline.

The tetracyclines vary widely in their bioavailability and the effect that food has on it. Doxycycline and minocycline have very high bioavailability, in the range of 90 to 100%, and the presence of food has an insignificant effect. The others have bioavailabilities approximating 58 to 77% and are significantly decreased by food. Calcium, aluminum, and magnesium form insoluble chelates with tetracyclines to decrease bioavailability. Milk is high in calcium and all of these ions are high in antacids so these should be avoided. Some laxatives have magnesium. Because tetracyclines are irritants that produce stomach upset, patients should be cautioned not to use milk or antacids to counteract the distress. Owners of animals should be similarly cautioned.


Doxycycline reaches therapeutic concentrations in the eye. Minocycline is also widely distributed, reaching high concentrations in saliva and tears. Both are used in treatment of genitourinary tract infections because they produce therapeutic concentrations in these tissues, including the prostate. All tetracyclines are distributed to most body fluids including such transcellular fluids as bile, sinus secretions, synovial, and pleural fluids. CSF concentrations are 10-25% of plasma concentrations. This is sufficiently low that they are not highly recommended for CNS infections.

Working with cattle, Ziv and Sulman (1974) found that approximately 20 minutes were required for intravenously administered doxycycline and minocycline to reach a milk:serum ratio over 1.5. Tetracycline and oxytetracycline took 60 minutes to reach ratios of 1.25 and 0.75, respectively. These values reflect the differences in ability of the drugs to cross membranes implied above. However, note that in all cases, the ratio approached 1 or more, a result not seen with such drugs as the beta-lactams or aminoglycosides.

Tetracyclines have high apparent volumes of distribution, ranging from 0.7 L/kg for doxycycline to as much as 1.9 for oxytetracycline. Tetracyclines typify the complexities of using Vd as an indicator of therapeutic concentrations in tissues. Tetracyclines localize in bones, teeth, liver, speen, and tumors. Because they are highly bound to these tissues and bone, they are non-homogeneously distributed outside the plasma. Paradoxically, doxycycline and minocycline cross membranes more easily than any of the others, but because high plasma protein binding offsets the accumulation in bone and other tissues, they have Vds of 0.14 to 0.7 L/kg.

Volumes of distribution for animals are in the same range as for humans, but significant differences do occur. For example, the Vd of minocycline is 1.9 L/kg in dogs versus 0.4 for humans. Oxytetracycline Vds are 1.4, 0.8, 2.1, and 2.1 L/kg for horses, cattle, dogs, and cats, respectively. Note that the value for humans, 0.9 to 1.9 L/kg, brackets the range for these species.


All tetracyclines are eliminated via renal and biliary pathways, but differ in their relative dependence on the two. All undergo significant enterohepatic circulation. Doxycycline and minocycline are primarily eliminated in the bile and less than a third is eliminated unchanged. Oxytetracycline, tetracycline, methacycline, and demeclocycline are eliminated primarily in urine with 42 to 70%, depending on the derivative, being eliminated unchanged.

Elimination half-lives range from 6-11 hours for tetracycline and oxytetracycline to 11 to 23 for doxycycline and minocycline. Anuria hardly changes the rate of elimination of doxycycline and minocycline, but tetracycline elimination half-life increases to 57 to 108 hours.

Elimination half-lives of oxytetracycline, tetracycline, and minocycline tend to be shorter in dogs, approximately 6 hours, than in humans (9.5, 10.6, and 17.5 hours, respectively). Horses and cattle have elimination half-lives of oxytetracycline similar to those of humans. [Horses/donkeys may have longer half-lives resulting in the toxicity frequently reported, Bowersock, T. 1995]

The data presented above for doxycycline and minocycline imply that they are biotransformed to some extent in the liver. Indeed, phenytoin or barbiturate induction of hepatic drug metabolizing enzymes may reduce the elimination half-life of doxycycline by more than 50%.

Adverse effects

Tetracyclines are generally regarded as relatively non-toxic, but they produce a fairly large number of adverse effects, some of which can be life threatening under the right circumstances. Therefore, they should not be used casually.


Allergic reactions are not a major problem with the tetracyclines although they do occur.

Biological adverse effects


Superinfection (suprainfection) may occur with the tetracyclines, particularly the older, more poorly absorbed ones when given orally. Because of their broad spectrum of activity, activity against commensal organisms of the gut, and effective concentration in the gut, they nearly always alter the intestinal flora. This may occur within 24 to 48 hours, but these changes are not always clinically evident as diarrhea. It is not unusual to find superinfection with yeasts or resistant pathogenic bacteria. Although frowned upon by the FDA, commercial preparations of tetracyclines combined with nystatin (an oral antifungal) have been prepared to help combat superinfection with yeasts. Many authorities believe that because such superinfections do not always occur, there is less risk to the patient if one waits until there is evidence of yeast superinfection before beginning therapy.


Diarrhea may occur and will usually be the result of change in microflora of the gut. See the discussion of superinfection.


Indigestion may occur for reasons already presented under the heading of superinfections. It may be difficult to differentiate indigestion due to changes in flora from that caused by direct irritation to the gastrointestinal mucosa.

Indigestion is potentially problematic in ruminants because of the large number of bacteria and protozoans in the rumen. Horses, rabbits and other animals with large cecum/colon microfloral populations are also sensitive to the effects of tetracyclines.

Sore mouth and perineal itching

Sore mouth and perineal itching due to overgrowth of yeasts are "more frequent" according to the USPDI11th90.

Direct toxicity

Most direct toxicity is due to the irritant properties of the drugs, the inhibition of protein synthesis, or their predilection for bony tissues.


Irritation of gastric mucosa leading to cramps or burning of the stomach can be of such severity as to cause poor patient compliance. This often results in nausea and vomiting. Note that minocycline and doxycycline may be taken with food to reduce the impact of this irritation.

The same irritant properties also limit the use of these drugs for IM or SC injections where all cause pain and most cause sterile abscesses.

Deposition in calcified tissues

Deposition in calcified tissues, e.g., teeth can result in discoloration, especially when given during developmental stages. Higher doses given at inopportune stages of growth can result in bone deformation. Nearly everyone who received tetracyclines as a child will have teeth that fluoresce under a UV light source whether their teeth are stained brown or not.

Dizziness/light headedness

Dizziness / light headedness is commonly seen with minocycline, but not the others. This is caused by vestibular or CNS toxicity and is of such severity and frequency that CDC has changed recommendations on its non-essential use.

Antianabolic effect

Antianabolic effect resulting from decreased protein synthesis. In the presence of reduced renal function this is evident as azotemia and increased serum urea nitrogen (SUN).


photosensitivity may be associated with the use of all tetracyclines, but is especially a problem with demeclocycline. Patients should be kept out of heavy sunlight when receiving tetracyclines.

Clinical application

The list of diseases for which tetracyclines can be used is long, but because of increasing resistance it is becoming shorter. It is advised that the reader consult a "current therapy", a "medicine" textbook, or a reference such as USPDI to see the range and types of infections for which they are regarded as effective therapy. Because they are effective against a wide range of bacteria and many protozoans their applications are broader than many antibacterials.

Tetracyclines are effective in many infections caused by Gram-negative and Gram-positive bacteria. Examples include Brucella, Francisella, Pseudomonas pseudomallei, Neisseria gonorrhoea, and Treponema pallidum.

Many Pasteurellae and Borrelia hurgdorferi (Lyme disease) ??? Most common use in vet med is in combination with sulfas (e.g., sulfadimethoxine [Albon] with which they are synergistic. Used to treat most Strept, Staph, Pasteurella infections in cattle [Bowersock 1995].

In addition, tetracyclines are effective in Rickettsial infections, such as Q fever and Rocky Mountain Spotted Fever, as well as those caused by Mycoplasma and Chlamydia. The latter two are often causes of pneumonia and genitourinary tract infections. Psittacosis, caused by Chlamydia psittaci, is treated with tetracyclines.

Problematic cases of malaria and ameobiasis may benefit from tetracyclines given in conjunction with more specific anti-infective therapy.

Demeclocycline may also be used to treat a non-infectious problem known as syndrome of inappropriate (excess) antidiuretic hormone (SIADH). It acts by inhibiting ADH-induced water reabsorption in the kidney to induce water diuresis. It is apparent that when used as an anti-infectious agent, this diuresis may be considered as an adverse effect.


  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.

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