tetracycline

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TETRACYCLINE ANTIBIOTICS

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Copyright, Purdue Research Foundation, 1996

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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.

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.

Resistance

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.

Pharmacokinetics

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.

Absorption/administration

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.

Distribution

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.

Elimination

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.

Hypersensitivity

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

do occur.

Biological adverse effects

Superinfection

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

Diarrhea may occur and will usually be the result of change in microflora of the

gut. See the discussion of superinfection.

Indigestion

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

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

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.

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 Mc, 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 and a

tetracycline like doxycycline result in a drug failure?

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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@...

Last modified 9:40 PM on 4/12/96 GLC