Tetracyclines

The antimicrobial activity of tetracyclines reflects reversible binding to the bacterial 30S ribosomal subunit, and specifically at the aminoacyl-tRNA acceptor ("A") site on the mRNA ribosomal complex, thus preventing ribosomal translation. This effect also is evident in mammalian cells, although microbial cells are selectively more susceptible because of the greater concentrations seen. Tetracyclines enter microorganisms in part by diffusion and in part by an energy-dependent, carrier-mediated system responsible for the high concentrations achieved in susceptible bacteria. The tetracyclines are generally bacteriostatic, and a responsive host-defense system is essential for their successful use. At high concentrations, as may be attained in urine, they become bactericidal because the organisms seem to lose the functional integrity of the cytoplasmic membrane. Tetracyclines are more effective against multiplying microorganisms and tend to be more active at a pH of 6–6.5. Antibacterial efficacy is described as time dependent.

The most common mechanism by which microbes become resistant to tetracyclines is decreased accumulation of drug into previously susceptible organisms. Two mechanisms include 1) impaired uptake into bacteria, which occurs in mutant strains that do not have the necessary transport system, and 2) the much more common plasmid- or transposon-mediated acquisition of active efflux pumps. The genomes for these capabilities may be transferred either by transduction (as in Staphylococcus aureus) or by conjugation (as in many enterobacteria). A second mechanism of resistance is the production of a "protective" protein that acts by either preventing binding, dislodging the bound drug, or altering the negative impact of binding on ribosomal function. Among the tetracyclines, tigecycline is characterized by less resistance due to efflux or ribosomal protection. Rarely, tetracyclines can be destroyed by acetylation. Resistance develops slowly in a multistep fashion but is widespread because of the extensive use of low concentrations of tetracyclines.

All tetracyclines are about equally active and typically have about the same broad spectrum, which comprises both aerobic and anaerobic gram-positive and gram-negative bacteria, mycoplasmas, rickettsiae, chlamydiae, and even some protozoa (amebae). Tetracyclines generally are the drug of choice to treat rickettsiae and mycoplasma. Among the susceptible organisms is Wolbachia, a rickettsial-like intracellular endosymbiont of nematodes, including Dirofilaria immitis. Strains of Pseudomonas aeruginosa, Proteus, Serratia, Klebsiella, and Trueperella spp frequently are resistant, as are many pathogenic Escherichia coli isolates. Even though there is general cross-resistance among tetracyclines, doxycycline and minocycline usually are more effective against staphylococci.

After usual oral dosage, tetracyclines are absorbed primarily in the upper small intestine, and effective blood concentrations are reached in 2–4 hr. GI absorption can be impaired by sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, iron, calcium salts, and (except for the lipid-soluble tetracyclines doxycycline and minocycline) milk and milk products. Oral bioavailability, however, can vary markedly among drugs, with chlortetracycline being the least and doxycycline the most orally bioavailable. Tetracyclines at therapeutic concentrations should not be administered PO to ruminants: they are poorly absorbed and can substantially depress ruminal microfloral activity. Specially buffered tetracycline solutions can be administered IM and IV. Through chemical manipulation (especially choice of carrier and high magnesium content), the absorption of oxytetracycline from IM sites may be delayed, which produces a long-acting effect. Tetracyclines can also be absorbed from the uterus and udder, although plasma concentrations remain low.

Tetracyclines distribute rapidly and extensively in the body, particularly after parenteral administration. They enter almost all tissues and body fluids; high concentrations are found in the kidneys, liver, bile, lungs, spleen, and bone. Lower concentrations are found in serosal fluids, synovia, CSF, ascitic fluid, prostatic fluid, and vitreous humor. The more lipid-soluble tetracyclines (doxycycline and minocycline) readily penetrate tissues such as the blood-brain barrier, and CSF concentrations reach ~30% of the plasma concentrations. Doxycycline is the most extensively distributed. Because tetracyclines tend to chelate calcium ions (less so for doxycycline), they are deposited irreversibly in the growing bones and in dentin and enamel of unerupted teeth of young animals, or even the fetus if transplacental passage occurs (see Special Clinical Concerns). Drug bound in this fashion is pharmacologically inactive. Tetracyclines are bound to plasma proteins to varying degrees (eg, oxytetracycline, 30%; tetracycline, 60%; doxycycline, 90%).

Biotransformation of the tetracyclines seems to be limited in most domestic animals, and generally about one-third of a given dose is excreted unchanged. Rolitetracycline is metabolized to tetracycline. Doxycycline and minocycline may be more extensively biotransformed than other tetracyclines (up to 40% of a given dose).

Tetracyclines are excreted via the kidneys (glomerular filtration) and the GI tract (biliary elimination and directly). Generally 50%–80% of a given dose is recoverable from the urine, although several factors may influence renal elimination, including age, route of administration, urine pH, glomerular filtration rate, renal disease, and the particular tetracycline used. Biliary elimination is always significant, commonly being ~10%–20%, even with parenteral administration. Doxycycline appears to be eliminated through feces predominantly through intestinal cells, rather than bile. Only ~16% of an IV dose of doxycycline is eliminated unchanged in the urine of dogs. A portion of doxycycline is also renally excreted in active form in some species. For minocycline, bile appears to be the major route of excretion. Tetracyclines are also eliminated in milk; concentrations peak 6 hr after a parenteral dose, and traces are still present up to 48 hr later. Concentrations in milk usually attain ~50%–60% of the plasma concentration and are often higher in mastitic milk. Tetracyclines also are excreted in saliva and tears.

The plasma half-lives of tetracyclines are 6–12 hr and can be longer depending on age (slower elimination in animals <1 mo old), disease, and the tetracycline itself (see Table: Elimination, Distribution, and Clearance of Tetracyclines). In large animals, daily injections of standard dosages usually are sufficient to maintain effective inhibitory concentrations. Long-acting formulations of oxytetracycline, when injected IM, generally produce plasma concentrations >0.5 mcg/mL for ~72 hr. Tetracyclines usually are administered PO bid-tid (every 12–24 hr for doxycycline and minocycline).

Because several diverse effects may result from administration of tetracyclines, caution should be exercised. Superinfection by nonsusceptible pathogens such as fungi, yeasts, and resistant bacteria is always a possibility when broad-spectrum antibiotics are used. This may lead to GI disturbances after either PO or parenteral administration or to “persistent infection” when they are applied topically (eg, in the ear). Severe and even fatal diarrhea can occur in horses receiving tetracyclines, especially if the animals are severely stressed or critically ill.

High doses administered PO to ruminants seriously disrupt microfloral activity in the ruminoreticulum, eventually producing stasis. Elimination of the gut flora in monogastric animals reduces the synthesis and availability of the B vitamins and vitamin K from the large intestine. With prolonged therapy, vitamin supplementation is a useful precaution.

Tetracyclines chelate calcium in teeth and bones; they become incorporated into these structures, inhibit calcification (eg, hypoplastic dental enamel), and cause yellowish then brownish discoloration. At extremely high concentrations, the healing processes in fractured bones is impaired.

Rapid IV injection of a tetracycline can result in hypotension and sudden collapse. This appears to be related to the ability of the tetracyclines to chelate ionized calcium, although a depressant effect by the propylene glycol carrier itself may also be involved. This effect can be avoided by slow infusion of the drug (>5 min) or by pretreatment with IV calcium gluconate.

The IV administration of undiluted propylene glycol–based preparations leads to intravascular hemolysis, which results in hemoglobinuria and possibly other reactions such as hypotension, ataxia, and CNS depression.

Because tetracyclines interfere with protein synthesis even in host cells and therefore tend to be catabolic, an increase in BUN can be expected. The combined use of glucocorticoids and tetracyclines often leads to a significant weight loss, particularly in anorectic animals.

Hepatotoxic effects due to large doses of tetracyclines have been reported in pregnant women and in other animals. The mortality rate is high.

The tetracyclines are also potentially nephrotoxic and are contraindicated (except for doxycycline) in renal insufficiency. Fatal renal failure has been reported in septicemic and endotoxemic cattle given high doses of oxytetracycline. The administration of expired tetracycline products may lead to acute tubular nephrosis.

Swelling, necrosis, and yellow discoloration at the injection site almost inevitably are seen. Phototoxic dermatitis may occur in people treated with demethylchlortetracycline and other analogues, but this reaction is rare in other animals. Hypersensitivity reactions occur; for example, cats may develop a “drug fever” reaction, often accompanied by vomiting, diarrhea, depression, inappetence, fever, and eosinophilia.

The tetracyclines can inhibit WBC chemotaxis and phagocytosis when present in high concentrations at sites of infection. This clearly hinders normal host defense mechanisms and compounds the bacteriostatic activity of tetracyclines. The use of immunosuppressive drugs such as glucocorticoids impairs immunocompetence even further.

Doxycycline administered in tablets has been associated with esophageal erosion in cats. The incidence is reduced if administration is followed by a 5-mL volume of fluid. Doxycycline may be associated with GI upset; this might be reduced by administering the drug with food.

Absorption of tetracyclines from the GI tract is decreased by milk and milk products (except for doxycycline and minocycline), antacids, kaolin, and iron preparations. Tetracyclines gradually lose activity when diluted in infusion fluids and exposed to ultraviolet light. Vitamins of the B-complex group, especially riboflavin, hasten this loss of activity in infusion fluids. Tetracyclines also bind to the calcium ions in Ringer’s solution.

Methoxyflurane anesthesia combined with tetracycline therapy may be nephrotoxic. Microsomal enzyme inducers such as phenobarbital and phenytoin may shorten the plasma half-lives of minocycline and doxycycline. Except for minocycline and doxycycline, the presence of food can substantially delay absorption of tetracyclines from the GI tract. The tetracyclines are less active in alkaline urine, and urine acidification can increase their antimicrobial efficacy.

Tetracyclines may increase amylase, BUN, bromsulphthalein (BSP^®), eosinophil count, AST, and ALT. Tetracyclines used in combination with diuretics are often associated with a marked rise in BUN. Cholesterol, glucose, potassium, and prothrombin time may be decreased. A false-positive urine glucose test is also possible.

Regulatory requirements for withdrawal times for food animals and milk discard times vary among countries. These must be followed carefully to prevent food residues and consequent public health implications. The withdrawal times listed in Drug Withdrawal and Milk Discard Times of Tetracyclines serve only as general guidelines.