Tetracyclines

Pharmacology and mechanism of action

Tetracyclines are bacteriostatic antibiotics with broad-spectrum activity. They are primarily used for the treatment of chlamydia, rickettsia, mycoplasma, spirochete as well as infections due to Gram-positive and Gram-negative bacteria. For the treatment of malaria, tetracyclines have a potent but slow blood schizontocidal effect, thus they are used together with quinine. They are also effective against the primary tissue stages of Plasmodium falciparum but lack gametocytocidal effect ^[1]. The mechanism of action of tetracyclines in bacteria is inhibition of protein synthesis by binding to the S-30 ribosome, inhibiting the access of tRNA to the mRNA-ribosome complex ^[2]. The mechanism of action against malaria is not known.
 

Indications

Tetracyclines are primarily used as a supplement to quinine in the treatment of P. falciparum malaria in areas with decreased susceptibility for quinine (i.e. in Thailand or adjacent countries).
Doxycycline is also used for prophylaxis against P. falciparum in areas where mefloquine resistance is frequent.
 

Side effects

Mild gastrointestinal symptoms such as epigastric pain, nausea, vomiting, diarrhoea, and pruritus ani are frequent. Irritative diarrhoea due to the substance should be distinguished from pseudomembraneous colitis due to the overgrowth of Clostridium difficile^[2]. Pronounced photosensitivity reactions of the skin occur and seem to be more common with more intense sun exposure ^[3]. Renal function, in patients with renal damage, is worsened by tetracycline (not by doxycycline). Children under 8 years may develop permanent brown discoloration of the teeth. Liver damage can also be seen especially in pregnant women.
Rare hypersensitivity skin reactions such as urticaria, angio-edema and serum sickness may occur ^[2].

Contraindications and precautions

Tetracycline should not be given to subjects with pre-existing kidney or liver damage. Doxycycline, however, can be given in unchanged dose to patients with severe kidney failure. Due to tooth staining, tetracyclines should not be given to children under 8 years unless absolutely necessary. Tetracyclines also deposit in the human skeleton and may cause growth retardation, but this effect is reversible in short-term treatment.
 

Interactions

Iron, milk, and antacids reduce the bioavailability of tetracyclines. The concurrent use of tetracycline with methoxyflurane is nephrotoxic and should be avoided ^[4]. There are no negative reports concerning the combination of tetracyclines with other antimalarials.
 

Preparations

Many tetracycline and doxycycline preparations are available apart from those mentioned below.

• Achromycin® (Lederle). Tablets and capsules 250 mg, 500 mg.
• Vibramycin® (Pfizer). Tablets and capsules 100 mg, 200 mg. Oral suspension 10 mg/ml.

References

1. Practical Chemotherapy of Malaria. Report of a WHO Scientific group. Technical Report Series no. 805 (1990). (Geneva: World Health Organization), pp. 35–37.
2. Sande MA, Mandell GL (1990). Antimicrobial agents. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 8th edn, edited by A.G.Gilman, T.W.Rall, A.S.Nies and P. Taylor, (New York: Pergamon Press), pp. 1117–1124.
3. Meyler’s Side Effects of Drugs, 12th edn (1993), edited by M.N.Dukes (Amsterdam: Elsevier), pp. 160–161, 212–216.
4. Kuzneu EY (1970). Methoxyflurane, tetracycline and renal failure. J Am Med Ass, 221, 62–64.

Antimicrobial activity

Tetracyclines are broad-spectrum, essentially bacteristatic agents. They share a similar spectrum of activity, though that of tigecycline is somewhat different from that of earlier tetracyclines.
In general, tetracyclines are active against many Gram-positive and Gram-negative bacteria, chlamydiae, mycoplasmas, rickettsiae, coxiellae, spirochetes and some mycobacteria. Most streptococci are sensitive, except Streptococcus agalactiae, and enterococci. Susceptible Gram-positive bacilli include Actinomyces israelii, Arachnia propionica, Listeria monocytogenes, most clostridia and Bacillus anthracis. Nocardia spp. are much less susceptible, minocycline demonstrating the greatest activity against them.
Among Gram-negative bacteria most enterobacteria and most strains of Moraxella catarrhalis, Neisseria meningitidis and Haemophilus influenzae are sensitive. Legionellae, brucellae, Francisella tularensis, Vibrio cholerae, Campylobacter spp., Helicobacter pylori, Plesiomonas shigelloides and Aeromonas hydrophila are all susceptible. Many anaerobic bacteria are susceptible, doxycycline and minocycline being the most active. Rickettsiae are generally sensitive, especially to doxycycline, minocycline and tetracycline. None is active against Pseudomonas aeruginosa, Proteus spp. or Providencia spp., but Burkholderia pseudomallei and Stenotrophomonas maltophilia are usually susceptible.

Acquired resistance

Resistance to tetracyclines has emerged in an ever-increasing number of bacterial species and is geographically widespread. Resistance arises primarily from acquisition of genes that either encode transporters of the major facilitator superfamily (MFS), which remove the antibiotics from the cell (e.g. TetB, TetK), or encode proteins that protect the ribosome from inhibition (e.g. TetM, TetO). Tigecycline is not affected by these resistance mechanisms and consequently is active against many species resistant to earlier tetracyclines. In some Gram-negative bacteria resistance can also be due to the activity of innate (endogenous) bacterial efflux proteins such as the chromosomally encoded resistance–nodulation– cell division efflux pumps that confer resistance to several structurally unrelated biocides and antibiotics, as well as all classes of tetracyclines. The presence of these pumps explains the inherent resistance of most Ps. aeruginosa and Proteus spp. to all tetracyclines.

Pharmaceutical Applications

A group of natural products derived from Streptomyces spp. and their semisynthetic derivatives. The minimum pharmacophore is a linear fused tetracyclic molecule, 6-deoxy-6-demethyltetracycline.
The various members of the class contain a variety of functional groups attached to the rings designated A, B, C and D. Natural products include chlortetracycline, oxytetracycline, tetracycline and demeclocycline (demethychlortetracycline). Semisynthetic derivatives include doxycycline, minocycline, methacycline, lymecycline, rolitetracycline and tigecycline, a glycylcycline that has been specifically developed to overcome problems of bacterial resistance to earlier tetracyclines.

Pharmacokinetics

Absorption
Tetracyclines are usually administered by mouth. However, tigecycline is available only for intravenous infusion.
Absorption of oral tetracyclines occurs largely in the proximal small bowel, but may be diminished by the simultaneous presence of food, milk or cations, which form nonabsorbable tetracycline chelates. Cimetidine and presumably other H2-receptor antagonists also impair absorption of tetracyclines by interfering with their dissolution, which is pH dependent.
The absorption problems of earlier compounds have been essentially overcome in the later tetracyclines. Improved absorption is claimed for lymecycline, demeclocycline and methacycline, but is best established for doxycycline and minocycline, which may be administered with food and for which the proportion of administered dose absorbed is more than 90%.
Distribution
For orally administered tetracyclines, peak serum concentrations follow 1–4 h after ingestion. Serum levels achieved after normal dosage of orally bioavailable tetracyclines are of the order of 1.5–4.0 mg/L. Most tetracyclines must be given four times daily to maintain therapeutic concentrations in the blood, but demeclocycline and minocycline can be administered twice daily and doxycycline once daily.
Tetracyclines penetrate moderately well into body fluids and tissues, reflected in relatively large volumes of distribution. Concentrations of most tetracyclines in the cerebrospinal fluid (CSF) are usually about 10–25% of those in the blood, although penetration of tigecycline into the CSF is poor. A unique feature of tetracyclines is deposition and persistence in areas where bone is being laid down. Radioactive tracer studies in animals suggest that tigecycline also concentrates in the bone but concentration at this site in humans remains unproven owing to technical difficulties with assay methods.
Older tetracyclines are known to penetrate into the sebum and are excreted in perspiration, properties which contribute to their usefulness in the management of acne. The older tetracyclines are also known to be concentrated in the eye.
Excretion
Excretory routes are the kidney and feces. Fecal excretion occurs even after parenteral administration as a result of passage of the drug into the bile. The concentrations obtained in bile are 5–25 times those in the blood, doxycycline attaining especially high levels. These concentrations are lowered in the presence of biliary obstruction. The proportion of administered dose found in the urine is, for most tetracyclines, in the range 20–60%, but is less for chlortetracycline and doxycycline and least for minocycline and tigecycline.

Clinical Use

The use of tetracyclines has significantly declined in most countries as the incidence of bacterial resistance has increased and more active and better tolerated antimicrobial agents have been introduced. However, some new applications have emerged, such as their use as part of multidrug regimens for the management of gastritis and peptic ulcer disease associated with H. pylori. Their activity against malaria has become important for prophylaxis following the rapid increase of chloroquine- and mefloquine-resistant Plasmodium falciparum.
Tigecycline is currently approved only for use in complicated skin and skin structure infections (including those caused by methicillin-resistant Staph. aureus), complicated intra-abdominal infections and community- acquired bacterial pneumonia, but use for other indications, may emerge if there is suitable clinical evidence.

Side effects

Known adverse effects are primarily based on studies with older tetracyclines and it is not yet clear whether they also apply to tigecycline. However, it might be expected that tigecycline will share at least some of the unwanted side effects associated with all members of the class.
The most important adverse effect is gastrointestinal intolerance, reported for all tetracyclines including tigecycline. Photosensitivity is a class phenomenon; it is most marked for demeclocycline but is not yet reported for tigecycline. Deposition in developing bones and teeth precludes the use of older tetracyclines in young children and during late pregnancy; tigecycline may also exhibit these properties and is contraindicated in these situations. Most compounds accumulate in renal failure, with the exception of doxycycline and tigecycline. Nausea and vomiting are presumed to be due to a direct irritant effect of the drug on the gastric mucosa, but diarrhea is probably the result of disturbance of the normal flora. The frequency and nature of superinfection with resistant organisms depends much on local ecology. Pseudomembranous colitis has been associated with the use of older tetracyclines, but they do not appear to be a common precursor of that complication. Other organisms that often become dominant in the fecal flora after administration of tetracyclines are Candida, Proteus or Pseudomonas spp. Staph. aureus enterocolitis, which was described in hospital patients when tetracyclines were widely prescribed, now seems to be rare.
Glossitis and pruritus ani, vulvitis and vaginitis are wellrecognized side effects associated with the use of older tetracyclines; less common side effects include esophageal ulceration and acute pancreatitis. Changes occur in the surface lipids of the skin, notably a decrease in fatty acids and reciprocal increase in triglycerides that probably results from inhibition of extracellular bacterial lipase production by Propionibacterium acnes.
Deaths have been reported in pregnant women given large intravenous doses (>1 g per day), usually for the treatment of pyelonephritis. The main lesion found at autopsy was diffuse fatty degeneration of the liver, which may also involve the pancreas, kidneys and brain. Mild derangements of liver enzyme function are not uncommon.
A number of infants have developed bulging of the anterior fontanelle; benign intracranial hypertension has also been described in older children and even in adults, with headache, photophobia and papilledema. Symptoms disappear quickly after the drug is withdrawn, but papilledema may persist in some patients for many months or reappear when tetracyclines are given again. The mechanism is unknown.
Hypersensitivity rashes, including exfoliation, occasionally occur, but skin reactions are more often manifestations of photosensitivity. A reaction may occur after administration of any tetracycline, but is especially associated with demeclocycline and may be less common with doxycycline and minocycline. Fixed drug eruptions, onycholysis and nail and thyroid pigmentation have also been reported. Angiodema and anaphylaxis are rare. Hypersensitivity reactions to one tetracycline generally infer cross-hypersensitivity to the other agents. Reported inhibitory effects on several human polymorphonuclear leukocyte and lymphocyte functions in vitro have yet to be shown to have any therapeutic significance.
Drug interactions include complexes with divalent and trivalent cations together with chelation by iron-containing preparations. The anticonvulsants carbamazepine, phenytoin and barbiturates decrease the half-life of doxycycline through enzyme induction. The anesthetic methoxyflurane has been reported to cause nephrotoxicity when co-administered with older tetracyclines. Tigecycline is reported to affect the pharmacokinetic profile of warfarin such that anticoagulation tests should be performed if it is administered with warfarin. The efficiency of oral contraceptives is reduced by tetracyclines, as with many other broad-spectrum antibiotics.

Raw materials

Preparation Products