Tetracycline

The tetracyclines constitute a group of antibiotics, some natural and others obtained by semi-synthesis, which cover a broad spectrum of antimicrobial activity. Chemically they are derivatives of polycyclic naphthacenecarboxamide, with a tetracyclic nucleus from which the name of the group derives.

Natural tetracyclines are extracted from bacteria of the genus Actinomyces. Chlortetracycline and demethylchlortetracycline are extracted from Streptomyces aurofaciens, from Streptomyces rimosus oxytetracycline is extracted, and tetracycline, the generic representative of the group, can be extracted from Streptomyces viridifaciens, although it can also be obtained semi-synthetically. A characteristic common to the group is its amphoteric character, which allows it to form salts with both acids and bases, usually using soluble hydrochlorides.

They fluoresce under ultraviolet light and have the ability to chelate di- or trivalent metals, such as calcium, manganese, or magnesium.

It is one of the most experienced antibacterials. As early as 1953, the approval of its nomenclature was recorded in the British Pharmacopoeia. Its use spread rapidly, so that already in 1955 there was talk of strains resistant to tetracycline and chlortetracycline. more than 14,000 articles on these antibiotics.

Pharmacokinetics

Tetracyclines are rapidly and completely absorbed in the digestive tract, mainly in the small intestine, and reach their maximum concentration in the blood within three to six hours. Parenterally they are optimally absorbed, highlighting rolitetracycline.

Its binding to plasma proteins is highly variable: from 20% of oxytetracycline to 90% of doxycycline.

They are distributed throughout all tissues, especially bone tissue, and penetrate into the interior of cells. They cross the placental barrier, and also the blood-brain barrier, but without reaching therapeutic concentrations in the cerebrospinal fluid. Consequence of these two properties is its contraindication in pregnancy.

They are partially metabolized throughout the body, eliminating most of them in unchanged form in the urine. Due to their high concentration in the bile, they present a phenomenon of entero-hepatic recirculation, being able to be found partially excreted in feces.

At the renal level, they present more or less intense tubular reabsorption phenomena depending on the type of tetracycline, which explains the differences regarding the half-life within the group. Chlortetracycline has the shortest half-life (about 5 hours), while doxycycline has more than 15.

Mechanism of action

They basically act as bacteriostatics at the usual doses, although they are bactericidal at high doses, generally toxic. They act by several mechanisms:

• Decouple the oxidative phosphorylation of the bacteria.
• They cause inhibition of protein synthesis in the ribosome of the bacteria. They act by inhibiting protein synthesis by joining the subunit 30 S of the ribosome and not allowing the binding of the ribonucleic acid of Transfer (tRNA) to it, nor the transport of amino acids to subunit 50 S.
• There is also preliminary evidence suggesting that tetracyclines alter the cytoplasmic membrane of susceptible organisms, allowing the output of intracellular components.

Bacterial resistance to tetracyclines appears slowly, although it is much faster if used topically. Among the bacterial mechanisms involved are the active pumping of the antibiotic abroad, or the synthesis of a protective protein that separates the antibiotic from the ribosome, allowing it to continue with protein synthesis. Any of these genes can be present on a plasmid, which explains the reluctance to use tetracyclines in the hospital setting to avoid the emergence of simultaneous resistance to several antibiotics. There are cross-resistances between members of the group.

Indications

• Groups: Streptococcus, Diplococcus, Clostridium.
• Gramnegative bacteria: Neisseria, Brucellas, Haemophilus, Shigella, Escherichia coli, Bordetella, Klebsiella, Vibrio and Pasteurella.
• Spirochetes.
• Some protozoa: Entamoeba.
• Actinomyces.
• Rickettsia.

This spectrum explains its use in the following pathologies, among others:

• Skin infections: acne, rosacea.
• urogenital infections: gonocotics, syphilis.
• Gastrointestinal infections: dysentery, cholera, amebiasis, gastric ulcer, periodontal infections.
• Respiratory infections: pharyingoamigdalitis, bronchitis and some forms of atypical pneumonia.
• Other infections: Recurrent fever, Q fever, exanthematic typhus, endemic typhus, actinomicosis, brucellosis.

It must be taken into account that although in vitro its activity is broader, in vivo we find many other antibiotics that may be more effective or have fewer adverse effects than tetracyclines, so these are relegated to second-choice antibiotics, when the first-choice ones fail.

Contraindications

• The use of tetracyclines during dental development (second half of pregnancy, breastfeeding and children under 8 years of age), can cause permanent discoloration of teeth (grey brown to yellowish). Although this adverse reaction is more frequent with long-term use, it has also been observed after the administration of repeated short treatments.
• In case of allergy to tetracyclines (doxycycline, minocycline, oxytetracycline, tetracycline).
• Tetracyclines should be avoided in patients with systemic erythematous lupus.
• They should not be eaten with milk as they are inactive.
• Oral retinoids should not be taken together (Roaccutane)^® or similar) since there is a risk of formation of benign intracranial tumors.

Adverse reactions

The following list includes only the adverse reactions described with a frequency higher than 0.1% (>1/1000). Numerous other reactions have been described that occur with a lower frequency (<1/1000; less than 0.1%).

Classification

Following the guidelines of the ATC Classification, the antibiotics that make up the group of tetracyclines would be:

Degradation

Some of the treatments carried out are the following:

• Absorption and dissipation: studies have been carried out on the absorption and dissipation of tetracyclines in the soil, in the porcine manure compost and in soil/compost mixtures with different amounts of organic carbon. Different treatments were performed, and in all of them tetracyclines were strongly absorbed into dung due to their high organic carbon content. In a soil/seed mixture treated at 25 °C (Grades Celsius) and dark, it was observed that tetracyclines are degraded by 50% after 20 or 41 days; and 90% between 68 and 137 days. If there is no compost on the ground, dissipation is very slow.
• Ozonation: With this method you get very good results if you work at high pH. In a study performed, tetracycline (20 mg/L) was completely degraded after 5 minutes of ozoning, although to decrease total organic carbon it was required 40 minutes. This suggests that ozonization does not mineralize tetracycline.
• Photodegradation in aqueous solution using UV radiation and UV/H2O2 oxidation processes: results obtained in this study show that degradation rates depend on the initial concentration of antibiotics and pH. If only UV radiation was used in this technique, it would be a very slow process, but by combining UV/H2O2, a faster degradation is obtained, the concentration of total organic carbon is reduced and the toxicity of tetracycline oxidation products decreases.
• Photodegradation in water in the presence of an iron/oxalate complex: using UV-vis light and a Fe(III)/oxalate complex, you can achieve total degradation of tetracycline, after 15 minutes of treatment. For this to happen, you have to control the light source, the Fe/oxalato ratio and the pH.
• Irradiation with an electron beam: this experiment was performed in a sample of pork dung. The results obtained from the degradation efficiency of tetracycline were: 42.77 % to 1 kGy, 64.20 % to 3 kGy, 77.83 % to 5 kGy, and 90.50 % to 10 kGy.

Metabolism

Tetracyclines can be used to inhibit matrix metalloproteases (MMPs). MMPs are present in tumors and metastases, as well as in inflammatory processes. Numerous studies have shown that tetracycline derivatives inhibit the activity of certain MMPs, but not all. So they can be used for the inhibition of metastasis and in particular for angiogenesis. Although the mechanisms by which tetracyclines act on angiogenesis are still not very well known, their effects have been demonstrated, so these substances could be used in the treatment of cancer.

Another characteristic of tetracyclines is that they reduce inflammation in neurological processes, bone, heart and airway conditions, etc.

Environmental impact

The impact of antibiotics on the environment is little known and is therefore under study. Both antibiotic residues and antibiotic-resistant bacteria are a problem in the environment and pose a risk to human health.

Several studies are being carried out focusing on the use of antibiotics in animal feed, since a large part of these antibiotics is excreted in urine or manure, and once this occurs, the antibiotics end up in the soil or waters (underground or surface).

Presence in remains of ancient populations

A team led by George Armelagos discovered the presence of high amounts of tetracycline in human bones from Nubia dated to the years 350-550, indicating chronic use of this antibiotic. By analyzing contemporary recipes for brewing, he found that its fermentation process might be the most plausible source.