Why tetracycline antibiotics

The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are associated with mobile plasmids or transposons and can be distinguished from each other using molecular methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing.

Besides the use in humans, the tetracyclines are used in animal therapy to treat infections and promote growth. Oxytetracycline and chlortetracycline are two of the ten antimicrobials authorized in the United States as growth promoters for cattle Jeong et al.

Tetracyclines are the third most consumed antibiotic, after penicillin and quinolones, and due to their indiscriminate use it has been detected an increasing number of bacteria resilient to tetracyclines Pereira-Maia et al.

Nova, v. The phenomenon of resistance is indeed nowadays a great concern as there are strains resilient to almost all currently known agents Rocha et al. In this work is presented the processes of obtaining tetracycline, the treatment of their waste and the environmental impact assessment of waste containing tetracycline.

The discovery of the first member of the family of tetracyclines was in by Benjamin Duggar, and received the name of aureomycin chlortetracycline , which is a product of natural fermentation of the bacteria Streptomyces aureofaciens , naturally present in the soil.

Two years later, a second isolated tetracycline, terramycin called oxytetracycline was synthesized by the bacteria Streptomyces rimosus. In , there was obtained the tetracycline molecule which has the simplest structure of this antibiotic family maintaining its functions.

It was obtained through a biological process followed by a chemical process, which consisted in obtaining a precursor molecule by fermentation, followed by a chemical reaction for introducing of functional groups in the precursor molecule.

It was observed that the basic structure of two antibiotics, aureomycin and terramycin, were the same, and the generic name tetracycline was suggested. After that many studies began to search for new tetracyclines Pereira-Maia et al.

Accessed on: 03 Aug. The three tetracycline antibiotics tetracycline, oxytetracycline and chlortetracycline were the basis for obtaining new derivatives in order to obtain less toxic drugs with better therapeutic use. Several byproducts were synthesized such as demeclocycline, rolitetracycline and the methacycline, which are considered first generation tetracyclines.

Thus, from to , several members of the tetracycline family had been obtained, as natural or semisynthetic products, and in this same period, tetracyclines remained among the most commonly used antibiotics in the United States Pereira-Maia et al. It acts as inhibitor of protein synthesis by preventing the binding of aminoacyl-tRNA to the A site of the bacterial ribosome Hasan et al.

Anhydrotetracycline is a major product of tetracycline photolysis. All tetracyclines have the same spectrum and mechanism of action, adverse effects and similar tolerances by resilient organisms. According to Pereira-Maia et al. The presence of the amide grouping at C-2 was also considered as a structural feature required for the biological action of tetracyclines.

Another important observation related to increased enzyme inhibitory power was the absence of methyl groups and hydroxyl at position C All these features are shown in Figure 1. The pharmacokinetics for most tetracyclines is generally oral or parenteral, and is mainly absorbed in the stomach and upper small intestine Pereira-Maia et al.

Solo, v. Despite the similarity of metabolism of various representatives of the tetracycline family one of the main differences among the tetracyclines is their half-life in the body, which is presented below Pereira-Maia et al. They are long-acting drugs with long half-live greater than 15 h. They are considered active drugs with short half-life of 6 to 9 h. Tetracyclines in the blood plasma are transported as calcium complex that once inside the cells of the bacteria, forms a complex with magnesium, which binds to the ribosome.

In this regard, it is known that the binding of the ribosome complex magnesium inhibits protein synthesis by triggering the bacteriostatic effect Rocha et al. Longer-duration uses of tetracyclines and penicillins in U. In aqueous solutions, depending on the pH, three different groups within the molecule may undergo protonation or deprotonation dimethylammonium, tricarbonylamide and phenolic diketone Zhao et al. Adsorption of tetracycline onto goethite in the presence of metal cations and humic substances.

Colloid Interface Sci. Tetracycline adsorption on kaolinite: pH, metal cations and humic acid effects. Ecotoxicology, v. The tetracyclines are strong chelating agents and pH dependent, and they have their antibacterial activity and pharmacokinetics decreased when associated with foods rich in calcium, iron, magnesium and other minerals or antacids such as sodium bicarbonate, which increase the pH in the stomach.

Doxycycline has been an exception, because the ingestion of substances that increase gastric pH does not decrease its absorption Pereira-Maia et al. Tetracyclines in normal use concentrations are bacteriostatic, helping the inhibition of protein synthesis by binding to the 30S fraction of the bacterial chromosome by preventing the attachment of tRNA, interfering with the supply and connecting the amino acids forming proteins.

In higher concentrations they can exercise bactericidal effect. In general, the more lipophilic molecules are more active than the hydrophilic due to their interaction with lipoprotein in biological membranes. Tetracycline have the ability to cross the cell membrane by passive diffusion process and by active transport due to its good diffusion inside the cells and therefore exhibit excellent antibiotic activity against intracellular bacteria Zhanel et al.

They are usually indicated for infections whose agents are Rickettsia , Chlamydia , Mycoplasma and Borrelia , Campylobacter , Ureaplasma urealyticum and Legionella. They are effective in treating spotted fever, epidemic typhus, Q fever and other rickettsial diseases. They also act on psittacosis, Lymphogranuloma venereum caused by the chlamydia ; in atypical pneumonias caused by Mycoplasma pneumoniae. They have action in the treatment of brucellosis, tularemia, bartonellosis, actinomycosis, recurrent fevers, cholera.

They are indicated for penicillin-allergic patients and patients with gonorrhea. They can be used for infections caused by group A Streptococcus , Staphylococcus , Pneumococcu s, Gram-positive and Gram-negative and espiroquetoses and as second choice in the treatment of Plasmodium falciparum malaria, amebiasis by the Entamoeba histolytica , peptic ulcers caused by Helicobacter pylori and the treatment and prevention of bacteria used as biological weapons in terrorism such as anthrax Cox, Popken, COX, L.

Assessing potential human health hazards and benefits from subtherapeutic antibiotics in the United States: tetracyclines as a case study.

Risk Anal. In relation to the pharmacological properties of these compounds, they possess a number of non-antibiotic properties and several studies have been conducted to use tetracyclines in the treatment of non-infectious diseases such as rheumatoid arthritis and cancer Regitano, Leal, REGITANO, J. Mathers et al. The main advantage of the antineoplasic action of tetracyclines especially doxycycline is compared to greater tolerance with increasing dose of the drug, allowing the synergistic treatment with drugs such as cisplatin, currently used in lower doses, while maintaining the efficacy of the treatment Pereira-Maia et al.

Wirtz et al. Trends in antibiotic utilization in eight Latin American countries, The results reported by WHO were based on national sales of antibiotics for the retail direct sales in private pharmacies and indirect sales in private clinics and hospitals , not providing information of antibiotics purchased by the public sector government contractors.

Figure 2 shows the daily consumption of various antibiotics consumed in many Latin American countries in According to data provided by Wirtz et al. Recent advances in LC-MS residue analysis of veterinary medicines in the terrestrial environment. Trends Anal. Pharmaceutical antibiotic compounds in soils — a review. Plant Nutr. Soil Sci. In a more recent estimate Kools et al. Estimating the use of veterinary medicines in the European Union. In Brazil, in general, there are no statistics about the amount of antibiotics sold for animal production.

According to Pereira et al. In Table I are shown some results of the in vitro activity of four tetracyclines for Gram-negative and Gram-positive bacteria with relevance in medical clinic. Interestingly, a study by Mathers et al.

Two mechanisms of clinical significance are primarily responsible for bacterial resistance to tetracyclines:. Removing active antibiotics from the cell through the mechanism known as efflux pumps, causing the antibiotic to be quickly pumped out of the cell.

Tecnical Center. The ribosomal protection through cytoplasmic proteins that protect the ribosome from the action of tetracyclines Pereira-Maia et al. Both mechanisms enable protein synthesis proceed normally.

Figure 3 outlines the mechanism of bacterial resistance to efflux mechanism. Recently, several research groups have shown that antibiotics containing metal complexes are often more active than the parent compound. The coordination platinum II to tetracycline and doxycycline through the ring A, shown in Figure 1 , results in active compounds against bacterial strains resistant to tetracycline and other antibiotics Pereira-Maia et al.

Some metal complexes are found in several articles presented in the work by Pereira-Maia et al. The palladium complex coordinated to tetracycline is sixteen times more potent than the free drug. The coordination of palladium to doxycycline also increases the activity on resistant strains of bacteria, the complex being two times more potent than the free drug Rocha et al. The coordination of antibiotic metal ions has been used not only as a mechanism for reversing resistance, but also as a strategy for developing new drugs, particularly those with activity in the treatment of tumors, studies for directing a new set of substances similar as the Chemically Modified Tetracyclines known as CMTs.

The removal of the dimethylamino group in C11 position Figure 1 eliminates the antibacterial action and potentiates side effects. The chemotherapeutic action occurs through inhibition of enzymes known as MMP matrix metalloprotease , focusing in prevention of angiogenesis and metastasis Pereira-Maia et al. Despite several trials in developing these modified molecules, their introduction in the market should be carefully evaluated because the bioaccumulation of a metal ion can cause severe side effects.

Therefore, their pharmacological and physiological actions must be studied in vivo, in animals, before their use in human clinic tests Rocha et al. Residues of antibiotics, including tetracyclines from Wastewater Treatment Plants WWTPs of urban and agricultural effluents are frequently detected in surface water, groundwater, soils and sediments Zhao et al. The antibiotics oxytetracycline and doxycycline are commonly detected in aquatic environment and WWTPs effluents Yuan et al.

Generally, they are present in relatively low concentrations ng or mg per L , below the threshold levels to show the effects of medicinal treatment on bacterial populations and other exposed species Boxall et al.

Are veterinary medicines causing environmental risks? Tetracycline may cause other side effects. Call your doctor if you have any unusual problems while taking this medication. Keep this medication in the container it came in, tightly closed, and out of reach of children.

Store it at room temperature and away from light and excess heat and moisture not in the bathroom. Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet.

Instead, the best way to dispose of your medication is through a medicine take-back program. It is important to keep all medication out of sight and reach of children as many containers such as weekly pill minders and those for eye drops, creams, patches, and inhalers are not child-resistant and young children can open them easily.

To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location — one that is up and away and out of their sight and reach. In case of overdose, call the poison control helpline at If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at Keep all appointments with your doctor and the laboratory.

Your doctor will order certain lab tests to check your response to tetracycline. Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking tetracycline. Do not let anyone else take your medication. Your prescription is probably not refillable. If you still have symptoms of infection after you finish the tetracycline, call your doctor. It is important for you to keep a written list of all of the prescription and nonprescription over-the-counter medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements.

You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies. Generic alternatives may be available. Tetracycline pronounced as tet ra sye' kleen.

Why is this medication prescribed?