The contradictory world of tetracyclines

Tetracyclines (TCs) are members of a group of broad-spectrum antibiotics, the polyketides, particularly effective against many gram-positive, gram-negative bacteria and protozoan parasites.1 There are 3 main classes of TCs: class 1 (chlortetracycline (CTC), oxytetracycline (OTC), tetracycline (TET) and demethylchlortetracycline, class 2 (demeclocycline and methacycline) and class 3 (doxycycline (DOXY), glycylcyclines and minocycline (MIN O). While TCs belonging to class 1 are used in agriculture (fish, bovine, porcine and poultry), class 2 and 3 are mainly used for diseases treatment in pets. Each year, the worldwide production of TCs is estimated to be in thousands of tons. For instance, the amount used in the European Union for therapeutic purpose end of last century was around 2294 tons, whereas during the period 2000-2001 the consumption in USA increased from 3000 to 3200 tons. Moreover, TCs are considered as one of the cheapest classes of antibiotics available and are employed in the prophylaxis and therapy of human and animal infections particularly in developing countries with limited health care budgets, especially in animal production, as growth promoters, where costs are always a concern.1 TCs have been recognized a safe and cheap classes of antibiotics present on the pharmaceutical market, a feature that made them attractive for developing countries, placing them among the first three groups of antibiotics produced and consumed worldwide. TCs have also shown a broad spectrum of activity against respiratory infections (Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci), malaria (Plasmodium falciparum and mefloquine-resistant Plasmodium falciparum), Entamoeba histolytica, Giardia lamblia, Leishmania major, Trichomonas vaginalisand Toxoplasma gondii infections and filarial nematodes. However, scientific literature revealed a wide number of nonantibacterial clinical applications including acne rosacea, bullous dermatoses, cicatricial pemphigoid, linear IgA disease, lichen planus pemphigoides, cutaneous sarcoidosis, Kaposi’s sarcoma, pyoderma gangrenosum, hidradenitis suppurativa, Sweet’s Syndrome, a1-antitrypsin deficiency panniculitis, and pityriasis lichenoides chronica, rheumatoid arthritis, scleroderma, cancer, cardiovascular diseases, periodontal disease, brain diseases. Despite their low toxicity, many side effects have been ascribed to TCs, including, but not limited to nausea, vomiting and diarrhea, photosensitivity, urticaria, headache, abdominal pain, hypertension, fever, mild leukopenia, anemia and thrombocytopenia. However, examples of toxic effects associated with the acute or chronic use of the TCs have been reported including superinfection with yeasts or resistant pathogenic bacteria within gut, decrease in fibula growth rate in premature infants, renal impairment, congenital anomalies, and even hypersensitivity. In this regard, allergic reactions generally take place after photosensitization, although recent papers hypothesized a possible involvement of TCs-loaded food as possible triggering factor of allergic reactions or intolerance responses in hypersensitive individuals.2 In production animals, TCs are added to feed to prevent disease, morbidity and mortality and increase overall development.1 In particular OTC and DOXY are still licensed as growth promoters in USA and Europe. For poultry alone, it is suggested that slightly more than 4.5 million kg of antimicrobials were used in production for 2012. It is worth noting that, beyond poultry, TCs are still employed for dairy cattle, pigs and livestock exposing the animals to a huge range of antimicrobials, with consequent effects on the overall individual health status pets or humans once consumed. One of the most employed TC in animal husbandry is OTC, due to its low cost, high efficacy, and almost lack of side effects.1 In 2009 OTC, but also TET, were detected in 24 samples of commercial chicken drumsticks and quantified in a range from 83.0 to 2049.3 ug/kg and from 197.8 to 2564.3 ug/kg, respectively.3 This study firstly posed a serious concern related to the potential toxicity associated with chronic consumption of poultry by animals and/or humans. A 2010 survey on commercial chicken eggs sold by smallholder farmers in a city of Tanzania confirmed the abuse of antimicrobial drugs as prophylaxis and treatment of common chicken diseases, in particular OTC, and evidenced the lack of awareness about the possible effects on humans.4 Few years later, Di Cerbo et al. assessed the cytotoxic effects of bone from poultry treated with OTC according to appropriate withdrawal periods on K562 cells and peripheral blood mononuclear cells (PBMC s).5 Despite OTC residues in the animal’s muscle were far below the established minimal residual limits (100 μg/kg) those detected in the bones were in the order of mg/Kg, thus suggesting potential health risks for animals and humans since OTC minimal residual limits have not been established in bone as it is considered inedible. Moreover, almost 20-30% of pet food composition is based on bone meal, which can therefore drag OTC residues and can accumulate in animal’s body fostering inflammatory phenomena. The widespread and imprudent use of antibiotics in animal production led to increased antibiotic resistant bacteria in livestock and poultry. Similarly, the accumulation of those products and their derivatives in the meat intended to human and animal consumption becomes a serious problem associated with potential direct or indirect toxicity and deserving serious attention and further scientific evaluations to allow the characterization of the potential threads those residues present in the food involve for the environment, the animal and human species.