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PubMed2006

Tetracyclines and tetracycline resistance in agricultural soils: microcosm and field studies.

The influence of the use of antibiotics on the prevalence of resistance genes in the environment is still poorly understood. We studied the diversity of tetracycline and sulfonamide resistance genes as influenced by fertilization with pig manure in soil microcosms and at two field locations. Manure contained a high diversity of resistance genes, regardless of whether it stemmed from a farm operation with low or regular use of antibiotics. In the microcosm soils, the influence of fertilization with manure was clearly shown by an increase in the number of resistance genes in the soil after manuring. Spiking of the tetracycline compounds to the microcosms had only little additional impact on the diversity of resistance genes. Overall, the tetracycline resistance genes tet(T), tet(W), and tet(Z) were ubiquitous in soil and pig slurries, whereas tet(Y), tet(S), tet(C), tet(Q), and tet(H) were introduced to the microcosm soil by manuring. The diversity of tetracycline and sulfonamide [sul(1), sul(2), and sul(3)] resistance genes on a Swiss pasture was very high even before slurry amendment, although manure from intensive farming had not been applied in the previous years. The additional effect of manuring was small, with the tetracycline and sulfonamide resistance diversity staying at high levels for the complete growth season. At an agricultural field site in Germany, the diversity of tetracycline and sulfonamide resistance genes was considerably lower, possibly reflecting regional differences in gene diversity. This study shows that there is a considerable pool of resistance genes in soils. Although it is not possible to conclude whether this diversity is caused by the global spread of resistance genes after 50 years of tetracycline use or is due to the natural background in soil resistance genes, it highlights a role that environmental reservoirs might play in resistance gene capture.

Agrochemicals↗
PubMed1988

Inhibitory effect of tetracycline and doxycycline on resistance of mice to infection with a tetracycline-resistant strain of Listeria monocytogenes.

By transposon mutagenesis a tetracycline-susceptible strain of Listeria monocytogenes (MIC 1 mg/l. for tetracycline and 0.25 mg/l. for doxycycline) was rendered resistant (MIC 64 mg/l. for tetracycline and 16 mg/l. for doxycycline). Infection of mice with this resistant strain led to an acute infection. Treatment with 2 x 2 mg tetracycline per day did not influence the course of infection during the first 3 days, indicating that the nonspecific resistance, mediated mainly by macrophages and granulocytes, was not affected by this treatment. The second phase of infection, characterized by a continuous resistance to infection due to macrophages activated by T-lymphocytes was, however, definitely hampered. Even acquired immunity to a secondary infection was impaired by treatment with tetracycline, indicating that cell-mediated immunity can be blocked. The course of infection of athymic, nude mice which are unable to build up a cell-mediated immune response, was not affected by tetracycline treatment. Doxycycline expressed the same activities as tetracycline.

Animals↗
PubMedDate not supplied

New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors.

The tetracyclines, discovered in the 1940s, are a well-established class of antibiotics that still have a role in treating microbial infections in man. However, the widespread emergence of bacterial resistance due to efflux and ribosomal protection mechanisms has severely limited their effectiveness. A new generation of tetracyclines, the glycylcyclines, has been developed to overcome resistance to earlier tetracyclines. One of the new glycylcyclines, 9-t-butylglyclamido-minocycline (GAR-936, tigecycline) is currently undergoing clinical trials. This review considers the current status of glycylcyclines and the possibility that resistance to these agents might arise in the future. Other approaches are also being taken to address the emergence of resistance to tetracyclines. Recently, a number of tetracycline efflux pump inhibitors have been discovered that might be used in combination with earlier tetracyclines to restore their activity against resistant organisms. However, the development of tetracycline efflux pump inhibitors is complicated by the occurrence of several efflux pump sub-families and by the presence of both efflux and ribosomal protection mechanisms in the same organism, especially in naturally occurring, Gram-positive clinical isolates.

Humans↗
PubMed1994

The Clostridium perfringens Tet P determinant comprises two overlapping genes: tetA(P), which mediates active tetracycline efflux, and tetB(P), which is related to the ribosomal protection family of tetracycline-resistance determinants.

The complete nucleotide sequence and mechanism of action of the tetracycline-resistance determinant, Tet P, from Clostridium perfringens has been determined. Analysis of the 4.4 kb of sequence data revealed the presence of two open reading frames, designated as tetA(P) and tetB(P). The tetA(P) gene appears to encode a 420 amino acid protein (molecular weight 46,079) with twelve transmembrane domains. This gene was shown to be responsible for the active efflux of tetracycline from resistant cells. Although there was some amino acid sequence similarity between the putative TetA(P) protein and other tetracycline efflux proteins, analysis suggested that TetA(P) represented a different type of efflux protein. The tetB(P) gene would encode a putative 652 amino acid protein (molecular weight 72,639) with significant sequence similarity to Tet(M)-like cytoplasmic proteins that specify a ribosomal-protection tetracycline-resistance mechanism. In both C. perfringens and Escherichia coli, tetB(P) encoded low-level resistance to tetracycline and minocycline whereas tetA(P) only conferred tetracycline resistance. The tetA(P) and tetB(P) genes appeared to be linked in an operon, which represented a novel genetic arrangement for tetracycline-resistance determinants. It is proposed that tetB(P) evolved from the conjugative transfer into C. perfringens of a tet(M)-like gene from another bacterium.

Amino Acid Sequence↗
PubMed1985

Metal ion-tetracycline interactions in biological fluids. Part 5. Formation of zinc complexes with tetracycline and some of its derivatives and assessment of their biological significance.

A series of studies was previously devoted to the dependence of the bioavailability of various tetracyclines on their coordination with calcium and magnesium ions. Several clinical investigations have also shown zinc to interfere with the gastrointestinal absorption of the drug in humans. On the other hand, the administration of tetracycline to rats was reported to result in the increase of the elimination rate of zinc, which could originate in zinc-tetracycline interactions in blood plasma. Formation constants for zinc complexes with tetracycline, oxytetracycline, doxycycline, minocycline, chlortetracycline and demethylchlortetracycline were thus determined at 37 degrees C in NaCl 0.15 mol. dm-3 aqueous medium. Computer simulations were then carried out to investigate the drug influence on the distribution of the low-molecular-weight fraction of zinc in human blood plasma. Zinc-tetracycline interactions in the gastrointestinal fluid were also simulated, using clinical data relative to fasting subjects as taken from the literature. No significant effect can be expected from tetracyclines on the distribution of zinc in plasma at the usual therapeutic levels. However, zinc-tetracycline interactions have been found to be determining factors for the bioavailabilities of the metal as well as of the antibiotic in the gastrointestinal fluid.

Biological Availability↗
PubMed1967

Resistance of Escherichia coli to tetracyclines. Changes in permeability to tetracyclines in Escherichia coli bearing transferable resistance factors.

1. When strains of Escherichia coli, bearing transferable factors for resistance to the tetracyclines (R-factors), and previously cultured in the absence of the tetracyclines, are grown for 15-30min. in a low, subinhibitory, concentration (10mug./ml.) of oxytetracycline or tetracycline, there is a rapid and striking increase in resistance to oxytetracycline or tetracycline, this being associated with a marked fall in the absorption of the drug by the cells. 2. Very short preincubation (1min.) with oxytetracycline, followed by growth for 15-30min. in drug-free medium, produces a marked fall in the absorption of the drug by the resistant cells. Preincubation for 30min. with very low concentrations (0.05mug./ml.) of oxytetracycline produces a similar effect. 3. beta-Apo-oxytetracycline, which has very little antibacterial activity, also induces a decreased absorption of oxytetracycline. 4. The ability to exclude oxytetracycline is retained by preincubated resistant cells after growth for 2hr. in drug-free medium. However, after growth for 16hr. in drug-free medium, the cells absorb oxytetracycline freely. 5. Chloramphenicol and proflavine inhibit the adaptive decrease in tetracycline absorption. 5-Fluorouracil has only a slight effect. 6. Spheroplasts prepared from resistant cells show an impaired response to preincubation with tetracycline, compared with intact cells. 7. The relevance of these results to the probable mechanism of tetracycline resistance in R-factor-bearing E. coli is discussed.

Acridines↗
PubMedDate not supplied

A placebo-controlled study to evaluate the efficacy of topical tetracycline and oral tetracycline in the treatment of mild to moderate acne. Dermatology Research Group.

This double-blind, parallel group multicentre study in 85 hospital out-patients with mild to moderate acne evaluated the efficacy of 2.2 mg/ml topical tetracycline or placebo applied twice daily for 16 weeks together with an initial course of oral tetracycline, at doses of 1000 mg/day during weeks 1-4 and 500 mg/day during weeks 5-8. Acne severity improved significantly (P less than 0.01) with both treatments after 8 and 16 weeks. After 4 weeks, 78% of patients using topical tetracycline showed reduced acne severity compared with 50% using placebo and, by week 16, improvements were 94% and 57%, respectively (P = 0.035). Global evaluations of patients and of investigators showed most improvement to occur within the first 8 weeks of treatment. Tingling and stinging were the most frequently reported adverse effects, occurring in similar frequencies in both treatment groups. Skin discoloration was more frequent in patients given topical tetracycline. Overall, 90% of patients rated topical tetracycline as 'cosmetically acceptable'. In conclusion, topical tetracycline is useful in treatment of mild to moderate acne when given with an initial course of oral tetracycline and may enhance efficacy without unacceptable side-effects.

Acne Vulgaris↗
PubMed1990

Metal-tetracycline/H+ antiporter of Escherichia coli encoded by a transposon, Tn10. The role of the conserved dipeptide, Ser65-Asp66, in tetracycline transport.

The transposon Tn10-encoded tetracycline resistance protein functions as a metal-tetracycline/H+ antiporter (Yamaguchi, A., Udagawa, T., and Sawai, T. (1990) J. Biol. Chem. 265, 4809-4813). The Ser65-Asp66 dipeptide is conserved in all known tetracycline antiporter proteins and is an important target for site-directed mutagenesis. When Asp66 was replaced by Asn, the transport activity was completely lost, whereas when it was replaced by Glu, the activity was reduced to 10% of the wild-type level, indicating that a negative charge at position 66 is essential for tetracycline transport. Replacement of Ser65 by Cys or Ala, in contrast, caused only a minor change in tetracycline transport activity. However, the Cys65 mutant antiporter was sensitive to sulfhydryl reagents. Complete inactivation of the Cys65 antiporter by N-ethylmaleimide was not prevented by the substrate. A less bulky reagent, methyl methanethiosulfonate, caused partial inactivation of the Cys65 antiporter without changing its affinity to the substrate. These results indicate that a region including the dipeptide plays an important role in metal-tetracycline transport except for substrate binding. It may act as a gate which opens on the charge-charge interaction between Asp66 and the metal-tetracycline.

Amino Acid Sequence↗
PubMed2003

Susceptibility of Escherichia coli and Enterococcus faecium isolated from pigs and broiler chickens to tetracycline degradation products and distribution of tetracycline resistance determinants in E. coli from food animals.

One hundred Escherichia coli isolates from diseased and healthy pigs, cattle and broiler chickens were screened for the presence of tetracycline resistance genes tet(A), (B), (C), (D) or (E). The tet(A) gene was the most abundant (71% of the 100 isolates) followed by tet(B) (25%). The predominance of tet(A) and tet(B) applied to all three animal species, and there was no difference between the distribution of tet(A) and tet(B) genes among non-pathogenic and pathogenic E. coli in any of the animal species. The susceptibility of 20 of these isolates together with 10 tetracycline sensitive E. coli and 18 tetracycline resistant and 10 sensitive Enterococcus faecium to tetracyclines and tetracycline degradation products was determined. The resistant isolates showed reduced resistance to anhydrotetracycline, 4-epi-anhydrotetracycline, anhydrochlortetracycline and 4-epi-anhydrochlortetracycline. In general both the tetracycline resistant and susceptible E. faecium were more susceptible to the compounds tested than E. coli.

Animals↗
PubMed2006

Tetracycline residues and tetracycline resistance genes in groundwater impacted by swine production facilities.

Antibiotics are used at therapeutic levels to treat disease; at slightly lower levels as prophylactics; and at low, subtherapeutic levels for growth promotion and improvement of feed efficiency. Over 88% of swine producers in the United States gave antimicrobials to grower/finisher pigs in feed as a growth promoter in 2000. It is estimated that ca. 75% of antibiotics are not absorbed by animals and are excreted in urine and feces. The extensive use of antibiotics in swine production has resulted in antibiotic resistance in many intestinal bacteria, which are also excreted in swine feces, resulting in dissemination of resistance genes into the environment. To assess the impact of manure management on groundwater quality, groundwater samples have been collected near two swine confinement facilities that use lagoons for manure storage and treatment. Several key contaminant indicators - including inorganic ions, antibiotics, and antibiotic resistance genes - were analyzed in groundwater collected from the monitoring wells. Chloride, ammonium, potassium, and sodium were predominant inorganic constituents in the manure samples and served as indicators of groundwater contamination. Based on these analyses, shallow groundwater has been impacted by lagoon seepage at both sites. Liquid chromatography-mass spectroscopy (LC-MS) was used to measure the dissolved concentrations of tetracycline, chlortetracycline, and oxytetracycline in groundwater and manure. Although tetracyclines were regularly used at both facilities, they were infrequently detected in manure samples and then at relatively trace concentrations. Concentrations of all tetracyclines and their breakdown products in the groundwater sampled were generally less than 0.5 microg/L. Bacterial tetracycline resistance genes served as distinct genotypic markers to indicate the dissemination and mobility of antibiotic resistance genes that originated from the lagoons. Applying PCR to genomic DNA extracted from the lagoon and groundwater samples, four commonly occurring tetracycline (tet) resistance genes - tet(M), tet(O), tet(Q), and tet(W) - were detected. The detection frequency of tet genes was much higher in wells located closer to and down-gradient from the lagoons than in wells more distant from the lagoons. These results suggested that in the groundwater underlying both facilities tetracycline resistance genes exist and are somewhat persistent, but that the distribution and potentially the flux for each tet gene varied throughout the study period.

Animal Husbandry↗
PubMed2004

Electrocatalytic tetracycline oxidation at a mixed-valent ruthenium oxide--ruthenium cyanide-modified glassy carbon electrode and determination of tetracyclines by liquid chromatography with electrochemical detection.

Mixed-valent films of ruthenium oxide-ruthenium cyanide were electrodeposited onto glassy carbon and characterized for the electrocatalytic oxidation of tetracycline. The currents produced by tetracycline were higher than from previously reported electrode modifications or pretreatments. In H(2)SO(4) pH 1.0 + 0.5 M K(2)SO(4), the second-order rate constant for the reaction between tetracycline and the Ru(III/IV) couple of ruthenium oxide was 3 x 10(5) +/- 1 x 10(5) mol(-1) cm(3) s(-1), and the rate of charge diffusion through the films was 4.5 x 10(-7) +/- 3.5 x 10(-7) cm(2) s(-1). Reaction was localized at the film-solution interface. When used as detectors in liquid chromatography (in H(3)PO(4) pH 2.5 + 0.1 M KH(2)PO(4) + 20% CH(3)CN, E = 1.10 V vs SCE), the electrodes gave limits of detection (>3 S/N) of 0.1 ppm for tetracycline and oxytetracycline and 0.5 ppm for doxycycline and chlorotetracycline. These limits were suitable for FDA and Codex Alimentarius guidelines for tetracyclines in food. Recoveries of the four tetracyclines from sea and freshwater shrimp were in the range 73-111%, which was higher or similar to the previously reported recoveries from shrimp.

Carbon↗
PubMed1975

Effectiveness of achievable urinary concentrations of tetracyclines against "tetracycline-resistant" pathogenic bacteria.

Hospitalized patients with urinary tract infections caused by Pseudomonas aeruginosa or other bacterial pathogens are frequently treated with parenteral antibiotics such as gentamicin. Many of these organisms are shown by Kirby-Bauer disk sensitivity testing to be resistant to tetracycline. One hundred seventy-one such tetracycline-resistant bacterial isolates were studied; 84% were found to be sensitive to achievable urinary concentrations of tetracycline. Two patients with long-standing chronic urinary tract infection with Pseudomonas were treated with tetracycline for a year and a half with excellent results. In a pilot clinical trial, eight of 12 hospitalized patients with urinary tract infection were treated successfully with tetracycline without regard to disk sensitivity data. Institution of tetracycline as soon as the microscopic diagnosis of urinary tract infection is made might be an acceptable empiric approach to the treatment of urinary infection in hospitalized patients who do not show evidence of sepsis.

Bacteriuria↗
PubMed2004

Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity.

Tetracyclines (TCN) were introduced in 1948 as broad-spectrum antibiotics that may be used in the treatment of many common infections in children and adults. One of the side-effects of tetracyclines is incorporation into tissues that are calcifying at the time of their administration. They have the ability to chelate calcium ions and to be incorporated into teeth, cartilage and bone, resulting in discoloration of both the primary and permanent dentitions. This permanent discoloration varies from yellow or gray to brown depending on the dose or the type of the drug received in relation to body weight. Minocycline hydrochloride, a semisynthetic derivative of tetracycline often used for the treatment of acne, has been shown to cause pigmentation of a variety of tissues including skin, thyroid, nails, sclera, teeth, conjunctiva and bone. Adult-onset tooth discoloration following long-term ingestion of tetracycline and minocycline has also been reported. The remarkable side-effect of minocycline on the oral cavity is the singular occurrence of "black bones", "black or green roots" and blue-gray to gray hue darkening of the crowns of permanent teeth. The prevalence of tetracycline and minocycline staining is 3-6%. The mechanism of minocycline staining is still unknown. Most of the reviewed literature consisted of case reports; longitudinal clinical trials are necessary to provide more information on the prevalence, severity, etiology and clinical presentation of tetracycline and TCN-derivative staining in the adult population.

Anti-Bacterial Agents↗
PubMed1996

Use of the polymeric matrix as internal standard for quantitation of in vivo delivery of tetracycline HCl from Actisite tetracycline fiber during periodontal treatment.

Actisite (tetracycline hydrochloride) periodontal fiber is a 23 cm monofilament containing 12.7 mg tetracycline HCl homogeneously dispersed in a polymer. This product is indicated as an adjunct to scaling and root planing to reduce pocket depth and bleeding on probing in patients with adult periodontitis. The sustained-release system, placed in the periodontal pocket for 10 d, releases the antibiotic through mechanisms of diffusion and osmosis. A study was conducted in 13 patients with moderate to severe adult periodontitis to evaluate the amount of tetracycline HCl released during therapy (based on residual drug content). Fibers placed in the pocket remained in place for an average of 9 d. Each patient had 1-4 teeth treated with fiber therapy. At the termination of therapy samples from 29 teeth were retrieved and analyzed. The amount of matrix polymer was used as an internal standard for the quantitation of tetracycline, eliminating any uncertainties with respect to recovery or contamination. An average of 31% (SD 9%) of the tetracycline HCl content was released from the fiber during the treatment period. No single fiber had less than 50% of the original drug remaining. The study demonstrated that a substantial amount of the tetracycline remains in the Actisite fiber at removal (about 70%), which indicates that substantial drug concentrations are maintained in the pocket for the duration of treatment.

Administration, Topical↗
PubMed1966

Tetracycline inhibition of cell-free protein synthesis. II. Effect of the binding of tetracycline to the components of the system.

Day, L. E. (Chas. Pfizer & Co., Inc., Groton, Conn.). Tetracycline inhibition of cell-free protein synthesis. II. Effect of the binding of tetracycline to the components of the system. J. Bacteriol. 92:197-203. 1966.-When tetracycline, an inhibitor of cell-free protein synthesis, was preincubated with each component of the Escherichia coli cell-free system, i.e., ribosomes, soluble ribonucleic acid (sRNA), polyuridylic acid (poly U), and S-100 (supernatant enzymes), only the ribosomal-bound antibiotic was inhibitory to the cell-free assay. Experiments designed to further localize the site of inhibition to either the 50S (Svedberg) or the 30S ribosomal subunit were not conclusive. Tritiated tetracycline (7-H(3)-tetracycline) was bound to isolated 50S ribosomes, and these were recombined with 30S subunits to form 70S ribosomes. When these ribosomes were dissociated and the subunits reisolated, the antibiotic was found with both the 50S and the 30S particles. The same results were observed when the tetracycline was initially bound to the 30S subunit.

Carbon Isotopes↗
PubMed1995

The tetracycline efflux protein encoded by the tet(K) gene from Staphylococcus aureus is a metal-tetracycline/H+ antiporter.

The tet(K) gene from Staphylococcus aureus was highly expressed in Escherichia coli by an alteration of its initiation codon from TTG to ATG and its ribosome-binding sequence from GAGG to GGAGG [Noguchi, N. et al. (1994) Biol. Pharm. Bull. 17, 352-355]. The inverted membrane vesicles prepared from the tet(K)-expressing cells showed respiration-dependent [3H]tetracycline transport comparable to the vesicles from the tet(B)-expressing cells. The affinity of Tet(K) vesicles to tetracycline was the same as that of Tet(B) vesicles, whereas the former Vmax value was about 60% of the latter one. Contrary to Tet(B) vesicles, Tet(K) vesicles showed no significant minocycline uptake, which was consistent with the low minocycline resistance of the Tet(K)-producing cells. The tetracycline transport mediated by Tet(K) vesicles was coupled with proton transport and the translocation of 60Co2+ ions as well as in Tet(B) vesicles. This observation indicates that the class K tetracycline resistance determinant from Gram-positive bacteria also encodes a metal-tetracycline/H+ antiporter that is functionally similar to that encoded by tet(B), although there is a considerable difference in the primary sequences and the putative topologies of these Tet proteins.

Antiporters↗
PubMed1983

Metal ion-tetracycline interactions in biological fluids. 2. Potentiometric study of magnesium complexes with tetracycline, oxytetracycline, doxycycline, and minocycline, and discussion of their possible influence on the bioavailability of these antibiotics in blood plasma.

The formation constants of the various complexes formed by magnesium with four tetracycline derivatives, namely, tetracycline itself, oxytetracycline, doxycycline, and minocycline, were determined by potentiometry over large pH ranges under experimental conditions pertaining to blood plasma (37 degrees C, NaCl 0.15 mol dm-3). The results were used, together with those previously obtained on the complexation of these tetracyclines with proton and calcium, to assess the influence of the two alkali earth metal ions on the bioavailability of these drugs in blood plasma. Accordingly, simulations of the distribution of the four tetracyclines into their different proton and metal complex species were calculated. The distributions confirm that, in combination with the protein-bound fraction of the tetracyclines, the metal-bound fraction represents more than 99% of these drugs in plasma, the extent of their free fraction commonly being less than 1%.

Biological Availability↗
PubMed1994

Inhibition of protein synthesis occurring on tetracycline-resistant, TetM-protected ribosomes by a novel class of tetracyclines, the glycylcyclines.

One of the two major mechanisms of tetracycline resistance is ribosomal protection. Of this resistance type, tet(M) is the best characterized. Although the mechanism of tet(M) resistance has not yet been fully elucidated, it has been demonstrated that ribosomes isolated from a tet(M) strain are resistant to inhibition of protein synthesis by tetracycline. A new generation of tetracycline compounds, the glycylcyclines, that are able to inhibit protein synthesis occurring on tetracycline-resistant, TetM-protected ribosomes, as well as wild-type, tetracycline-sensitive ribosomes, have been identified.

Anti-Bacterial Agents↗