Chest. 1995 Oct;108(4):1080-3.
Comparison of silver nitrate and tetracycline as pleural sclerosing agents in rabbits.

Vargas FS, Teixeira LR, Silva LM, Carmo AO, Light RW.

Instituto do Coracao, Faculty of Medicine, University of Sao Paulo, Brazil.

The ideal agent to produce pleurodesis has not been identified. Tetracycline, the drug used most commonly in the 1980s, is no longer available. Talc either aerosolized or in a slurry is the agent used just most commonly at the present time, but there are concerns about its safety. Another possibility is silver nitrate, which was widely used in the past, but was abandoned on account of side effects. We hypothesized that lower concentrations of silver nitrate than had been used in the past would be effective in creating a pleurodesis in rabbits. The following medications in a total volume of 2 mL were instilled intrapleurally in three groups of ten anesthetized rabbits: 0.25% or 0.50% silver nitrate and 35 mg/kg tetracycline. Twenty-eight days after the injection, the animals were sacrificed and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The intrapleural injection of 0.50% silver nitrate produced an effective pleurodesis. The mean degree of gross pleurodesis in the rabbits that received 0.50% silver nitrate (3.4 +/- 1.2) did not differ significantly from that of the rabbits that received tetracycline (3.5 +/- 0.7) (scale 0 to 4). The mean degree of microscopic pleural fibrosis in the rabbits that received 0.50% silver nitrate (3.4 +/- 0.7) did not differ significantly from that of the rabbits that received tetracycline (3.9 +/- 0.3). However, 0.25% silver nitrate was ineffective in creating pleural fibrosis, either grossly or microscopically. No rabbits died after the intrapleural injection of the drugs. There were no observed side effects after the injection of silver nitrate. The present study demonstrates that 0.50% silver nitrate instilled into the pleural space is an effective agent for producing pleurodesis in the rabbit; its effect is comparable to tetracycline 35 mg/kg. This agent should be compared with tetracycline derivatives and talc in studies in humans.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7555123&dopt=Abstract antibiotics, tetracycline

fougeres.afssa.fr

In order to evaluate an in vivo model system for assessing the effect of therapeutic and residue levels of tetracycline on human intestinal microflora, tetracycline was administered via drinking water (1, 10, and 100 mg/liter) to human-flora-associated (HFA) male and female mice. The effects of the antibiotic on fecal aerobic and anaerobic populations, selection of bacteria resistant to tetracycline, metabolic parameters of the microflora, and maintenance of the intestinal barrier against exogenous Salmonella (resistance to colonization) were recorded. In both sexes of mice, tetracycline exposure at 10 and 100 mg/liter induced the selection of several resistant bacterial species (Gram-positive anaerobes, Bacteroides fragilis, enterobacteria, and enterococci). This effect was also observed at the lowest dose (1 mg/liter) in female mice and indicates the potential sensitivity of this endpoint for evaluating the microbiological risk of tetracycline residues. The resistance to colonization was impaired at 100 mg/liter, a concentration corresponding to about half of the therapeutic doses in humans and animals. Metabolic parameters of the microflora were not affected by tetracycline at all levels. In this study, the no-observed-effect level (NOEL) of tetracycline on intestinal flora in this study was less than 1 mg of tetracycline per liter of drinking water. This concentration in the mouse corresponds to 0.125 mg of tetracycline per kilogram of body weight per day. Within the constraints of the experimental design employed here, the HFA mice model proved to be acceptable for studying dose-related effects of tetracycline on human intestinal microflora. Copyright 2001 Academic Press.

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J Bacteriol. 1987 Jun;169(6):2516-22.
Role of oxygen radicals in the phototoxicity of tetracyclines toward Escherichia coli B.

Martin JP Jr, Colina K, Logsdon N.

Photoillumination of tetracycline derivatives with low-intensity (320- to 400-nm) light and visible light generated superoxide, observed as the reduction of ferricytochrome c. The rate of reduction was dependent on the tetracycline concentration and on the derivative being examined, with doxycycline greater than or equal to demeclocycline greater than tetracycline greater than oxytetracycline. Tetracycline-mediated cytochrome c reduction was oxygen dependent and inhibited up to 70% by superoxide dismutase. Illuminated tetracyclines were lethal to Escherichia coli B incubated in a glucose minimal medium containing chloramphenicol. This lethality was light dependent, oxygen dependent, and dependent on the concentration of tetracycline. Kill rates also varied according to the derivative under study, with doxycycline greater than or equal to demeclocycline greater than tetracycline greater than oxytetracycline. The addition of superoxide dismutase and catalase to the incubation medium partially protected E. coli B against the light-dependent lethality. Preinduction of intracellular superoxide dismutase and catalase substantially protected E. coli B against the phototoxicity of tetracyclines. Iron EDTA augmented the phototoxicity of tetracyclines, while diethylenetriaminepentaacetic acid protected against their lethality. Hydroxyl radical scavengers also conferred protection against tetracycline phototoxicity. The extent of protection was in order of the in vitro reactivity of the scavengers with the hydroxyl radical. These results indicate that superoxide, hydrogen peroxide, and the hydroxyl radical are generated by illuminated tetracyclines and are molecular agents of tetracycline phototoxicity in E. coli B.

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Lab Invest. 1979 Jul;41(1):5-12.
The morphologic changes of the rat type II pneumocytes induced by oxytetracycline.

Gottschall JL, Walzer PD, Yoneda K.

Ultrastructural changes in pulmonary alveoli of adult Sprague-Dawley rats administered oxytetracycline (1 mg. per ml.) in their drinking water were compared with those of control rats whose drinking water contained no antibiotics. Groups of rats were sacrificed after 4 and 8 weeks of oxytetracycline treatment. Type II pneumocytes of oxytetracycline-treated rats showed an increase in size and number of lamellar bodies, as well as in their cell volume, when compared with controls. Electron microscopic morphometry confirmed these findings; the lamellar inclusion bodies increased 6 and 10 per cent and the cell volume increased 3 and 5 per cent at 4 and 8 weeks, respectively. The type I pneumocyte and alveolar macrophage showed engulfed myelin figures, and the Clara cells appeared quiescent. These findings suggest that the type II pneumocyte hypertrophy can be induced independently from the diffuse alveolar damage. The oxytetracycline treatment may provide a model system in which the pathologic morphology and function of the type II pneumocyte can be studied independently.

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Microbios. 1978;21(83):7-21.
Transport of tetracyclines through the bacterial cell membrane assayed by fluorescence: a study with susceptible and resistant strains of Staphylococcus aureus and Escherichia coli.

Samra Z, Krausz-Steinmetz J, Sompolinsky D.

The fluorescence of 12 tetracyclines in buffered solutions was measured by excitation at 400 nm and emission at 520 nm. The fluorescence varied markedly for different tetracyclines at equivalent concentrations. Demethylchlortetracycline exhibited more fluorescence than both chlortetracycline and demthyltetracycline; minocycline was virtually non-fluorescent at the conditions of the study. Fluorescence was highly dependent on the polarity of the solvent; when the buffer solution in water was replaced by a solvent containing 50% methanol, fluorescence increased significantly, but to various degrees for different tetracyclines. The most striking influence of the addition of methanol was observed for doxycycline (5-oxy 6-deoxy-tetracycline), whereas the influence on anhydrotetracycline was negligible. When suspensions of a susceptible strain of Staphylococcus aureus were added to solutions of tetracyclines, membrane permeation of the drugs could be monitored by an increase in fluorescence. This increase varied strikingly with the different drugs and could not be correlated with the concentrations for 50% growth inhibition (Ki). This might be due to the quantitative variations in the intracellular level corresponding to a certain external concentration of the respective drug. When tetracycline-resistant strains of S. aureus and Escherichia coli were exposed to tetracycline, the intensity of fluorescence observed was less than for the corresponding susceptible strains; in spite of this, the quantitative differences of fluorescence exhibited by the susceptible and resistant strains seemed slight in relation to the differences in susceptibility. It was demonstrated that minocycline inhibits the membrane transport of tetracycline in S. aureus and E. coli. This inhibition seems to be competitive for S. aureus, but not for E. coli.

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Biochem Pharmacol. 1985 Oct 15;34(20):3689-91.
Quantitative assessment of the polysome profile of the livers of mice treated with tetracycline or doxycycline.

Hopf G, Bocker R, Neumeier P, Guggenmoos-Holzmann I, Estler CJ.

The influence of tetracycline and doxycycline (10-100 micrograms/g i.v.) on the aggregational state of ribosomes from mouse liver was tested. Both drugs caused a disaggregation of the ribosomes as evidenced by a rise of the monosomes + disomes/polysomes ratio. Tetracycline was much more potent than doxycycline, the minimum effective doses for tetracycline being 10 micrograms/g i.v. as compared to 100 micrograms/g for doxycycline. The results show that tetracycline but not doxycycline at therapeutic dose range may interfere with the protein synthesis of the liver.

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Antimicrob Agents Chemother. 1980 Mar;17(3):372-8.
Effects of tetracycline on the streptococcal flora of periodontal pockets.

Hawley RJ, Lee LN, LeBlanc DJ.

The effects of tetracycline on the subgingival streptococcal flora of periodontal patients were examined. Before antibiotic treatment, tetracycline-resistant isolates were obtained from 24 to 25 patients. In most patients, the proportion of the subgingival flora resistant to tetracycline increased after 2 weeks of therapy (1,000 mg of tetracycline/day) and then decreased after the cessation of treatment. Cultural conditions used for primary isolation were designed to favor the growth of facultative streptococci. Consequently, the majority (99%) of resistant isolates were identified as streptococci. Among 407 tetracycline-resistant Streptococcus isolates chosen for further classification, 9 species were identified, with S. sanguis (63%) and S. mitis (19%) predominating. There were no significant differences in the distribution of species isolated before and after treatment and after the cessation of tetracycline treatment. Plasmids were isolated from only 23 of 121 resistant streptococcal strains examined, suggesting that tetracycline resistance is not plasmid mediated in the majority of these oral streptococci.

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J Periodontol. 1995 Feb;66(2):102-8.
Detection and incidence of the tetracycline resistance determinant tet(M) in the microflora associated with adult periodontitis.

Lacroix JM, Walker CB.

Subgingival plaque samples were collected from 68 patients with adult periodontitis, enumerated on Trypticase-soy blood agar plates, with and without tetracycline at 4 micrograms/ml, and incubated anaerobically for 5 days. Each different colony morphotype was enumerated, and a representative colony was subcultured for identification and examined for the tetracycline resistance gene tet(M). Both PCR amplification and DNA hybridization, using a fragment of tet(M) from Tn1545, were used to detect tet(M). The PCR primers (5'-GACACGCCAGGACATATGG-3' and 5'-TGCTTTCCTCTTGTTCGAG-3') were chosen to amplify a 397 bp region of tet(M). Tetracycline-resistant bacteria represented approximately 12% of the total viable count. The percentage of tet(M)-positive bacteria in the tetracycline resistant microflora varied from < or = 0.05 to 83% (mean of 10%). tet(M) was detected in 60% of 204 tetracycline-resistant strains subcultured and identified. The tet(M) containing strains consisted of streptococci (55%, mainly S. intermedius, S. oralis, S. sanguis, and Streptococcus SM4), Actinomyces D01 (14%), Bifidobacterium D05 (11%), and Veillonella spp. (10%). Tetracycline-resistant strains in which tet(M) was not detected included the Prevotella and Bacteroides species (41%, mainly Bacteroides D28, P. intermedia, P. nigrescens, and P. oris). These results suggest that tet(M) is widely spread in the adult periodontal microflora, but it appears, with the exception of S. intermedius, to be mainly associated with microorganisms not considered to be periodontopathogens. Assessment of other tetracycline-resistant genes in oral organisms is needed to fully evaluate the nature of resistance to this antibiotic in the oral flora.

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