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Journal of Antimicrobial Chemotherapy Advance Access published March 18, 2011
J Antimicrob Chemotherdoi:10.1093/jac/dkr108 In vitro synergistic effects of baicalin with oxytetracycline and tetracycline against Staphylococcus aureus Pavel Novy1, Jan Urban2, Olga Leuner1, Jaroslav Vadlejch3 and Ladislav Kokoska1,3* 1Department of Crop Sciences and Agroforestry, Institute of Tropics and Subtropics, Czech University of Life Sciences Prague, Kamycka 129, 165 21 Prague 6—Suchdol, Czech Republic; 2National Reference Laboratory for Disinfection and Sterilization, National Institute of Public Health, Srobarova 48, 100 42 Prague 10, Czech Republic; 3Department of Zoology and Fisheries, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague, Kamycka 129, 165 21 Prague 6—Suchdol, Czech Republic *Corresponding author. Tel: +420-224382180; Fax: +420-234381829; E-mail: kokoska@its.czu.cz.
Received 29 November 2010; returned 6 January 2011; revised 4 February 2011; accepted 18 February 2011 Objectives: In this study we examined the in vitro synergistic effect of baicalin, the flavone constituent ofScutellaria spp., in combinations with oxytetracycline and tetracycline on the growth of Staphylococcus aureus.
Methods: The MICs were determined by the broth microdilution method and the effect of combinations wasevaluated according to the sum of fractional inhibitory concentration indices (FICIs).
Results: Synergistic activity (FICI≤0.5) was observed for combinations of baicalin with oxytetracycline or tetra-cycline against 4 of 10 strains tested, whereas the baicalin/oxytetracycline combination possessed the stron-gest synergistic effect (FICI¼ 0.418).
Conclusions: Baicalin acts synergistically with oxytetracycline and tetracycline, enhancing its antimicrobialactivity against S. aureus, including methicillin- and tetracycline-resistant strains.
Keywords: antimicrobial agents, flavonoid, staphylococci, synergy with penicillin binding proteinsDespite the fact that the synergyof baicalin with b-lactams against S. aureus has already been Staphylococcus aureus has become one of the most serious human reported, its ability to potentiate antistaphylococcal activity in pathogens during recent decades owing to its acquisition of anti- other antibiotics has not previously been scrutinized. Therefore, biotic resistance, whereas methicillin-resistant S. aureus (MRSA) is we decided to perform a screening test focused on determining at the present time one of the most important causes of its combined effect with representatives of the main antibiotic antibiotic-resistant healthcare-associated infections worldwide, groups, namely b-lactams (ampicillin, cefamandole, oxacillin, peni- resulting in prolonged hospital stays and increased mortality.
cillin), tetracyclines (doxycycline, minocycline, oxytetracycline, Because of its exceptional ability to also acquire resistance to tetracycline), aminoglycosides (streptomycin), quinolones (cipro- other commonly used classes of antibiotics, such as aminoglyco- floxacin), macrolides (erythromycin), lincosamides (lincomycin), sides, fluoroquinolones, macrolides and tetracyclines, the contin- glycopeptides (vancomycin) and sulphonamides (sulfanilamide), ual development of new antibacterial compounds and, more against three standard strains of S. aureus. Together with importantly, new templates with novel modes of action, b-lactams, tetracyclines produced results worth further investi- represented for example by synergistically acting plant-derived gation (P. Novy and L. Kokoska, unpublished data). As a continuation compounds, is urgently needed to eradicate the resistance of of this work, the present study reports on a detailed examination of S. aureus and to slow down its spread and development.
the synergistic effect of oxytetracycline and tetracycline with baica- Among a number of potential candidates of this type of agent is lin against four standard strains and six clinical isolates of S. aureus.
baicalin (Figure ), a flavonoid present in Scutellaria baicalensisGeorgi. It exerts, along with other medicinal properties,remark- able synergistic antistaphylococcal activity with antibiotics. Ithas been reported to restore the effectiveness of b-lactam anti- biotics against MRSA and other strains of b-lactam-resistant Oxacillin, oxytetracycline and tetracycline were purchased from S. aureus, probably via its direct antibacterial action on cell Sigma-Aldrich (Prague, CZ). DMSO, ethanol (Lach-Ner, Neratovice, CZ) growth or due to the inhibition of b-lactamase, or by interactions and deionised water were used as solvents.
# The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com oxytetracycline and tetracycline. The combination of baicalinand oxytetracycline showed the strongest synergistic effect, whereas the addition of baicalin in concentrations of 75 and 50 mg/L resulted in an 8- and 4-fold reduction (FICI ¼0.418 and 0.445), respectively, in oxytetracycline MIC against S.
aureus ATCC 29213. The baicalin/oxytetracycline combination showed synergistic activity against 4 of 10 S. aureus strains tested, of which 1 was a MRSA strain and 1 was a TRSA strain.
The baicalin/tetracycline combination had a synergistic effectagainst one S. aureus strain, where the addition of 50 mg/L bai- Figure 1. Chemical structure of baicalin.
calin resulted in a 4-fold reduction in the MIC of tetracycline(FICI¼ 0.445). In contrast to a report by Fujita et al.,describing that baicalin at concentrations below its MIC does not signifi-cantly affect the growth-inhibitory activity of tetracycline The standard strains [ATCC 25923, ATCC 29213, ATCC 43300 (MRSA) and against MRSA, our results showed that 50, 75 and 100 mg/L bai- ATCC BAA-976] were purchased from Oxoid (Basingstoke, UK), whereas calin (,1/2 MIC) caused a 2- to 8-fold reduction in the MIC of clinical isolates (M02, M05), including MRSA (M238) and tetracycline- tetracycline against TRSA and MRSA strains (FICI¼ 0.516 – resistant S. aureus (TRSA) strains (M003, M079, M926), were obtained from the Motol University Hospital in Prague, Czech Republic. For antibac- 0.793). Despite the differences in results obtained from both terial assays, the strains were grown in cation-adjusted Mueller– Hinton studies, which may be influenced by variations in experimental broth (MHB; Oxoid, Basingstoke, UK), which was equilibrated with Tris- design (e.g. only two strains were tested in the above mentioned buffered saline (Sigma-Aldrich, Prague, CZ).
report), our findings suggest a certain degree of combined anti-staphylococcal effect of baicalin and tetracycline against resist-ant strains. Combinations of baicalin with doxycycline and minocycline exerted no interaction when tested against three A broth microdilution method was used to determine the MICs of test standard S. aureus ATCC strains (FICI¼ 0.73–1.5), while baicalin antimicrobial agents following the guidelines described by the CLSI at concentrations below its MIC caused a 2-fold reduction in using 96-well microtitre plates. Briefly, the samples were 2-fold diluted in MHB (100 mL), inoculated with bacterial suspension to obtain the Our positive results on the synergy of baicalin with oxytetracy- final concentration of 5×105 cfu/mL and then incubated at 378C for cline or tetracycline can also be supported by the fact that the 24 h. The bacterial growth was measured as turbidity by a Multiscan FICI of both combinations reached values of ,0.6 for 75% of Ascent Microplate Photometer (Thermo Fisher Scientific, Waltham, MA, S. aureus strains tested, which would be assessed as a strong USA) at 405 nm. The MIC was defined as the lowest concentration ofthe compound that inhibited the growth of the test bacteria by ≥80%.
additive effect if evaluated according to the European Commit- Oxacillin and tetracycline were used as markers of methicillin and tetra- tee for Antimicrobial Susceptibility Testingcriteria for synergy.
cycline resistance, respectively, and S. aureus ATCC 29213 was used as a Thus, although synergistic interactions of baicalin with oxytetra- reference strain for the standardization of antibiotic susceptibility testing.
cycline and baicalin with tetracycline were observed against 4 All tests were performed as three independent experiments, each carried and 1 of 10 strains, respectively, we can conclude that baicalin significantly potentiated the antimicrobial effect of oxytetracy-cline and tetracycline against S. aureus. These results suggest baicalin is a promising compound for the development of newsynergistically acting drugs with the potential to extend the Initially, 2-fold serial dilutions of an antibiotic were tested in combination pharmacological action of tetracyclines, which, as antistaphylo- with 2-fold serial dilutions of baicalin, where individual MICs of each com- coccal agents, are clinically applied in limited cases only (e.g. in pound were used as starting concentrations. The most promising combi- the treatment of skin or skin structure infections due to nations were then selected for detailed testing, where 2-fold serial S. aureus susceptible strIn addition, since the effectiveness dilutions of antibiotics starting at quadruple concentration of their par- of oxytetracycline and tetracycline (FICI ¼0.42 –0.7) was signifi- ticular MICs were combined with constant concentrations of baicalin cantly more improved than the action of doxycycline and mino- (100, 75 and 50 mg/L). The fractional inhibitory concentration (FIC) wascalculated as the ratio of the MIC of agents A and B in combination cycline (FICI ¼0.75 –1.25) when tested against S. aureus ATCC with the MIC of agent A (or B) alone. The FIC index (FICI) was then calcu- 29213, 25923 and 43300 (P. Novy and L. Kokoska, unpublished lated using the combined FICs of agents A and The obtained results data), we estimate that baicalin has the ability to augment the were interpreted in accordance with the BSAC recommendation as antistaphylococcal effect of the short-acting tetracyclines to a follows: synergy (FICI≤0.5); no interaction (FICI.0.5–4); antagonism much greater extent than the representatives of the long-acting Previously it has been suggested that baicalein, the aglycone of baicalin, may produce a similar effect on the cell wall as epi-gallocatechin which interferes with cell wall integrity The susceptibilities of S. aureus strains to the antibiotics tested, through direct binding to peptidoglycanand exhibits the charac- either alone or in the presence of baicalin, are summarized in teristics of a cell wall active agent against enterococci.Since Table . The results show that baicalin possesses only a weak both baicalin and baicalein possess a flavone structure and antistaphylococcal effect (MICs ranging from 128 –512 mg/L), similar pharmacological activity, both have a weak antimicrobial but its addition resulted in significant MIC reduction in effect against S. aureus and both exert synergistic antimicrobial Antistaphylococcal synergistic effect of baicalin with tetracyclines Table 1. In vitro inhibitory activity of baicalin in combination with oxytetracycline and tetracycline against S. aureus OXY with B at following concentrations (mg/L): TET with B at following concentrations (mg/L): B, baicalin; OXA, oxacillin; OXY, oxytetracycline; TET, tetracycline.
FICI: ≤0.5, synergy (bold font indicates synergistically acting combinations); .0.5–4, no interaction; .4, antagonism.
can surmise that their modes of action could possibly be similar. In addition, since baicalein has previously been reported to restore the effectiveness of tetracycline against MRSA due tothe inhibition of TetK-mediated tetracycline efflux and possiblyinhibits TetM or some other we can presume that also baicalin may act as an efflux pump inhibitor. Moreover, the 1 Ruhe JJ, Monson T, Bradsher RW et al. Use of long-acting tetracyclines synergistic effect of the baicalin/tetracycline combination for methicillin-resistant Staphylococcus aureus infections: case series and against one TRSA strain tested in this study may indicate its review of the literature. Clin Infect Dis 2005; 40: 1429–34.
selectivity for particular tetracycline resistances mechanisms, for instance, against a specific efflux pump. On the other hand, weaknesses and opportunities. Planta Med 2008; 74: 594– 602.
the fact that we did not observe any significant difference 3 Li-Weber M. New therapeutic aspects of flavones: the anticancer between the FICIs of effective combinations obtained against properties of Scutellaria and its main active constituents wogonin, resistant and susceptible S. aureus strains indicates that baicalin baicalein and baicalin. Cancer Treat Rev 2009; 35: 57– 68.
does not affect resistance mechanisms of resistant strains but 4 Liu IX, Durham DG, Richards RME. Baicalin synergy with b-lactam affects some other processes common to both susceptible and antibiotics against methicillin-resistant Staphylococcus aureus and resistant S. aureus strains. In view of this, we suggest that baica- other b-lactam-resistant strains of S. aureus. J Pharm Pharmacol 2000; lin may have a direct antimicrobial effect on cell growth and the synergistic activity of baicalin with tetracyclines is probably pro- 5 Clinical and Laboratory Standards Institute. Methods for Dilution duced by a multitarget effect of combined compounds.
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically— In conclusion, this is the first report on the synergistic effect of Eighth Edition: Approved Standard M07-A8. CLSI, Wayne, PA, USA, 2009.
oxytetracycline and tetracycline with baicalin against S. aureus, including its MRSA and TRSA strains. Regarding the synergy Terminology relating to methods for determination of susceptibility mechanism of its antistaphylococcal effect, direct enhancement bacteria to antimicrobial agents. Clin Microbiol Infect 2000; 6: 503– 8.
of antibiotic activity rather than a resistance reversal effect is 7 Odds FC. Synergy, antagonism, and what the chequerboard puts probably responsible for the inhibition of resistant strains. In between them. J Antimicrob Chemother 2003; 52: 1.
addition, because of its ability to potentiate the effect of tetra- 8 Fujita M, Shiota S, Kuroda T et al. Remarkable synergies between cyclines against S. aureus and its low toxicity,baicalin seems baicalein and tetracycline, and baicalein and b-lactams against to be an attractive candidate for the development of new syner- methicillin-resistant Staphylococcus aureus. Microbiol Immunol 2005; gistically acting antistaphylococcal drugs.
9 Zhao WH, Hu ZQ, Okubo S et al. Mechanism of synergy betweenepigallocatechin-gallate and b-lactams against methicillin-resistantStaphylococcus aureus. Antimicrob Agents Chemother 2001; 45:1737– 42.
10 Chang P-C, Li H-Y, Tang H-J et al. In vitro synergy of baicalein and This research was supported by projects CSF 525/08/H060 and gentamycin against vancomycin-resistant Enterococcus. J Microbiol

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