Skip to main content
Top
Published in: Inflammation Research 3/2013

01-03-2013 | Original Research Paper

Azithromycin in combination with riboflavin decreases the severity of Staphylococcus aureus infection induced septic arthritis by modulating the production of free radicals and endogenous cytokines

Authors: Pinky Mal, Kallol Dutta, Debasish Bandyopadhyay, Anirban Basu, Rajni Khan, Biswadev Bishayi

Published in: Inflammation Research | Issue 3/2013

Login to get access

Abstract

Objective and design

To determine alternate therapeutic measures to combat Staphylococcus aureus induced arthritis. Thus, azithromycin was combined with riboflavin, which may combat the ROS production and inflammation.

Methods

An in vivo model of S. aureus infection-induced arthritis was set up by infecting mice with 5 × 106 bacterial cell/mouse. S. aureus was administered intravenously. Azithromycin and riboflavin was injected intraperitoneally at a single dose of 100 and 20 mg/kg body, respectively. The mice were sacrificed at 3, 9, 15 days post infection (dpi). TNF-α, IFN-γ, IL-6 and IL-10 from serum and SOD, catalase and reduced glutathione concentration were observed in hepatic, cardiac, renal and splenic tissue.

Results

CFU was found very prominent in spleen and joints and reduced in blood at 3 and 9 dpi. However, treatment with azithromycin and riboflavin completely eradicated the bacteria from blood and spleen. TNF-α, IFN-γ, IL-6, and MCP-1 were induced due to infection which were downregulated by treatment with azithromycin and riboflavin. Infected mice were also found to have altered antioxidant status, measured in terms of reduced glutathione and anti-oxidant enzymes such as SOD and catalase.

Conclusion

These changes were found to be ameliorated when the animals were co-treated with azithromycin and riboflavin.
Literature
1.
go back to reference Anwar S, Prince LR, Foster SJ, Whyte MK, Sabroe I. The rise and rise of Staphylococcus aureus: laughing in the face of granulocytes. Clin Exp Immunol. 2009;157:216–24.PubMedCrossRef Anwar S, Prince LR, Foster SJ, Whyte MK, Sabroe I. The rise and rise of Staphylococcus aureus: laughing in the face of granulocytes. Clin Exp Immunol. 2009;157:216–24.PubMedCrossRef
2.
go back to reference Canvin JM, Goutcher SC, Hagig M, Gemmell CG, Sturrock RD. Persistence of Staphylococcus aureus as detected by polymerase chain reaction in the synovial fluid of a patient with septic arthritis. Br J Rheumatol. 1997;36:203–6.PubMedCrossRef Canvin JM, Goutcher SC, Hagig M, Gemmell CG, Sturrock RD. Persistence of Staphylococcus aureus as detected by polymerase chain reaction in the synovial fluid of a patient with septic arthritis. Br J Rheumatol. 1997;36:203–6.PubMedCrossRef
3.
go back to reference Mathews CJ, Weston VC, Jones A, Field M, Coakley G. Bacterial septic arthritis in adults. Lancet. 2010;375:846–55.PubMedCrossRef Mathews CJ, Weston VC, Jones A, Field M, Coakley G. Bacterial septic arthritis in adults. Lancet. 2010;375:846–55.PubMedCrossRef
4.
go back to reference Abdelnour A, Bremell T, Holmdahl R, Tarkowski A. Role of T lymphocytes in experimental Staphylococcus aureus arthritis. Scand J Immunol. 1994;39:403–8.PubMedCrossRef Abdelnour A, Bremell T, Holmdahl R, Tarkowski A. Role of T lymphocytes in experimental Staphylococcus aureus arthritis. Scand J Immunol. 1994;39:403–8.PubMedCrossRef
6.
go back to reference Darley ES, MacGowan AP. Antibiotic treatment of gram-positive bone and joint infections. J Antimicrob Chemother. 2004;53:928–35.PubMedCrossRef Darley ES, MacGowan AP. Antibiotic treatment of gram-positive bone and joint infections. J Antimicrob Chemother. 2004;53:928–35.PubMedCrossRef
7.
go back to reference Nair SP, Williams RJ, Henderson B. Advances in our understanding of the bone and joint pathology caused by Staphylococcus aureus infection. Rheumatology (Oxford). 2000;39:821–34.CrossRef Nair SP, Williams RJ, Henderson B. Advances in our understanding of the bone and joint pathology caused by Staphylococcus aureus infection. Rheumatology (Oxford). 2000;39:821–34.CrossRef
8.
9.
go back to reference Sakiniene E, Bremell T, Tarkowski A. Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis. Arthritis Rheum. 1996;39:1596–605.PubMedCrossRef Sakiniene E, Bremell T, Tarkowski A. Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis. Arthritis Rheum. 1996;39:1596–605.PubMedCrossRef
10.
go back to reference Nizet V. Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J Allergy Clin Immunol. 2007;120:13–22.PubMedCrossRef Nizet V. Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J Allergy Clin Immunol. 2007;120:13–22.PubMedCrossRef
11.
go back to reference Dormandy TL. Free-radical pathology and medicine. A review. J R Coll Physicians Lond. 1989;23:221–7.PubMed Dormandy TL. Free-radical pathology and medicine. A review. J R Coll Physicians Lond. 1989;23:221–7.PubMed
12.
go back to reference Mirshafiey A, Mohsenzadegan M. The role of reactive oxygen species in immunopathogenesis of rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2008;7:195–202.PubMed Mirshafiey A, Mohsenzadegan M. The role of reactive oxygen species in immunopathogenesis of rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2008;7:195–202.PubMed
13.
go back to reference Bodamyali T, Stevens CR, Billingham ME, Ohta S, Blake DR. Influence of hypoxia in inflammatory synovitis. Ann Rheum Dis. 1998;57:703–10.PubMedCrossRef Bodamyali T, Stevens CR, Billingham ME, Ohta S, Blake DR. Influence of hypoxia in inflammatory synovitis. Ann Rheum Dis. 1998;57:703–10.PubMedCrossRef
14.
go back to reference Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother. 1987;31:1948–54.PubMedCrossRef Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother. 1987;31:1948–54.PubMedCrossRef
15.
go back to reference Girard AE, Girard D, Retsema JA. Correlation of the extravascular pharmacokioetics of azithromycin with in vivo efficacy in models of localized infection. J Antimicrob Chemother. 1990;25:61–71.PubMedCrossRef Girard AE, Girard D, Retsema JA. Correlation of the extravascular pharmacokioetics of azithromycin with in vivo efficacy in models of localized infection. J Antimicrob Chemother. 1990;25:61–71.PubMedCrossRef
16.
go back to reference Meyer AP, Bril-Bazuin C, Matfie H, Van Den Broek PJ. Uptake of azithromycin by human monocytes and enhanced intracellular antibacterial activity against Staphylococcus aureus. Antimicrob Agents Chemother. 1993;37:2318–22.PubMedCrossRef Meyer AP, Bril-Bazuin C, Matfie H, Van Den Broek PJ. Uptake of azithromycin by human monocytes and enhanced intracellular antibacterial activity against Staphylococcus aureus. Antimicrob Agents Chemother. 1993;37:2318–22.PubMedCrossRef
17.
go back to reference Cheung AL, Bayer AS, Zhang G, Gresham H, Xiong YQ. Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus. FEMS Immunol Med Microbiol. 2004;40:1–9.PubMedCrossRef Cheung AL, Bayer AS, Zhang G, Gresham H, Xiong YQ. Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus. FEMS Immunol Med Microbiol. 2004;40:1–9.PubMedCrossRef
18.
go back to reference Mazur-Bialy AI, Majka A, Wojtas L, Kolaczkowska E, Plytycz B. Strain-specific effects of riboflavin supplementation on zymosan-induced peritonitis in C57BL/6 J, BALB/c and CBA mice. Life Sci. 2011;88:265–71.PubMedCrossRef Mazur-Bialy AI, Majka A, Wojtas L, Kolaczkowska E, Plytycz B. Strain-specific effects of riboflavin supplementation on zymosan-induced peritonitis in C57BL/6 J, BALB/c and CBA mice. Life Sci. 2011;88:265–71.PubMedCrossRef
19.
go back to reference Martins SA, Combs JC, Noguera G, Camacho W, Wittmann P, Walther R, et al. Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci. 2008;49:3402–8.PubMedCrossRef Martins SA, Combs JC, Noguera G, Camacho W, Wittmann P, Walther R, et al. Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci. 2008;49:3402–8.PubMedCrossRef
20.
go back to reference Mal P, Ghosh D, Bandyopadhyay D, Bishayi B. Ampicillin alone and in combination with riboflavin modulates Staphylococcus aureus infection induced septic arthritis in mice. Indian J Exp Biol. 2012. In press. Mal P, Ghosh D, Bandyopadhyay D, Bishayi B. Ampicillin alone and in combination with riboflavin modulates Staphylococcus aureus infection induced septic arthritis in mice. Indian J Exp Biol. 2012. In press.
21.
go back to reference Majumdar S, Dutta K, Manna SK, Basu A, Bishayi B. Possible protective role of chloramphenicol in TSST-1 and coagulase-positive Staphylococcus aureus-induced septic arthritis with altered levels of inflammatory mediators. Inflammation. 2011;34:269–82.PubMedCrossRef Majumdar S, Dutta K, Manna SK, Basu A, Bishayi B. Possible protective role of chloramphenicol in TSST-1 and coagulase-positive Staphylococcus aureus-induced septic arthritis with altered levels of inflammatory mediators. Inflammation. 2011;34:269–82.PubMedCrossRef
22.
go back to reference Sen R, Das D, Bishayi B. Staphylococcal catalase regulates its virulence and induces arthritis in catalase deficient mice. Indian J Physiol Pharmacol. 2009;53:307–17.PubMed Sen R, Das D, Bishayi B. Staphylococcal catalase regulates its virulence and induces arthritis in catalase deficient mice. Indian J Physiol Pharmacol. 2009;53:307–17.PubMed
23.
go back to reference Yao L, Berman JW, Factor SM, Lowy FD. Correlation of histopathologic and bacteriologic changes with cytokine expression in an experimental murine model of bacteremic Staphylococcus aureus infection. Infect Immun. 1997;65:3889–95.PubMed Yao L, Berman JW, Factor SM, Lowy FD. Correlation of histopathologic and bacteriologic changes with cytokine expression in an experimental murine model of bacteremic Staphylococcus aureus infection. Infect Immun. 1997;65:3889–95.PubMed
24.
go back to reference Tissi L, von Hunolstein C, Mosci P, Campanelli C, Bistoni F, Orefici G. In vivo efficacy of azithromycin in treatment of systemic infection and septic arthritis induced by type IV group B Streptococcus strains in mice: comparative study with erythromycin and penicillin G. Antimicrob Agents Chemother. 1995;39:1938–47.PubMedCrossRef Tissi L, von Hunolstein C, Mosci P, Campanelli C, Bistoni F, Orefici G. In vivo efficacy of azithromycin in treatment of systemic infection and septic arthritis induced by type IV group B Streptococcus strains in mice: comparative study with erythromycin and penicillin G. Antimicrob Agents Chemother. 1995;39:1938–47.PubMedCrossRef
25.
go back to reference Verdrengh M, Tarkowski A. Riboflavin in innate and acquired immune responses. Inflamm Res. 2005;54:390–3.PubMedCrossRef Verdrengh M, Tarkowski A. Riboflavin in innate and acquired immune responses. Inflamm Res. 2005;54:390–3.PubMedCrossRef
26.
go back to reference Burchill MA, Nardelli DT, England DM, DeCoster DJ, Christopherson JA, Callister SM, et al. Inhibition of interleukin-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi. Infect Immun. 2003;71:3437–42.PubMedCrossRef Burchill MA, Nardelli DT, England DM, DeCoster DJ, Christopherson JA, Callister SM, et al. Inhibition of interleukin-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi. Infect Immun. 2003;71:3437–42.PubMedCrossRef
27.
go back to reference Dixon RA. Curative effects of tobramycin or gentamicin therapy on mouse arthritis caused by Mycoplasma pulmonis. Antimicrob Agents Chemother. 1981;20:321–6.PubMedCrossRef Dixon RA. Curative effects of tobramycin or gentamicin therapy on mouse arthritis caused by Mycoplasma pulmonis. Antimicrob Agents Chemother. 1981;20:321–6.PubMedCrossRef
28.
go back to reference Chattopadhyay A, Biswas S, Bandyopadhyay D, Sarkar C, Datta AG. Effect of isoproterenol on lipid peroxidation and antioxidant enzymes of myocardial tissue of mice and protection by quinidine. Mol Cell Biochem. 2003;245:43–9.PubMedCrossRef Chattopadhyay A, Biswas S, Bandyopadhyay D, Sarkar C, Datta AG. Effect of isoproterenol on lipid peroxidation and antioxidant enzymes of myocardial tissue of mice and protection by quinidine. Mol Cell Biochem. 2003;245:43–9.PubMedCrossRef
29.
go back to reference Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellmanʼs reagent. Anal Biochem. 1968;25:192–205.PubMedCrossRef Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellmanʼs reagent. Anal Biochem. 1968;25:192–205.PubMedCrossRef
30.
go back to reference Martin JP, Dailey M, Sugarman E. Negative and positive assays of superoxide dismutase based on hematoxylin autoxidation. Arch Biochem Biophys. 1987;255:329–36.PubMedCrossRef Martin JP, Dailey M, Sugarman E. Negative and positive assays of superoxide dismutase based on hematoxylin autoxidation. Arch Biochem Biophys. 1987;255:329–36.PubMedCrossRef
31.
go back to reference Beers RF Jr, Sizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 1952;195:133–40.PubMed Beers RF Jr, Sizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 1952;195:133–40.PubMed
32.
go back to reference Dutta K, Mishra MK, Nazmi A, Kumawat KL, Basu A. Minocycline differentially modulates macrophage mediated peripheral immune response following Japanese encephalitis virus infection. Immunobiology. 2010;215:884–93.PubMedCrossRef Dutta K, Mishra MK, Nazmi A, Kumawat KL, Basu A. Minocycline differentially modulates macrophage mediated peripheral immune response following Japanese encephalitis virus infection. Immunobiology. 2010;215:884–93.PubMedCrossRef
33.
go back to reference Johnson WM, Tyler SD, Ewan EP, Ashton FE, Pollard DR, Rozee KR. Detection of genes for enterotoxins, exfoliative toxins, and toxic shock syndrome toxin 1 in Staphylococcus aureus by the polymerase chain reaction. J Clin Microbiol. 1991;29:426–30.PubMed Johnson WM, Tyler SD, Ewan EP, Ashton FE, Pollard DR, Rozee KR. Detection of genes for enterotoxins, exfoliative toxins, and toxic shock syndrome toxin 1 in Staphylococcus aureus by the polymerase chain reaction. J Clin Microbiol. 1991;29:426–30.PubMed
34.
go back to reference Becker K, Roth R, Peters G. Rapid and specific detection of toxigenic Staphylococcus aureus: use of two multiplex PCR enzyme immunoassays for amplification and hybridization of staphylococcal enterotoxin genes, exfoliative toxin genes, and toxic shock syndrome toxin 1 gene. J Clin Microbiol. 1998;36:2548–53.PubMed Becker K, Roth R, Peters G. Rapid and specific detection of toxigenic Staphylococcus aureus: use of two multiplex PCR enzyme immunoassays for amplification and hybridization of staphylococcal enterotoxin genes, exfoliative toxin genes, and toxic shock syndrome toxin 1 gene. J Clin Microbiol. 1998;36:2548–53.PubMed
35.
go back to reference Das D, Das A. Analysis of variance. In: Das D, editor. Statistics in biology and psychology. Calcutta: Academic; 2005. pp. 280–93. Das D, Das A. Analysis of variance. In: Das D, editor. Statistics in biology and psychology. Calcutta: Academic; 2005. pp. 280–93.
36.
go back to reference Bremell T, Lange S, Yacoub A, Ryden C, Tarkowski A. Experimental Staphylococcus aureus arthritis in mice. Infect Immun. 1991;59:2615–23.PubMed Bremell T, Lange S, Yacoub A, Ryden C, Tarkowski A. Experimental Staphylococcus aureus arthritis in mice. Infect Immun. 1991;59:2615–23.PubMed
37.
go back to reference Sasaki H, Hou L, Belani A, Wang CY, Uchiyama T, Muller R, et al. IL-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol. 2000;165:3626–30.PubMed Sasaki H, Hou L, Belani A, Wang CY, Uchiyama T, Muller R, et al. IL-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol. 2000;165:3626–30.PubMed
38.
go back to reference Yoshii T, Magara S, Miyai D, Nishimura H, Kuroki E, Furudoi S, et al. Local levels of interleukin-1beta, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to staphylococcus aureus. Cytokine. 2002;19:59–65. Yoshii T, Magara S, Miyai D, Nishimura H, Kuroki E, Furudoi S, et al. Local levels of interleukin-1beta, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to staphylococcus aureus. Cytokine. 2002;19:59–65.
39.
go back to reference Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165–90. Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165–90.
40.
go back to reference Hultgren OH, Stenson M, Tarkowski A. Role of IL-12 in Staphylococcus aureus-triggered arthritis and sepsis. Arthritis Res. 2001;3:41–7.PubMedCrossRef Hultgren OH, Stenson M, Tarkowski A. Role of IL-12 in Staphylococcus aureus-triggered arthritis and sepsis. Arthritis Res. 2001;3:41–7.PubMedCrossRef
41.
go back to reference Mal P, Dutta S, Bandyopadhyay D, Dutta K, Basu A, Bishayi B. Gentamicin in combination with ascorbic acid regulates the severity of Staphylococcus aureus infection induced septic arthritis in mice. Scand J Immunol. 2012. In press. Mal P, Dutta S, Bandyopadhyay D, Dutta K, Basu A, Bishayi B. Gentamicin in combination with ascorbic acid regulates the severity of Staphylococcus aureus infection induced septic arthritis in mice. Scand J Immunol. 2012. In press.
Metadata
Title
Azithromycin in combination with riboflavin decreases the severity of Staphylococcus aureus infection induced septic arthritis by modulating the production of free radicals and endogenous cytokines
Authors
Pinky Mal
Kallol Dutta
Debasish Bandyopadhyay
Anirban Basu
Rajni Khan
Biswadev Bishayi
Publication date
01-03-2013
Publisher
SP Birkhäuser Verlag Basel
Published in
Inflammation Research / Issue 3/2013
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-012-0574-z

Other articles of this Issue 3/2013

Inflammation Research 3/2013 Go to the issue