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. 1991 Dec;35(12):2625–2629. doi: 10.1128/aac.35.12.2625

Stimulation with cytokines enhances penetration of azithromycin into human macrophages.

L E Bermudez 1, C Inderlied 1, L S Young 1
PMCID: PMC245442  PMID: 1667256

Abstract

An effective intracellular concentration of an antimicrobial agent is essential for therapy of infections caused by organisms of the Mycobacterium avium complex. We previously reported on the effect of the combination of azithromycin and tumor necrosis factor (TNF) against M. avium infection in macrophages. We now report that stimulation of macrophages either with recombinant human gamma interferon (IFN-gamma, 10(2) U/ml) or with recombinant human TNF-alpha (10(2) U/ml) resulted in an increase in the intracellular concentration of azithromycin by approximately 200% within 3 h, compared with the concentration in unstimulated macrophages. Infection of macrophages with M. avium complex led to a decrease in the uptake of [14C]azithromycin by infected cells, compared with that by uninfected controls. Stimulation of infected macrophages with recombinant IFN-gamma or TNF-alpha overcame the inhibitory effect associated with infection. These results suggest that the increased bactericidal activity of the TNF-alpha-azithromycin or IFN-gamma-azithromycin combination against M. avium is related to enhanced uptake of the antibiotic by the stimulated phagocyte.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bermudez L. E., Young L. S. Activities of amikacin, roxithromycin, and azithromycin alone or in combination with tumor necrosis factor against Mycobacterium avium complex. Antimicrob Agents Chemother. 1988 Aug;32(8):1149–1153. doi: 10.1128/aac.32.8.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bermudez L. E., Young L. S. Phagocytosis and intracellular killing of Mycobacterium avium complex by human and murine macrophages. Braz J Med Biol Res. 1987;20(2):191–201. [PubMed] [Google Scholar]
  3. Bermudez L. E., Young L. S. Tumor necrosis factor, alone or in combination with IL-2, but not IFN-gamma, is associated with macrophage killing of Mycobacterium avium complex. J Immunol. 1988 May 1;140(9):3006–3013. [PubMed] [Google Scholar]
  4. Black C. M., Bermudez L. E., Young L. S., Remington J. S. Co-infection of macrophages modulates interferon gamma and tumor necrosis factor-induced activation against intracellular pathogens. J Exp Med. 1990 Sep 1;172(3):977–980. doi: 10.1084/jem.172.3.977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davidson P. T., Khanijo V., Goble M., Moulding T. S. Treatment of disease due to Mycobacterium intracellulare. Rev Infect Dis. 1981 Sep-Oct;3(5):1052–1059. doi: 10.1093/clinids/3.5.1052. [DOI] [PubMed] [Google Scholar]
  6. Foulds G., Shepard R. M., Johnson R. B. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother. 1990 Jan;25 (Suppl A):73–82. doi: 10.1093/jac/25.suppl_a.73. [DOI] [PubMed] [Google Scholar]
  7. Gladue R. P., Bright G. M., Isaacson R. E., Newborg M. F. In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrob Agents Chemother. 1989 Mar;33(3):277–282. doi: 10.1128/aac.33.3.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gladue R. P., Snider M. E. Intracellular accumulation of azithromycin by cultured human fibroblasts. Antimicrob Agents Chemother. 1990 Jun;34(6):1056–1060. doi: 10.1128/aac.34.6.1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hawkins C. C., Gold J. W., Whimbey E., Kiehn T. E., Brannon P., Cammarata R., Brown A. E., Armstrong D. Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1986 Aug;105(2):184–188. doi: 10.7326/0003-4819-105-2-184. [DOI] [PubMed] [Google Scholar]
  10. Heifets L. B., Iseman M. D., Crowle A. J., Lindholm-Levy P. J. Pyrazinamide is not active in vitro against Mycobacterium avium complex. Am Rev Respir Dis. 1986 Dec;134(6):1287–1288. doi: 10.1164/arrd.1986.134.6.1287. [DOI] [PubMed] [Google Scholar]
  11. Inderlied C. B., Kolonoski P. T., Wu M., Young L. S. In vitro and in vivo activity of azithromycin (CP 62,993) against the Mycobacterium avium complex. J Infect Dis. 1989 May;159(5):994–997. doi: 10.1093/infdis/159.5.994. [DOI] [PubMed] [Google Scholar]
  12. Inderlied C. B., Young L. S., Yamada J. K. Determination of in vitro susceptibility of Mycobacterium avium complex isolates to antimycobacterial agents by various methods. Antimicrob Agents Chemother. 1987 Nov;31(11):1697–1702. doi: 10.1128/aac.31.11.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Johnson J. D., Hand W. L., Francis J. B., King-Thompson N., Corwin R. W. Antibiotic uptake by alveolar macrophages. J Lab Clin Med. 1980 Mar;95(3):429–439. [PubMed] [Google Scholar]
  14. Klatt E. C., Jensen D. F., Meyer P. R. Pathology of Mycobacterium avium-intracellulare infection in acquired immunodeficiency syndrome. Hum Pathol. 1987 Jul;18(7):709–714. doi: 10.1016/s0046-8177(87)80242-3. [DOI] [PubMed] [Google Scholar]
  15. Retsema J., Girard A., Schelkly W., Manousos M., Anderson M., Bright G., Borovoy R., Brennan L., Mason R. Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother. 1987 Dec;31(12):1939–1947. doi: 10.1128/aac.31.12.1939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Shepard R. M., Falkner F. C. Pharmacokinetics of azithromycin in rats and dogs. J Antimicrob Chemother. 1990 Jan;25 (Suppl A):49–60. doi: 10.1093/jac/25.suppl_a.49. [DOI] [PubMed] [Google Scholar]
  17. Wallace J. M., Hannah J. B. Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome. A clinicopathologic study. Chest. 1988 May;93(5):926–932. doi: 10.1378/chest.93.5.926. [DOI] [PubMed] [Google Scholar]
  18. Yeager H., Jr, Raleigh J. W. Pulmonary disease due to Mycobacterium intracellulare. Am Rev Respir Dis. 1973 Sep;108(3):547–552. doi: 10.1164/arrd.1973.108.3.547. [DOI] [PubMed] [Google Scholar]
  19. Young L. S., Inderlied C. B., Berlin O. G., Gottlieb M. S. Mycobacterial infections in AIDS patients, with an emphasis on the Mycobacterium avium complex. Rev Infect Dis. 1986 Nov-Dec;8(6):1024–1033. doi: 10.1093/clinids/8.6.1024. [DOI] [PubMed] [Google Scholar]

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