Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Mar;39(3):680–685. doi: 10.1128/AAC.39.3.680

In vitro and ex vivo activities of antimicrobial agents used in combination with clarithromycin, with or without amikacin, against Mycobacterium avium.

L Fattorini 1, B Li 1, C Piersimoni 1, E Tortoli 1, Y Xiao 1, C Santoro 1, M L Ricci 1, G Orefici 1
PMCID: PMC162605  PMID: 7793873

Abstract

MICs of clarithromycin, amikacin, isoniazid, rifabutin, ciprofloxacin, sparfloxacin, ethambutol, and clofazimine were determined for six isolates of Mycobacterium avium complex (MAC) from AIDS patients both by the radiometric method and by an ex vivo model of infection in human macrophages. The median MICs in macrophages were similar or slightly lower than values found in broth, except for amikacin, which had slightly higher MICs inside the cells. Combinations of clarithromycin with other antimicrobial agents showed that clarithromycin-clofazimine and clarithromycin-rifabutin were synergistic on five of six strains while clarithromycin-amikacin and clarithromycin-isoniazid were antagonistic on one and two strains, respectively. The addition of amikacin made the combinations of clarithromycin-clofazimine and clarithromycin-ethambutol synergistic against all the MAC strains. In the macrophage model, the combination of clarithromycin-clofazimine (mean survival, 21%) and clarithromycin-rifabutin (mean survival, 29%) showed a strong reduction in viable counts compared with single drugs, while clarithromycin-amikacin was less active than single drugs alone. In general, the addition of amikacin did not improve the activity of the combinations, except for clarithromycin-isoniazid-amikacin (mean survival, 19%), which was significantly more active than either clarithromycin-isoniazid or clarithromycin-amikacin. The use of the macrophage model can suggest new combinations of antimicrobial agents with anti-MAC activity which, on the basis of their in vitro effectiveness, would probably be disregarded for assay in animal models.

Full Text

The Full Text of this article is available as a PDF (286.5 KB).

Selected References

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

  1. Banerjee A., Dubnau E., Quemard A., Balasubramanian V., Um K. S., Wilson T., Collins D., de Lisle G., Jacobs W. R., Jr inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994 Jan 14;263(5144):227–230. doi: 10.1126/science.8284673. [DOI] [PubMed] [Google Scholar]
  2. Barradell L. B., Plosker G. L., McTavish D. Clarithromycin. A review of its pharmacological properties and therapeutic use in Mycobacterium avium-intracellulare complex infection in patients with acquired immune deficiency syndrome. Drugs. 1993 Aug;46(2):289–312. doi: 10.2165/00003495-199346020-00007. [DOI] [PubMed] [Google Scholar]
  3. Berenbaum M. C. A method for testing for synergy with any number of agents. J Infect Dis. 1978 Feb;137(2):122–130. doi: 10.1093/infdis/137.2.122. [DOI] [PubMed] [Google Scholar]
  4. Bermudez L. E., Stevens P., Kolonoski P., Wu M., Young L. S. Treatment of experimental disseminated Mycobacterium avium complex infection in mice with recombinant IL-2 and tumor necrosis factor. J Immunol. 1989 Nov 1;143(9):2996–3000. [PubMed] [Google Scholar]
  5. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  6. Cohen Y., Perronne C., Truffot-Pernot C., Grosset J., Vilde J. L., Pocidalo J. J. Activities of WIN-57273, minocycline, clarithromycin, and 14-hydroxy-clarithromycin against Mycobacterium avium complex in human macrophages. Antimicrob Agents Chemother. 1992 Oct;36(10):2104–2107. doi: 10.1128/aac.36.10.2104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fattorini L., Hu C. Q., Jin S. H., Santoro C., Tsang A. Y., Mascellino M. T., Mandler F., Orefici G. Activity of antimicrobial agents against Mycobacterium avium-intracellulare complex (MAC) strains isolated in Italy from AIDS-patients. Zentralbl Bakteriol. 1992 Apr;276(4):512–520. [PubMed] [Google Scholar]
  8. Fernandes P. B., Hardy D. J., McDaniel D., Hanson C. W., Swanson R. N. In vitro and in vivo activities of clarithromycin against Mycobacterium avium. Antimicrob Agents Chemother. 1989 Sep;33(9):1531–1534. doi: 10.1128/aac.33.9.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gevaudan M. J., Bollet C., Mallet M. N., de Micco P. In-vitro evaluation of clarithromycin, temafloxacin, and ethambutol in combination against Mycobacterium avium complex. J Antimicrob Chemother. 1993 May;31(5):725–730. doi: 10.1093/jac/31.5.725. [DOI] [PubMed] [Google Scholar]
  10. Heifets L. B., Lindholm-Levy P. J., Flory M. Comparison of bacteriostatic and bactericidal activity of isoniazid and ethionamide against Mycobacterium avium and Mycobacterium tuberculosis. Am Rev Respir Dis. 1991 Feb;143(2):268–270. doi: 10.1164/ajrccm/143.2.268. [DOI] [PubMed] [Google Scholar]
  11. Heifets L., Mor N., Vanderkolk J. Mycobacterium avium strains resistant to clarithromycin and azithromycin. Antimicrob Agents Chemother. 1993 Nov;37(11):2364–2370. doi: 10.1128/aac.37.11.2364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hoffner S. E., Heurlin N., Petrini B., Svenson S. B., Källenius G. Mycobacterium avium complex develop resistance to synergistically active drug combinations during infection. Eur Respir J. 1994 Feb;7(2):247–250. [PubMed] [Google Scholar]
  13. Holdiness M. R. Clinical pharmacokinetics of clofazimine. A review. Clin Pharmacokinet. 1989 Feb;16(2):74–85. doi: 10.2165/00003088-198916020-00002. [DOI] [PubMed] [Google Scholar]
  14. Inderlied C. B., Kemper C. A., Bermudez L. E. The Mycobacterium avium complex. Clin Microbiol Rev. 1993 Jul;6(3):266–310. doi: 10.1128/cmr.6.3.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ji B., Lounis N., Truffot-Pernot C., Grosset J. Effectiveness of various antimicrobial agents against Mycobacterium avium complex in the beige mouse model. Antimicrob Agents Chemother. 1994 Nov;38(11):2521–2529. doi: 10.1128/aac.38.11.2521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klemens S. P., DeStefano M. S., Cynamon M. H. Activity of clarithromycin against Mycobacterium avium complex infection in beige mice. Antimicrob Agents Chemother. 1992 Nov;36(11):2413–2417. doi: 10.1128/aac.36.11.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Masur H. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex. N Engl J Med. 1993 Sep 16;329(12):898–904. doi: 10.1056/NEJM199309163291228. [DOI] [PubMed] [Google Scholar]
  18. Meylan P. R., Richman D. D., Kornbluth R. S. Characterization and growth in human macrophages of Mycobacterium avium complex strains isolated from the blood of patients with acquired immunodeficiency syndrome. Infect Immun. 1990 Aug;58(8):2564–2568. doi: 10.1128/iai.58.8.2564-2568.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mor N., Heifets L. MICs and MBCs of clarithromycin against Mycobacterium avium within human macrophages. Antimicrob Agents Chemother. 1993 Jan;37(1):111–114. doi: 10.1128/aac.37.1.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mor N., Vanderkolk J., Heifets L. Inhibitory and bactericidal activities of levofloxacin against Mycobacterium tuberculosis in vitro and in human macrophages. Antimicrob Agents Chemother. 1994 May;38(5):1161–1164. doi: 10.1128/aac.38.5.1161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nakagawara A., Nathan C. F. A simple method for counting adherent cells: application to cultured human monocytes, macrophages and multinucleated giant cells. J Immunol Methods. 1983 Jan 28;56(2):261–268. doi: 10.1016/0022-1759(83)90418-0. [DOI] [PubMed] [Google Scholar]
  22. Nightingale S. D., Byrd L. T., Southern P. M., Jockusch J. D., Cal S. X., Wynne B. A. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis. 1992 Jun;165(6):1082–1085. doi: 10.1093/infdis/165.6.1082. [DOI] [PubMed] [Google Scholar]
  23. Perronne C., Gikas A., Truffot-Pernot C., Grosset J., Pocidalo J. J., Vilde J. L. Activities of clarithromycin, sulfisoxazole, and rifabutin against Mycobacterium avium complex multiplication within human macrophages. Antimicrob Agents Chemother. 1990 Aug;34(8):1508–1511. doi: 10.1128/aac.34.8.1508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rastogi N., Labrousse V. Extracellular and intracellular activities of clarithromycin used alone and in association with ethambutol and rifampin against Mycobacterium avium complex. Antimicrob Agents Chemother. 1991 Mar;35(3):462–470. doi: 10.1128/aac.35.3.462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rastogi N., Labrousse V., Goh K. S., De Sousa J. P. Antimycobacterial spectrum of sparfloxacin and its activities alone and in association with other drugs against Mycobacterium avium complex growing extracellularly and intracellularly in murine and human macrophages. Antimicrob Agents Chemother. 1991 Dec;35(12):2473–2480. doi: 10.1128/aac.35.12.2473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ruf B., Schürmann D., Mauch H., Jautzke G., Fehrenbach F. J., Pohle H. D. Effectiveness of the macrolide clarithromycin in the treatment of Mycobacterium avium complex infection in HIV-infected patients. Infection. 1992 Sep-Oct;20(5):267–272. doi: 10.1007/BF01710792. [DOI] [PubMed] [Google Scholar]
  27. Saito H., Tomioka H. Susceptibilities of transparent, opaque, and rough colonial variants of Mycobacterium avium complex to various fatty acids. Antimicrob Agents Chemother. 1988 Mar;32(3):400–402. doi: 10.1128/aac.32.3.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Van der Auwera P. Interactions between antibiotics and phagocytosis in bacterial killing. Scand J Infect Dis Suppl. 1990;74:42–48. [PubMed] [Google Scholar]
  29. Woodley C. L., David H. L. Effect of temperature on the rate of the transparent to opaque colony type transition in Mycobacterium avium. Antimicrob Agents Chemother. 1976 Jan;9(1):113–119. doi: 10.1128/aac.9.1.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Yajko D. M. In vitro activity of antimicrobial agents against the Mycobacterium avium complex inside macrophages from HIV1-infected individuals: the link to clinical response to treatment? Res Microbiol. 1992 May;143(4):411–419. doi: 10.1016/0923-2508(92)90055-s. [DOI] [PubMed] [Google Scholar]
  31. Yajko D. M., Kirihara J., Sanders C., Nassos P., Hadley W. K. Antimicrobial synergism against Mycobacterium avium complex strains isolated from patients with acquired immune deficiency syndrome. Antimicrob Agents Chemother. 1988 Sep;32(9):1392–1395. doi: 10.1128/aac.32.9.1392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yajko D. M., Nassos P. S., Sanders C. A., Gonzalez P. C., Hadley W. K. Comparison of the intracellular activities of clarithromycin and erythromycin against Mycobacterium avium complex strains in J774 cells and in alveolar macrophages from human immunodeficiency virus type 1-infected individuals. Antimicrob Agents Chemother. 1992 May;36(5):1163–1165. doi: 10.1128/aac.36.5.1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yajko D. M., Nassos P. S., Sanders C. A., Hadley W. K. Effects of antimicrobial agents on survival of Mycobacterium avium complex inside alveolar macrophages obtained from patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1991 Aug;35(8):1621–1625. doi: 10.1128/aac.35.8.1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yajko D. M., Nassos P. S., Sanders C. A., Hadley W. K. Killing by antimycobacterial agents of AIDS-derived strains of Mycobacterium avium complex inside cells of the mouse macrophage cell line J774. Am Rev Respir Dis. 1989 Nov;140(5):1198–1203. doi: 10.1164/ajrccm/140.5.1198. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES