Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 Oct;40(10):2271–2275. doi: 10.1128/aac.40.10.2271

Direct evidence for antipseudomonal activity of macrolides: exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin.

K Tateda 1, Y Ishii 1, T Matsumoto 1, N Furuya 1, M Nagashima 1, T Matsunaga 1, A Ohno 1, S Miyazaki 1, K Yamaguchi 1
PMCID: PMC163517  PMID: 8891128

Abstract

Several previous investigators have reported that long-term administration of certain macrolides is efficacious in patients with persistent pulmonary Pseudomonas aeruginosa infections, even though the clinically achievable concentrations of these medications are far below their MICs. In the present study, we examined how sub-MICs of macrolide antibiotics affect the viability of and protein synthesis in several strains of P. aeruginosa. We report that 48 h, but not 12 or 24 h, of growth on agar containing a clinically achievable concentration of azithromycin (0.5 microgram/ml, 1/128 the MIC) significantly reduces the viability of strain PAO-1. Similar effects were seen with erythromycin and clarithromycin at 2 micrograms/ml (1/128 and 1/64 the respective MICs), whereas josamycin, oleandomycin, ceftazidime, tobramycin, minocycline, and ofloxacin had no effect on viability, even following 48 h of incubation with concentrations representing relatively high fractions of their MICs. The bactericidal activity of azithromycin seen following 48 h of incubation was not limited to strain PAO-1 but was also seen against 13 of 14 clinical isolates, including both mucoid and nonmucoid strains. Although viability was not decreased prior to 48 h, we found that 4 micrograms of azithromycin per ml inhibits protein synthesis after as little as 12 h and that protein synthesis continues to decrease in a time-dependent manner. We likewise found that P. aeruginosa accumulates azithromycin intracellulary over the period from 12 to 36 h. These results suggested that sub-MICs of certain macrolides are bactericidal to P. aeruginosa when the bacteria are exposed to these antibiotics for longer periods. Exposure-dependent intracellular accumulation of the antibiotic and inhibition of protein synthesis may partially account for the antipseudomonal activity of macrolides over relatively prolonged incubation periods.

Full Text

The Full Text of this article is available as a PDF (358.1 KB).

Selected References

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

  1. Capobianco J. O., Goldman R. C. Erythromycin and azithromycin transport into Haemophilus influenzae ATCC 19418 under conditions of depressed proton motive force (delta mu H). Antimicrob Agents Chemother. 1990 Sep;34(9):1787–1791. doi: 10.1128/aac.34.9.1787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. DOGGETT R. G., HARRISON G. M., WALLIS E. S. COMPARISON OF SOME PROPERTIES OF PSEUDOMONAS AERUGINOSA ISOLATED FROM INFECTIONS IN PERSONS WITH AND WITHOUT CYSTIC FIBROSIS. J Bacteriol. 1964 Feb;87:427–431. doi: 10.1128/jb.87.2.427-431.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Darveau R. P., Cunningham M. D. Influence of subinhibitory concentrations of cephalosporins on the serum sensitivity of Pseudomonas aeruginosa. J Infect Dis. 1990 Oct;162(4):914–921. doi: 10.1093/infdis/162.4.914. [DOI] [PubMed] [Google Scholar]
  4. Essig P., Martin H. H., Gmeiner J. Murein and lipopolysaccharide biosynthesis in synchronized cells of Escherichia coli K 12 and the effect of penicillin G, mecillinam and nalidixic acid. Arch Microbiol. 1982 Sep;132(3):245–250. doi: 10.1007/BF00407959. [DOI] [PubMed] [Google Scholar]
  5. Fernandes A. C., Anderson R., Theron A. J., Jooné G., Van Rensburg C. E. Enhancement of human polymorphonuclear leucocyte motility by erythromycin in vitro and in vivo. S Afr Med J. 1984 Aug 4;66(5):173–177. [PubMed] [Google Scholar]
  6. Fraschini F., Scaglione F., Ferrara F., Marelli O., Braga P. C., Teodori F. Evaluation of the immunostimulating activity of erythromycin in man. Chemotherapy. 1986;32(3):286–290. doi: 10.1159/000238425. [DOI] [PubMed] [Google Scholar]
  7. Georgopoulos C., Welch W. J. Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol. 1993;9:601–634. doi: 10.1146/annurev.cb.09.110193.003125. [DOI] [PubMed] [Google Scholar]
  8. Gilligan P. H. Microbiology of airway disease in patients with cystic fibrosis. Clin Microbiol Rev. 1991 Jan;4(1):35–51. doi: 10.1128/cmr.4.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hendrick J. P., Hartl F. U. Molecular chaperone functions of heat-shock proteins. Annu Rev Biochem. 1993;62:349–384. doi: 10.1146/annurev.bi.62.070193.002025. [DOI] [PubMed] [Google Scholar]
  10. Hirakata Y., Kaku M., Mizukane R., Ishida K., Furuya N., Matsumoto T., Tateda K., Yamaguchi K. Potential effects of erythromycin on host defense systems and virulence of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1992 Sep;36(9):1922–1927. doi: 10.1128/aac.36.9.1922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Homma H., Yamanaka A., Tanimoto S., Tamura M., Chijimatsu Y., Kira S., Izumi T. Diffuse panbronchiolitis. A disease of the transitional zone of the lung. Chest. 1983 Jan;83(1):63–69. doi: 10.1378/chest.83.1.63. [DOI] [PubMed] [Google Scholar]
  12. Ichimiya T., Yamasaki T., Nasu M. In-vitro effects of antimicrobial agents on Pseudomonas aeruginosa biofilm formation. J Antimicrob Chemother. 1994 Sep;34(3):331–341. doi: 10.1093/jac/34.3.331. [DOI] [PubMed] [Google Scholar]
  13. Kita E., Sawaki M., Nishikawa F., Mikasa K., Yagyu Y., Takeuchi S., Yasui K., Narita N., Kashiba S. Enhanced interleukin production after long-term administration of erythromycin stearate. Pharmacology. 1990;41(4):177–183. doi: 10.1159/000138716. [DOI] [PubMed] [Google Scholar]
  14. Kita E., Sawaki M., Oku D., Hamuro A., Mikasa K., Konishi M., Emoto M., Takeuchi S., Narita N., Kashiba S. Suppression of virulence factors of Pseudomonas aeruginosa by erythromycin. J Antimicrob Chemother. 1991 Mar;27(3):273–284. doi: 10.1093/jac/27.3.273. [DOI] [PubMed] [Google Scholar]
  15. Kudoh S., Uetake T., Hagiwara K., Hirayama M., Hus L. H., Kimura H., Sugiyama Y. [Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis]. Nihon Kyobu Shikkan Gakkai Zasshi. 1987 Jun;25(6):632–642. [PubMed] [Google Scholar]
  16. Lam J., Chan R., Lam K., Costerton J. W. Production of mucoid microcolonies by Pseudomonas aeruginosa within infected lungs in cystic fibrosis. Infect Immun. 1980 May;28(2):546–556. doi: 10.1128/iai.28.2.546-556.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mizukane R., Hirakata Y., Kaku M., Ishii Y., Furuya N., Ishida K., Koga H., Kohno S., Yamaguchi K. Comparative in vitro exoenzyme-suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1994 Mar;38(3):528–533. doi: 10.1128/aac.38.3.528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Molinari G., Guzmán C. A., Pesce A., Schito G. C. Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics. J Antimicrob Chemother. 1993 May;31(5):681–688. doi: 10.1093/jac/31.5.681. [DOI] [PubMed] [Google Scholar]
  19. Molinari G., Paglia P., Schito G. C. Inhibition of motility of Pseudomonas aeruginosa and Proteus mirabilis by subinhibitory concentrations of azithromycin. Eur J Clin Microbiol Infect Dis. 1992 May;11(5):469–471. doi: 10.1007/BF01961867. [DOI] [PubMed] [Google Scholar]
  20. Morikawa K., Oseko F., Morikawa S., Iwamoto K. Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro. Antimicrob Agents Chemother. 1994 Nov;38(11):2643–2647. doi: 10.1128/aac.38.11.2643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Neu H. C. The role of Pseudomonas aeruginosa in infections. J Antimicrob Chemother. 1983 May;11 (Suppl B):1–13. doi: 10.1093/jac/11.suppl_b.1. [DOI] [PubMed] [Google Scholar]
  22. Nikaido H., Vaara M. Molecular basis of bacterial outer membrane permeability. Microbiol Rev. 1985 Mar;49(1):1–32. doi: 10.1128/mr.49.1.1-32.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Takeda H., Miura H., Kawahira M., Kobayashi H., Otomo S., Nakaike S. [Long-term administration study on TE-031 (A-56268) in the treatment of diffuse panbronchiolitis]. Kansenshogaku Zasshi. 1989 Jan;63(1):71–78. doi: 10.11150/kansenshogakuzasshi1970.63.71. [DOI] [PubMed] [Google Scholar]
  24. Tamaoki J., Sakai N., Tagaya E., Konno K. Macrolide antibiotics protect against endotoxin-induced vascular leakage and neutrophil accumulation in rat trachea. Antimicrob Agents Chemother. 1994 Jul;38(7):1641–1643. doi: 10.1128/aac.38.7.1641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tateda K., Hirakata Y., Furuya N., Ohno A., Yamaguchi K. Effects of sub-MICs of erythromycin and other macrolide antibiotics on serum sensitivity of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1993 Apr;37(4):675–680. doi: 10.1128/aac.37.4.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tateda K., Ishii Y., Hirakata Y., Matsumoto T., Ohno A., Yamaguchi K. Profiles of outer membrane proteins and lipopolysaccharide of Pseudomonas aeruginosa grown in the presence of sub-MICs of macrolide antibiotics and their relation to enhanced serum sensitivity. J Antimicrob Chemother. 1994 Dec;34(6):931–942. doi: 10.1093/jac/34.6.931. [DOI] [PubMed] [Google Scholar]
  27. Vaara M. Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria. Antimicrob Agents Chemother. 1993 Feb;37(2):354–356. doi: 10.1128/aac.37.2.354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Veringa E., Box A., Rozenberg-Arska M., Verhoef J. Monobactam antibiotics in subinhibitory concentrations enhance opsonophagocytosis and serum bacteriolysis in certain Escherichia coli strains. Drugs Exp Clin Res. 1988;14(1):1–8. [PubMed] [Google Scholar]
  29. Wood R. E., Boat T. F., Doershuk C. F. Cystic fibrosis. Am Rev Respir Dis. 1976 Jun;113(6):833–878. doi: 10.1164/arrd.1976.113.6.833. [DOI] [PubMed] [Google Scholar]
  30. Yamashino T., Ueguchi C., Mizuno T. Quantitative control of the stationary phase-specific sigma factor, sigma S, in Escherichia coli: involvement of the nucleoid protein H-NS. EMBO J. 1995 Feb 1;14(3):594–602. doi: 10.1002/j.1460-2075.1995.tb07035.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES