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. 1997 Feb;41(2):308–313. doi: 10.1128/aac.41.2.308

Immunomodulating effect of fosfomycin on gut-derived sepsis caused by Pseudomonas aeruginosa in mice.

T Matsumoto 1, K Tateda 1, S Miyazaki 1, N Furuya 1, A Ohno 1, Y Ishii 1, Y Hirakata 1, K Yamaguchi 1
PMCID: PMC163706  PMID: 9021184

Abstract

We evaluated the protective effect of fosfomycin (FOM) and an enantiomer of fosfomycin [FOM (+); an isomer of FOM with no bactericidal activity] on murine gut-derived sepsis caused by Pseudomonas aeruginosa. Endogenous bacteremia was induced by administering cyclophosphamide (CY) and ampicillin to specific-pathogen-free mice fed P. aeruginosa. Treatment of mice with FOM at 250 mg/kg of body weight per day twice a day after the second CY administration significantly increased the survival rate compared to that for control mice treated with saline. Treatment with FOM (+) at 20 and 100 mg/kg also significantly increased the survival rate (from 30% for control mice to 80% for treated mice). The bacterial counts in the liver and blood were both significantly lower in FOM(+)-treated mice in comparison with those in liver and blood of saline-treated control mice. FOM(+) administration affected neither the bacterial colonization in the intestinal tract nor the leukocyte counts in the peripheral blood of the mice. After intravascular inoculation of P. aeruginosa, treatment of mice with FOM (+) did not enhance bacterial clearance from the blood of mice pretreated or not enhance bacterial clearance from the blood of mice pretreated or not pretreated with CY, FOM(+) significantly suppressed tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 levels in the serum of mice after gut-derived sepsis. These results indicate that both FOM and FOM(+) have protective effects against P. aeruginosa bacteremia, despite a lack of specific activity of FOM(+), and suggest that FOM may possess immunomodulating activity and that it induces a protective effect. The protective mechanism is speculated to be that FOM modulates the vivo production of inflammatory cytokines.

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Selected References

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  1. Adinolfi L. E., Bonventre P. F. Enhanced phagocytosis, killing, and serum sensitivity of Escherichia coli and Staphylococcus aureus treated with sub-MICs of imipenem. Antimicrob Agents Chemother. 1988 Jul;32(7):1012–1018. doi: 10.1128/aac.32.7.1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander H. R., Doherty G. M., Venzon D. J., Merino M. J., Fraker D. L., Norton J. A. Recombinant interleukin-1 receptor antagonist (IL-1ra): effective therapy against gram-negative sepsis in rats. Surgery. 1992 Aug;112(2):188–194. [PubMed] [Google Scholar]
  3. Andreana A., Perna P., Utili R., Dilillo M., Ruggiero G. Increased phagocytosis and killing of Escherichia coli treated with subinhibitory concentrations of cefamandole and gentamicin in isolated rat livers. Antimicrob Agents Chemother. 1984 Feb;25(2):182–186. doi: 10.1128/aac.25.2.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berg R. D., Garlington A. W. Translocation of Escherichia coli from the gastrointestinal tract to the mesenteric lymph nodes in gnotobiotic mice receiving Escherichia coli vaccines before colonization. Infect Immun. 1980 Dec;30(3):894–898. doi: 10.1128/iai.30.3.894-898.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  6. Bryan C. S., Reynolds K. L., Brenner E. R. Analysis of 1,186 episodes of gram-negative bacteremia in non-university hospitals: the effects of antimicrobial therapy. Rev Infect Dis. 1983 Jul-Aug;5(4):629–638. doi: 10.1093/clinids/5.4.629. [DOI] [PubMed] [Google Scholar]
  7. Deitch E. A., Winterton J., Berg R. Thermal injury promotes bacterial translocation from the gastrointestinal tract in mice with impaired T-cell-mediated immunity. Arch Surg. 1986 Jan;121(1):97–101. doi: 10.1001/archsurg.1986.01400010111015. [DOI] [PubMed] [Google Scholar]
  8. Dick J. D., Shull V., Karp J. E., Valentine J. Bacterial and host factors affecting Pseudomonas aeruginosa colonization versus bacteremia in granulocytopenic patients. Eur J Cancer Clin Oncol. 1988;24 (Suppl 1):S47–S54. [PubMed] [Google Scholar]
  9. Goto S. Fosfomycin, antimicrobial activity in vitro and in vivo. Chemotherapy. 1977;23 (Suppl 1):63–74. doi: 10.1159/000222028. [DOI] [PubMed] [Google Scholar]
  10. Hirakata Y., Kaku M., Tomono K., Tateda K., Furuya N., Matsumoto T., Araki R., Yamaguchi K. Efficacy of erythromycin lactobionate for treating Pseudomonas aeruginosa bacteremia in mice. Antimicrob Agents Chemother. 1992 Jun;36(6):1198–1203. doi: 10.1128/aac.36.6.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hirakata Y., Tomono K., Tateda K., Matsumoto T., Furuya N., Shimoguchi K., Kaku M., Yamaguchi K. Role of bacterial association with Kupffer cells in occurrence of endogenous systemic bacteremia. Infect Immun. 1991 Jan;59(1):289–294. doi: 10.1128/iai.59.1.289-294.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ida S., Shindoh Y., Takishima T. Effect of antibiotics on immediate hypersensitivity reactions in vitro: suppression of IgE-mediated histamine release from peripheral blood basophils by fosfomycin. Microbiol Immunol. 1987;31(10):975–984. doi: 10.1111/j.1348-0421.1987.tb01330.x. [DOI] [PubMed] [Google Scholar]
  13. Inouye S., Niizato T., Komiya I., Yuda Y., Yamada Y. Mode of protective action of fosfomycin against dibekacin-induced nephrotoxicity in the dehydrated rats. J Pharmacobiodyn. 1982 Dec;5(12):941–950. doi: 10.1248/bpb1978.5.941. [DOI] [PubMed] [Google Scholar]
  14. Kahan F. M., Kahan J. S., Cassidy P. J., Kropp H. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci. 1974 May 10;235(0):364–386. doi: 10.1111/j.1749-6632.1974.tb43277.x. [DOI] [PubMed] [Google Scholar]
  15. Knothe H., Schäfer V., Sammann A., Shah P. M. Influence of fosfomycin on the intestinal and pharyngeal flora of man. Infection. 1991 Jan-Feb;19(1):18–20. doi: 10.1007/BF01643751. [DOI] [PubMed] [Google Scholar]
  16. Libert C., Vink A., Coulie P., Brouckaert P., Everaerdt B., Van Snick J., Fiers W. Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. Eur J Immunol. 1992 Oct;22(10):2625–2630. doi: 10.1002/eji.1830221023. [DOI] [PubMed] [Google Scholar]
  17. Maejima K., Deitch E. A., Berg R. D. Bacterial translocation from the gastrointestinal tracts of rats receiving thermal injury. Infect Immun. 1984 Jan;43(1):6–10. doi: 10.1128/iai.43.1.6-10.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maejima K., Deitch E., Berg R. Promotion by burn stress of the translocation of bacteria from the gastrointestinal tracts of mice. Arch Surg. 1984 Feb;119(2):166–172. doi: 10.1001/archsurg.1984.01390140032006. [DOI] [PubMed] [Google Scholar]
  19. Matsumoto T., Kaku M., Furuya N., Usui T., Kohno S., Tomono K., Tateda K., Hirakata Y., Yamaguchi K. Amphotericin B-induced resistance to Pseudomonas aeruginosa infection in mice. J Antibiot (Tokyo) 1993 May;46(5):777–784. doi: 10.7164/antibiotics.46.777. [DOI] [PubMed] [Google Scholar]
  20. Milatovic D. Influence of subinhibitory concentrations of antibiotics on opsonization and phagocytosis of Pseudomonas aeruginosa by human polymorphonuclear leukocytes. Eur J Clin Microbiol. 1984 Aug;3(4):288–293. doi: 10.1007/BF01977475. [DOI] [PubMed] [Google Scholar]
  21. Morikawa K., Oseko F., Morikawa S. Immunomodulatory effect of fosfomycin on human B-lymphocyte function. Antimicrob Agents Chemother. 1993 Feb;37(2):270–275. doi: 10.1128/aac.37.2.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Morikawa K., Oseko F., Morikawa S., Sawada M. Immunosuppressive activity of fosfomycin on human T-lymphocyte function in vitro. Antimicrob Agents Chemother. 1993 Dec;37(12):2684–2687. doi: 10.1128/aac.37.12.2684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Morikawa K., Watabe H., Araake M., Morikawa S. Modulatory effect of antibiotics on cytokine production by human monocytes in vitro. Antimicrob Agents Chemother. 1996 Jun;40(6):1366–1370. doi: 10.1128/aac.40.6.1366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ohtani I., Ohtsuki K., Aikawa T., Anzai T., Ouchi J., Saito T. Reduction of cisplatin ototoxicity by fosfomycin in animal model. ORL J Otorhinolaryngol Relat Spec. 1985;47(5):229–235. doi: 10.1159/000275777. [DOI] [PubMed] [Google Scholar]
  25. Ohtani I., Ohtsuki K., Aikawa T., Sato Y., Anzai T., Ouchi J., Saito T. Protective effect of fosfomycin against aminoglycoside ototoxicity. ORL J Otorhinolaryngol Relat Spec. 1985;47(1):42–48. doi: 10.1159/000275744. [DOI] [PubMed] [Google Scholar]
  26. Pérez Fernández P., Herrera I., Martínez P., Gómez-Lus M. L., Prieto J. Enhancement of the susceptibility of Staphylococcus aureus to phagocytosis after treatment with fosfomycin compared with other antimicrobial agents. Chemotherapy. 1995 Jan-Feb;41(1):45–49. doi: 10.1159/000239323. [DOI] [PubMed] [Google Scholar]
  27. Remick D. G., Strieter R. M., Lynch J. P., 3rd, Nguyen D., Eskandari M., Kunkel S. L. In vivo dynamics of murine tumor necrosis factor-alpha gene expression. Kinetics of dexamethasone-induced suppression. Lab Invest. 1989 Jun;60(6):766–771. [PubMed] [Google Scholar]
  28. Riesbeck K., Sigvardsson M., Leanderson T., Forsgren A. Superinduction of cytokine gene transcription by ciprofloxacin. J Immunol. 1994 Jul 1;153(1):343–352. [PubMed] [Google Scholar]
  29. Ritts R. E. Antibiotics as biological response modifiers. J Antimicrob Chemother. 1990 Nov;26 (Suppl 100):31–36. doi: 10.1093/jac/26.suppl_c.31. [DOI] [PubMed] [Google Scholar]
  30. Roche Y., Fay M., Gougerot-Pocidalo M. A. Interleukin-1 production by antibiotic-treated human monocytes. J Antimicrob Chemother. 1988 May;21(5):597–607. doi: 10.1093/jac/21.5.597. [DOI] [PubMed] [Google Scholar]
  31. Roche Y., Gougerot-Pocidalo M. A., Fay M., Etienne D., Forest N., Pocidalo J. J. Comparative effects of quinolones on human mononuclear leucocyte functions. J Antimicrob Chemother. 1987 Jun;19(6):781–790. doi: 10.1093/jac/19.6.781. [DOI] [PubMed] [Google Scholar]
  32. Roche Y., Gougerot-Pocidalo M. A., Fay M., Forest N., Pocidalo J. J. Macrolides and immunity: effects of erythromycin and spiramycin on human mononuclear cell proliferation. J Antimicrob Chemother. 1986 Feb;17(2):195–203. doi: 10.1093/jac/17.2.195. [DOI] [PubMed] [Google Scholar]
  33. Sack K., Schulz E., Marre R., Kreft B. Fosfomycin protects against tubulotoxicity induced by cis-diaminedichloroplatin and cyclosporin A in the rat. Klin Wochenschr. 1987 Jun 1;65(11):525–527. doi: 10.1007/BF01721040. [DOI] [PubMed] [Google Scholar]
  34. Schweitzer V. G., Dolan D. F., Abrams G. E., Davidson T., Snyder R. Amelioration of cisplatin-induced ototoxicity by fosfomycin. Laryngoscope. 1986 Sep;96(9 Pt 1):948–958. [PubMed] [Google Scholar]
  35. Singer C., Kaplan M. H., Armstrong D. Bacteremia and fungemia complicating neoplastic disease. A study of 364 cases. Am J Med. 1977 May;62(5):731–742. doi: 10.1016/0002-9343(77)90876-2. [DOI] [PubMed] [Google Scholar]
  36. Starnes H. F., Jr, Pearce M. K., Tewari A., Yim J. H., Zou J. C., Abrams J. S. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol. 1990 Dec 15;145(12):4185–4191. [PubMed] [Google Scholar]
  37. Tancrède C. H., Andremont A. O. Bacterial translocation and gram-negative bacteremia in patients with hematological malignancies. J Infect Dis. 1985 Jul;152(1):99–103. doi: 10.1093/infdis/152.1.99. [DOI] [PubMed] [Google Scholar]
  38. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  39. Umeki S., Watanabe M., Yagi S., Soejima R. Supplemental fosfomycin and/or steroids that reduce cisplatin-induced nephrotoxicity. Am J Med Sci. 1988 Jan;295(1):6–10. doi: 10.1097/00000441-198801000-00003. [DOI] [PubMed] [Google Scholar]
  40. Wallach D., Holtmann H., Engelmann H., Nophar Y. Sensitization and desensitization to lethal effects of tumor necrosis factor and IL-1. J Immunol. 1988 May 1;140(9):2994–2999. [PubMed] [Google Scholar]
  41. Yoshimoto T., Nakanishi K., Hirose S., Hiroishi K., Okamura H., Takemoto Y., Kanamaru A., Hada T., Tamura T., Kakishita E. High serum IL-6 level reflects susceptible status of the host to endotoxin and IL-1/tumor necrosis factor. J Immunol. 1992 Jun 1;148(11):3596–3603. [PubMed] [Google Scholar]
  42. Young L. S., Stevens P., Kaijser B. Gram-negative pathogens in septicaemic infections. Scand J Infect Dis Suppl. 1982;31:78–94. [PubMed] [Google Scholar]

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