1887

Abstract

Purpose. Fidaxomicin, a macrocyclic antibiotic, has been approved for the treatment of Clostridium difficile infection (CDI). Previous work by our group has demonstrated that some antibiotics at sub-inhibitory concentrations stimulate early toxin production and sporulation by C. difficile. Prior studies revealed that fidaxomicin, when added to late stationary-phase organisms, reduced exotoxin production and spore formation by C. difficile. However, the ability of fidaxomicin to trigger early virulence factor production and spore formation has never been investigated.

Methodology. Sub-inhibitory concentrations of the RNA synthesis inhibitor fidaxomicin (1/4×, 1/8×, 1/16× MIC) were added immediately to lag-phase cultures of historical (strain 9689) and epidemic BI/NAP1/027 (strain 5325) strains of C. difficile, and their effects on sporulation and toxin A (TcdA) and toxin B (TcdB) production were compared.

Results/Key findings. Even at sub-inhibitory concentrations, all doses of fidaxomicin reduced both TcdA and TcdB gene expression and protein production in the historical and epidemic C. difficile strains. Fidaxomicin also dose-dependently reduced viable spore production by the 9689 and 5325 strains. Reductions in spore formation were also observed in both strains treated with tigecycline and vancomycin. However, all concentrations of metronidazole stimulated a ~2 log increase in spore production by the 5325 isolate.

Conclusion. The ability of fidaxomicin to suppress early exotoxin production and endospore formation by historical and epidemic strains of C. difficile may explain its clinical success in treating severe and recurrent cases of CDI disease.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000580
2017-09-12
2019-10-16
Loading full text...

Full text loading...

/deliver/fulltext/jmm/66/10/1393.html?itemId=/content/journal/jmm/10.1099/jmm.0.000580&mimeType=html&fmt=ahah

References

  1. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012;55:S88–S92 [CrossRef][PubMed]
    [Google Scholar]
  2. Hookman P, Barkin JS. Clostridium difficile associated infection, diarrhea and colitis. World J Gastroenterol 2009;15:1554–1580 [CrossRef][PubMed]
    [Google Scholar]
  3. Labbé AC, Poirier L, Maccannell D, Louie T, Savoie M et al. Clostridium difficile infections in a Canadian tertiary care hospital before and during a regional epidemic associated with the BI/NAP1/027 strain. Antimicrob Agents Chemother 2008;52:3180–3187 [CrossRef][PubMed]
    [Google Scholar]
  4. Marsh JW, Arora R, Schlackman JL, Shutt KA, Curry SR et al. Association of relapse of Clostridium difficile disease with BI/NAP1/027. J Clin Microbiol 2012;50:4078–4082 [CrossRef][PubMed]
    [Google Scholar]
  5. Johnson AP. New antibiotics for selective treatment of gastrointestinal infection caused by Clostridium difficile. Expert Opin Ther Pat 2010;20:1389–1399 [CrossRef][PubMed]
    [Google Scholar]
  6. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422–431 [CrossRef][PubMed]
    [Google Scholar]
  7. Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis 2012;55:S93–S103 [CrossRef][PubMed]
    [Google Scholar]
  8. Aldape MJ, Packham AE, Nute DW, Bryant AE, Stevens DL. Effects of ciprofloxacin on the expression and production of exotoxins by Clostridium difficile. J Med Microbiol 2013;62:741–747 [CrossRef][PubMed]
    [Google Scholar]
  9. Gerber M, Walch C, Löffler B, Tischendorf K, Reischl U et al. Effect of sub-MIC concentrations of metronidazole, vancomycin, clindamycin and linezolid on toxin gene transcription and production in Clostridium difficile. J Med Microbiol 2008;57:776–783 [CrossRef][PubMed]
    [Google Scholar]
  10. Drummond LJ, Smith DG, Poxton IR. Effects of sub-MIC concentrations of antibiotics on growth of and toxin production by Clostridium difficile. J Med Microbiol 2003;52:1033–1038 [CrossRef][PubMed]
    [Google Scholar]
  11. Babakhani F, Bouillaut L, Sears P, Sims C, Gomez A et al. Fidaxomicin inhibits toxin production in Clostridium difficile. J Antimicrob Chemother 2013;68:515–522 [CrossRef][PubMed]
    [Google Scholar]
  12. Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L et al. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis 2012;55:S162–S169 [CrossRef][PubMed]
    [Google Scholar]
  13. CLSI Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, Approved Standard, 6th ed. NCCLS document M11-A6 Wayne, PA: NCCLS; 2004
    [Google Scholar]
  14. Aldape MJ, Heeney DD, Bryant AE, Stevens DL. Tigecycline suppresses toxin A and B production and sporulation in Clostridium difficile. J Antimicrob Chemother 2015;70:153–159 [CrossRef][PubMed]
    [Google Scholar]
  15. Lawley TD, Croucher NJ, Yu L, Clare S, Sebaihia M et al. Proteomic and genomic characterization of highly infectious Clostridium difficile 630 spores. J Bacteriol 2009;191:5377–5386 [CrossRef][PubMed]
    [Google Scholar]
  16. Akerlund T, Persson I, Unemo M, Norén T, Svenungsson B et al. Increased sporulation rate of epidemic Clostridium difficile type 027/NAP1. J Clin Microbiol 2008;46:1530–1533 [CrossRef][PubMed]
    [Google Scholar]
  17. Miller M. Fidaxomicin (OPT-80) for the treatment of Clostridium difficile infection. Expert Opin Pharmacother 2010;11:1569–1578 [CrossRef][PubMed]
    [Google Scholar]
  18. Eiland EH, Sawyer AJ, Massie NL. Fidaxomicin use and clinical outcomes for Clostridium difficile-associated diarrhea. Infect Dis Clin Pract 2015;23:32–35 [CrossRef][PubMed]
    [Google Scholar]
  19. Sears P, Crook DW, Louie TJ, Miller MA, Weiss K. Fidaxomicin attains high fecal concentrations with minimal plasma concentrations following oral administration in patients with Clostridium difficile infection. Clin Infect Dis 2012;55:S116–S120 [CrossRef][PubMed]
    [Google Scholar]
  20. Morrow T. Fewer recurrent infections of C. difficile seen with fidaxomicin. This new class of antibiotic–the macrocycles–has a greater sustained response against re-infection than vancomycin. Manag Care 2011;20:49–50[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000580
Loading
/content/journal/jmm/10.1099/jmm.0.000580
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error