Abstract
Rifalazil is a novel rifamycin that, like other members of this class, inhibits bacterial transcription by targeting the β subunit of prokaryotic DNA-dependent RNA polymerase. To address the high-frequency resistance seen with rifamycins, we assessed the ability of rifalazil, alone and in combination with vancomycin, to both kill cells and to suppress the appearance of resistant mutants in log and stationary phase Staphylococcus aureus cultures, using high cell densities in an in vitro kill curve model. We found that 1) rifalazil alone killed log-phase cultures more rapidly than rifampicin, but both drugs quickly selected for resistant mutants, 2) co-treatment of log phase cultures with rifalazil and vancomycin increased bacterial killing by about 3-Log10 over either drug used alone and delayed the appearance of rifamycin-resistant mutants, 3) rifalazil and vancomycin in combination killed stationary phase cultures by 3∼4 Log10 by 48 hours.
Similar content being viewed by others
Article PDF
References
Rothstein DM, Hartman AD, Cynamon M, Eisenstein BI . Development potential of Rifalazil. Expert Opin Investig Drugs 12: 1–17 ( 2003)
Morse R, O'Hanlon K, Collins MD . Phylogenetic, amino acid content and indel analyses of the beta subunit of DNA-dependent RNA polymerase of Gram-positive and Gram-negative bacteria. Int J Syst Evol Microbiol 52 ( Pt 5): 1477–1484 ( 2002)
Bayer AS, Morrison JO . Disparity between time-killed and checkerboard methods for determination of in vitro bactericidal interactions of vancomycin plus rifampicin versus methicillin-susceptible and -resistant Staphylococcus aureus. Antimicrob Agents Chemother 26: 220–223 ( 1984)
Palmer SM, Rybak MJ . Pharmacodynamics of once- or twice- daily levofloxacin versus vancomycin, with or without rifampin, against Staphylococcus aureus in an in vitro model with infected platelet-fibrin clots. Antimicrob Agents Chemother 40: 701–705 ( 1996)
Schierholz JM, Beuth J, Pulverer G . Killing effects of antibiotics and two-fold antimicrobial combinations on proliferating and non growing staphylococci. Zentralbl Bacteriol 288: 527–539 ( 1998)
Fujii K, Tsuji A, Miyazaki S, Yamaguchi K, Goto S . In vitro and in vivo antibacterial activities of KRM-1648 and KRM-1657, new rifamycin derivatives. Antimicrob Agents Chemother 38: 1118–1122 ( 1994)
Pearson RD, Seigbigel RT, Davis HT, Chapman S . Method for reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother 18: 699–708 ( 1980)
Krogstad DJ, Moellering RC . Antimicrobial combinations. In: Lorian V, ed. Antibiotics in Laboratory Medicine, 2nd ed. Baltimore MD: Williams & Wilkins Co, pp. 537–595 ( 1986)
Drlica K . The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 52: 11–17 ( 2003)
Shelburne SA, Musher DM, Hulten K, Ceasar H, Lu MY, Bhaila I, Hamill RJ . In vitro killing of community-associated methicillin-resistant Staphylococcus aureus with drug combinations. Antimicrob Agents Chemother 48: 4016–4019 ( 2004)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Osburne, M., Rothstein, D., Farquhar, R. et al. In Vitro Time-kill Activities of Rifalazil, Alone and in Combination with Vancomycin, against Logarithmic and Stationary Cultures of Staphylococcus aureus. J Antibiot 59, 80–85 (2006). https://doi.org/10.1038/ja.2006.11
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ja.2006.11
Keywords
This article is cited by
-
Enhanced Activity of Rifalazil in Combination with Levofloxacin, Linezolid, or Mupirocin against Staphylococcus aureus In Vitro
The Journal of Antibiotics (2006)