Abstract
Rifalazil is a potent second-generation ansamycin that kills bacterial cells by inhibiting the β subunit of RNA polymerase. Rifalazil has several improved properties compared with rifampicin, but retains rifampicin's propensity to develop resistant mutants at high frequency. To explore strategies to overcome resistance development, we studied the effects of rifalazil in combination with several different antibiotics in an in vitro time-kill model, against both log phase and stationary phase Staphylococcus aureus cells. Experiments were carried out at high initial cell density so that the frequency and proliferation of resistant mutants could be monitored. We found that each combination was advantageous in terms of enhanced killing and the suppression of mutants, compared with each drug used alone. None of the three combinations was effective against stationary phase cells.
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Rothstein DM, Hartman AD, Cynamon M, Eisenstein BI . Development potential of Rifalazil. Expert Opin Investig Drugs 12: 1–17 ( 2003)
Krogstad DJ, Moellering RC . Antimicrobial combinations. In Antibiotics in Laboratory Medicine, 2nd Edition. Ed., Lorian V . . The Williams & Wilkins, Baltimore, MD, pp. 537–595 (1986)
Osburne MS, Rothstein DM, Farquhar R, Murphy CK . 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)
Casewell MW, Hill RL . In vitro activity of mupirocin (“pseudomonic acid”) against clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 15: 523–531 ( 1985)
Grohs P, Kitzis MD, Gurmann L . In vitro bactericidal activities of linezolid in combination with vancomycin, gentamicin, ciprofloxacin, fusidic acid, and rifampin against Staphylococcus aureus. Antimicrob Agents Chemother 47: 418–420 ( 2003)
Jacqueline C, Caillon J, Le Mabecque V, Miegeville AF, Donnio PY, Bugnon D, Potel G . In vitro activity of linezolid alone and in combination with gentamicin, vancomycin or rifampicin against methicillin-resistatnt Staphylococcus aureus by time-kill curve methods. J Antimicrob Chemother 51: 857–864 ( 2003)
Zurenko GE, Yagi BH, Schaadt RD, Allison JW, Kilburn JO, Glickman SE, Hutchinson DK, Barbachyn MR, Brickner SH . In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob Agents Chemother 40: 839–845 ( 1996)
Gisby J, Bryant J . Efficacy of a new cream formulation of mupirocin: comparison with oral and topical agents in experimental skin infections. Antimicrob Agents Chemother 44: 255–260 ( 2000)
Sutherland RR, Boon J, Friffin KE, Masters PJ, Slocombe B, White AR . Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 27: 495–498 ( 1985)
Kalmeijer MD, Coertjens H, van Nieuwland-Bolland PM, Bogaers-Hofman D, de Baere GA, Stuurman A, van Belkum A, Kluytmans JA . Surgical site infections in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study. Clin Infect Dis 35: 353–358 ( 2002)
Alou L, Cafini F, Sevillano D, Unzueta I, Prieto J . In vitro activity of mupirocin and amoxicillin-clavulanate alone and in combination against Staphylococci including those resistant to methicillin. International J Antimicrob Agents 23: 513–516 ( 2004)
Bahl DD, Miller A, Leviton I, Gialanella P, Wolin MJ, Liu W, Perkins R, Miller MH . In vitro activities of ciprofloxacin and rifampin alone and in combination against growing and non-growing strains of methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 41: 1293–1297 ( 1997)
Kang SL, Rybak MJ, McGrath BJ, Kaatz GW, Seo SM . Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model. Antimicrob Agents Chemother 38: 2702–2709 ( 1994)
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: 1118–1122 ( 1994)
Norden DW, Wentzel H, Keleti E . Comparison of techniques for measurement of in vitro antibiotic synergism. J Infect Dis 140: 629–633 ( 1979)
Pearson RD, Seigbigel RT, Davis HT, Chapman S . Method for reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother 18: 699–708 ( 1980)
Cappelletty DM, Rybak MJ . Comparison of methodologies for synergism testing of drug combinations against resistant strains of Pseudomonas aeruginosa. Antimicrob Agents Chemother 40: 677–683 ( 1996)
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Osburne, M., Murphy, C. & Rothstein, D. Enhanced Activity of Rifalazil in Combination with Levofloxacin, Linezolid, or Mupirocin against Staphylococcus aureus In Vitro. J Antibiot 59, 303–308 (2006). https://doi.org/10.1038/ja.2006.43
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DOI: https://doi.org/10.1038/ja.2006.43