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Antimicrobial Agents and Chemotherapy, April 2007, p. 1268-1273, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01325-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activities of Ceragenins against Clinical Isolates of Resistant Staphylococcus aureus{triangledown}

Judy N. Chin,1 Michael J. Rybak,1 Chrissy M. Cheung,1 and Paul B. Savage2

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detriot, Michigan 48201,1 Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 846022

Received 24 October 2006/ Returned for modification 29 November 2006/ Accepted 22 December 2006

The rise in the rates of glycopeptide resistance among Staphylococcus aureus isolates is concerning and underscores the need for the development of novel potent compounds. Ceragenins CSA-8 and CSA-13, cationic steroid molecules that mimic endogenous antimicrobial peptides, have previously been demonstrated to possess broad-spectrum activities against multidrug-resistant bacteria. We examined the activities of CSA-8 and CSA-13 against clinical isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), as well as vancomycin-resistant S. aureus (VRSA) and compared them to those of daptomycin, linezolid, and vancomycin by susceptibility testing and killing curve analysis. We also examined CSA-13 for its concentration-dependent activity, inoculum effect, postantibiotic effect (PAE), and synergy in combination with various antimicrobials. Overall, the MICs and minimal bactericidal concentrations of CSA-13 were fourfold lower than those of CSA-8. Time-kill curve analysis of the VRSA, VISA, and hVISA clinical isolates demonstrated concentration-dependent bactericidal killing. An inoculum effect was also observed when a higher starting bacterial density was used, with the time required to achieve 99.9% killing reaching 1 h with a 6-log10-CFU/ml starting inoculum, whereas it was ≥24 h with a 8- to 9-log10-CFU/ml starting inoculum with 10x the MIC (P ≤ 0.001). A concentration-dependent PAE was demonstrated with CSA-13, nearly doubling from 2x to 4x the MIC (P = 0.03). With respect to the CSA-13 antimicrobial combinations, time-kill curve analysis showed no difference in the log10 CFU/ml at 24 h for the majority of the organisms tested. However, early synergy at 4 to 8 h was detected against the VRSA Pennsylvania strain (2002) when CSA-13 was tested in combination with gentamicin, while early additivity was demonstrated against all of the other organisms.

* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Pharmacy Practice-4148, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201. Phone: (313) 577-4376. Fax: (313) 577-8915. E-mail: m.rybak{at}wayne.edu

{triangledown} Published ahead of print on 8 January 2007.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1268-1273, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01325-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bucki, R., Namiot, D. B., Namiot, Z., Savage, P. B., Janmey, P. A. (2008). Salivary mucins inhibit antibacterial activity of the cathelicidin-derived LL-37 peptide but not the cationic steroid CSA-13. J Antimicrob Chemother 62: 329-335 [Abstract] [Full Text]  
  • Chin, J. N., Jones, R. N., Sader, H. S., Savage, P. B., Rybak, M. J. (2008). Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa. J Antimicrob Chemother 61: 365-370 [Abstract] [Full Text]  


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