Affiliation:
1. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detriot, Michigan 48201
2. Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602
Abstract
ABSTRACT
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-log
10
-CFU/ml starting inoculum, whereas it was ≥24 h with a 8- to 9-log
10
-CFU/ml starting inoculum with 10× the MIC (
P
≤ 0.001). A concentration-dependent PAE was demonstrated with CSA-13, nearly doubling from 2× to 4× the MIC (
P
= 0.03). With respect to the CSA-13 antimicrobial combinations, time-kill curve analysis showed no difference in the log
10
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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