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 vancomycinintermediate 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.

Telavancin demonstrated concentration-dependent bactericidal activity against GISS, hGISS and VRSA at concentrations equal to or above 4x MIC, which corresponds to therapeutic levels against GISS and clinically achieved concentrations against the VRSA. Similar to daptomycin, telavancin activity was diminished in the presence of serum but bactericidal activity was maintained. Further investigation with telavancin against GISS, hGISS and VRSA is warranted.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has continued to increase at a dramatic rate in recent years (20,21). This organism is associated with higher rates of morbidity and mortality than methicillin-susceptible strains (16). Vancomycin is the primary treatment for this pathogen; however, the increasing use of this agent for a variety of gram-positive organisms, including MRSA, contributes to the growing burden of nonsusceptible strains in both the community and hospital settings (17). Unfortunately, vancomycin-intermediate S. aureus (VISA) and heteroresistant VISA (hVISA) strains have now been reported and are associated with vancomycin treatment failures (7,10,27). Although the presence of VISA is routinely screened for on the basis of the vancomycin MIC exceeding the breakpoint for susceptibility (27, 33), screening for hVISA is not routinely performed (15,33,37). The reasons for this discrepancy include the fact that the vancomycin MIC for these strains determined by routine testing is reported to be in the susceptible range. Screening for hVISA requires additional testing to reveal its heterovariant phenotype, and these methods are more labor-intensive and costly then routine susceptibility testing. In addition, the methods used for evaluating hVISA are not standardized. Despite these shortcomings, there is a growing need to begin screening for this organism on the basis of an increasing number of reports of vancomycin treatment failure for patients (2,4,12,13,19,24).The objectives of the present study were to screen and characterize clinical isolates of MRSA demonstrating heteroresistance to vancomycin from a collection of isolates spanning a 22-year period.(This report was presented in part at the 17th European Congress of Clinical Microbiology and Infectious Diseases, Munich, Germany, March 2007 [abstr. 302].) MATERIALS AND METHODSBacterial isolates. MRSA isolates from 1986 to 2007 in the Detroit metropolitan area were collected from Detroit Receiving Hospital and Henry Ford Hospital, Detroit, MI, and William Beaumont Hospital, Royal Oak, MI, and from the SENTRY Antimicrobial Surveillance Database on the basis of oxacillin resistance and year (as available). These isolates were part of collections that had been previously used for surveillance studies by investigators in the area or by the SENTRY Surveillance Program. Mu3 (archetype hVISA) (11) was used as the control strain for population analysis profile (PAP)-area under the concentration-time curve (AUC) ratio determination. The infection source of the derived organisms was identified when available. All susceptibility testing and hVISA, VISA, and molecular testing were completed by the Anti-Infective Research Laboratory for the purpose of this investigation during a 1-year time period.Antimicrobial agents and susceptibility testing. Vancomycin analytical powder was obtained from Sigma Chemical Company, St. Louis, MO. Teicoplanin analytical powder was provided by Sanofi-Aventis. Stock solutions of each antibiotic were prep...