IntroductionVancomycin (VAN) failures associated with the treatment of complicated methicillin-resistant Staphylococcus aureus (MRSA) infections have been well described. The reported “seesaw effect” demonstrates improved β-lactam activity when VAN and/or daptomycin (DAP) susceptibility decreases. However, there are minimal data comparing ceftaroline (CPT) susceptibility with these agents or teicoplanin (TEI). Therefore, to further explore the seesaw effect, we evaluated the relationship between CPT and VAN, TEI, and DAP susceptibilities.MethodsOne hundred and fifty clinical MRSA isolates from the Anti-Infective Research Laboratory (Detroit, MI, USA) from 2008 to 2012 were analyzed. VAN, TEI, DAP and CPT minimum inhibitory concentrations (MIC) were determined via Etest methodology. MIC50 and MIC90 were calculated for each antibiotic. Additionally, four isogenic strain pairs were randomly selected for evaluation by time–kill methodology for the potential of enhanced killing by CPT as MICs increased to VAN, TEI, and DAP.ResultsCPT MICs were inversely correlated with VAN, DAP, and TEI MICs with correlation coefficients of −0.535, −0.483, and −0.386, respectively (P ≤ 0.05). Comparison of the MIC relationship for glycopeptides and lipopeptides resulted in a positive correlation for all agent combinations. In time–kill evaluations, CPT demonstrated greater reductions in log10 colony-forming unit (CFU)/mL against mutant strains (3.73 ± 0.67) versus parents (2.79 ± 0.75) despite no change in CPT MIC (P = 0.112).ConclusionThis study demonstrated a marked “seesaw effect” whereby CPT displayed increased susceptibility as the VAN, DAP, and TEI MICs increased. Additionally, we observed a positive linear correlation between VAN, DAP, and TEI MICs for all agent combinations. Enhanced activity was noted with CPT in mutant strains versus the parent strains despite no change in MIC. Based upon the enhanced CPT activity observed against strains with decreased susceptibility to VAN, DAP and TEI, CPT may provide an option for infections with reduced susceptibility to glycopeptides or lipopeptides. Further evaluation is warranted to investigate the clinical implications of the seesaw effect.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0023-0) contains supplementary material, which is available to authorized users.

Daptomycin is used off-label for enterococcal infections; however, dosing targets for resistance prevention remain undefined. Doses of 4 to 6 mg/kg of body weight/day approved for staphylococci are likely inadequate against enterococci due to reduced susceptibility. We modeled daptomycin regimens in vitro to determine the minimum exposure to prevent daptomycin resistance ( Enterococcus spp. are among the leading causes of nosocomial infections (1). Vancomycin-resistant Enterococcus faecium has been recognized as an important multidrug-resistant pathogen for which new or improved therapies are urgently needed (2, 3). Daptomycin is a lipopeptide antibiotic with potent in vitro bactericidal activity against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE). Although daptomycin lacks an approved indication from the FDA, it is frequently utilized as an alternative agent for the management of VRE infections. However, the optimal pharmacokinetic/pharmacodynamic (PK/PD) targets for resistance prevention and therapeutic success with daptomycin have not been defined (4). In fact, the susceptibility breakpoint designating resistance in enterococci also remains questionable; however, for ease of presentation, we will use the term resistance to refer to nonsusceptible enterococci with daptomycin MICs of Ͼ4 mg/liter. Most experts agree that the daptomycin doses of 4 to 6 mg/kg of body weight/day used for staphylococcal infections are likely inadequate for VRE infections due to reduced susceptibility observed in enterococci (3-5). Daptomycin MIC 50 and MIC 90 are 2 and 4 mg/liter for E. faecium, and 0.5 and 1 mg/liter for Enterococcus faecalis versus 0.25 and 0.5 mg/liter for staphylococci (6). Reports of daptomycin resistance are now becoming more common, emphasizing the need for improved daptomycin dosing paradigms to help preserve the utility of this drug against these difficult to treat pathogens (7-10). Due to the substantial morbidity and mortality associated with enterococcal infections, it is critical to identify characteristics that correlate with treatment failure and therefore improve antimicrobial optimization and patient outcomes.In order to derive daptomycin exposure targets for resistance prevention, we evaluated simulated daptomycin regimens from 4 to 12 mg/kg/day in a 14-day PK/PD model of simulated endocardial vegetations (SEVs) against two daptomycin-susceptible clinical VRE strains (E. faecium S447 and E. faecalis S613). Resistant strains derived from these models were then subjected to a variety of phenotypic and genotypic analyses to evaluate characteristics associated with development of daptomycin resistance. MATERIALS AND METHODSBacterial strains. Two daptomycin-susceptible and vancomycin-resistant enterococcal strains, E. faecalis S613 and E. faecium S447 recovered from the bloodstream and urine, respectively, of patients before daptomycin therapy, were evaluated (11, 12). Both isolates developed daptomycin-resistant derivatives in vivo during daptomycin therapy (11, 12) and

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